WO2023142996A1 - 预防或治疗与抗肿瘤剂相关的疾病或病症的方法 - Google Patents

预防或治疗与抗肿瘤剂相关的疾病或病症的方法 Download PDF

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WO2023142996A1
WO2023142996A1 PCT/CN2023/071255 CN2023071255W WO2023142996A1 WO 2023142996 A1 WO2023142996 A1 WO 2023142996A1 CN 2023071255 W CN2023071255 W CN 2023071255W WO 2023142996 A1 WO2023142996 A1 WO 2023142996A1
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use according
nsaid
agent
group
administration
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PCT/CN2023/071255
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French (fr)
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张诗宜
刘世岚
吴诚光
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上海岸阔医药科技有限公司
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Priority to KR1020247027416A priority Critical patent/KR20240144944A/ko
Priority to CN202380018471.2A priority patent/CN118742325A/zh
Publication of WO2023142996A1 publication Critical patent/WO2023142996A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present application relates to the field of biomedicine, in particular to a method for preventing, alleviating and/or treating diseases or conditions related to the administration of antitumor agents in subjects.
  • Anti-tumor agents eg, targeted anti-tumor drugs, chemotherapy drugs and/or immunotherapy, such as immune checkpoint inhibitors, etc.
  • Anti-tumor agents often cause serious side effects, especially those that occur in the skin, facial organs and gastrointestinal tract. Severe side effects caused by these antineoplastic agents will impair the quality of life of patients, cause patients to reduce medication compliance and tolerance, lead to drug withdrawal or insufficient dosage, thereby adversely affecting the therapeutic effect, and even lead to accelerated disease progression. Shortened lifespan.
  • the compounds, pharmaceutical compositions and methods provided in this application effectively solve the above problems, and can effectively prevent, relieve and/or treat side effects associated with the administration of antineoplastic agents in subjects.
  • the present application provides the use of NO-NSAID compound or its pharmaceutically acceptable salt in the preparation of medicament for preventing, alleviating and/or treating diseases associated with administration of antineoplastic agents in subjects or illness.
  • the NO-NSAID compound comprises a nitric oxide (NO) releasing moiety and a non-steroidal anti-inflammatory agent (NSAID) moiety, and the NO-releasing moiety and the NSAID moiety covalently linked directly or via a spacer.
  • NO nitric oxide
  • NSAID non-steroidal anti-inflammatory agent
  • the non-steroidal anti-inflammatory agent moiety comprises a cyclooxygenase (COX) inhibitory moiety.
  • COX cyclooxygenase
  • the COX-inhibiting moiety comprises a moiety capable of reducing the expression of the COX, and/or a moiety that reduces the activity of the COX.
  • the COX inhibitory moiety acts directly on the COX protein and/or nucleic acid encoding the COX protein.
  • the COX-inhibiting moiety is capable of inhibiting cyclooxygenase-1 (COX-1 ) and/or cyclooxygenase-2 (COX-2).
  • the COX-inhibiting moiety is capable of selectively inhibiting COX-2.
  • the COX-inhibiting moiety is capable of non-selectively inhibiting COX-1 and COX-2.
  • the COX inhibitory moiety comprises one or more molecules selected from the group consisting of prodrugs, active derivatives and/or active metabolites thereof: acetaminophen, acetaminophen, Acemetacin, aceclofenac, aceclofenac, alminoprofen, arnfenac, bendazac, benoxaprofen, bromfenac, butylclofenac bucloxic acid, butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, biphenyl Felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, bufen ibufenac, ibuprofen, indomethacin, isofenzolac, isoxepac, indoprofen, ketopro
  • the COX inhibitory moiety comprises one or more molecules selected from the group consisting of prodrugs, active derivatives and/or active metabolites thereof: naproxen, aspirin ( aspirin, diclofenac, ketoprofen, flurbiprofen and ibuprofen.
  • the NO releasing moiety is capable of generating at least one of NO + , NO ⁇ , N 2 O, NO, N 2 O 3 , NO 2 , NO 3 ⁇ , and NO 2 ⁇ .
  • the NO releasing moiety produces NO directly or indirectly.
  • the NO releasing moiety includes organic molecules, inorganic molecules and/or polymers or nanomaterials.
  • the NO-releasing moiety comprises a component selected from the group consisting of nitroglycerin, isosorbide mononitrate, butanediol mononitrate, pentaerythritol tetranitrate, isosorbide dinitrate, trinithanolamine, Nicorandil, nitrobutanol, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazole, isoamyl nitrite, 3,3-bis(aminoethyl base)-1-hydroxy-2-carbonyl-1-triazene (NOC-18), sulfo nucleophilic complex disodium salt (Sulfo NONOate disodium salt), S-nitrosoglutathione (S- Nitrosoglutathione), S-Nitroso-N-acetylpenicillamine, 4-Phenyl-3-furoxancarbonitrile, ( ⁇ )-(E )-4-Ethyl, 5-a
  • the NO releasing moiety comprises a component selected from the group consisting of nitroxyl complexes, Metal nitrosyl complexes, metal nitrosyl complexes, nitrates and nitrites .
  • the NO releasing moiety comprises a component selected from the group consisting of S-nitrosothiol nanosilica spheres, S-nitrosoethanedithiol chitin and oligopropylenediamine grafted shell Glycan NONOate.
  • the NO releasing part has a function of less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900 Daltons 800 Daltons or less, 700 Daltons or less, 600 Daltons or less, 500 Daltons or less, 400 Daltons or less, 300 Daltons or less , a molecular weight of less than or equal to 200 Daltons and/or a molecular weight of less than or equal to 100 Daltons.
  • the NO releasing moiety has one or more of the following groups: azonium dialkoxide, hydroxydiazenesulfonic acid, S-nitrosothiol, furazanoxide, Oxime, N-Nitrosamine, N-Hydroxyguanidine, Nitrate, Nitrite, Nitrate, Nitrite, Stiltonimine, Stilton, Oxatriazole-5-imine, Oxatriazole- 5-keto, hydroxylamine, dioxadiazetidine, N-hydroxynitrosamine, N-nitrosamine, hydroxyurea and metal nitrosamino complexes.
  • the NO releasing moiety comprises -NO2 or -ONO2 .
  • the NO-releasing moiety is connected to the NSAID moiety through a cleavable linker.
  • the NO-releasing moiety is connected to the NSAID moiety through a linker comprising an ester bond and/or a disulfide bond.
  • a spacer is included between the NO-releasing moiety and the NSAID moiety.
  • the spacer comprises: one or more optionally substituted -CH2- , optionally substituted phenyl, and/or combinations thereof.
  • the NO-NSAID compound further comprises a H2S releasing moiety.
  • the NO-NSAID compound comprises a structure shown in formula (1):
  • Z is O or NH
  • R 1 , R 2 , R 3 and R 4 are each independently H, halogen, NO 2 , N 3 , C 1 -C 10 alkyl, OR, OC(O)R, N(R) 2 , NH-C (O)R, S(O)R or N ⁇ NR, wherein each R is independently C 1 -C 10 alkyl or aryl;
  • L 1 comprises a structure selected from the group consisting of -C(O)-, -(CH 2 ) m -, -(CH 2 ) m -O-, -(CH 2 ) m -C(O)-, -( CH 2 ) m -C(O)O-, -(CH 2 ) m -OC(O)O-, -C(O)-(CH 2 ) m -O-, -C(O)-(CH 2 ) m -C(O)-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -C(O)- and -OC(O)-(CH 2 ) m -C(O)O-, wherein m is 1, 2, 3, 4, 5, 6
  • L 2 comprises a structure selected from the group consisting of: -C(O)-, -(CH 2 ) m -, -(CH 2 ) m -O-, -(CH 2 ) m -C(O)-, -( CH 2 ) m -C(O)O-, -(CH 2 ) m -OC(O)O-, -C(O)-(CH 2 ) m -O-, -C(O)-(CH 2 ) m -C(O)-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -C(O)- and -OC(O)-(CH 2 ) m -C(O)O-, wherein m is 1, 2, 3, 4, 5,
  • P and q are each independently 0 or 1;
  • X is the H 2 S releasing moiety or the NO releasing moiety
  • Y is the NO releasing moiety or the H 2 S releasing moiety, and the Y and the X are not both the NO releasing moiety and the H 2 S releasing moiety;
  • the NO releasing moiety is -C(O)-(CH 2 ) n -ONO 2 or -(CH 2 ) n -ONO 2 , wherein n is 1, 2, 3, 4, 5, 6 or 7; and the The H 2 S release part is:
  • the NO-NSAID compound comprises a structure shown in formula (2):
  • p and q are each independently 0 or 1;
  • L 1 and L 2 each independently comprise a structure selected from the group consisting of -C(O)-, -(CH 2 ) m -, -(CH 2 ) m -O-, -(CH 2 ) m -C( O)-, -(CH 2 ) m -C(O)O-, -(CH 2 ) m -OC(O)O-, -C(O)-(CH 2 ) m -O-, -C( O)-(CH 2 ) m -C(O)-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -C(O)- and -OC (O)-( CH2 ) m -C(O)O-, wherein m is 1, 2, 3, 4, 5, 6 or 7;
  • X is the H 2 S releasing moiety or the NO releasing moiety
  • Y is the NO releasing moiety or the H 2 S releasing moiety, and the Y and the X are not both the NO releasing moiety and the H 2 S releasing moiety;
  • the NO releasing moiety is selected from: -NO, -C(O)-(CH 2 ) n -ONO 2 , -O-(CH 2 ) n -ONO 2 , -(CH 2 ) n -ONO 2 , -C (O)-CH 2 -C(CH 3 ) 2 -SNO, -NH-CH 2 -C(CH 3 ) 2 -SNO, -CH 2 -C(CH 3 ) 2 -SNO, where n is 1, 2, 3, 4, 5, 6 or 7, R a is H, C 1 -C 10 alkyl, aryl, S(O) 2 -aryl, CN or CON(R b ) 2 , and each R b is independently H or C 1 -C 10 alkyl; and
  • the H2S releasing moiety is selected from:
  • the NO-NSAID compound comprises a structure selected from the group consisting of:
  • X is -(CH 2 ) n1 -Z-(CH 2 ) n2 -, n1 and n2 are each independently 0, 1, 2, 3, 4 or 5;
  • Z is O, N, S, C, A is O, N, S or C;
  • the NO-NSAID compound comprises a structure shown in formula (3):
  • M is a structure selected from the group consisting of:
  • RA is a hydrogen atom or -C(O)CH 3 ;
  • X is -O-, -S- or -NR 1 -, wherein R 1 is H or straight or branched C 1 -C 6 alkyl;
  • Y is a divalent group with the following definitions:
  • C 1 -C 20 alkylene which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, -ONO 2 , -OC(O)(C 1 -C 10 alkyl)-ONO 2 and -O(C 1 -C 10 alkyl)-ONO 2 ;
  • n is an integer selected from 0-20, n' is an integer of 1-20;
  • n is an integer selected from 0-20, n' is an integer of 1-20;
  • X 1 is -OCO- or -COO-
  • R 2 is H or CH 3
  • na is an integer of 1-20
  • n 2 is an integer of 0-2;
  • Y 1 is -CH 2 -CH 2 -(CH 2 )n 2 -, or -CH ⁇ CH-(CH 2 )n 2 -, X 1 , na, n 2 and R 2 are as defined above;
  • na and R2 are as defined above, and R3 is H or -COCH3 ;
  • X 2 is -O- or -S-
  • n 3 is an integer of 1-6
  • R 2 is as defined above.
  • the NO-NSAID compound comprises a structure shown in formula (3):
  • M is selected from the following structures:
  • the NO-NSAID compound comprises a structure shown in formula (4):
  • c0 is 0 or 1
  • b0 is 0 or 1
  • at least one of c0 and b0 is not 1;
  • X2 is a group selected from the following compounds of formula HX2 -H: hydroxy acid, gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, p-coumaric acid and aroma oxalic acid;
  • Y is Yp , YO or YAr ,
  • Yp is Wherein nIX is an integer in 0-3, nIIX is an integer in 1-3, R TIX , R TIX' , R TIIX and R TIIX' are each independently H or linear or branched C 1 -C 4 alkyl, Y3 is a saturated, unsaturated or aromatic heterocycle containing one or two nitrogen atoms and has 6 atoms;
  • Y O is selected from the group consisting of C 1 -C 20 linear or branched alkyleneoxy, Wherein nf' is an integer in 1-6, and R 1f is H or CH 3 ,
  • Y Ar is wherein n3 is an integer from 0-3, and n3' is an integer from 1-3;
  • the NO-NSAID compound comprises a structure shown in formula (5):
  • p is 0 or 1;
  • A is RT 1 , where R is the residue of the prodrug and has the formula:
  • R AI is H or CH 3 ;
  • R 1 is OCOR 3 , NHCOR 3 , OH, CH 2 CH(CH 3 ) 2 , phenyl, benzoyl or 4,6-dichloroanilino, and R 3 is
  • R 6 is H or halogen
  • R has the structure of:
  • T 1 is (CO) t or (X) t′ , wherein X is O, S or NR 1c , R 1c is H or a linear or branched chain alkyl group having 1 to 5 carbon atoms, and t and t′ are 0 or 1, t is 1 when t' is 0, and t is 0 when t' is 1;
  • X 1 is -T B -YT BI , wherein T B and T BI can be the same or different, when t is 0, T B is (CO), when t' is 0, T B is X, and X is as above; T BI is (CO) tx or (X) txx , where tx and txx are 0 or 1, when txx is 0, tx is 1, when txx is 1, tx is 0, and X is as above;
  • Y is a divalent linking group selected from:
  • nIX is an integer of 0-3, nIIX is an integer of 1-3, R TIX , R TIX' , R TIIX and R TIIX' are each independently selected from H and C 1 -C 4 straight or branched chain alkyl ; Y3 is a saturated, unsaturated or aromatic heterocycle with 5 or 6 atoms and contains 1 or 2 nitrogen atoms;
  • C 1 -C 20 linear or branched alkylene which is optionally substituted by a substituent selected from the group consisting of NHCOR 3 , -NH 2 and -OH, R 3 is C 1 -C 5 linear or branched Residues;
  • a cycloalkylene group having 5-7 carbon atoms which is optionally substituted by a C 1 -C 20 straight chain or branched chain alkylene side chain, said C 1 -C 20 straight chain or branched chain alkylene group Optionally substituted by a substituent selected from the group consisting of: NHCOR 3 , -NH 2 and -OH, R 3 is a C 1 -C 5 linear or branched residue, wherein one of the cycloalkylene rings or more carbon atoms are optionally replaced by heteroatoms;
  • n3 is an integer of 0-3, and n3' is an integer of 1-3;
  • n3 is an integer of 0-3, and n3' is an integer of 1-3;
  • R 4 is hydroxyl, hydrogen or R 5 O
  • R 5 is C 1 -C 10 straight chain or branched chain or cyclic alkyl
  • R 1f is H or CH 3 , and nf is an integer of 0-6;
  • L is a covalent bond, CO or X, where X is as described above;
  • W is Y T O, Y T and Y have the same meaning, and in the compound of formula (5), Y and Y T may be the same or different.
  • the NO-NSAID compound comprises a structure shown in formula (5):
  • said p is 0 or 1
  • A is RT 1 -, where R has the structure and
  • T 1 is (CO) t or (X) t' , t and t' are 0 or 1, t' is 0 when t is 1, and t' is 1 when t is 0;
  • X 1 is -T B -YT B1 -, wherein T B and T B1 are the same or different, when t is 0, T B is (CO), and when t' is 0, T B is X;
  • T B1 is (CO) tx or (X) txx , wherein tx and txx are each independently 0 or 1, when txx is 0, tx is 1, and when txx is 1, tx is 0;
  • X is O, S or NR 1C , R 1C is H or a linear or branched alkyl group with 1-5 carbon atoms;
  • Y selected from where n3 is an integer of 0-3, n3' is an integer of 0-3, R 4 is hydroxyl, hydrogen or R 5 O-alkoxy, wherein R 5 is C 1 -C 10 straight chain, branched chain or cyclic Alkyl, R 2 is C 2 -C 10 straight chain or straight chain alkenylene and optionally contains one or more double bonds;
  • L is a covalent bond, CO or X, X is O, S or NR 1C , R 1C is H or straight or branched chain alkyl having 1 to 5 carbon atoms;
  • W is Y T O
  • Y T is selected from where n3 is an integer of 0-3, n3' is an integer of 0-3, R 4 is hydroxyl, hydrogen or R 5 O-alkoxy, wherein R 5 is C 1 -C 10 straight chain, branched chain or cyclic Alkyl, R 2 is C 2 -C 10 straight chain or straight chain alkenylene and optionally contains one or more double bonds.
  • the NO-NSAID compound comprises a structure shown in formula (16):
  • R m is H or lower alkyl
  • R n is a structure selected from the group consisting of:
  • s 0 or 1
  • X is -Y-(CR 4 R 4' ) o -C(R 4 )(ONO 2 )-(CR 4 R 4' ) q -(T) o -(W) q (T) o -(CR 4 R 4' ) o -R 5 ;
  • Each R 4 and R 4 ' is independently hydrogen, lower alkyl, -OH, -CH 2 OH, -ONO 2 , -NO 2 or -CH 2 ONO 2 , or R 4 and R 4 ' and their The linked carbon atoms together form a cycloalkyl or heterocycle;
  • W is a covalent bond or a carbonyl group
  • each T is independently oxygen, (S(O) o ) o or NR j ;
  • R j is hydrogen, alkyl, aryl, heterocycle, alkylcarbonyl, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonylamino, N - alkylsulfonylamino, N,N-diarylsulfonamido, N-arylsulfonamido, N-alkyl-N-arylsulfonamido, carboxamide and/or hydroxyl;
  • each q is independently 1, 2 or 3;
  • each o is independently 0, 1 or 2;
  • Y is oxygen or sulfur
  • R5 is hydrogen, hydroxyl, alkyl, aryl, alkylsulfonyl, arylsulfonyl, carboxylate, alkylcarbonyl, arylcarbonyl, formamido, alkoxyalkyl, alkoxyaryl , cycloalkyl and/or heterocycle.
  • the NO-NSAID compound comprises a structure shown in formula (17) or formula (18):
  • Y is a bond, S, O or NR 1 , wherein R 1 is hydrogen or C 1 -C 6 alkyl;
  • R is hydrogen or C 1 -C 6 alkyl
  • the Linker is a linker, which is selected from the following group:
  • C 3 -C 6 cycloalkyl which is optionally substituted by a group selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, NO, CO 2 , CF 3 , CN, CH 2 COOH, CH 2 COO-C 1-3 alkyl and C 1 -C 3 thioalkyl;
  • Heteroaryl which is optionally substituted by a group selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, NO 2 , CO 2 , CF 3 , CN, CH 2 COOH, CH 2 COO-C 1-3 alkyl and C 1 -C 3 thioalkyl.
  • the NO-NSAID compound comprises a structure shown in formula (19):
  • A is a drug selected from the group consisting of residues of (A-OH or AH): non-steroidal anti-inflammatory drugs, analgesics, antipyretics and COX-2 inhibitors;
  • T is -O-, -NH-, -S-, -CO- or -(CH 2 ) n1 OCO-, wherein n1 is an integer from 1 to 20;
  • A is selected from the group consisting of:
  • R B is selected from: H, straight or branched C 1 -C 12 alkyl and C 2 -C 12 alkenyl;
  • RA is a structure selected from the group:
  • R c is selected from the group consisting of H, halogen, amino, R E CONH- and -OCOR E ,
  • R D is selected from the group consisting of H, OH, halogen, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 alkoxy, trifluoromethyl, amino and mono- or Di-(C 1 -C 4 )alkylamino,
  • R E is selected from H and straight or branched C 1 -C 5 alkyl
  • e 0 or 1
  • M is C or N
  • RA is a structure selected from the group consisting of:
  • R E1 is H or CH 3 , and R C1 is Cl or F;
  • RA is a structure selected from the group consisting of:
  • R A is a structure selected from the group:
  • R G is a structure selected from the group consisting of:
  • R H is phenyl or cyclohexyl
  • Y is a divalent group with the following meanings:
  • n is an integer of 0-20, and n1 is an integer of 1-20;
  • n is an integer of 0-20, and n1 is an integer of 1-20;
  • n1 is an integer of 1-20, and n2 is an integer of 0-2, X 1 is -OCO- or -COO-, and R 2 is H or CH 3 ;
  • n1 and R 2 are as above, R 3 is H or COCH 3 ;
  • X 2 is -O- or -S-, n3 is an integer of 1-6, and R 2 is as described above;
  • n4 is an integer of 0-10
  • n5 is an integer of 1-10
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H and linear or branched C 1 -C 4 alkyl, and -ONO 2 with connected
  • n5 is as described above
  • Y2 is a 5- or 6-membered saturated, unsaturated or aromatic ring, and contains 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the NO-NSAID compound comprises a structure represented by formula (21):
  • X is a linker
  • M is a structure selected from the group:
  • the NO-NSAID compound comprises a compound selected from the group consisting of:
  • the molar ratio of said NO-releasing moiety to said NSAID moiety is from about 2:1 to about 1:2.
  • the antineoplastic agents include small molecule compounds, small molecule conjugates, proteins and/or polynucleotides.
  • the antineoplastic agents include chemotherapeutics, targeted therapeutics and/or immunotherapeutics.
  • the antineoplastic agent is a targeted therapeutic agent.
  • the targeted therapeutic agent includes small molecule compounds and/or antibodies or antigen-binding fragments thereof.
  • the antibodies include monoclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies and/or antibody drug conjugates.
  • the antigen-binding fragment comprises Fab, Fab', F(ab )2 , Fv fragment, F(ab') 2 , scFv, di-scFv and/or dAb.
  • the targeted therapeutic agent targets molecules inside tumor cells, on the surface of tumor cells and/or in the tumor microenvironment.
  • the targeted therapeutic agents target proteins and/or nucleic acid molecules.
  • the targeted therapeutic targets a tumor-associated antigen.
  • the targeted therapeutic agent targets one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR- ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and others mutants.
  • targets selected from the group consisting of VEGF, EGFR, EGFR
  • the targeted therapeutic inhibits the activity of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2 , VEGFR3, VEGFR4, PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR -ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants.
  • targets selected from the group consisting of VEGF,
  • the targeted therapeutic reduces the expression of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2 , VEGFR3, VEGFR4, PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR -ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants.
  • targets selected from the group consisting of VEGF,
  • the targeted therapeutic agents include hormones, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors and/or toxin delivery molecules.
  • the targeted therapeutic agent is a tyrosinase inhibitor.
  • the targeted therapeutic agent is a VEGFR inhibitor and/or a VEGF inhibitor.
  • the VEGFR inhibitor inhibits VEGFR1, VEGFR2 and/or VEGFR3.
  • the targeted therapeutic agent is an EGFR inhibitor. In certain embodiments, the targeted therapeutic agent is a BRAF inhibitor. In certain embodiments, the targeted therapeutic agent is a PDGFR inhibitor. In certain embodiments, the targeted therapeutic agent is a FGFR inhibitor. In certain embodiments, the targeted therapeutic agent is an mTOR inhibitor. In certain embodiments, the targeted therapeutic agent is a HER2 inhibitor.
  • the targeted therapeutic agent is selected from one or more of the following group: afatinib, dacomitinib, osimertinib, EAI045, gefitinib, amotinib Ni, Pirotinib, Brigatinib, Neratinib, Omentotinib, Bosutinib, Icotinib, Vandetanib, Lapatinib, Aflutinib, BPI-7711 , mobotinib, dovitinib, zoritinib, vallitinib, abrutinib, rabrutinib, brutinib, ibrutinib, dasatinib, pirtobrutinib, tolebrutinib, rilzabrutinib, fenebrutinib , evobrutinib, selumetinib, tivozanib, dovitinib
  • the targeted therapeutic agent is administered in combination with one or more other therapies.
  • the antineoplastic agent is a chemotherapeutic agent.
  • the chemotherapeutic agent comprises a pyrimidine nucleoside analog and/or a prodrug thereof.
  • the chemotherapeutic agent includes one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5- FU), floxuridine, tegafur, idarubicin, paclitaxel, epirubicin,fugin (NUC-1031), doxorubicin, leucovorin, cisplatin, paclitaxel, cyclophosphamide, vincristine and 5-FU prodrugs.
  • the 5-FU prodrugs include fluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, prodrug derivatives of floxuridine, Prodrug derivatives of 2'-deoxyfluorouridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine and/or 3-deazauridine.
  • the chemotherapeutic agent is administered in combination with one or more other therapies.
  • the one or more other therapies include one or more other antineoplastic therapies.
  • the disease or condition results from administration of the antineoplastic agent.
  • the disease or condition occurs or is exacerbated after administration of the antineoplastic agent.
  • said subject was free of said disease or condition prior to administration of said antineoplastic agent.
  • the disease or disorder comprises an epithelial tissue disease or disorder.
  • the epithelial tissue disease or disorder comprises a disease or disorder associated with an endothelial cell disorder, and/or a disease or disorder associated with an epithelial cell disorder.
  • the endothelial cells comprise vascular endothelial cells.
  • the epithelial cells include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the disease or condition comprises a skin disease or condition, a five sense organ disease or condition and/or a gastrointestinal disease or condition.
  • the skin disease or condition comprises alopecia, body odor, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, lipoatrophy, altered hair color, abnormal hair texture, Hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, fat hypertrophy, nail changes, nail discoloration, nail loss, nail bumps, skin pain, hands and feet Syndrome, photosensitivity, pruritus, purpura, acneiform rash, maculopapular rash, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin induration, skin ulceration, Stevens - Johnson's syndrome, subcutaneous emphysema, telangiectasia, toxic epidermal necrosis, rash and/or urticaria.
  • the skin disease or condition is hand-foot syndrome.
  • the severity of the skin disease or condition is NCI-CTCAE grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above , or level 5.
  • the subject comprises a cancer patient.
  • the disease or condition is affected in a different location than the cancer.
  • the drug does not substantially affect the therapeutic effect of the antineoplastic agent.
  • the medicament is formulated for topical administration.
  • the medicament is formulated for transdermal administration.
  • the medicament is formulated as a cream, lotion, gel, ointment, salves, spray, liposomal formulation, liniment and/or aerosol.
  • the site of administration of the drug is different from the site of administration of the antineoplastic agent.
  • the site of administration of the drug is not the site of occurrence of cancer or the site of potential metastasis of cancer.
  • the drug is administered differently than the antineoplastic agent.
  • the concentration of the NO-NSAID compound in the medicament is from about 0.005% w/w to about 40% w/w.
  • the concentration of the NO-NSAID compound in the medicament is from about 0.5% w/w to about 10% w/w.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject, the method comprising administering an effective amount of NO to a subject in need thereof.
  • An NSAID compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
  • the present application provides a NO-NSAID compound or a pharmaceutically acceptable salt thereof, which is used for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the present application provides a pharmaceutical combination, which comprises: 1) an antineoplastic agent; and 2) a NO-NSAID compound.
  • said antineoplastic agent and said NO-NSAID compound are not admixed with each other.
  • said antineoplastic agent and said NO-NSAID compound are each independently present in separate containers.
  • said NO-NSAID compound in said pharmaceutical combination, is formulated for transdermal administration.
  • said NO-NSAID compound in said pharmaceutical combination, is formulated as an ointment.
  • the concentration of the NO-NSAID compound in the pharmaceutical combination is from about 0.005% w/w to about 40% w/w.
  • the concentration of the NO-NSAID compound in the pharmaceutical combination is from about 0.5% w/w to about 10% w/w.
  • the NO-NSAID compound in 2) can prevent, alleviate and/or treat the disease or condition associated with the antineoplastic agent in 1).
  • the NO-NSAID compound in 2) does not substantially affect the therapeutic effect of the antineoplastic agent in 1).
  • the NO-NSAID compound of 2) is administered before, simultaneously with or after the antineoplastic agent of 1).
  • the present application provides the use of the NO releasing agent and NSAID in the preparation of a medicament for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject, the method comprising administering an effective amount of NO to a subject in need thereof. Release agents and NSAIDs.
  • the present application provides a pharmaceutical combination, which comprises: 1) antitumor agent; 2) NO releasing agent; and 3) NSAID.
  • Figure 1 shows a model of hand-foot syndrome in rats.
  • Figure 2 shows the condition of rat paws after being treated with the drug or drug combination of the present application.
  • Figure 3 shows the pathological detection results of the paws of rats in each group.
  • Figure 4 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 5 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 6 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 7 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 8 shows the pain measurement effect after administration of drugs in each group, and Blank is the blank control.
  • Figure 9 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 10 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 11 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 12 shows the pain measurement effect after administration of drugs in each group, and Blank is the blank control.
  • Figure 13 shows the pain measurement effects of each group of drugs after administration, and Blank is the blank control.
  • Figure 14 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 15 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 16 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 17 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 18 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 19 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 20 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 21 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 22 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 23 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 24 shows the cytotoxic mitigation effect of each group of drugs.
  • Figure 25 shows the cytotoxic mitigation effect of each group of drugs.
  • NSAID generally refers to "non-steroidal anti-inflammatory drug”.
  • non-steroidal is used to distinguish these drugs from steroidal drugs, whose numerous actions include eicosanoid-depressing, anti-inflammatory actions, and the like.
  • NSAIDs are unique in that they are non-narcotic.
  • NSAIDs include aspirin, ibuprofen, and naproxen.
  • Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes.
  • Cyclooxygenase catalyzes the formation of prostaglandins and thromboxanes from arachidonic acid (itself derived from cellular phospholipid bilayers by phospholipase A2).
  • NO-NSAID compound generally refers to an NSAID derivative capable of releasing nitric oxide (NO).
  • NO-NSAID compound can include a nitroxy derivative of the NSAID.
  • spacer generally refers to a group that separates one compound or part thereof from another compound or part thereof.
  • the spacer can be a chemical bond, group or linker that connects one compound or portion thereof to another compound or portion thereof.
  • cyclooxygenase (COX) inhibitory moiety generally refers to a molecule or part thereof capable of reducing the activity and/or function of cyclooxygenase in vivo and/or in vitro.
  • cyclooxygenase also known as prostaglandin endoperoxide synthase (PTGS)
  • PTGS prostaglandin endoperoxide synthase
  • COX cyclooxygenase
  • PTGS prostaglandin endoperoxide synthase
  • an enzyme such as the isoenzyme family, EC 1.14.99.1
  • It is capable of forming prostaglandins, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid.
  • It is a member of the animal-type heme peroxidase family, also known as prostaglandin G/H synthase.
  • the specific reaction catalyzed by the COX is the conversion of arachidonic acid to prostaglandin H2 via the short-lived prostaglandin G2 intermediate.
  • the COX may include COX-1 and COX-2.
  • COX-1 and COX-2 those specific for COX-2 isozymes are called COX-2 selective inhibitors.
  • COX-1 and COX-2 have similar molecular weights, about 70 kDa and 72 kDa, respectively, and both have 65% amino acid sequence homology and almost the same catalytic site. Both proteins have three domains: an N-terminal EGF-like domain, a small 4-helix membrane anchor, and a core heme peroxidase catalytic domain. Both form dimers.
  • the isoleucine at position 523 in COX-1 was replaced by valine in COX-2.
  • the smaller Val523 residue in COX-2 allows access to a hydrophobic side pocket in the enzyme (Ile523 steric hindrance). Molecules that bind to this alternative site can be considered selective inhibitors of COX-2.
  • VEGFR generally refers to the Vascular Endothelial Grow Factor Receptor, which belongs to the Receptor tyrosine kinases (RTKs) family of tyrosine kinases. It has been reported to include three main subtypes, namely VEGFR1, VEGFR2 and VEGFR3. Among them, VEGFR1 and VEGFR2 are mainly distributed on the surface of tumor vascular endothelium, mediating the formation of tumor blood vessels, and VEGFR3 is mainly distributed on the surface of lymphatic endothelium, mediating the formation of tumor lymphatic vessels. VEGFR2 has been reported to be the main VEGF signaling receptor during angiogenesis and mitosis.
  • RTKs Receptor tyrosine kinases
  • the VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PGF). It has been reported that VEGF-A binds to VEGFR-1 and VEGFR-2 and can regulate almost all cellular responses to VEGF. Activation of VEGFR-2 on endothelial cells results in increased cell proliferation, migration, survival and increased vascular permeability (see Waldner, Maximilian J. et al., The Journal of Experimental Medicine 207.13, 2010). Increased expression of VEGFR or its kinase activity is associated with a range of human cancers.
  • VEGF Vascular Endothelial Growth Factor
  • VEGF Vascular Endothelial Growth Factor
  • VEGF receptor Inhibition of tyrosine kinase signaling blocks the formation of new blood vessels in tumor growth, leading to arrest or regression of angiogenic tumors (see Gerald McMahon, The Oncologist 2000, 5:3-10).
  • VEGFR inhibitor generally refers to any substance or agent known in the art or discovered in the future that can cause the expression, quantity or activity of VEGFR to decrease, including any Any substance that causes the inhibition of biological activity related to VEGFR activity (including the inhibition of any downstream biological effects produced by the binding of VEGFR to its natural ligand) in the subject.
  • a VEGFR inhibitor can include any agent capable of blocking VEGFR activity or any of its downstream biological effects in the treatment of cancer.
  • the VEGFR inhibitors can be used to treat tumors.
  • the VEGFR inhibitor can directly inhibit one or more functions of VEGFR.
  • the VEGFR inhibitor can bind to a nucleic acid sequence encoding VEGFR.
  • the VEGFR inhibitor can reduce the transcript level of VEGFR protein.
  • VEGF inhibitor generally refers to any substance or agent known in the art or discovered in the future that can cause the expression, quantity or activity of VEGF to decrease, including any Any substance that causes inhibition of a biological activity related to VEGF activity in a subject, when used.
  • a VEGF inhibitor can include any agent capable of blocking VEGF activity or any of its downstream biological effects.
  • a VEGF inhibitor may include any agent capable of blocking VEGF activity or any of its downstream biological effects in the treatment of cancer.
  • the VEGF inhibitors can be used to treat tumors.
  • the VEGF inhibitor can directly inhibit one or more functions of VEGF.
  • the VEGF inhibitor can bind to a nucleic acid sequence encoding VEGF.
  • the VEGF inhibitor can reduce the transcriptional level of VEGF protein.
  • VEGF and/or VEGFR inhibited levels are common in the art, and said methods can also be used for identification, standardization, screening and/or Or evaluate the VEGF inhibitors and/or VEGFR inhibitors described herein.
  • tumor usually refers to a neoplasm formed by the proliferation of local tissue cells under the action of various tumorigenic factors. biology. According to the cell characteristics of new organisms and the degree of harm to the body, tumors are divided into two types: benign tumors and malignant tumors.
  • Cancer is the general term for malignant tumors.
  • Said tumor may be selected from the group consisting of epithelial malignancies (carcinomas of epithelial origin), lung cancer (eg, non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, bowel cancer, prostate cancer, Cancers of the pancreas, uterus, cervix, ovary, esophagus, head and neck, stomach, and larynx.
  • the tumor may be cancer of the liver, kidney, colorectum, stomach, esophagus, or thyroid.
  • the VEGFR inhibitors may include small molecule VEGFR inhibitors, protein macromolecules that specifically bind VEGFR, RNAi that inhibits VEGFR protein expression, and/or antisense oligonucleotides that inhibit VEGFR protein expression.
  • small molecule VEGFR inhibitor may include a small molecule VEGFR inhibitor that binds reversibly or irreversibly to VEGFR or a small molecule VEGFR inhibitor that specifically binds a mutated VEGFR.
  • the small molecule VEGFR inhibitors may include regorafenib, ponatinib, cabozantinib, lenvatinib, sorafenib, apatinib, axitinib, nintedanib , vandetanib, sunitinib, midostaurin, tivozanib, fruquintinib, cediranib, brinib, donafini, surufatinib, anlotinib , Famitinib, Tesevatinib, Vorolanib, Motesanib, Linifanib, Semaxanib, Dovitinib, Orantinib, Vacitinib, Tiratinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, Foretinib, ningetinib, Tafetinib, Alti
  • the term "specifically binds" generally means that in a complex mixture, the VEGFR inhibitor can specifically recognize and bind VEGFR without substantially recognizing or binding other components in the complex mixture.
  • the inhibitor may have an affinity for VEGFR that is at least 2-fold (e.g., at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold greater) than its affinity for other non-specific binding components. , 9 times, 10 times or more).
  • the value of the equilibrium dissociation constant of the VEGFR inhibitor binding to VEGFR is less than or equal to 10 -6 (for example, may be less than or equal to 10 -7 M, less than or equal to 10 -8 M, less than or equal to equal to 10 -9 M, less than or equal to 10 -10 M or less).
  • the protein macromolecule specifically binding to VEGFR may be an antibody, antibody variant, fusion protein, derivative or fragment thereof against VEGFR.
  • it may be an antibody or antigen-binding fragment thereof that specifically binds VEGFR.
  • the antibody generally refers to a polypeptide molecule capable of specifically recognizing and/or neutralizing a specific antigen.
  • an antibody may comprise an immunoglobulin composed of at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, and includes any molecule comprising an antigen-binding portion thereof.
  • the term "antibody” may include monoclonal antibodies, antibody fragments, or antibody derivatives, including but not limited to human antibodies (fully human antibodies), humanized antibodies, chimeric antibodies, single chain antibodies (e.g., scFv), and Antigen-binding antibody fragments (eg, Fab, Fab' and (Fab)2 fragments).
  • the chimeric antibody may have a part of the heavy chain or light chain amino acid sequence homologous to the corresponding amino acid sequence in an antibody from one species, or belong to a specific class, while the rest of the chain is similar to another species
  • the humanized antibody can refer to a chimeric antibody, which contains less sequence from non-human immunoglobulin, thereby reducing the immunogenicity of heterologous antibodies when introduced into humans, while maintaining the complete antigenicity of the antibody Binding affinity and specificity.
  • the fully human antibody may refer to comprising amino acid sequences corresponding to antibodies produced by humans or human immune cells, or derived from non-human sources such as transgenic non-human animals using human antibody libraries, or other human antibody-encoding Antibodies derived from the sequence of the antibody.
  • the antigen-binding fragment antibody may be one or more fragments that specifically bind to an antigen.
  • the antigen-binding function of antibodies can be realized by full-length fragments of antibodies.
  • the antigen-binding function of an antibody can also be achieved by comprising a heavy chain of a fragment of Fv, ScFv, dsFv, Fab, Fab' or F(ab'), or by comprising a Fv, ScFv, dsFv, Fab, Fab' or Light chain of a fragment of F(ab') 2 .
  • Fab fragment that is, a monovalent fragment composed of VL, VH, CL and CH domains
  • F(ab') 2 fragment comprising two Fab fragments linked by a disulfide bond at the hinge region Bivalent fragments
  • Fd fragments consisting of VH and CH domains
  • Fv fragments consisting of VL and VH domains of an antibody single arm
  • dAb fragments consisting of VH domains (Ward et al.
  • the "antigen-binding portion” may also include an immunoglobulin fusion protein comprising a binding domain selected from: (1) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; (2) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; an immunoglobulin heavy chain CH2 constant region fused to the hinge region; and (3) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region.
  • an immunoglobulin fusion protein comprising a binding domain selected from: (1) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; (2) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; an immunoglobulin heavy chain CH2 constant region fused to the hinge region; and (3) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region.
  • the protein macromolecule specifically binding to VEGFR may be ramucirumab, an antigen-binding fragment thereof or a functional variant thereof.
  • VEGF capture agent generally refers to an agent capable of capturing VEGF by binding it.
  • the VEGF trap may be selected from the group consisting of bevacizumab and aflibercept.
  • the term "agent for reducing the expression level of VEGF” generally refers to a substance capable of directly or indirectly reducing the expression level of VEGF in a subject.
  • the agent for reducing the expression level of VEGF may be selected from the group consisting of Temsirolimus and Thalidomide.
  • RNAi generally refers to RNA interference (RNA interference), which is usually exogenous or endogenous double-stranded RNA molecules or small RNA molecules, and generally inhibits mRNA by targeting mRNA and degrading it specifically. Expression or translation of the target gene.
  • RNAi involves two types of small RNAs: microRNAs (miRNAs) and small interfering RNAs (siRNAs), which bind to other mRNA molecules to increase or decrease their activity, such as preventing mRNAs from being translated into proteins.
  • miRNAs microRNAs
  • siRNAs small interfering RNAs
  • RNAi pathway cleaves long double-stranded RNA (dsRNA) into siRNA double-stranded fragments about 20-23 nucleotides in length by RNaseIII enzymes (eg, Dicer, DCL, or Drosha).
  • dsRNA double-stranded RNA
  • RISC RNA-induced silencing complex
  • the RNAi that inhibits the expression of VEGFR protein can inhibit the expression or translation of VEGFR by targeting the mRNA encoding VEGFR, thereby specifically degrading the mRNA.
  • the RNAi that inhibits the expression of VEGF protein can inhibit the expression or translation of VEGF by targeting the mRNA encoding VEGF, thereby specifically degrading the mRNA.
  • oligonucleotide generally refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or any mimetic or structurally modified nucleic acid thereof.
  • the oligonucleotides can include oligonucleotides composed of naturally occurring nucleobases, sugars, and covalent internucleoside (backbone) linkages, as well as non-naturally occurring oligonucleotides that serve similar functions. Modified or substituted oligonucleotides are generally preferred over native forms because of, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.
  • antisense oligonucleotide generally refers to a single-stranded oligonucleotide having a nucleobase sequence that allows at least partial hybridization to a corresponding region or fragment of a target nucleic acid.
  • the antisense oligonucleotide may comprise about 8 to about 50 nucleobases.
  • the VEGFR inhibitor can inhibit VEGFR1, VEGFR2 and/or VEGFR3.
  • the VEGFR inhibitor can inhibit one, two or three of VEGFR1, VEGFR2 and VEGFR3.
  • the antineoplastic agent may include ramucirumab, bevacizumab, regorafenib, ponatinib, cabozantinib, lenvatinib, sorafenib , pazopanib, apatinib, axitinib, nintedanib, vandetanib, sunitinib, midostaurin, tivozanib, fruquintinib, cediranib , Brisnib, Donafanib, Surufatinib, Anlotinib, Famitinib, Tesevatinib, Vorolanib, Motesanib, Linifanib, Semaxanib, Dovitinib, Orantinib, Vatanidine , Tiratinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, For
  • the "pharmaceutically acceptable salt” may refer to a pharmaceutically acceptable salt of the compound.
  • the pharmaceutically acceptable salt can be selected from the group consisting of Sorafenib Tosylate, Sunitinib Malate, Pazopanib Hydrochloride and Dovitinib (TKI258) Lactic Acid Salt.
  • the VEGFR inhibitor and/or VEGF inhibitor may be administered in combination with one or more other therapies.
  • the one or more other therapies may include one or more other antineoplastic therapies.
  • such other antineoplastic therapies may include cytotoxic anticancer agents, immunotherapeutic anticancer agents, and/or hormonal therapeutic anticancer agents.
  • Such other antineoplastic therapies may also include radiation therapy or surgery.
  • VEGFR inhibitor and/or a VEGF inhibitor in combination with other anti-tumor therapies, they may be administered to the subject at the same time, or administered separately at certain intervals.
  • said other antineoplastic therapy may be part of a single agent, which is mixed with said VEGFR inhibitor and/or VEGF inhibitor into a single composition.
  • the other anti-tumor therapy can be a separate agent, which is administered separately from the VEGFR inhibitor and/or VEGF inhibitor.
  • the VEGFR inhibitor and/or VEGF inhibitor may be present in an amount of about 1-99% relative to the total dose. % (e.g. about 5-95%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about A dosage level of 90%, about 95%, or about 99%) is present and/or administered.
  • % e.g. about 5-95%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about A dosage level of 90%, about 95%, or about 99%
  • the term "skin disease or disorder” generally refers to pathological changes in the morphology, structure and/or function of the skin (including hair and nails).
  • the skin disease or condition may include, but is not limited to, rashes, hand-foot syndrome, pruritus, erythema, dry skin, hair loss, paronychia, pigmentation disorders, and the like.
  • rash generally refers to changes in the skin that affect the color, appearance, or texture of the skin.
  • the rash can be confined to one part of the body, or affect the entire skin.
  • Rashes also include hives.
  • HFS Hand Foot Syndrome
  • PPE Palmar Plantar Erythrodysesthesia
  • HFSR Hand-foot skin reaction
  • the pathological manifestations of HFS mainly include, for example, vacuolar degeneration of basal keratinocytes, perivascular lymphocyte infiltration in the skin, keratinocyte apoptosis, and skin edema.
  • HFS may include dysesthesia on the palms and soles, or acral erythema caused by chemotherapy. Cancer patients may experience corresponding symptoms during chemotherapy or molecular targeted therapy (such as VEGFR inhibitors and/or VEGF inhibitors).
  • Hand-foot syndrome currently has a variety of grading methods, among which the National Cancer Institute (NCI) grading standard is more commonly used, which divides hand-foot syndrome into 3 grades: grade 1 is mild skin changes or dermatitis with sensation Abnormalities (such as disappearance of fingerprints, hyperpigmentation, erythema, peeling, paresthesia, insensitivity, skin numbness, etc.), but do not affect daily activities; Grade 2 refers to skin changes that are the same as Grade 1, accompanied by pain, which slightly affects daily activities. The surface is intact; grade 3 is ulcerative dermatitis or skin changes accompanied by severe pain, seriously affecting daily life, with obvious tissue damage (such as desquamation, blisters, bleeding, edema, etc.).
  • NCI National Cancer Institute
  • grade 1 is dysesthesia, paresthesia or tingling in the hands and feet
  • grade 2 is discomfort, painless swelling or erythema when holding objects and walking
  • Grade 3 is painful erythema and edema of the palms and soles, erythema and swelling around the nail
  • Grade 4 is peeling, ulceration, swelling and severe pain.
  • the term "erythema” generally refers to a localized or generalized red macule caused by localized or systemic dilation of the capillary network in the papillary dermis.
  • paronychia usually refers to an infectious lesion of the soft tissue around the (toe) nail, which is usually caused by bacteria invading the subcutaneous tissue through tiny breaks in the paranail skin and multiplying, and the clinical manifestation is redness and swelling of the affected area Pain, accompanied by inflammatory exudation and granulation tissue hyperplasia.
  • pigmentation disorder generally refers to a condition in which the skin is lighter or darker than normal, blotchy or discolored. Hypopigmentation is caused by the body not producing enough pigment and hyperpigmentation is caused by the body producing too much pigment.
  • the term "disease or disorder of five sense organs” generally refers to pathological changes in the shape, structure and/or function of ears, eyebrows, eyes, nose, mouth and other organs.
  • the five sense organs diseases or conditions may include, but are not limited to, oral mucositis, dry mouth, epistaxis, nasopharyngitis and/or cheilitis.
  • nasopharyngitis generally refers to the inflammatory response of the nasopharyngeal mucosa, submucosal and lymphoid tissues, and can be divided into acute nasopharyngitis and chronic nasopharyngitis.
  • Symptoms include but are not limited to dryness and discomfort in the nasopharynx, sticky secretions that are difficult to cough up, often accompanied by nausea, and severe cases have local or systemic symptoms such as hoarseness, sore throat, headache, dizziness, fatigue, indigestion, and low-grade fever.
  • Nasopharyngeal examination showed chronic congestion, hyperplasia, hypertrophy of the mucosa, covered with secretions or dry scabs.
  • cheilitis generally refers to an inflammatory disease or condition that occurs on the lips.
  • it may include inflammation of the perioral skin, vermilion border, and/or labial mucosa, among others.
  • acute cheilitis and chronic cheilitis According to the course of the disease, it can be divided into acute cheilitis and chronic cheilitis; according to clinical symptoms, it can be divided into erosive cheilitis, eczematous cheilitis, and desquamative cheilitis; according to the etiology and pathology, it can be divided into chronic nonspecific cheilitis, glandular cheilitis Cheilitis, benign lymphoproliferative cheilitis, granulomatous cheilitis, Meyerau syndrome, actinic cheilitis and allergic cheilitis, etc.
  • gastrointestinal disease or disorder generally refers to pathological changes in the morphology, structure and/or function of stomach or intestinal tissue (eg, digestive tract tissue from gastric pylorus to anus).
  • the gastrointestinal diseases or disorders may include, but are not limited to, diarrhea (diarrhea), vomiting (vomitting), nausea (nausea), anorexia (anorexia), constipation (constipation) and/or abdominal pain (abdominal pain) and the like.
  • epithelial tissue includes one or more layers of cells covering free and enclosed surfaces throughout the body, including skin, mucus, cavities, serous and glandular spaces. All epithelial layers contain two specialized domains: the apical domain facing the mucosal (or luminal) space and the basolateral membrane facing the serosal (or deep) space. Therefore, an important function of epithelial tissue is to provide an appropriate barrier function to separate and control many physiological processes between these two spaces.
  • Epithelial tissue includes epithelial cells as well as endothelial cells.
  • epithelial tissue disease or disorder generally refers to a disease or disorder caused by epithelial and/or endothelial cell lesions.
  • the epithelial tissue disease or condition may include rash, acne, pruritus, alopecia, hair changes, erythema, skin exfoliation, herpes impetigo, hirsutism, hyper-pigmentation, nail disease ( nail disorders), paronychia and cleft nails, dry skin, hypersensitivity, mucositis, nasopharyngitis, epistaxis, dry mouth, cheilitis, oral ulcers, and/or gastrointestinal mucosal injury.
  • the epithelial tissue disease or disorder may also include skin epithelial cell disease or disorder (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, acne, hyperpigmentation, melasma, vitiligo, urticaria, tinea corporis, pruritus, alopecia, hair changes, erythema, paronychia and cleft nails, dry skin, hypersensitivity, and psoriasis), oral epithelial disease or Conditions (eg, pemphigus, cold sores, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, Sjoglin's syndrome, Behcet's syndrome, and oral sarcoidosis, etc.), Nasal epithelial cell diseases or disorders (epistaxis, sinusitis,
  • nitric oxide releasing moiety generally refers to any substance capable of contributing to, generating and/or releasing nitric oxide production.
  • the nitric oxide releasing moiety can directly contribute, produce and/or release nitric oxide.
  • a nitric oxide releasing moiety may contribute, produce and/or release nitric oxide by stimulating other substances.
  • a nitric oxide releasing moiety may serve as a reactant in a chemical or enzymatic reaction by which nitric oxide is donated, produced and/or released.
  • the nitric oxide releasing moiety can act as a catalyst for chemical or enzymatic reactions by which other substances are stimulated to contribute, produce and/or release nitric oxide.
  • the nitric oxide releasing moiety may also include nitric oxide itself.
  • organic molecule generally refers to compounds containing carbon elements, and does not include carbon oxides, carbonic acid, carbonates, cyanides, cyanides, oxycyanides, cyanates, thiocyanates, metal carbides things etc.
  • polymer generally refers to a molecular weight greater than 2000 Daltons, greater than 3000 Daltons, greater than 4000 Daltons, greater than 5000 Daltons, greater than 6000 Daltons, greater than 7000 Daltons , greater than 8000 daltons, greater than 9000 daltons, greater than 10000 daltons, greater than 12000 daltons, greater than 15000 daltons or greater than 20000 daltons.
  • small molecule generally refers to molecular weight less than or equal to 2000 daltons, less than or equal to 1500 daltons, less than or equal to 1200 daltons, less than or equal to 1000 daltons, less than or equal to 900 daltons Dalton, less than or equal to 800 dalton, less than or equal to 700 dalton, less than or equal to 600 dalton, less than or equal to 500 dalton, less than or equal to 400 dalton, less than or equal to 300 dalton Any compound having a molecular weight of less than or equal to 200 Daltons or less than or equal to 100 Daltons.
  • the nitric oxide releasing moiety may have one or more of the following groups: azonium dialkoxide, hydroxydiazenesulfonic acid, S-nitrosothiol, furazanoxide , oxime, N-nitrosamine, N-hydroxyguanidine, azonium dialkoxide, nitrate, nitrite, nitrate ester, nitrite ester, stiltonimine, styrone, oxatriazole-5 -Imines, oxatriazol-5-ones, hydroxylamines, dioxadiazetidines, N-hydroxynitrosamines, N-nitrosamines, hydroxyureas and metal nitrosamino complexes.
  • the nitric oxide releasing moiety may have one or more groups selected from Table 1:
  • prevention in this application generally means preventing the onset, recurrence or spread of a disease or one or more symptoms thereof by taking certain measures in advance.
  • treating generally refers to eliminating or ameliorating a disease, or alleviating one or more symptoms associated with a disease.
  • the term "subject” generally refers to a human or non-human animal (including mammals, rodents and birds, etc.) that needs to receive diagnosis, prognosis, improvement, prevention and/or treatment of diseases.
  • the subject can be a livestock animal (e.g., cow, pig, sheep, chicken, rabbit, or horse), or a rodent (e.g., rat and mouse), or a primate (e.g., orangutans and monkeys), or domestic animals (for example, dogs and cats).
  • the term "effective amount” generally refers to the amount of a drug that can alleviate or eliminate the disease or symptom of the subject, or preventively inhibit or prevent the occurrence of the disease or symptom.
  • the specific effective amount is determined according to the condition and potential of cross-infection, allergy, hypersensitivity and side effects, and/or the degree of development of epithelial (or endothelial) tissue diseases. Dosages may be proportionally reduced or increased by those skilled in the art (eg, physician or veterinarian) according to these or other conditions or requirements.
  • the "substantially no influence” may mean that the effect is equivalent, or no significant disadvantage occurs.
  • the resulting reduction in tumor volume is the same for any subject, or the reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, Not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001%, or less.
  • the term "susceptible to suffering” generally means that the subject has a higher probability of suffering from the disease or condition associated with the administration of the antineoplastic agent.
  • said greater probability may mean that the probability that a subject suffers from said disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor is increased by about at least 10% compared to a healthy subject , at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, or more.
  • the term "skin tissue features" generally refers to features that can reflect skin diseases or disorders.
  • the characteristics can include characteristics that reflect a skin disease or condition associated with administration of the antineoplastic agent.
  • the characteristics may include skin rashes associated with administration of antineoplastic agents, hand-foot syndrome associated with administration of antineoplastic agents, pruritus associated with administration of antineoplastic agents, skin erythema associated with administration of antineoplastic agents, and/or or purpura, dry and/or chapped skin associated with administration of antineoplastic agents, alopecia associated with administration of antineoplastic agents, paronychia associated with administration of antineoplastic agents, and/or, pigmentation associated with administration of antineoplastic agents characteristic of the disorder.
  • the characteristics may include area and extent of erythema, area and extent of purpura, number and extent of papules, number and extent of pustules, number and extent of nodules, extent and extent of skin swelling, extent of skin ulceration, extent of skin dryness, chapped skin degree, degree of skin keratinization, degree of skin lichenification, area and degree of skin desquamation, skin tightness, degree of skin itching, degree of vascular inflammation at the junction of dermis and subcutaneous tissue, degree of necrosis of skin tissue, degree of skin erosion and ulceration, reticular The area of green spots, the degree of skin pigmentation, the number of blisters and bullae, the location/area/degree of hair loss, the degree of skin granulation hyperplasia, the degree of skin seborrheia, the degree of folliculitis, the degree of periungual redness, the degree of periungual abscess, the degree of periungual Skin pigmentation, nail bed atrophy, deck thinning
  • the term "features of the five sense organs” generally refers to the characteristics that can reflect diseases or diseases of the five sense organs.
  • the characteristics may include characteristics reflecting a disease or disorder of the five sense organs associated with the administration of the antineoplastic agent.
  • the characteristics can include oral ulcers that can reflect oral ulcers associated with the administration of anti-neoplastic agents, dry mouth associated with the administration of anti-neoplastic agents, epistaxis associated with the administration of anti-neoplastic agents, nasopharyngitis associated with the administration of anti-neoplastic agents, and or, features of cheilitis associated with administration of antineoplastic agents.
  • the features may include the degree of oral mucosa hyperemia, oral mucosal edema, oral mucosal herpes, oral mucosal ulcers, oral submucosal periglandular defects, lingual/sublingual/parotid salivary gland atrophy, oral Degree of dryness, degree of caries, degree of tongue swelling, degree of dent marks around tongue, frequency of nosebleeds, amount of nosebleeds, degree of edema of oropharyngeal and nasopharyngeal mucosa, degree of herpes of oropharyngeal and nasopharyngeal mucosa, degree of oropharyngeal and nasopharyngeal mucosa Ulcer degree, oropharyngeal and nasopharyngeal mucosal hyperplasia, oropharynx and nasopharyngeal follicular hyperplasia, lip and lip swelling, lip and lip herpes, lip
  • the term "gastrointestinal characteristics" generally refers to characteristics that can reflect diseases or disorders of the gastrointestinal tract.
  • the characteristics can include characteristics that reflect a gastrointestinal disease or disorder associated with administration of the antineoplastic agent.
  • the features may include those reflecting esophageal mucositis associated with the administration of antineoplastic agents, gastric mucositis associated with the administration of antineoplastic agents, gastric ulcers associated with the administration of antineoplastic agents, diarrhea associated with the administration of antineoplastic agents, Features of vomiting associated with administration of antineoplastic agent, nausea associated with administration of antineoplastic agent, anorexia associated with administration of antineoplastic agent, constipation associated with administration of antineoplastic agent, and/or, abdominal pain associated with administration of antineoplastic agent .
  • the characteristics may include the degree of loss of appetite, degree of epigastric belching, degree of dysphagia, degree of retrosternal burning, degree of retrosternal pain, time (on an empty or full stomach) and degree of epigastric pain, degree of abdominal distension, diarrhea Severity, frequency of defecation, defecation time, abdominal pain before defecation, tenesmus, abnormal stool (such as black blood stool, bloody stool, mucus stool, mucus pus and blood stool, watery stool, egg drop soup-like stool, etc.), frequency of vomiting, and vomitus , Hematemesis, nausea, degree of malnutrition, degree of trace element deficiency, etc.
  • the term "substantially free of cancer cells” generally refers to tissues, organs or parts in a subject whose content of cancer cells is so low that they are considered substantially free of cancer cells.
  • the substantially free may mean that the number of cancer cells accounts for less than 0.01% of the total number of cells in the site, for example, less than 0.005%, less than 0.001%, less than 0.0001%, less than 0.00001% or lower.
  • non-cancer site generally refers to a site in a subject that is not a cancer lesion and not an area of cancer metastasis.
  • the cancer focus can be the primary site of cancer.
  • the cancer metastasis region may be the region where the tumor of the same type as the tumor at the primary site is located.
  • the cancer metastases can be formed through lymphatic metastasis, vascular metastasis or implantation metastasis.
  • EGFR generally refers to Epidermal Growth Factor Receptor (Epidermal Growth Factor Receptor), also known as ErbB1 or HER1, which is a 170kDa transmembrane glycoprotein encoded by the c-erbB1 proto-oncogene.
  • EGFR is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs), which also includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4).
  • HER human epidermal growth factor receptor
  • RTKs receptor tyrosine kinases
  • EGFR signaling is initiated by ligand binding, followed by induction of conformational changes of the receptor with other ErbB family members, homodimerization or heterodimerization, and trans-autophosphorylation of the receptor, etc. (see, Ferguson et al., Annu Rev Biophys, 37:353-73, 2008), to initiate signal transduction cascades that ultimately affect various cellular functions (eg, cell proliferation and survival).
  • EGFR or its kinase activity is associated with a range of human cancers (see, Mendelsohn et al., Oncogene 19:6550-6565, 2000; GrUnwald et al., J Natl Cancer Inst 95:851-67, 2003; Mendelsohn et al. , Semin Oncol 33:369-85, 2006). It is known that the expression of EGFR is increased in many cancers, such as brain glioma, breast cancer, ovarian cancer, cervical cancer and the like.
  • the term "EGFR is inhibited” includes any reason (for example, caused by treatment or caused by the subject's own physical condition) that EGFR activity, expression or quantity is reduced.
  • EGFR is inhibited generally means that the activity or amount of EGFR is reduced by at least 10%.
  • inhibition of EGFR generally refers to a decrease in the activity or amount of EGFR by at least 20%, 40%, 50%, 80%, 90%, 95% or more.
  • the reduction is compared to a standard value in a similar subject (eg, the same normal person or the same type of patient). In some embodiments, the reduction is compared to a previous value in the same subject over a period of time.
  • EGFR inhibitor generally refers to any EGFR inhibitor known in the art or discovered in the future, including any EGFR inhibitor that, when administered to a subject, results in a EGFR-related activity in the subject. Any substance that inhibits the biological activity of EGFR (including the inhibition of any downstream biological effects produced by the binding of EGFR to its natural ligand).
  • an EGFR inhibitor includes any agent capable of blocking EGFR activity or any of its downstream biological effects during the treatment of cancer.
  • small molecule EGFR inhibitor may include small molecule EGFR inhibitors that bind reversibly to EGFR (for example, gefitinib, erlotinib, Sapitinib, and icotinib), small molecule inhibitors that bind irreversibly to EGFR Small molecule EGFR inhibitors (eg, afatinib, dacomitinib, lapatinib (eg, GW572016 GlaxoSmithKline), Vandetanib (eg ZACTIMA TM, ZD6474), Lenvatinib, Canertinib, Valitinib and Neratinib) and/or small molecules EGFR that specifically bind mutant EGFR Inhibitors (eg, osimertinib, toartinib, norsustinib, ocimertinib (ocimertinib), avitinib, and EAI045).
  • small EGFR inhibitors that
  • a pharmaceutically acceptable compound, material, composition, and/or dosage form is one approved by a regulatory agency (such as the U.S. Food and Drug Administration, China Food and Drug Administration, or European Medicines Agency) or listed on a generally recognized Those in pharmacopoeias, such as the US Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia, for animals, more particularly for humans.
  • a regulatory agency such as the U.S. Food and Drug Administration, China Food and Drug Administration, or European Medicines Agency
  • the application provides a use of a NO-NSAID compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, alleviating and/or treating a subject related to the administration of an antineoplastic agent disease or condition.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject, the method comprising administering an effective amount of NO to a subject in need thereof.
  • An NSAID compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
  • the present application provides a NO-NSAID compound or a pharmaceutically acceptable salt thereof, which is used for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the present application provides a pharmaceutical combination, which comprises: 1) an antineoplastic agent; and 2) a NO-NSAID compound.
  • the present application provides the use of the NO releasing agent and NSAID in the preparation of a medicament for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject, the method comprising administering an effective amount of NO to a subject in need thereof. Release agents and NSAIDs.
  • the present application provides a pharmaceutical combination, which comprises: 1) antitumor agent; 2) NO releasing agent; and 3) NSAID.
  • the NO-NSAID compound may include a nitric oxide (NO) releasing moiety and a non-steroidal anti-inflammatory agent (NSAID) moiety, and the NO-releasing moiety is combined with the NSAID
  • NO nitric oxide
  • NSAID non-steroidal anti-inflammatory agent
  • the agent moieties can be directly linked covalently or via a spacer.
  • the NO-releasing moiety and the NSAID moiety may be linked via a cleavable linker.
  • the NO-releasing moiety is connected to the NSAID moiety through a linker comprising an ester bond and/or a disulfide bond.
  • a spacer may be included between the NO-releasing moiety and the NSAID moiety.
  • the spacer comprises: one or more optionally substituted -CH2- , optionally substituted phenyl, and/or combinations thereof.
  • the spacer may comprise/can be: one or more -CH2- , one or more substituted -CH2- , one or more phenyl, one or more substituted phenyl, or any combination of .
  • the non-steroidal anti-inflammatory agent (NSAID) moiety may comprise a cyclooxygenase (COX) inhibiting moiety.
  • the (COX) inhibitory moiety may comprise a small molecule COX inhibitory moiety that reversibly binds COX and/or a small molecule COX inhibitory moiety that irreversibly binds COX.
  • the small molecule COX inhibiting moiety may have a molecular weight of less than or equal to 2000 daltons, less than or equal to 1500 daltons, less than or equal to 1200 daltons, less than or equal to 1000 daltons, less than or equal to 900 daltons, less than or equal to or equal to 800 daltons, less than or equal to 700 daltons, less than or equal to 600 daltons, less than or equal to 500 daltons, less than or equal to 400 daltons, less than or equal to 300 daltons, less than or equal to 200 Daltons and/or a molecular weight less than or equal to 100 Daltons.
  • the COX-inhibiting moiety comprises a moiety capable of reducing the expression of the COX, and/or a moiety that reduces the activity of the COX.
  • the COX inhibitory moiety can act directly on the COX protein and/or the nucleic acid encoding the COX protein.
  • the COX inhibiting moiety is capable of inhibiting cyclooxygenase-1 (COX-1 ) and/or cyclooxygenase-2 (COX-2).
  • the COX-inhibiting moiety selectively inhibits COX-2.
  • the COX-inhibiting moiety is capable of non-selectively inhibiting COX-1 and COX-2.
  • the COX inhibitory moiety may comprise one or more molecules selected from the group consisting of prodrugs, active derivatives and/or active metabolites thereof: acetaminophen, acemetacin ( acemetacin, aceclofenac, aceclofenac, alminoprofen, arnfenac, bendazac, benoxaprofen, bromfenac, bucloxac acid), butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, felbinac , fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac , ibuprofen, indomethacin, isofenzolac, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprof
  • the COX inhibitory moiety comprises one or more molecules selected from the group consisting of prodrugs, active derivatives and/or active metabolites thereof: naproxen, aspirin ( aspirin, diclofenac, ketoprofen, flurbiprofen and ibuprofen.
  • the NO releasing part is capable of generating at least one of NO + , NO ⁇ , N 2 O, NO, N 2 O 3 , NO 2 , NO 3 ⁇ and NO 2 ⁇ .
  • the NO releasing moiety can directly or indirectly generate NO.
  • the NO releasing moiety may comprise organic molecules, inorganic molecules and/or polymer or nanomaterials.
  • the NO-releasing moiety may comprise a component selected from the group consisting of nitroglycerin, isosorbide mononitrate, butanediol mononitrate, pentaerythritol tetranitrate, isosorbide dinitrate, trinithanolamine , Nicorandil, Nitromethol, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazole, isoamyl nitrite, 3,3-bis(ammonia Ethyl)-1-hydroxy-2-carbonyl-1-triazene (NOC-18), Sulfo NONOate disodium salt, S-nitrosoglutathione (S -Nitrosoglutathione), S-nitroso-N-acetylpenicillamine (S-Nitroso-N-acetylpenicillamine), 4-phenyl-3-furoxanitrile (4-Phenyl-3-furoxancarbonitrile
  • the NO releasing moiety may include a component selected from the group consisting of nitroxyl complexes, Metal nitrosyl complexes, metal nitrosyl complexes, nitrates and nitrites.
  • the NO releasing moiety comprises a component selected from the group consisting of S-nitrosothiol nanosilica spheres, S-nitrosoethanedithiol chitin and oligopropylenediamine grafted shell Glycan NONOate.
  • the NO releasing part has a function of less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900 Daltons 800 Daltons or less, 700 Daltons or less, 600 Daltons or less, 500 Daltons or less, 400 Daltons or less, 300 Daltons or less , a molecular weight of less than or equal to 200 Daltons and/or a molecular weight of less than or equal to 100 Daltons.
  • the NO-releasing moiety may have one or more of the following groups: azonium dialkoxide, hydroxydiazenesulfonic acid, S-nitrosothiol, furazanoxide, oxime, N- Nitrosamines, N-hydroxyguanidine, nitrates, nitrites, nitrates, nitrites, stiltonimine, styrone, oxatriazole-5-imine, oxatriazol-5-one, Hydroxylamine, dioxadiazetidine, N-hydroxynitrosamines, N-nitrosamines, hydroxyurea and metal nitrosamino complexes.
  • groups include azonium dialkoxide, hydroxydiazenesulfonic acid, S-nitrosothiol, furazanoxide, oxime, N- Nitrosamines, N-hydroxyguanidine, nitrates, nitrites, nitrates, n
  • the NO releasing moiety may comprise -NO2 or -ONO2 .
  • the NO-NSAID compound further comprises a H2S releasing moiety.
  • it may be a NO-NSAID compound described in WO2013025790A2.
  • the NO-NSAID compound comprises a structure shown in formula (1):
  • Z is O or NH;
  • R 1 , R 2 , R 3 and R 4 are each independently H, halogen, NO 2 , N 3 , C 1 -C 10 alkyl, OR, OC(O)R, N(R ) 2 , NH-C(O)R, S(O)R or N ⁇ NR, wherein each R is independently C 1 -C 10 alkyl or aryl;
  • L 1 comprises a structure selected from the group consisting of: -C(O)-, -(CH 2 ) m -, -(CH 2 ) m -O-, -(CH 2 ) m -C(O)-, -(CH 2 ) m -C(O)O -, -(CH 2 ) m -OC(O)O-, -C(O)-(CH 2 ) m -O-, -C(O)-(CH 2 ) m -C(O)-, -OC(
  • the NO-NSAID compound may comprise a structure shown in formula (2):
  • L 1 and L 2 each independently comprise a structure selected from the group consisting of: -C(O)-, -(CH 2 ) m -, -(CH 2 ) m -O -, -(CH 2 ) m -C(O)-, -(CH 2 ) m -C(O)O-, -(CH 2 ) m -OC(O)O-, -C(O)-( CH 2 ) m -O-, -C(O)-(CH 2 ) m -C(O)-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -O-, -OC(O)-(CH 2 ) m -C(O)- and -OC(O)-(
  • R a is H, C 1 -C 10 alkyl, aryl, S(O) 2 -aryl, CN or CON(R b ) 2 , and each R b is independently H or C 1 -C 10 alkyl; and the H 2 S releasing moiety is selected from:
  • the NO-NSAID compound may be a compound described in US10450260B2.
  • the NO-NSAID compound comprises a structure selected from the group consisting of:
  • X is -(CH 2 ) n1 -Z-(CH 2 ) n2 -, n1 and n2 are each independently 0, 1, 2, 3, 4 or 5; Z is O, N, S, C, A is O, N, S or C; and Y is
  • the NO-NSAID compound comprises a structure shown in formula (3):
  • M is a structure selected from the group consisting of:
  • RA is a hydrogen atom or -C(O)CH 3 ;
  • X is -O-, -S- or -NR 1 -, wherein R 1 is H or straight or branched C 1 -C 6 alkyl;
  • Y is a divalent group with the following definitions:
  • C 1 -C 20 alkylene which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, -ONO 2 , -OC(O)(C 1 -C 10 alkyl)-ONO 2 and -O(C 1 -C 10 alkyl)-ONO 2 ;
  • n is an integer selected from 0-20, n' is an integer of 1-20;
  • n is an integer selected from 0-20, n' is an integer of 1-20;
  • X 1 is -OCO- or -COO-
  • R 2 is H or CH 3
  • na is an integer of 1-20
  • n 2 is an integer of 0-2;
  • Y 1 is -CH 2 -CH 2 -(CH 2 )n 2 -, or -CH ⁇ CH-(CH 2 )n 2 -, X 1 , na, n 2 and R 2 are as defined above;
  • na and R2 are as defined above, and R3 is H or -COCH3 ;
  • X 2 is -O- or -S-
  • n 3 is an integer of 1-6
  • R 2 is as defined above.
  • the NO-NSAID compound comprises a structure shown in formula (3): MXY-ONO 2 (3), wherein M is selected from the following structures: X is -O-; Y is a linear or branched C 1 -C 10 alkylene group.
  • the NO-NSAID compound may comprise the structure shown in formula (4): A-(B) b0 -(D) c0 -NO 2 (4)
  • c0 0 or 1
  • b0 0 or 1
  • at least one of c0 and b0 is not 1
  • B is T B -X 2 -T BI -, T B is X, T BI is (CO) or X, X is O, S, N or NR 1C , R 1C is H or a linear or branched chain alkyl group having 1 to 5 carbon atoms
  • X 2 is a group selected from compounds of the formula HX 2 -H: hydroxyl acid, gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, p-coumaric acid and vanillic acid
  • D is a divalent group: -T c
  • the NO-NSAID compound may comprise a structure represented by formula (5): AX 1 -L-(W) p -NO 2 (5).
  • p is 0 or 1
  • A is RT 1 , wherein R is the residue of the prodrug and has the following formula: wherein s is 0 or 1
  • R AI is H or CH 3
  • R 1 is OCOR 3 , NHCOR 3 , OH, CH 2 CH(CH 3 ) 2 , phenyl, benzoyl or 4,6-dichloroanilino
  • R 3 is a C 1 -C 5 linear or branched residue
  • R 6 is H or halogen
  • R has the structure of: T 1 is (CO) t or (X) t′ , wherein X is O, S or NR 1c , R 1c is H or a linear or branched chain alkyl group having 1 to 5 carbon atoms, and t and t′ are 0 or 1, when t' is 0, t is 1, and when t' is 1, t is 0; X 1 is -T B -YT BI , where T B and T BI can be the same or different, when t is 0 When T B is (CO), when t' is 0, T B is X, and X is as above; T BI is (CO) tx or (X) txx , where tx and txx are 0 or 1, when txx is 0 When tx is 1, when txx is 1, tx is 1, tx is 1, tx is 1, tx is 1, tx is 1, tx is 1, tx is 1, tx is 1,
  • the NO-NSAID compound may comprise the structure shown in formula (5): AX 1 -L-(W) p -NO 2 (5), wherein: the p is 0 or 1, and A is RT 1 - , where R has the structure and T 1 is (CO) t or (X) t′ , t and t′ are 0 or 1, t′ is 0 when t is 1, and t′ is 1 when t is 0; X 1 is -T B -YT B1 -, where T B and T B1 are the same or different, T B is (CO) when t is 0, T B is X when t' is 0; T B1 is (CO) tx or (X) txx , where tx and txx are each independently 0 or 1, when txx is 0, tx is 1, and when txx is 1, tx is 0; X is O, S or NR 1C , R 1C is H or has 1- Straight chain or
  • the NO-NSAID compound may comprise a structure shown in formula (16): Wherein R m is H or lower alkyl, and R n is a structure selected from the group:
  • X is -Y-(CR 4 R 4' ) o -C(R 4 )(ONO 2 )-(CR 4 R 4' ) q -(T) o -(W) q (T ) o -(CR 4 R 4' ) o -R 5 ;
  • each R 4 and R 4 ' is independently hydrogen, lower alkyl, -OH, -CH 2 OH, -ONO 2 , -NO 2 or -CH 2 ONO 2 , or R 4 and R 4 ' together with the carbon atoms attached to them form a cycloalkyl or heterocyclic ring;
  • W is a covalent bond or a carbonyl group;
  • each T is independently oxygen, (S(O) o ) o or NR j ;
  • R j is hydrogen, alkyl, aryl, heterocycle, alkylcarbonyl, alkylaryl, alkylsulfinyl, alkylsul
  • the NO-NSAID compound may comprise a structure shown in formula (17) or formula (18):
  • Each s is independently 1 or 2; k is 1, 2, 3 or 4; each m is independently 0, 1, 2, 3 or 4; each x is independently 0 or S; Y is a bond, S, O or NR 1 , wherein R 1 is hydrogen or C 1 -C 6 alkyl; R is hydrogen or C 1 -C 6 alkyl; the Linker is a linker, which is selected from the following group: 1 )-(CH 2 ) n , n is 0, 1, 2, 3 or 4; 2) C 3 -C 6 cycloalkyl, which is optionally substituted by a group selected from the group consisting of halogen, C 1 - C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, NO, CO 2 , CF 3 , CN, CH 2 COOH, CH 2 COO-C 1-3 alkyl and C 1 -C 3 thioalkyl 3) aryl selected from phenyl and naphthyl, said aryl optionally substitute
  • the NO-NSAID compound comprises a structure shown in formula (19):
  • A is a drug selected from the group consisting of residues of (A-OH or AH): NSAIDs, analgesics, antipyretics and COX-2 inhibitors ;
  • T is -O-, -NH-, -S-, -CO- or -(CH 2 ) n1 OCO-, wherein n1 is an integer from 1 to 20;
  • A is selected from the group consisting of: Wherein c and d are each independently 0 or 1, RB is selected from: H, straight chain or branched C 1 -C 12 alkyl and C 2 -C 12 alkenyl; when c is 0, d is 1,
  • RA is a structure selected from the group consisting of:
  • R c is selected from the following group: H, halogen, amino, R E CONH- and -OCOR E
  • R D is selected from the following group: H, OH, halogen, straight chain or branched C 1 -C 4 alkyl, straight
  • R E1 is H or CH 3 , and R C1 is Cl or F;
  • R A is a structure selected from the group:
  • R G is a structure selected from the group consisting of: Wherein R H is phenyl or cyclohexyl;
  • Y is a divalent group with the following meanings:
  • n is an integer of 0-20, and n1 is an integer of 1-20;
  • n is an integer of 0-20, and n1 is an integer of 1-20;
  • n1 is an integer of 1-20, and n2 is an integer of 0-2, X 1 is -OCO- or -COO-, and R 2 is H or CH 3 ;
  • n1 and R 2 are as above, R 3 is H or COCH 3 ;
  • X 2 is -O- or -S-, n3 is an integer of 1-6, and R 2 is as described above;
  • n4 is an integer of 0-10
  • n5 is an integer of 1-10
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H and linear or branched C 1 -C 4 alkyl, and -ONO 2 with connected
  • n5 is as described above
  • Y2 is a 5- or 6-membered saturated, unsaturated or aromatic ring, and contains 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the NO-NSAID compound comprises a structure represented by formula (21): (21), wherein X is a linker, and M is a structure selected from the group consisting of:
  • the NO-NSAID compound comprises a compound selected from the group consisting of:
  • the molar ratio of the NO-releasing moiety to the NSAID moiety may be from about 10:1 to about 1:10.
  • the molar ratio of the NO releasing moiety to the NSAID moiety can be from about 9:1 to about 1:1, from about 8:1 to about 1:1, from about 7:1 to about 1:1, about 6:1 1 to about 1:1, about 5:1 to about 1:1, about 4:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1.
  • the molar ratio of the NO releasing moiety to the NSAID moiety is from about 1:1 to about 1:8, from about 1:1 to about 1:7, from about 1:1 to about 1:6 , about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about 1:1 to about 1:2. In certain embodiments, the molar ratio of said NO releasing moiety to said NSAID moiety is about 3:1. In certain embodiments, the molar ratio of said NO releasing moiety to said NSAID moiety is about 2:1. In certain embodiments, the molar ratio of said NO releasing moiety to said NSAID moiety is about 1:1. In certain embodiments, the molar ratio of said NO releasing moiety to said NSAID moiety is about 1:2. In certain embodiments, the molar ratio of said NO releasing moiety to said NSAID moiety is about 1:3.
  • the anti-tumor agent may include small molecule compounds, small molecule conjugates, proteins and/or polynucleotides.
  • the antineoplastic agents may include chemotherapeutics, targeted therapeutics and/or immunotherapeutics.
  • the antineoplastic agent is a targeted therapeutic agent.
  • the targeted therapeutic agents may include small molecule compounds and/or antibodies or antigen-binding fragments thereof.
  • the antibodies may include monoclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies and/or antibody drug conjugates.
  • the antigen-binding fragment may comprise Fab, Fab', F(ab )2 , Fv fragment, F(ab') 2 , scFv, di-scFv and/or dAb.
  • the targeted therapeutic agent targets molecules inside tumor cells, on the surface of tumor cells and/or in the tumor microenvironment.
  • the targeted therapeutics can target proteins and/or nucleic acid molecules.
  • the targeted therapeutic may target a tumor-associated antigen.
  • the targeted therapeutic agent targets one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR- ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and others mutants.
  • targets selected from the group consisting of VEGF, EGFR, EGFR
  • the targeted therapeutic agent may inhibit the activity of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4 , PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF -1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants .
  • targets selected from the group consisting of VEGF
  • the targeted therapeutic agent can reduce the expression of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4 , PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF -1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants .
  • targets selected from the group consisting of VEGF
  • the targeted therapeutic agents may include hormones, signal transduction inhibitors, gene expression regulators, apoptosis inducers, angiogenesis inhibitors and/or toxin delivery molecules.
  • the targeted therapeutic agent is a tyrosinase inhibitor.
  • the targeted therapeutic agent is a VEGFR inhibitor and/or a VEGF inhibitor.
  • the VEGFR inhibitor can inhibit VEGFR1, VEGFR2 and/or VEGFR3.
  • the targeted therapeutic agent is an EGFR inhibitor.
  • the targeted therapeutic agent is a BRAF inhibitor.
  • the targeted therapeutic agent is a PDGFR inhibitor.
  • the targeted therapeutic agent is a FGFR inhibitor.
  • the targeted therapeutic agent is an mTOR inhibitor.
  • the targeted therapeutic agent is a HER2 inhibitor.
  • the EGFR (e.g., Her2) inhibitor can be selected from the following compounds and pharmaceutically acceptable salts thereof: afatinib, ombrutinib, lapatinib , gefitinib and dacomitinib.
  • the VEGFR inhibitor and/or VEGF inhibitor can be selected from the following compounds and pharmaceutically acceptable salts thereof: ramucirumab, bevacizumab, and Rotinib, regorafenib, cabozantinib, lenvatinib, sorafenib, fruquintinib, famitinib, apatinib, axitinib, and nintedanib.
  • the BRAF inhibitor can be selected from the following compounds and pharmaceutically acceptable salts thereof: vemurafenib, encorafenib, selumetinib and dabrafil Ni.
  • the PDGFR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: sunitinib and nintedanib.
  • the FGFR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: erdafitinib and infigratinib.
  • the mTOR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: everolimus.
  • the targeted therapeutic agent described in this application can be selected from one or more of the following group: afatinib, dacomitinib, osimertinib, EAI045, gefitinib, amotinib , Pirotinib, Brigatinib, Neratinib, Omorutinib, Bosutinib, Icotinib, Vandetanib, Lapatinib, Aflutinib, BPI-7711, Mobotinib, dovitinib, zoritinib, vallitinib, abrutinib, rabrutinib, brutinib, ibrutinib, dasatinib, pirtobrutinib, tolebrutinib, rilzabrutinib, fenebrutinib, evobrutinib, selumetinib, tivozanib, dovitinib
  • the targeted therapeutic agent may be administered in combination with one or more other therapies.
  • the antineoplastic agent is a chemotherapeutic agent.
  • the chemotherapeutic agents may include pyrimidine nucleoside analogs and/or prodrugs thereof.
  • the chemotherapeutic agent includes one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), Floxuridine, tegafur, idarubicin, paclitaxel, epirubicin,fugin (NUC-1031), doxorubicin, leucovorin, cisplatin, paclitaxel, cyclophosphamide, vincristine and 5- FU prodrug.
  • the chemotherapeutic agent includes one or more selected from the group consisting of furanfluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, fluridine Prodrug derivatives of glycosides, prodrug derivatives of 2'-deoxyfluorouridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine and 3-deazauridine.
  • the chemotherapeutic agents may be administered in combination with one or more other therapies.
  • the one or more other therapies comprise one or more other antineoplastic therapies (eg, antineoplastic agents) described herein.
  • the antineoplastic agents may include alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, Thiotepa, isothiocyanate, busulfan, nimustine hydrochloride, mitogen bromide, melphalan, dacarbazine, ramustine, imofol sodium phosphate, ethylenetriamine, Carmustine, lomustine, streptozotocin, pipobroman, ethoglucid, carboplatin, cisplatin, miplatin, nedaplatin, tenetamide, Mustin, diclopyridine, flupisteine, prednipixitine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, diclofenac, trovafloxacin,
  • alkylating agents such as nitrogen mustard, nitrogen mustard N-
  • Tumor agents such as bevacizumab
  • VEGF inhibitors such as bevacizumab
  • PCT patent applications WO 2005/012359, WO 2005/044853, WO 98/45332, WO 96/30046, WO 94/10202 US patent US7,060,269, US6,582,959, US6,703,020, US6,054,297, US patent applications US2006/009360, US2005/0186208, US2003/0206899, US2003/0190317, US2003/0203409 and US2005/0112126 Those VEGF inhibitors.
  • the anti-tumor agent may be an immunotherapy anti-tumor agent, which may include, for example: bubinanil, crestin, etofuran, lentinan, ubenmetacin, interferon, leukocyte Interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, small coryneform bacteria, everolimus, levamisole, polysaccharide K, procodazole and/or or immune checkpoint inhibitors (eg, CTLA4 inhibitors, TIM-3 inhibitors, PD-1 inhibitors (eg, Nivolumab (Nivolumab), Pembrolizumab (Pembrolizumab), Pidilizumab, AMP514 (Amplimmune), AMP-224, and other PD-1 inhibitors disclosed in PCT patent applications WO2006/121168, WO2009/114335, WO2009/10
  • the antineoplastic agent may comprise a hormone therapy antineoplastic agent.
  • a hormone therapy antineoplastic agent may include fusastatin, diethylstilbestrol, chloromycetes, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, cyproterone acetate, danazol, allylestradiol, progesterone Ketones, mepartricin, raloxifene or meloxifene, levofloxacin, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), Birth control pills, prostacyclanes, testosterone lactones, aminosuccinimide, LH-RH agonists (for example, goserelin acetate, buserelin, leuprolide, etc.), droloxifene, Epiandrostanol, ethinylestradiol sulf
  • the disease or condition associated with the administration of the anti-tumor agent may be caused by the anti-tumor agent alone, or may be caused by multiple treatment regimens, but including the anti-tumor agent .
  • the disease or condition results from administration of the antineoplastic agent.
  • the disease or condition may appear or be exacerbated after administration of the antineoplastic agent.
  • said subject was free of said disease or condition prior to administration of said antineoplastic agent.
  • the disease or disorder can include an epithelial tissue disease or disorder.
  • the epithelial tissue disease or disorder may include a disease or disorder associated with endothelial cell pathology, and/or a disease or disorder associated with epithelial cell pathology.
  • the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the endothelial cells comprise vascular endothelial cells.
  • Lesions of vascular endothelial cells may include endothelial dysfunction.
  • the vascular endothelial cell pathology can include degenerative vascular diseases (e.g., atherosclerosis, arteriosclerosis, and arteriosclerosis (e.g., hyaline degenerative arteriosclerosis and hyperplastic arteriosclerosis)), inflammatory Vascular disease (eg, infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular disease (eg, Raynaud's disease, cyanosis of the extremities, and erythematous extremities pain) and/or congenital vascular disease (eg, congenital arteriovenous fistula), etc.
  • degenerative vascular diseases e.g., atherosclerosis, arteriosclerosis, and arteriosclerosis
  • the epithelial cells may include skin epithelial cells, oral cavity epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the epithelial cell lesion can include a skin epithelial cell lesion (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, pecycosis, pigmentation, Melasma, vitiligo, urticaria, tinea corporis, pruritus, alopecia, hair changes, erythema, paronychia and cleft nails, dry skin, hypersensitivity, and psoriasis), oral epithelial lesions (eg, pemphigus, Cold sores, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphi
  • antitumor agents can cause damage to endothelial cells and endothelial tissues, thereby causing diseases or disorders in skin tissues, oral tissues, nasal cavity tissues and/or gastrointestinal tract tissues.
  • the course of disease usually begins with damage/lesions of endothelial cells and endothelial tissues, while epithelial cells also have pathological changes, and finally end with endothelial cell lesions associated with the administration of antineoplastic agents , and/or forms of epithelial cell lesions associated with the administration of antineoplastic agents manifest in the patient.
  • the disease or condition may include a disease or condition of the skin, a disease or condition of the five sense organs, and/or a disease or condition of the gastrointestinal tract.
  • the skin disease or condition comprises alopecia, body odor, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, lipoatrophy, altered hair color, abnormal hair texture, Hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, fat hypertrophy, nail changes, nail discoloration, nail loss, nail bumps, skin pain, hands and feet Syndrome, photosensitivity, pruritus, purpura, acneiform rash, maculopapular rash, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin induration, skin ulceration, Stevens - Johnson's syndrome, subcutaneous emphysema, telangiectasia, toxic epidermal necrosis, rash and/or urticaria.
  • the skin disease or condition is hand-foot syndrome.
  • the present application relates to the use of the NO-NSAID compound to prevent, alleviate and/or treat in a subject associated with the administration of the antineoplastic agent (eg, a VEGFR inhibitor and/or a VEGF inhibitor) diseases or conditions (for example, hand-foot syndrome).
  • the antineoplastic agent eg, a VEGFR inhibitor and/or a VEGF inhibitor
  • diseases or conditions for example, hand-foot syndrome
  • the present application relates to the use of said NO-NSAID to prevent, alleviate and/or treat a disease or condition (eg, rash).
  • a disease or condition eg, rash
  • the severity of the skin disease or condition is NCI-CTCAE grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above , or level 5.
  • the subject comprises a cancer patient.
  • the skin disease or disorder is affected in a different location than the cancer.
  • the disease or condition associated with the administration of an anti-tumor agent may have a statistically significant correlation with the anti-tumor agent.
  • the disease or condition associated with the administration of an antineoplastic agent may be caused by the antineoplastic agent.
  • the diseases or disorders associated with the administration of anti-tumor agents may include skin diseases or disorders, facial features diseases or disorders, and/or gastrointestinal tract diseases or disorders associated with the administration of anti-tumor agents.
  • the skin diseases or disorders, facial features diseases or disorders, and/or gastrointestinal diseases or disorders associated with the administration of anti-tumor agents may include Disease or condition of epithelial tissue.
  • the disease or condition associated with the administration of the anti-tumor agent may include side effects or adverse reactions caused by the administration of the anti-tumor agent.
  • the disease or disease associated with the administration of antitumor agents may be a new indication, which may be different from any other disease or disease in the past.
  • diagnosis, treatment and/or symptoms of the disease or condition associated with the administration of the antineoplastic agent are unique.
  • erythromycin ointment can treat rashes, but has no therapeutic effect on rashes associated with the administration of antineoplastic agents.
  • the disease or condition associated with the administration of an antineoplastic agent may include rash associated with the administration of an antineoplastic agent, hand-foot syndrome associated with the administration of an antineoplastic agent, pruritus associated with the administration of an antineoplastic agent, Erythema associated with administration of antineoplastic agents, dry skin associated with administration of antineoplastic agents, alopecia associated with administration of antineoplastic agents, paronychia associated with administration of antineoplastic agents, pigmentation disorders associated with administration of antineoplastic agents, Oral ulcers associated with administration of antitumor agents, dry mouth associated with administration of antitumor agents, epistaxis associated with administration of antitumor agents, nasopharyngitis associated with administration of antitumor agents, cheilitis associated with administration of antitumor agents, Esophageal mucositis associated with administration of antitumor agents, gastric mucositis associated with administration of antitumor agents, gastric ulcer associated with administration of antit
  • the disease or condition associated with the administration of an antineoplastic agent includes hand-foot syndrome associated with the administration of an antineoplastic agent.
  • the severity of the disease or condition associated with the administration of antineoplastic agents is grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above in NCI-CTCAE V5.0 , and/or Level 5.
  • the disease or condition may include rash, hand-foot syndrome, pruritus, erythema, dry skin, alopecia, paronychia, pigmentation disorders, oral ulcers, dry mouth, epistaxis, nasopharyngitis, lip inflammation, esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
  • the disease or condition includes hand-foot syndrome.
  • the disease or condition associated with antineoplastic agents cannot be treated or alleviated substantially by administering an agent selected from the group consisting of 1% sildenafil, urea cream, vaseline ointment, urea ointment , Brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, vitamin K1 ointment (0.1%), erythromycin ointment and triamcinolone acetonide ointment.
  • an agent selected from the group consisting of 1% sildenafil, urea cream, vaseline ointment, urea ointment , Brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, vitamin K1 ointment (0.1%), erythromycin
  • the severity of said disease or condition may increase after said administration of an antineoplastic agent.
  • the severity of the disease or condition can be increased by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more % or more, about 40% or more, about 45% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more Above, about 200% or above or more.
  • the subject may not suffer from the disease or condition before the administration of the anti-tumor agent.
  • the term "the subject does not suffer from the disease or disorder” generally means that the subject has no past medical history related to the disease or disorder associated with the administration of the antineoplastic agent. For example, more than 1 day, more than 1 week, more than 1 month, more than 1 year, more than 10 years before the administration of the anti-tumor agent, or since the subject was born, he has not suffered from the anti-tumor agent described in the present application. Drug-related diseases or conditions.
  • the drug does not substantially affect the therapeutic effect of the antineoplastic agent.
  • the "substantially does not affect” may mean that compared with the therapeutic effect of using the anti-tumor agent alone, the therapeutic effect of using the NO-NSAID compound and the anti-tumor agent is equivalent, or does not have significant disadvantages.
  • the degree of reduction in tumor volume caused by the use of the NO-NSAID compound and the anti-tumor agent is the same as compared with the therapeutic effect of the anti-tumor agent alone, or, The degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01% , not less than about 0.001% or less.
  • the medicament or the NO-NSAID compound is formulated for topical administration.
  • the drug or the NO-NSAID compound may be formulated for transdermal administration.
  • the medicament or the NO-NSAID compound is formulated for topical skin administration.
  • the medicament is formulated as a cream, lotion, gel, ointment, salves, spray, liposomal formulation, liniment and/or aerosol.
  • the drug or the NO-NSAID compound may be formulated as an ointment.
  • the drug or the NO-NSAID compound is an oral formulation. In some embodiments, the drug or the NO-NSAID compound may be an injectable formulation. In some embodiments, the drug or the NO-NSAID compound may be for topical administration in the oral cavity.
  • the site of administration of the drug is different from the site of administration of the antineoplastic agent. In some embodiments, the site of administration of the drug is not the site of occurrence of cancer or the site of potential metastasis of cancer.
  • the drug is administered differently than the antineoplastic agent.
  • the concentration of the NO-NSAID compound in the medicament may be from about 0.0001% to about 50%.
  • the concentration of the NO-NSAID compound can be from about 0.0001% (w/w) to about 40% (w/w), for example, can be from about 0.0001% (w/w) to about 10% (w/w) ), about 0.0001% (w/w) to about 9.5% (w/w), about 0.0001% (w/w) to about 9% (w/w), about 0.0001% (w/w) to about 8.5% (w/w), about 0.0001% (w/w) to about 8% (w/w), about 0.0001% (w/w) to about 7.5% (w/w), about 0.0001% (w/w) to about 7% (w/w), about 0.0001% (w/w) to about 6.5% (w/w), about 0.0001% (w/w) to about 6% (w/w), about 0.0001% ( w/w) to about 5.5% (w/w), about 0.0001% (w/w) to about
  • the concentration of the NO-NSAID compound may be from about 0.0001% (w/w) to about 1% (w/w), from about 0.0001% (w/w) to about 0.9% ( w/w), about 0.0001% (w/w) to about 0.6% (w/w), about 0.05% (w/w) to about 0.5% (w/w), about 0.05% (w/w) to about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% (w /w) to about 0.2% (w/w) or less.
  • the concentration of the NO-NSAID compound may be from about 0.5% to about 10%.
  • the concentration of the NO-NSAID compound is about 5% (w/w). In certain embodiments, the concentration of the NO-NSAID compound is about 2.5% (w/w). In certain embodiments, the concentration of the NO-NSAID compound is about 1% (w/w).
  • the medicine may also include one or more other active ingredients.
  • the active ingredient may refer to a monomeric compound having medical utility or physiological activity.
  • said other active ingredients may be selected from the group consisting of anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, antiseptics, immunosuppressants and anti-hemorrhagic agents.
  • the drug may also include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants and emulsifiers.
  • the antineoplastic agent and the NO-NSAID compound are not mixed with each other.
  • the antineoplastic agent and the NO-NSAID compound are each independently present in separate containers.
  • the drug combination may include 2 or more drugs packaged independently of each other, wherein at least one of the drugs contains the antineoplastic agent described in the application, and wherein at least one other drug contains the anti-tumor agent described in the application. Said NO-NSAID compound.
  • the NO-NSAID compound in 2) in the pharmaceutical combination, can prevent, alleviate and/or treat the disease or condition associated with the anti-tumor agent in 1).
  • the NO-NSAID compound in 2) does not substantially affect the therapeutic effect of the antineoplastic agent in 1).
  • the NO-NSAID compound of 2) is administered before, simultaneously or after the antitumor agent of 1).
  • the subject may include humans or non-human animals.
  • the non-human animal can be selected from the group consisting of monkeys, chickens, geese, cats, dogs, mice and rats.
  • non-human animals may also include any animal species other than humans, such as livestock animals, or rodents, or primates, or domestic animals, or poultry animals.
  • the human can be Caucasian, African, Asian, Semitic, or other ethnicity, or a hybrid of various ethnicities.
  • the human can be elderly, adult, adolescent, child or infant.
  • the effective amount in humans can be inferred from the effective amount in experimental animals.
  • Freireich et al. describe the correlation of doses in animals and humans (based on milligrams per square meter of body surface) (Freiheim et al., Cancer Chemother. Rep. 50, 219 (1966)).
  • Body surface area can be approximately determined from the patient's height and weight. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970).
  • the antineoplastic agent may result from administering an antineoplastic agent to the subject.
  • the NO-NSAID compound can be administered before, simultaneously with, or after the antineoplastic agent is administered to the subject.
  • the antitumor agent described in the present application is administered simultaneously with the NO-NSAID compound
  • the NO-NSAID compound is used in an amount of about 0.0001-10% (eg, about 0.005-10%, about 0.01-10%, about 0.01-10%, about 0.05-10%, about 0.1-10%, about 0.2-10%, about 0.3-10%, about 0.4-10%, about 0.5-10%, about 0.6-10%, about 0.7-10%, about 0.8 -10%, about 0.9-10%, about 0.95-10%, about 1-10%, about 2-10%, about 3-10%, about 5-10%, about 6-10%, about 8-10% % or less) at dose levels administered.
  • 0.0001-10% eg, about 0.005-10%, about 0.01-10%, about 0.01-10%, about 0.05-10%, about 0.1-10%, about 0.2-10%, about 0.3-10%, about
  • the NO-NSAID compound may be administered at intervals before or after administration of the antineoplastic agent.
  • the interval time can be 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours Hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.
  • the present application also provides a method, which comprises administering a NO-NSAID compound to a subject, wherein the subject has been, is and/or will be administered an antineoplastic agent and suffers from or is prone to be associated with the administration of an antineoplastic agent related diseases or conditions.
  • the present application also provides a method for preventing or treating a disease or disorder, comprising administering a NO-NSAID compound to a subject susceptible to or suffering from the disease or disorder, wherein the subject has been, is and / or to be administered antineoplastic agents in the future.
  • the subject may already suffer from a disease or disorder related to the administration of an anti-tumor agent, or the subject may have a higher probability of suffering from a disease or disorder related to the administration of an anti-tumor agent.
  • the present application also provides a method comprising the steps of: 1) monitoring one or more side effects of a subject administered an antineoplastic agent, such as skin tissue, facial features and/or gastrointestinal tract characteristics; 2) when When the monitoring shows that the subject has side effects related to the administration of the antineoplastic agent, such as skin diseases or disorders, facial features diseases or disorders and/or gastrointestinal diseases or disorders, NO is administered to the subject.
  • antineoplastic agent such as skin tissue, facial features and/or gastrointestinal tract characteristics
  • the method may also include continuing to monitor the skin disease or disorder, facial organ disease or disorder and/or gastrointestinal disease or disorder, and optionally reducing or stopping the antineoplastic agent.
  • the continuing monitoring can refer to about at least 1 day, at least 1 week, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months or longer after administration of the antineoplastic agent to monitor.
  • said reduction or discontinuation may be directed to administering said subject with a dose of said antineoplastic agent that is reduced by about at least 5%, at least 10% compared to the dose of said antineoplastic agent in step 1) of said method , at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100%.
  • the severity of the disease or condition associated with the administration of the anti-tumor agent may increase after the administration of the anti-tumor agent.
  • the severity can be an increase of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more many.
  • the subject may not suffer from the disease or condition before the administration of the anti-tumor agent.
  • the NO-NSAID compound may be topically administered to the subject.
  • the NO-NSAID compound can be administered topically to a site in the subject that is substantially free of cancer cells.
  • the NO-NSAID compound can be administered to a non-cancer site in the subject.
  • NO-NSAID compounds of the present application are shown in Table 2-1:
  • NO-NSAIDs are able to prevent/treat antineoplastic agent-induced hand-foot syndrome in vivo
  • Rat animal model was constructed, and the antitumor agents shown in Table 2-2 were administered respectively to 8-week-old female SD rats by intragastric administration every day. After a few days, the paws of the rats showed symptoms of hand-foot syndrome (as shown in Fig. 1). Similar to humans, rats will develop symptoms of hand-foot syndrome after taking the antitumor agent, and the symptoms are very similar. Therefore, rats are good animal models for simulating side effects caused by antineoplastic agents, such as hand-foot syndrome.
  • the rats (about 200 g) were fed and adapted for one week, they were divided into NO-NSAID group and control group, with 10 rats in each group, and the test was carried out by intragastric administration.
  • intragastric administration smear the ointment containing NO-NSAID on the hind paws of the rats, and at the same time, the control group was smeared with a blank preparation.
  • the rats were placed in a fixed cylinder for 4 hours, and the rats were released after 4 hours and wiped off with clean water. The residual drug at the application site was released and the mice were returned to their cages.
  • the frequency of intragastric administration of inhibitors is shown in Table 2-2, and NO-NSAIDs are only applied once a day. Gavage and smear operations were repeated daily until the end of the experiment. After counting 15-18 days of drug application, the number of rats with hand-foot syndrome in the drug-coated group that remained normal or significantly lighter than that of the blank control group was counted as the number of rats that effectively inhibited hand-foot syndrome.
  • the results in Table 2-2 show that the NO-NSAID can effectively prevent and treat hand-foot syndrome caused by antineoplastic agents.
  • the results in Figure 2 also show that the NO-NSAID can effectively prevent and treat hand-foot syndrome caused by antineoplastic agents.
  • the paws of different groups of rats were taken, and histological observations were carried out on different groups (Fig. 3). It was found that the NO-NSAID of the present application can effectively alleviate the hand-foot syndrome caused by anti-tumor agents, improve capillaries, Reduce keratinocyte necrosis, epidermal separation, inflammation and other phenomena.
  • the control rate of hand-foot syndrome associated with the administration of antineoplastic agents is better.
  • NO-NSAID can prevent/treat hand-foot syndrome induced by protein macromolecule inhibitors in vivo
  • Dilute Ramucirumab or Bevacizumab with saline to the desired concentration.
  • rats about 200 g
  • they were divided into groups, 10 rats in each group, and the injection test was carried out.
  • the experimental group was smeared with NO-NSAID ointment, and the control group was smeared with blank preparation.
  • the specific operation was the same as above. The experiment lasted for 2-4 weeks, and the experimental phenomena were observed.
  • the NO-NSAID ointment of the present application has a certain preventive effect on hand-foot syndrome caused by macromolecular antineoplastic agents.
  • NO-NSAID ointment relieves pain in hand-foot syndrome induced by antineoplastic agents
  • rat is carried out pain analysis, and pain evaluation model is the mechanical sensitivity (von Frey) of rat;
  • pain evaluation model is the mechanical sensitivity (von Frey) of rat;
  • Experimental procedure is as follows: First let the rats adapt to the room for 1 hour, then put the rats into an observation box with a metal mesh floor, and let the mice stay in the box for 20 minutes to adapt to the environment of the experimental platform. Then use von Frey equipment to detect the pain of the paw, and use special cilia to stimulate the surface of the palm of the rat to detect the mechanical sensitivity of the animal.
  • Rats were defined as responding by withdrawing the paw or licking immediately after the specified pressure was applied, while failure to withdraw the paw within 6 s was defined as non-responsive. The rat movement response was considered an ambiguous response, in which case the stimulus experiment was repeated.
  • NO-NSAID has obvious relieving effect on the pain of hand-foot syndrome caused by antineoplastic agents.
  • NO-NSAID ointment can treat hand-foot syndrome caused by antineoplastic agents
  • NO-NSAID of the present application can treat hand-foot syndrome caused by antineoplastic agents.
  • the pain relief of some experimental groups was evaluated, as shown in Figure 11, the results showed that NO-NSAID ointment also relieved the pain to a certain extent while treating the hand-foot syndrome caused by antineoplastic agents.
  • NO-NSAID ointment can prevent/treat chemotherapy-induced hand-foot syndrome in rat models
  • Rat animal model was constructed.
  • the chemotherapeutic drugs were given to female SD rats for 6 weeks by intragastric administration daily (dosage and drugs, see Table 5). After a few days, hand-foot syndrome appeared in the paws of the rats.
  • the rats were divided into 10 in each group, and then the oral administration test was carried out.
  • the chemotherapeutic drug was dissolved, and each mouse was fed with 1 mL/100 g, and the dosage was shown in Table 5.
  • the rats were fixed with a fixing cylinder, NO-NSAID ointment was applied to the paws of the rats in the drug-applied group, and a blank ointment was applied to the rats in the blank group (as a blank control).
  • NO-NSAID ointment NO-NSAID ointment was applied to the paws of the rats in the drug-applied group
  • a blank ointment was applied to the rats in the blank group (as a blank control).
  • the number of rats whose paw skin in the smearing group remains normal or whose symptoms are significantly lighter than the hand-foot syndrome of the blank group is calculated as the effective
  • ointments with different mechanisms NO release agent group, NO release agent combined with clinical drug group, NSAID group
  • the hand-foot syndrome caused by NSAID ointment anti-tumor agents is basically ineffective or the effective rate is very low, and in the relieved rats, the symptom relief is relatively mild; from the results of the combination of nitroglycerin and clinical drugs, Compared with nitroglycerin, the combined use of NO release agents and other clinical drug mechanisms did not significantly improve the effect of hand-foot syndrome.
  • HUVEC cells Digest and suspend cultured HUVEC cells, count the cells, and inoculate into 96-well plates with 5000-10000 cells per well. Each well was divided into: blank control group, antineoplastic agent group, antineoplastic agent+NO-NSAID group, antineoplastic agent solvent group, and NO-NSAID control group. Each well of each group contained basal medium, and each The final volume of liquid contained in the wells is approximately 100 ⁇ L.
  • the specific groups are as follows:
  • Antineoplastic agent group add antineoplastic agent solution (the final concentration is shown in Table 7-1 and Table 7-2, and the solvent of antineoplastic agent solution is DMSO);
  • Antineoplastic agent + NO-NSAID group add antineoplastic agent solution and NO-NSAID solution (the final concentrations of antineoplastic agent and NO-NSAID are shown in Table 7-1 and Table 7-2, and according to the NO-NSAID The solubility of the NO-NSAID solution is selected as ethanol or sterile water as the solvent of the NO-NSAID solution, and the slight difference in the total volume of each group is filled by adding the selected corresponding solvent);
  • Antineoplastic agent solvent group adding the same volume of DMSO contained in the antineoplastic agent solution corresponding to group 2);
  • NO-NSAID control group add the same volume and the same type of solvent (for example, ethanol or sterile water) contained in the corresponding NO-NSAID in group 3).
  • solvent for example, ethanol or sterile water
  • the antineoplastic agent solvent group was not involved in data processing, and was only used as a reference for evaluating the experimental system error.
  • the NO-NSAID solvent control group was used for data correction, thereby excluding the influence of solvent on the results.
  • Table 7-1 and Table 7-2 have listed the combination of various antineoplastic agents and NO-NSAIDs, and corresponding experimental results (wherein, the data identification of cell viability column is compared with antineoplastic agents, corresponding antineoplastic agents Increased percentage of surviving cells in tumor agent and NO-NSAID groups).
  • 14 to 21 respectively show exemplary results of cell proliferation toxicity measured by CCK-8 method 24 hours after administration of antitumor agents and NO-NSAID to HUVEC cells.
  • the abscissa represents different experimental groups and control groups; the ordinate represents the survival rate of the cells (calculate the survival percentage of cells in other experimental groups or the solvent control group with the cell survival rate of the blank control group as 100%).
  • * means P ⁇ 0.05, which has a significant difference compared with the corresponding antineoplastic agent alone administration group; t-test statistical test is used.
  • HaCaT human immortalized epithelial cells
  • HK human oral mucosal epithelial keratinocytes
  • FHs 74Int human small intestinal epithelial cells
  • GES-1 gastric epithelial cells
  • Examples 47-51 used human immortalized epidermal cells (HaCaT), and the results corresponded to Table 8-1;
  • Examples 52-56 used human oral mucosa epithelial keratinocytes (HOK), and the results Corresponds to Table 8-2;
  • Examples 57-61 use gastric epithelial cells (GES-1), and the results correspond to Table 8-3;
  • Examples 62-66 use human small intestinal epithelial cells (FHs74Int), and the results correspond to Table 8-4.
  • each well contains basal medium, each The final volume of liquid contained in the wells is approximately 100 ⁇ L.
  • the specific groups are as follows:
  • Antineoplastic agent group add antineoplastic agent solution (the final concentration is shown in Table 8-1 to Table 8-4, and the solvent of antineoplastic agent solution is DMSO);
  • Antineoplastic agent + NO-NSAID group add antineoplastic agent solution and NO-NSAID solution (the final concentrations of antineoplastic agent and NO-NSAID are shown in Table 8-1 to Table 8-4, and according to the NO-NSAID The solubility of the NO-NSAID solution is selected as ethanol or sterile water as the solvent of the NO-NSAID solution, and the slight difference in the total volume of each group is filled by adding the selected corresponding solvent);
  • Antineoplastic agent solvent group adding the same volume of DMSO contained in the antineoplastic agent solution corresponding to group 2);
  • NO-NSAID solvent control group add the same volume and type of solvent (for example, ethanol or sterile water) contained in the corresponding NO-NSAID in group 3).
  • the antineoplastic agent solvent group was not involved in data processing, and was only used as a reference for evaluating the experimental system error.
  • the NO-NSAID solvent control group was used for data correction, thereby excluding the influence of solvent on the results.
  • Table 8-1 to Table 8-4 have listed the combination of various antineoplastic agents and NO-NSAID, and corresponding experimental results (wherein, the data mark of cell viability column is compared with antineoplastic agent group, corresponding Increased percentage of surviving cells in antineoplastic agent + NO-NSAID group).
  • Figure 22 represents the experimental results on HaCaT cells
  • Figure 23 represents the experimental results on HOK cells
  • Figure 24 represents the experimental results on GES-1 cells
  • Figure 25 represents the experimental results on FHs 74 Int cells.
  • the abscissa represents different experimental groups and control groups; the ordinate table cell viability (calculate the survival percentage of cells in other experimental groups or solvent control groups with the cell viability of the blank control group as 100%).
  • * means P ⁇ 0.05, which has a significant difference compared with the corresponding antineoplastic agent alone administration group; t-test statistical test is used.
  • antitumor agents have proliferative toxicity to skin cells (HaCaT), while NO-NSAIDs can obviously alleviate the proliferative toxicity caused by antitumor agents.
  • antineoplastic agents have proliferative toxicity to human oral mucosal epithelial keratinocytes (HOK), while NO-NSAIDs can significantly alleviate the proliferative toxicity caused by antineoplastic agents.
  • antineoplastic agents have proliferative toxicity to human small intestinal epithelial cells (FHs 74Int), while NO-NSAID has a significant alleviating effect on the proliferative toxicity caused by antineoplastic agents.

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Abstract

预防、缓解和/或治疗与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用NO-NSAID化合物或其药学上可接受的盐。

Description

预防或治疗与抗肿瘤剂相关的疾病或病症的方法 技术领域
本申请涉及生物医药领域,具体的涉及一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关疾病或病症的方法。
背景技术
抗肿瘤剂(例如,靶向抗肿瘤药物,化疗药物和/或免疫疗法,例如免疫检查点抑制剂等)经常会引起严重的副作用,特别是在皮肤,五官和胃肠道发生的副作用。这些抗肿瘤剂引起的严重副作用会损害患者的生活质量,引起患者用药的依从性和耐受性降低,导致停药或用药剂量不足,从而对治疗效果产生不利影响,甚至导致疾病进展加速,患者生存期缩短。
目前,尚没有有效的治疗方案来控制与施用抗肿瘤剂相关的副作用。因此,迫切需要能够成功控制该等副作用的治疗方案。
发明内容
本申请提供的化合物,药物组合物和方法有效解决了上述问题,能够有效地预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的副作用。
一方面,本申请提供了NO-NSAID化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
在某些实施方式中,所述NO-NSAID化合物包括一氧化氮(NO)释放部分和非甾体抗炎剂(NSAID)部分,且所述NO释放部分与所述非甾体抗炎剂部分之间共价直接连接或通过间隔基连接。
在某些实施方式中,所述非甾体抗炎剂部分包含环氧合酶(COX)抑制部分。
在某些实施方式中,所述COX抑制部分包括能够减少所述COX表达的部分,和/或降低所述COX活性的部分。
在某些实施方式中,所述COX抑制部分直接作用于所述COX蛋白和/或编码所述COX蛋白的核酸。
在某些实施方式中,所述COX抑制部分能够抑制环氧合酶-1(COX-1)和/或环氧合酶-2(COX-2)。
在某些实施方式中,所述COX抑制部分能够选择性抑制COX-2。
在某些实施方式中,所述COX抑制部分能够非选择性地抑制COX-1和COX-2。
在某些实施方式中,所述COX抑制部分包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:对乙酰氨基酚(acetaminophen),阿西美辛(acemetacin),醋氯,芬酸(aceclofenac),氨洛芬(alminoprofen),阿芬酸(arnfenac),bendazac,苯诺沙洛芬(benoxaprofen),溴芬酸(bromfenac),丁氯芬酸(bucloxic acid),布替布芬(butibufen),卡洛芬(carprofen),辛美辛(cinmetacin),氯吡酸(clopirac),双氯芬酸(diclofenac),依托度酸(etodolac),联苯乙酸(felbinac),芬氯苯丙酸(fenclozic acid),芬布芬(fenbufen),氟丁苯丙胺(fenoprofen),fentiazac,氟诺沙洛芬(flunoxaprofen),氟比洛芬(flurbiprofen),布芬酸(ibufenac),布洛芬(ibuprofen),吲哚美辛(indomethacin),异芬唑酸(isofezolac),isoxepac,吲哚洛芬(indoprofen),酮洛芬(ketoprofen),lonazolac,洛索洛芬(loxoprofen),甲嗪酸(metiazinic acid),莫非唑酸(mofezolac),米洛芬(miroprofen),萘普生(naproxen),恶丙嗪(oxaprozin),pirozolac,普拉洛芬(pranoprofen),普罗替尼酸(protizinic acid),水杨酰胺(salicylamide),sulindac,舒洛芬(suprofen),suxibuzone,噻洛芬酸(tiaprofenic acid),托美汀(tolmetin),xenbucin,西莫洛芬(ximoprofen),zaltoprofen,zomepirac,阿司匹林(aspirin),acemetcin,bumadizon,卡洛芬酸(carprofenac),clidanac,二氟尼柳(diflunisal),氟尼酸(enfenamic acid),芬多沙(fendosal),氟芬那酸(flufenamic acid),氟尼辛(flunixin),龙胆酸(gentisic acid),酮咯酸(ketorolac),甲氯芬那酸(meclofenamic acid),甲芬那酸(mefenamic acid)和美沙拉嗪(mesalamine)。
在某些实施方式中,所述COX抑制部分包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:萘普生(naproxen),阿司匹林(aspirin),双氯芬酸(diclofenac),酮洛芬(ketoprofen),氟比洛芬(flurbiprofen)和布洛芬(ibuprofen)。
在某些实施方式中,所述NO释放部分能够产生NO +、NO -、N 2O、NO、N 2O 3、NO 2、NO 3 -和NO 2 -之中的至少一种。
在某些实施方式中,所述NO释放部分直接或者间接产生NO。
在某些实施方式中,所述NO释放部分包括有机分子、无机分子和/或高分子或纳米材料。
在某些实施方式中,所述NO释放部分包括选自下组的成分:硝酸甘油、单硝酸异山梨酯、丁二醇单硝酸酯、季戊四醇四硝酸酯、硝酸异山梨酯、三硝乙醇胺、尼可地尔、硝二羟甲丁醇、5-氨基-3-(4-吗啉基)-1,2,3-恶二唑、亚硝酸异戊酯、3,3-二(氨乙基)-1-羟基-2-羰基-1-三氮烯(NOC-18)、磺基亲核复合体二钠盐(Sulfo NONOate disodium salt)、S-亚硝基谷胱 甘肽(S-Nitrosoglutathione)、S-亚硝基-N-乙酰青霉胺(S-Nitroso-N-acetylpenicillamine)、4-苯基-3-呋腈(4-Phenyl-3-furoxancarbonitrile)、(±)-(E)-4-乙基-2-(E)-肟基-5-硝基-3-己酰胺((±)-(E)-4-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide)、链脲菌素(Streptozocin)、NG-羟基-L-精氨酸合乙酸(NG-Hydroxy-L-arginine acetate salt)、O 2-(2,4-二硝基苯基)1-[(4-乙氧基羰基)哌嗪-1-基]1,2-二醇二氮烯-1-鎓(O 2-(2,4-Dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate)、N-亚硝基二丁胺、3-吗啉-斯得酮亚胺(3-morpholinosydnonimine(SIN-1))、林西多明(Linsidomine)、吗多明(Molsidomine)、3-(4-乙酰苯基)悉尼酮(3-(4-acetylphenyl)sydnone)、二乙胺亲核复合体/AM(Diethylamine NONOate/AM)和Itramin。
在某些实施方式中,所述NO释放部分包括选自下组的成分:硝酰配合物、亚硝酰配合物(Metal nitrosyl complex)、金属亚硝氨基络合物、硝酸盐和亚硝酸盐。
在某些实施方式中,所述NO释放部分包括选自下组的成分:S-亚硝基硫醇纳米硅球、S-亚硝基乙二硫醇甲壳素和寡聚丙二胺接枝壳聚糖NONOate。
在某些实施方式中,所述NO释放部分具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
在某些实施方式中,所述NO释放部分具有下述的一个或多个基团:偶氮鎓二醇盐、羟基二氮烯磺酸、S-亚硝基硫醇、呋咱氮氧、肟、N-亚硝胺、N-羟基胍、硝酸盐、亚硝酸盐、硝酸酯、亚硝酸酯、斯得酮亚胺、斯得酮、恶三唑-5-亚胺、恶三唑-5-酮、羟胺、二氧二氮杂环丁烯、N-羟基亚硝胺、N-亚硝亚胺、羟基脲和金属亚硝氨基络合物。
在某些实施方式中,所述NO释放部分包括-NO 2或-ONO 2
在某些实施方式中,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间通过可裂解连接子连接。
在某些实施方式中,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间通过包含酯键和/或二硫键的连接子连接。
在某些实施方式中,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间包含间隔基。
在某些实施方式中,所述间隔基包含:一个或多个任选取代的-CH 2-,任选取代的苯基和/或它们的组合。
在某些实施方式中,所述NO-NSAID化合物还包含H 2S释放部分。
在某些实施方式中,所述NO-NSAID化合物包含式(1)所示的结构:
Figure PCTCN2023071255-appb-000001
其中:
Z为O或NH,
R 1,R 2,R 3和R 4各自独立地为H,卤素,NO 2,N 3,C 1-C 10烷基,OR,OC(O)R,N(R) 2,NH-C(O)R,S(O)R或N═N-R,其中每个R各自独立地为C 1-C 10烷基或芳香基;
L 1包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m-O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;
L 2包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m-O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;
P和q各自独立地为0或1;
X为所述H 2S释放部分或所述NO释放部分;
Y为所述NO释放部分或所述H 2S释放部分,且所述Y与所述X不同时为所述NO释放部分且不同时为所述H 2S释放部分;
所述NO释放部分为-C(O)-(CH 2) n-ONO 2或-(CH 2) n-ONO 2,其中n为1,2,3,4,5,6或7;且所述H 2S释放部分为:
Figure PCTCN2023071255-appb-000002
在某些实施方式中,所述NO-NSAID化合物包含式(2)所示的结构:
Figure PCTCN2023071255-appb-000003
其中:
p和q各自独立地为0或1;
L 1和L 2各自独立地包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m- O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;
X为所述H 2S释放部分或所述NO释放部分;
Y为所述NO释放部分或所述H 2S释放部分,且所述Y与所述X不同时为所述NO释放部分且不同时为所述H 2S释放部分;
所述NO释放部分选自:-NO,-C(O)-(CH 2) n-ONO 2,-O-(CH 2) n-ONO 2,-(CH 2) n-ONO 2,-C(O)-CH 2-C(CH 3) 2-SNO,-NH-CH 2-C(CH 3) 2-SNO,-CH 2-C(CH 3) 2-SNO,
Figure PCTCN2023071255-appb-000004
Figure PCTCN2023071255-appb-000005
其中n为1,2,3,4,5,6或7,R a为H,C 1-C 10烷基,芳香基,S(O) 2-芳香基,CN或CON(R b) 2,且每个R b各自独立地为H或C 1-C 10烷基;且
所述H 2S释放部分选自:
Figure PCTCN2023071255-appb-000006
Figure PCTCN2023071255-appb-000007
在某些实施方式中,所述NO-NSAID化合物包含选自下组的结构:
Figure PCTCN2023071255-appb-000008
其中,X为-(CH 2) n1-Z-(CH 2) n2-,n1和n2各自独立地为0,1,2,3,4或5;
Z为O,N,S,C,
Figure PCTCN2023071255-appb-000009
A为O,N,S或C;且
Y为
Figure PCTCN2023071255-appb-000010
在某些实施方式中,所述NO-NSAID化合物包含式(3)所示的结构:
M-X-Y-ONO 2(3),
其中M为选自下组的结构:
Figure PCTCN2023071255-appb-000011
其中R A为氢原子或-C(O)CH 3
Figure PCTCN2023071255-appb-000012
Figure PCTCN2023071255-appb-000013
Figure PCTCN2023071255-appb-000014
X是-O-,-S-或-NR 1-,其中R 1是H或者是直链或支链的C 1-C 6烷基;
Y是具有如下定义的二价基团:
a)
-直链或支链的C 1-C 20亚烷基,其任选地被一个或多个选自下组的取代基取代:卤素,羟基,-ONO 2,-OC(O)(C 1-C 10烷基)-ONO 2和-O(C 1-C 10烷基)-ONO 2
-C 5-C 7亚环烷基,其任选地被直链或支链C 1-C 10烷基取代;
b)
Figure PCTCN2023071255-appb-000015
其中n为选自0-20的整数,n’为1-20的整数;
c)
Figure PCTCN2023071255-appb-000016
其中n为选自0-20的整数,n’为1-20的整数;
d)
Figure PCTCN2023071255-appb-000017
其中X 1为-OCO-或-COO-,并且R 2是H或CH 3,na是1-20的整数,n 2是0-2的整数;
e)
Figure PCTCN2023071255-appb-000018
其中Y 1是-CH 2-CH 2-(CH 2)n 2-,或-CH=CH-(CH 2)n 2-,X 1,na,n 2和R 2的定义同上;
f)
Figure PCTCN2023071255-appb-000019
其中na和R 2的定义同上,R 3是H或-COCH 3;或
g)
Figure PCTCN2023071255-appb-000020
其中X 2是-O-或-S-,n 3是1-6的整数,R 2的定义同上。
在某些实施方式中,所述NO-NSAID化合物包含式(3)所示的结构:
M-X-Y-ONO 2(3),
其中M选自以下结构:
Figure PCTCN2023071255-appb-000021
Figure PCTCN2023071255-appb-000022
X是-O-;Y是直链或支链的C 1-C 10亚烷基。
在某些实施方式中,所述NO-NSAID化合物包含式(4)所示的结构:
A-(B) b0-(D) c0-NO 2(4)
其中:
c0为0或1,b0为0或1,且c0与b0种至少有1个不为1;
A为R-T 1-,其中R-T 1-是式R-T 1-OH的自由基或前体药物乙酰水杨酸,其中T 1=(CO),R是乙酰水杨酸的剩余基团;
B为T B-X 2-T BI-,T B为X,T BI为(CO)或X,X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;X 2为选自以下的式H-X 2-H化合物的基团:羟基酸,没食子酸,阿魏酸,龙胆酸,柠檬酸,咖啡酸,对香豆酸和香草酸;
D为二价基团:-T c-Y-,其中当b0为1时,T BI为X时T c为(CO),或者T BI为(CO)时T c为X,且X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;当b0为0时,T c=X,且X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;
Y为Y p,Y O或Y Ar
Y p
Figure PCTCN2023071255-appb-000023
其中nIX为0-3中的整数,nIIX为1-3中的整数,R TIX,R TIX′,R TIIX和R TIIX′各自独立地为H或者线性或分支的C 1-C 4烷基,Y 3为含有一个或两个氮原子的饱和的,不饱和的或芳香杂环且具有6个原子;
Y O选自下组:C 1-C 20线性或分支亚烷基氧基,
Figure PCTCN2023071255-appb-000024
Figure PCTCN2023071255-appb-000025
其中nf′为1-6中的整数,且R 1f为H或CH 3
Y Ar
Figure PCTCN2023071255-appb-000026
其中n3为0-3中的整数,且n3’为1-3中的整数;且
当b0为1时,c0为1且Y为Y O,或者当b0为0时,c0为1且Y为Y p或Y Ar
在某些实施方式中,所述NO-NSAID化合物包含式(5)所示的结构:
A-X 1-L-(W) p-NO 2(5)
其中:
p为0或1;
A为R-T 1,其中R为前药的残基并具有下式:
Figure PCTCN2023071255-appb-000027
其中s为0或1;R AI为H或CH 3
R 1为OCOR 3,NHCOR 3,OH,CH 2CH(CH 3) 2,苯基,苯甲酰基或4,6-二氯苯氨基,R 3
C 1-C 5线性或分支的残基;R 6为H或卤素;
或者,当R 1和R 6位于式(6)的芳香环上相邻的4位和5位时,形成式(7)的结构:
Figure PCTCN2023071255-appb-000028
或者,R具有下式的结构:
Figure PCTCN2023071255-appb-000029
T 1为(CO) t或(X) t′,其中X为O,S或NR 1c,R 1c为H或具有1-5个碳原子的直链或支链烷基,t和t’为0或1,当t’为0时t为1,且当t’为1时t为0;
X 1为-T B-Y-T BI,其中T B与T BI可相同或不同,当t为0时T B为(CO),当t’为0时T B为X,X如上所述;T BI为(CO) tx或(X) txx,其中tx和txx为0或1,当txx为0时tx为1,当txx为1时tx为0,X如上所述;
Y是选自下述的二价连接基团:
Figure PCTCN2023071255-appb-000030
其中:nIX为0-3的整数,nIIX为1-3的整数,R TIX,R TIX′,R TIIX和R TIIX′各自独立地选自H和C 1-C 4直链或支链烷基;Y 3为具有5个或6个原子的饱和,不饱和或芳香杂环且含有1或2个氮原子;
C 1-C 20直链或支链亚烷基,其任选地被选自下组的取代基取代:NHCOR 3,-NH 2和-OH,R 3为C 1-C 5线性或分支的残基;
具有5-7个碳原子的亚环烷基,其任选地被C 1-C 20直链或支链亚烷基侧链取代,所述C 1-C 20直链或支链亚烷基任选地被选自下组的取代基取代:NHCOR 3,-NH 2和-OH,R 3为C 1-C 5线性或分支的残基,其中所述亚环烷基环中的1个或多个碳原子任选地被杂原子替代;
Figure PCTCN2023071255-appb-000031
其中n3为0-3的整数,且n3’为1-3的整数;
Figure PCTCN2023071255-appb-000032
其中n3为0-3的整数,且n3’为1-3的整数;
Figure PCTCN2023071255-appb-000033
其中R 4为羟基,氢或R 5O,R 5为C 1-C 10直链或支链或环状烷基,R 2
为C 2-C 10直链或支链的含有一个或多个双键的亚烯基;
Figure PCTCN2023071255-appb-000034
Figure PCTCN2023071255-appb-000035
其中R 1f为H或CH 3,且nf为0-6的整数;
L为共价键,CO或X,X如上所述;且
W为Y TO,Y T与Y的含义相同,且式(5)的化合物中Y与Y T可相同或不同。
在某些实施方式中,所述NO-NSAID化合物包含式(5)所示的结构:
A-X 1-L-(W) p-NO 2(5),其中:
所述p为0或1,
A为R-T 1-,其中R具有结构
Figure PCTCN2023071255-appb-000036
T 1为(CO) t或(X) t′,t和t’为0或1,当t为1时t’为0,且当t为0时t’为1;
X 1为-T B-Y-T B1-,其中T B和T B1相同或不同,当t为0时T B为(CO),当t’为0时T B为X;
T B1为(CO) tx或(X) txx,其中tx和txx各自独立地为0或1,当txx为0时tx为1,且当txx为1时tx为0;
X为O,S或NR 1C,R 1C为H或者具有1-5个碳原子的直链或支链烷基;
Y选自
Figure PCTCN2023071255-appb-000037
其中n3为0-3的整数,n3’为0-3的整数,R 4为羟基,氢或R 5O-烷氧基,其中R 5为C 1-C 10直链,支链或环状烷基,R 2为C 2-C 10直链或直链亚烯基且任选地包含一个或多个双键;
L为共价键,CO或X,X为O,S或NR 1C,R 1C为H或者具有1-5个碳原子的直链或支链烷基;且
W为Y TO,Y T选自
Figure PCTCN2023071255-appb-000038
其中n3为0-3的整数,n3’为0-3的整数,R 4为羟基,氢或R 5O-烷氧基,其中R 5为C 1-C 10直链,支链或环状烷基,R 2为C 2-C 10直链或直链亚烯基且任选地包含一个或多个双键。
在某些实施方式中,所述NO-NSAID化合物包含式(16)所示的结构:
Figure PCTCN2023071255-appb-000039
其中R m为H或低级烷基,
R n为选自下组的结构:
Figure PCTCN2023071255-appb-000040
s为0或1,
X为-Y-(CR 4R 4’) o-C(R 4)(ONO 2)-(CR 4R 4’) q-(T) o-(W) q(T) o-(CR 4R 4’) o-R 5;,
每个R 4和R 4’各自独立地为氢,低级烷基,-OH,-CH 2OH,-ONO 2,-NO 2或-CH 2ONO 2,或者R 4和R 4’与和它们相连的碳原子一起形成环烷基或杂环;
W为共价键或羰基;
每个T独立地为氧,(S(O) o) o或NR j
R j为氢,烷基,芳基,杂环,烷基羰基,烷基芳基,烷基亚磺酰基,烷基磺酰基,芳基亚磺酰基,芳基磺酰基,磺酰氨基,N-烷基磺酰氨基,N,N-二芳基磺酰胺基,N-芳基磺酰胺基,N-烷基-N-芳基磺酰胺基,甲酰胺基和/或羟基;
每个q独立地为1,2或3;
每个o独立地为0,1或2;
Y为氧或硫;且
R 5为氢,羟基,烷基,芳基,烷基磺酰基,芳基磺酰基,羧酸酯,烷基羰基,芳基羰基,甲酰胺基,烷氧基烷基,烷氧基芳基,环烷基和/或杂环。
在某些实施方式中,所述NO-NSAID化合物包含式(17)或式(18)所示的结构:
Figure PCTCN2023071255-appb-000041
每个s各自独立地为1或2;k为1,2,3或4;每个m各自独立地为0,1,2,3或4;每个X各自独立地为O或S;
Y为键,S,O或NR l,其中R l为氢或C 1-C 6烷基;
R为氢或C 1-C 6烷基;
所述Linker为连接子,其选自下组:
1)-(CH 2) n,n为0,1,2,3或4;
2)C 3-C 6环烷基,其任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基;
3)芳基,所述芳基选自苯基和萘基,所述芳基任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO 2,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基;和
4)杂芳基,所述杂芳基任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO 2,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基。
在某些实施方式中,所述NO-NSAID化合物包含式(19)所示的结构:
A-T-Y-ONO 2(19),其中:
A为选自下组的药物:(A-OH或AH)的残基:非甾体抗炎药,镇痛药,退热药和COX-2抑制剂;
T为-O-,-NH-,-S-,-CO-或-(CH 2) n1OCO-,其中n1是1至20的整数;
A选自由以下组成的组:
Figure PCTCN2023071255-appb-000042
其中c和d各自独立地为0或1,
R B选自:H,直链或支链C 1-C 12烷基和C 2-C 12烯基;
当c为0,d为1时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000043
Figure PCTCN2023071255-appb-000044
R c选自下组:H,卤素,氨基,R ECONH-和-OCOR E
R D选自下组:H,OH,卤素,直链或支链C 1-C 4烷基,直链或支链C 1-C 4烷氧基,三氟甲基,氨基和单-或二-(C 1-C 4)烷基氨基,
R E选自H和直链或支链C 1-C 5烷基,
e为0或1,
M为C或N;
当c为1,d为1,R B为氢时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000045
Figure PCTCN2023071255-appb-000046
其中R E1为H或CH 3,且R C1为Cl或F;
当c为1,d为1,R B为CH 3时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000047
当c为0,d为0,时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000048
其中:
R D如上所述,
R G为选自下组的结构:
Figure PCTCN2023071255-appb-000049
Figure PCTCN2023071255-appb-000050
其中R H为苯基或环己基;
Figure PCTCN2023071255-appb-000051
Y是具有以下含义的二价基团:
a)
-直链或支链C 1-C 20亚烷基;
-亚环烷基,该亚环烷基的环中有5至7个碳原子,该环任选地被侧链R 1取代,其中R 1为具有1至10个碳原子的直链或支链烷基;
b)
Figure PCTCN2023071255-appb-000052
其中n为0-20的整数,且n1为1-20的整数;
c)
Figure PCTCN2023071255-appb-000053
其中n为0-20的整数,且n1为1-20的整数;
d)
Figure PCTCN2023071255-appb-000054
n1为1-20的整数,且n2为0-2的整数,X 1为-OCO-或-COO-,且R 2为H或CH 3
e)
Figure PCTCN2023071255-appb-000055
其中n1,n2,R 2和X 1如上所述,Y 1为-CH 2-CH 2-或-CH=CH-(CH 2) n2-;
f)
Figure PCTCN2023071255-appb-000056
其中n1和R 2如上所述,R 3为H或COCH 3
g)
Figure PCTCN2023071255-appb-000057
其中X 2为-O-或-S-,n3为1-6的整数,R 2如上所述;
h)
Figure PCTCN2023071255-appb-000058
n4为0-10的整数,n5为1-10的整数,R 4,R 5,R 6,R 7各自独立地选自H以及直链或支链C 1-C 4烷基,且-ONO 2
Figure PCTCN2023071255-appb-000059
相连,n5如上所述,Y 2为5或6元饱和、不饱和或芳香环,且包含1个或多个选自下组的杂原子:氮、氧和硫。
在某些实施方式中,所述NO-NSAID化合物包含式(21)所示的结构:
Figure PCTCN2023071255-appb-000060
其中
X为连接子,M为选自下组的结构:
Figure PCTCN2023071255-appb-000061
在某些实施方式中,所述NO-NSAID化合物包括选自下组的化合物:
Figure PCTCN2023071255-appb-000062
在某些实施方式中,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分的摩尔比为约2:1至约1:2。
在某些实施方式中,所述抗肿瘤剂包括小分子化合物,小分子偶联物,蛋白质和/或多核苷酸。
在某些实施方式中,所述抗肿瘤剂包括化疗剂,靶向治疗剂和/或免疫治疗剂。
在某些实施方式中,所述抗肿瘤剂为靶向治疗剂。
在某些实施方式中,所述靶向治疗剂包括小分子化合物和/或抗体或其抗原结合片段。
在某些实施方式中,所述抗体包括单克隆抗体,多特异性抗体,嵌合抗体,人源化抗体,全人源抗体和/或抗体药物偶联物。
在某些实施方式中,所述抗原结合片段包括Fab,Fab’,F(ab )2,Fv片段,F(ab’) 2,scFv,di-scFv和/或dAb。
在某些实施方式中,所述靶向治疗剂靶向肿瘤细胞内部,肿瘤细胞表面和/或肿瘤微环境 中的分子。
在某些实施方式中,所述靶向治疗剂靶向蛋白质和/或核酸分子。
在某些实施方式中,所述靶向治疗剂靶向肿瘤相关抗原。
在某些实施方式中,所述靶向治疗剂靶向选自下组的一个或多个靶标:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
在某些实施方式中,所述靶向治疗剂抑制选自下组的一个或多个靶标的活性:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
在某些实施方式中,所述靶向治疗剂降低选自下组的一个或多个靶标的表达:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
在某些实施方式中,所述靶向治疗剂包括激素,信号转导抑制剂,基因表达调节剂,细胞凋亡诱导剂,血管生成抑制剂和/或毒素递送分子。
在某些实施方式中,所述靶向治疗剂为酪氨酸酶抑制剂。
在某些实施方式中,所述靶向治疗剂为VEGFR抑制剂和/或VEGF抑制剂。
在某些实施方式中,所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。
在某些实施方式中,所述靶向治疗剂为EGFR抑制剂。在某些实施方式中,所述靶向治疗剂为BRAF抑制剂。在某些实施方式中,所述靶向治疗剂为PDGFR抑制剂。在某些实施方式中,所述靶向治疗剂为FGFR抑制剂。在某些实施方式中,所述靶向治疗剂为mTOR抑制剂。在某些实施方式中,所述靶向治疗剂为HER2抑制剂。在某些实施方式中,所述靶向 治疗剂选自下组中的一种或多种:阿法替尼,达克替尼,奥希替尼,EAI045,吉非替尼,阿莫替尼,吡罗替尼,布加替尼,来那替尼,奥木替尼,博舒替尼,埃克替尼,凡德他尼,拉帕替尼,阿氟替尼,BPI-7711,莫波替尼,多维替尼,佐立替尼,瓦利替尼,奥布替尼,拉布替尼,布鲁替尼依鲁替尼,达沙替尼,pirtobrutinib,tolebrutinib,rilzabrutinib,fenebrutinib,evobrutinib,司美替尼(selumetinib),tivozanib,dovitinib,索凡替尼,binimetinib,cobimetinib,trametinib,瑞戈非尼(regorafenib),GSK-1120212,alpelisib,duvelisib,copanlisib,idelalisib,去甲替林,inavolisib,dactolisib,apitolisib,parsaclisib,buparlisib,rigosertib,enzastaurin,paxalisib,leniolisib,ipatasertib,zotarolimus,sirolimus,依维莫司,temsirolimus,索拉非尼(sorafenib),阿帕替尼(apatinib),乐伐替尼(lenvatinib),舒尼替尼(sunitinib),卡博替尼(cabozantinib),阿昔替尼(axitinib),尼达尼布(nintedanib),brivanib,vatalanib,呋喹替尼(fruquintinib),达拉非尼(dabrafenib),威罗非尼(vemurafenib),恩科拉非尼(encorafenib),pazopanib,crizotinib,panobinostat,erlotinib,rituximab,panitumumab,cetuximab,erfonrilimab,efactinib,cadonilimab,ramucirumab,bevacizumab,安罗替尼(anlotinib),ponatinib,法米替尼(famitinib),厄达替尼(erdafitinib),AZD4547,英菲格拉替尼(infigratinib,在本申请中也称为英飞替尼),BCD-217,amivantamab,MCLA-129,EMB-01,LY3164530,JNJ-61186372,抗EGFR及cMet双特异性抗体,GB263,它们的可药用盐以及它们的任意组合。
在某些实施方式中,所述靶向治疗剂与一种或多种其它疗法联合施用。
在某些实施方式中,所述抗肿瘤剂为化疗剂。
在某些实施方式中,所述化疗剂包括嘧啶核苷类似物和/或其前药。
在某些实施方式中,所述化疗剂包括选自下组中的一种或多种:卡培他滨(Capecitabine)、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
在某些实施方式中,所述5-FU药物前体包括喃氟啶、5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物、2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和/或3-脱氮杂尿苷。
在某些实施方式中,所述化疗剂与一种或多种其它疗法联合施用。
在某些实施方式中,所述一种或多种其它疗法包括一种或多种其它抗肿瘤疗法。
在某些实施方式中,所述疾病或病症是由施用所述抗肿瘤剂引起的。
在某些实施方式中,所述疾病或病症在施用所述抗肿瘤剂之后出现或加重。
在某些实施方式中,在施用所述抗肿瘤剂之前,所述受试者未患有所述疾病或病症。
在某些实施方式中,所述疾病或病症包括上皮组织疾病或病症。
在某些实施方式中,所述上皮组织疾病或病症包括与内皮细胞病变相关的疾病或病症,和/或与上皮细胞病变相关的疾病或病症。
在某些实施方式中,所述内皮细胞包括血管内皮细胞。
在某些实施方式中,所述上皮细胞包括皮肤上皮细胞,口腔上皮细胞,鼻腔上皮细胞,胃上皮细胞和/或肠上皮细胞。
在某些实施方式中,所述疾病或病症包括皮肤疾病或病症,五官疾病或病症和/或胃肠道疾病或病症。
在某些实施方式中,所述皮肤疾病或病症包括脱发症,体臭,大疱性皮炎,皮肤干燥,湿疹,多形性红斑,红皮病,脂肪萎缩症,发色改变,毛发质地异常,多毛症(hirsutism),多汗症(hyperhidrosis),角化过度症,肥大症(hypertrichosis),少汗症(hypohidrosis),脂肥大,指甲改变,指甲变色,指甲丢失,指甲隆起,皮肤疼痛,手足综合征,光敏感性,瘙痒症,紫癜,痤疮样皮疹,斑丘疹,头皮疼痛,皮肤萎缩,皮肤色素沉着过多(skin hyperpigmentation),皮肤色素减退(skin hypopigmentation),皮肤硬结,皮肤溃疡,Stevens-Johnson综合征,皮下气肿,毛细血管扩张,中毒性表皮坏死,皮疹和/或荨麻疹。
在某些实施方式中,所述皮肤疾病或病症为手足综合征。
在某些实施方式中,所述皮肤疾病或病症的严重程度为依据NCI-CTCAE中的第1级或其以上,第2级或其以上,第3级或其以上,第4级或其以上,或者第5级。
在某些实施方式中,所述受试者包括癌症患者。
在某些实施方式中,所述疾病或病症的患处与癌症的患处不同。
在某些实施方式中,所述药物基本上不影响所述抗肿瘤剂的治疗效果。
在某些实施方式中,所述药物被制备为适用于局部给药。
在某些实施方式中,所述药物被制备为适用于透皮给药。
在某些实施方式中,所述药物被制备为乳膏,洗液,凝胶,软膏,油膏,喷剂,脂质体制剂,擦剂和/或气雾剂。
在某些实施方式中,所述药物的给药部位和所述抗肿瘤剂的给药部位不同。
在某些实施方式中,所述药物的给药部位不为癌症的发生部位或癌症的潜在转移部位。
在某些实施方式中,所述药物的给药方式和所述抗肿瘤剂的给药方式不同。
在某些实施方式中,所述药物中,所述NO-NSAID化合物的浓度为约0.005%w/w至约 40%w/w。
在某些实施方式中,所述药物中,所述NO-NSAID化合物的浓度为约0.5%w/w至约10%w/w。
另一方面,本申请提供了一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的NO-NSAID化合物或其药学上可接受的盐。
另一方面,本申请提供了NO-NSAID化合物或其药学上可接受的盐,其用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面,本申请提供了一种药物组合,其包含:1)抗肿瘤剂;以及2)NO-NSAID化合物。
在某些实施方式中,在所述药物组合中,所述抗肿瘤剂与所述NO-NSAID化合物彼此不混合。
在某些实施方式中,在所述药物组合中,所述抗肿瘤剂与所述NO-NSAID化合物各自独立地存在于单独的容器中。
在某些实施方式中,在所述药物组合中,所述NO-NSAID化合物被制备为适用于透皮给药。
在某些实施方式中,在所述药物组合中,所述NO-NSAID化合物被制备为软膏剂。
在某些实施方式中,在所述药物组合中,所述NO-NSAID化合物的浓度为约0.005%w/w至约40%w/w。
在某些实施方式中,在所述药物组合中,所述NO-NSAID化合物的浓度为约0.5%w/w至约10%w/w。
在某些实施方式中,在所述药物组合中,2)中的所述NO-NSAID化合物能够预防,缓解和/或治疗与1)中的所述抗肿瘤剂相关的疾病或病症。
在某些实施方式中,在所述药物组合中,2)中的所述NO-NSAID化合物基本上不影响1)中的所述抗肿瘤剂的治疗效果。
在某些实施方式中,在所述药物组合中,在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的所述NO-NSAID化合物。
另一方面,本申请提供了NO释放剂和NSAID在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面,本申请提供了一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病 或病症的方法,所述方法包括向有需要的受试者施用有效量的NO释放剂和NSAID。
另一方面,本申请提供了一种药物组合,其包含:1)抗肿瘤剂;2)NO释放剂;以及3)NSAID。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下:
图1显示的是大鼠手足综合征的模型。
图2显示的是经本申请的药物或药物组合治疗后的大鼠爪子情况。
图3显示的是各组大鼠爪子的病理学检测结果。
图4显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图5显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图6显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图7显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图8显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图9显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图10显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图11显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图12显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图13显示的是各组药物施用后的疼痛测定效果,Blank即空白对照。
图14显示的是各组药物的细胞毒性缓解效果。
图15显示的是各组药物的细胞毒性缓解效果。
图16显示的是各组药物的细胞毒性缓解效果。
图17显示的是各组药物的细胞毒性缓解效果。
图18显示的是各组药物的细胞毒性缓解效果。
图19显示的是各组药物的细胞毒性缓解效果。
图20显示的是各组药物的细胞毒性缓解效果。
图21显示的是各组药物的细胞毒性缓解效果。
图22显示的是各组药物的细胞毒性缓解效果。
图23显示的是各组药物的细胞毒性缓解效果。
图24显示的是各组药物的细胞毒性缓解效果。
图25显示的是各组药物的细胞毒性缓解效果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中,术语“NSAID”通常指“非甾体抗炎药”。术语“非甾体”用于将这些药物与甾体类药物区分开,所述甾体类药物的众多作用中包括阻抑花生四烯酸(eicosanoid-depressing)、抗炎作用等。作为止痛药,NSAID是独特的,因为它们是非麻醉性的。NSAID包括阿司匹林(aspirin)、布洛芬(ibuprofen)和萘普生(naproxen)等。大多数NSAID用作酶即环氧合酶的非选择性抑制剂,抑制环氧合酶-1(COX-1)和环氧合酶-2(COX-2)同工酶。环氧合酶催化由花生四烯酸(本身是通过磷脂酶A2从细胞磷脂双层衍生的)形成前列腺素和血栓烷。
在本申请中,术语“NO-NSAID化合物”通常是指一种NSAID衍生物,其能够释放一氧化氮(NO)。例如,所述NO-NSAID化合物可以包括所述NSAID的硝基氧基衍生物。
在本申请中,术语“间隔基”通常是指将一个化合物或其部分与另一个化合物或其部分间隔开的基团。例如,所述间隔基可以为将一个化合物或其部分与另一个化合物或其部分连接起来的化学键、基团或连接子。
在本申请中,术语“环氧合酶(COX)抑制部分”通常是指能够在体内和/或体外降低环氧合酶的活性和/或功能的分子或其部分。
在本申请中,术语“环氧合酶(COX)”又被称为前列腺素内过氧化物合酶(PTGS),通常是指一种酶(例如同工酶家族,EC 1.14.99.1),其能够从花生四烯酸中形成前列腺素,包括血栓素和前列腺素,如前列环素酸。其为动物型血红素过氧化物酶家族的成员,也称为前列腺素G/H合酶。所述COX催化的特定反应是从花生四烯酸通过短寿命的前列腺素G2中间体转化为前列腺素H2。所述COX可包括COX-1和COX-2。其中,对COX-2同工酶具有特异 性的那些被称为COX-2选择性抑制剂。COX-1和COX-2具有相似的分子量,分别约为70kDa和72kDa,二者具有65%的氨基酸序列同源性和几乎相同的催化位点。这两种蛋白质都具有三个结构域:一个N端EGF样结构域、一个小的4螺旋膜锚和一个核心血红素过氧化物酶催化结构域。两者都形成二聚体。其中,COX-1中523位的异亮氨酸被COX-2中的缬氨酸取代。COX-2中较小的Val523残基允许进入酶中的疏水侧袋(Ile523空间阻碍)。与该替代位点结合的分子,能够被认为是COX-2的选择性抑制剂。
在本申请中,术语“VEGFR”通常是指血管内皮生长因子受体(Vascular Endothelial Grow Factor Receptor),属于酪氨酸激酶受体Receptor tyrosine kinases(RTKs))家族。据报道其包括三种主要的亚型,分别为VEGFR1,VEGFR2和VEGFR3。其中VEGFR1和VEGFR2主要分布在肿瘤血管内皮表面,调解肿瘤血管的生成,VEGFR3主要分布于淋巴内皮表面,调解肿瘤淋巴管的生成。据报道VEGFR2是血管新生和有丝分裂过程主要的VEGF信号转导受体。VEGF家族包括VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E和胎盘生长因子(PGF)。据报道VEGF-A与VEGFR-1和VEGFR-2结合,可以调节几乎所有的对VEGF的细胞应答。VEGFR-2在内皮细胞上的激活导致细胞的增殖,迁移,存活率增加以及血管通透性的提高(参见Waldner,Maximilian J.等人,The Journal of Experimental Medicine 207.13,2010)。VEGFR的表达或其激酶活性的增加与一系列人类癌症相关。
在本申请中,术语“VEGF”通常是指血管内皮生长因子(Vascular Endothelial Grow Factor),据报道,其被认为是病理性血管生成信号通路所需的关键内皮细胞特异性生长因子,VEGF受体酪氨酸激酶信号通路的抑制阻断了肿瘤生长中新血管的形成,导致血管生成肿瘤的停滞或消退(参见Gerald McMahon,The Oncologist 2000,5:3-10)。
在本申请中,术语“VEGFR抑制剂”通常是指本领域中已知的或将来发现的任何能够引起VEGFR的表达、数量或活性降低的物质或试剂,包括任何当其被施用至受试者时,导致了受试者中与VEGFR活性相关的生物活性的抑制(包括任何VEGFR与其天然配体结合产生的下游生物效应的抑制)的任何物质。在某些实施方式中,VEGFR抑制剂可以包括在治疗癌症过程中任何能够阻断VEGFR活性或其任何下游生物效应的试剂。例如,所述VEGFR抑制剂可用于治疗肿瘤。例如,所述VEGFR抑制剂可以直接抑制VEGFR的一种或多种功能。例如,所述VEGFR抑制剂可以与编码VEGFR的核酸序列结合。例如,所述VEGFR抑制剂可以降低VEGFR蛋白的转录水平。
在本申请中,术语“VEGF抑制剂”通常是指本领域中已知的或将来发现的任何能够引起VEGF的表达、数量或活性降低的物质或试剂,包括任何当其被施用至受试者时,导致了受 试者中与VEGF活性相关的生物活性的抑制的任何物质。在某些实施方式中,VEGF抑制剂可以包括任何能够阻断VEGF活性或其任何下游生物效应的试剂。在某些实施方式中,VEGF抑制剂可以包括在治疗癌症过程中任何能够阻断VEGF活性或其任何下游生物效应的试剂。例如,所述VEGF抑制剂可用于治疗肿瘤。例如,所述VEGF抑制剂可以直接抑制VEGF的一种或多种功能。例如,所述VEGF抑制剂可以与编码VEGF的核酸序列结合。例如,所述VEGF抑制剂可以降低VEGF蛋白的转录水平。
在本申请中,无论在体内还是体外,检测和/或评价所述VEGF和/或VEGFR被抑制的水平的方法在本领域是常见的,并且所述方法也可用于鉴定、标准、筛选和/或评价本申请所述的VEGF抑制剂和/或VEGFR抑制剂。
在本申请中,术语“肿瘤”通常是指机体在各种致瘤因子作用下,局部组织细胞增生所形成的新生物,由于这种新生物多呈占位性块状凸起,也称赘生物。根据新生物的细胞特性及对机体的危害程度,又将肿瘤分为良性肿瘤和恶性肿瘤两类,癌症是恶性肿瘤的总称。所述的肿瘤可以选自下组:上皮的恶性肿瘤(上皮来源的癌)、肺癌(例如,非小细胞肺癌)、乳腺癌、皮肤癌、膀胱癌、结肠癌、肠道癌、前列腺癌、胰腺癌、子宫癌、宫颈癌、卵巢癌、食管癌、头颈部癌、胃癌和喉癌。例如,所述肿瘤可以为肝癌、肾癌、结直肠癌、胃癌、食道癌或甲状腺癌。
例如,所述VEGFR抑制剂可包括小分子VEGFR抑制剂、特异性结合VEGFR的蛋白大分子、抑制VEGFR蛋白表达的RNAi和/或抑制VEGFR蛋白表达的反义寡核苷酸。
在本申请中,术语“小分子VEGFR抑制剂”可以包括与VEGFR可逆或不可逆结合的小分子VEGFR抑制剂或者是特异性结合突变的VEGFR的小分子VEGFR抑制剂。例如,所述小分子VEGFR抑制剂可以包括瑞格非尼、普纳替尼、卡博替尼、乐伐替尼、索拉非尼、阿帕替尼、阿西替尼、尼达尼布、凡德他尼、舒尼替尼、米哚妥林、替沃扎尼、呋喹替尼、西地尼布、布立尼布、多纳非尼、索凡替尼、安罗替尼、法米替尼、Tesevatinib、Vorolanib、莫特塞尼、Linifanib、Semaxanib、多韦替尼、orantinib、瓦它尼丁、替拉替尼、Glesatinib、德立替尼、Ilorasertib、Rebastinib、Golvatinib、Foretinib、ningetinib、Tafetinib、Altiratinib、TAS-115、Chiauranib、Henatinib、4SC-203、AAL-993、ACTB-1003、AEE-788、AMG-628、沙蟾蜍精、BAW2881、BIBF-1202、BMS-690514、BMS-794833、CEP-11981、CEP-5214、CP-547632、CYC116、DW532、ENMD-2076、FIIN-1、GFB-204、BFH-772、BMS599626、BMS690514、PP 121、MGCD 265类似物、AC480、Ki 8751、KRN 633、WHI-P 154、TAK593、JI 101、AZD-2932、SCR-1481B1、异甘草素、JNJ-26483327、KI-20227、LY2457546、ODM-203、OSI-930、 PF-00337210、CGP41231、R1530、RAF265、SAR131675、Semaxinib、SIM010603、SKLB1002、SKLB610、SU 5205、SU11652、SU14813、SU-1498、SU-4312、SU5402、T-1840383、丹参酮IIA、TAS-115、TG 100572、TG 100801、TG100572HCl、Toceranib、酪氨酸磷酸化抑制剂A9、Tesevatinib、XL-844、XL999、ZD4190HCl、ZM-306416、ZM323881HCl、ABT-510、NVP-ACC789、ADT-OH、BMS-645737、EG 00229、XL-820、SGI-7079、内皮抑素(Endostatin)和/或紫杉叶素。
在本申请中,术语“特异性结合”通常是指在复杂混合物中,所述VEGFR抑制剂可以特异性地识别并结合VEGFR,而基本上不识别或结合该复杂混合物中的其他组分。例如,所述抑制剂与VEGFR的亲和力可以为其与其他非特异性结合组分的亲和力的至少2倍(例如,至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍或更多)。在某些实施方式中,所述VEGFR抑制剂与VEGFR结合的平衡解离常数的数值小于或等于10 -6(例如,可以小于或等于10 -7M、小于或等于10 -8M、小于或等于10 -9M、小于或等于10 -10M或更小)。
在本申请中,所述特异性结合VEGFR的蛋白大分子可以是针对VEGFR的抗体、抗体变体、融合蛋白、衍生物或其片段。例如,其可以是特异性结合VEGFR的抗体或其抗原结合片段。
在本申请中,所述抗体通常是指一种能够特异性识别和/或中和特定抗原的多肽分子。例如,抗体可包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链组成的免疫球蛋白,并且包括任何包含其抗原结合部分的分子。术语“抗体”可包括单克隆抗体、抗体片段或抗体衍生物,包括但不限于人抗体(全人源抗体)、人源化抗体、嵌合抗体、单链抗体(例如,scFv),以及与抗原结合的抗体片段(例如,Fab、Fab’和(Fab)2片段)。其中,所述嵌合抗体可以为重链或轻链氨基酸序列的一部分与来自于一个物种的抗体中相应氨基酸序列同源,或者属于特定的类别,而该链的其余区段则与另一物种中的相应序列同源的抗体。其中,所述人源化抗体可以指一种嵌合抗体,其含有较少的来自非人免疫球蛋白的序列,从而降低异种抗体引入到人类中时的免疫原性,同时保持抗体的完全抗原结合亲和力和特异性。其中,所述全人源抗体可以指包含对应于由人或人免疫细胞产生的、或从例如利用人源抗体库的转基因非人动物等非人来源衍生的抗体的氨基酸序列,或者其他编码人源抗体的序列的抗体。
在本申请中,所述抗原结合片段抗体可以为发挥特异性结合抗原功能的一个或多个片段。抗体的抗原结合功能可通过抗体的全长片段来实现。抗体的抗原结合功能也可通过以下来实现:包括Fv、ScFv、dsFv、Fab、Fab’或F(ab’) 2的片段的重链,或者,包括Fv、ScFv、dsFv、 Fab、Fab’或F(ab’) 2的片段的轻链。(1)Fab片段,即由VL、VH、CL和CH结构域组成的一价片段;(2)F(ab’) 2片段,包含通过铰链区处的二硫键连接的两个Fab片段的二价片段;(3)由VH和CH结构域组成的Fd片段;(4)由抗体单臂的VL和VH结构域组成的Fv片段;(5)由VH结构域组成的dAb片段(Ward等,(1989)Nature 341:544-546);(6)分离的互补决定区(CDR);(7)可任选地通过接头连接的两个或以上分离的CDR的组合;(8)骆驼化单域抗体(Camelized single domain antibody),包含两个重链可变区而不含有轻链的抗体和(9)纳米抗体,包含重链可变区、CH2和CH3。此外,还可包括由VL和VH配对形成的一价单链分子Fv(scFv)(参见Bird等(1988)Science 242:423-426;以及Huston等(1988)Proc.Natl.Acad.Sci.85:5879-5883)。所述”抗原结合部分”还可包括免疫球蛋白融合蛋白,所述融合蛋白包含选自以下的结合结构域:(1)与免疫球蛋白铰链区多肽融合的结合结构域多肽;(2)与铰链区融合的免疫球蛋白重链CH2恒定区;和(3)与CH2恒定区融合的免疫球蛋白重链CH3恒定区。
例如,所述特异性结合VEGFR的蛋白大分子可以为雷莫芦单抗,其抗原结合片段或其功能性变体。
在本申请中,术语“VEGF捕获剂”通常是指能够通过结合VEGF而将其捕获的试剂。例如,所述VEGF捕获剂可以选自下组:贝伐珠单抗和阿柏西普。
在本申请中,术语“降低VEGF表达量的试剂”通常是指能够直接或间接降低受试者中VEGF表达量的物质。例如,所述降低VEGF表达量的试剂可以选自下组:坦西莫斯(Temsirolimus)和沙利度胺(Thalidomide)。
在本申请中,术语“RNAi”通常是指RNA干扰(RNA interference),其通常是外源或内源的双链RNA分子或小分子RNA,一般通过靶向mRNA并将其特异性降解而抑制目标基因的表达或翻译。通常,RNAi包括两种小分子RNA:微型RNA(miRNA)和小干扰RNA(siRNA),这些小RNA能够结合其他mRNA分子,进而提高或降低其活性,例如阻止mRNA被翻译成蛋白质。在真核动物中,RNAi途径通过RNaseIII酶(例如,Dicer、DCL或Drosha)将长的双链RNA(dsRNA)切割成为长度为约20-23个核苷酸的siRNA双链片段。每个siRNA被拆分成两个单链RNA(ssRNA),即过客(passenger)链和引导(guide)链。过客(passenger)链被降解,而引导链整合进RNA诱导的沉默复合物(RISC)。当引导链与mRNA分子互补时,RISC切割该mRNA分子,从而导致该mRNA分子的降解。
在本申请中,抑制VEGFR蛋白表达的RNAi可以通过靶向编码VEGFR的mRNA,从而将该mRNA特异性降解来抑制VEGFR的表达或翻译。在本申请中,抑制VEGF蛋白表达的 RNAi可以通过靶向编码VEGF的mRNA,从而将该mRNA特异性降解来抑制VEGF的表达或翻译。
在本申请中,术语“寡核苷酸”通常是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其任何模拟物或结构修饰的核酸的低聚物或聚合物。所述寡核苷酸可包括由天然存在的核碱基、糖和共价核苷(主链)间键组成的寡核苷酸,以及具有类似功能的非天然存在的寡核苷酸。经过修饰或取代的寡核苷酸通常优于天然形式,因为其具有例如增强的细胞摄取、对靶核酸的增强的亲和性以及在核酸酶存在下的增加的稳定性。
在本申请中,术语“反义寡核苷酸”通常是指具有允许与靶核酸的对应区域或片段至少部分地杂交的核碱基序列的单链寡核苷酸。在本申请中,所述反义寡核苷酸可包含约8至约50个核碱基。
在本申请中,所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。例如,所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和VEGFR3中的一种、两种或三种。
在某些实施方式中,所述抗肿瘤剂可包括雷莫芦单抗、贝伐珠单抗、瑞格非尼、普纳替尼、卡博替尼、乐伐替尼、索拉非尼、帕唑帕尼、阿帕替尼、阿西替尼、尼达尼布、凡德他尼、舒尼替尼、米哚妥林、替沃扎尼、呋喹替尼、西地尼布、布立尼布、多纳非尼、索凡替尼、安罗替尼、法米替尼、Tesevatinib、Vorolanib、莫特塞尼、Linifanib、Semaxanib、多韦替尼、orantinib、瓦它尼丁、替拉替尼、Glesatinib、德立替尼、Ilorasertib、Rebastinib、Golvatinib、Foretinib、ningetinib、Tafetinib、Altiratinib、TAS-115、Chiauranib、Henatinib、4SC-203、AAL-993、ACTB-1003、AEE-788、AMG-628、沙蟾蜍精、BAW2881、BIBF-1202、BMS-690514、BMS-794833、CEP-11981、CEP-5214、CP-547632、CYC116、DW532、ENMD-2076、FIIN-1、GFB-204、BFH-772、BMS599626、BMS690514、PP 121、MGCD 265类似物、AC480、Ki 8751、KRN 633、WHI-P 154、TAK593、JI 101、AZD-2932、SCR-1481B1、异甘草素、JNJ-26483327、KI-20227、LY2457546、ODM-203、OSI-930、PF-00337210、CGP41231、R1530、RAF265、SAR131675、Semaxinib、SIM010603、SKLB1002、SKLB610、SU 5205、SU11652、SU14813、SU-1498、SU-4312、SU5402、T-1840383、丹参酮IIA、TAS-115、TG 100572、TG 100801、TG100572HCl、Toceranib、酪氨酸磷酸化抑制剂A9、Tesevatinib、XL-844、XL999、ZD4190HCl、ZM-306416、ZM323881HCl、ABT-510、NVP-ACC789、ADT-OH、BMS-645737、EG00229、XL-820、SGI-7079、内皮抑素(Endostatin)、紫杉叶素、阿柏西普、和/或,上述物质的可药用盐。
在本申请中,所述“可药用盐”可以指所述化合物在药学上可接受的盐。在某些实施方式 中,所述可药用盐可以选自下组:索拉非尼甲苯磺酸盐、舒尼替尼苹果酸盐、帕唑帕尼盐酸盐和Dovitinib(TKI258)乳酸盐。
在本申请中,所述VEGFR抑制剂和/或VEGF抑制剂可以与一种或多种其他疗法联合施用。在某些实施方式中,所述一种或多种其他疗法可以包括一种或多种其他抗肿瘤疗法。例如,所述其他抗肿瘤疗法可以包括细胞毒抗癌剂、免疫治疗抗癌剂和/或激素治疗抗癌剂。所述其他抗肿瘤疗法也可以包括放射治疗或手术治疗。
在本申请中,在将VEGFR抑制剂和/或VEGF抑制剂与其他抗肿瘤疗法组合使用的情况下,它们可以同时施用于受试者,或者以一定间隔分开施用。例如,所述其他抗肿瘤疗法可以是单一药剂的一部分,其与所述的VEGFR抑制剂和/或VEGF抑制剂混合成为单一组合物。又例如,所述其他抗肿瘤疗法可以是单独的药剂,其与所述的VEGFR抑制剂和/或VEGF抑制剂分别施用。在本申请中,如果所述其他抗肿瘤疗法与所述VEGFR抑制剂和/或VEGF抑制剂作为单一组合物,所述VEGFR抑制剂和/或VEGF抑制剂可以以相对于总剂量约1-99%(例如约5-95%、约1%、约5%、约10%、约20%、约30%、约40%、约50%、约60%、约70%、约80%、约90%、约95%或约99%)的剂量水平存在和/或被施用。
在本申请中,术语”皮肤疾病或病症”通常是指皮肤(包括毛发和甲)的形态、结构和/或功能发生的病理性变化。例如,所述所述皮肤疾病或病症可包括但不限于皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱等。
在本申请中,术语”皮疹”通常是指会影响皮肤颜色、外观或纹理的皮肤变化。皮疹可以仅局限在在身体的一部分,或影响整个皮肤。皮疹还包括荨麻疹。
在本申请中,术语”手足综合征”又称为Hand Foot Syndrome(HFS),或Palmar Plantar Erythrodysesthesia(PPE)或Hand-foot skin reaction(HFSR,手足皮肤反应),其是由哈佛医学院新英格兰戴肯尼斯医院的Jacob Lokich和Cery Moor于1984年首次描述的。典型的临床表现呈进展性,临床主要表现为指(趾)热、痛、红斑性肿胀,严重者发展至脱屑、溃疡和剧烈疼痛等。HFS的病理表现主要包括,例如基底角质细胞空泡变性、皮肤血管周围淋巴细胞浸润、角质细胞凋亡和皮肤水肿等。例如,HFS可包括手掌、足底感觉迟钝或化疗引起的肢端红斑等。肿瘤患者在接受化疗或者分子靶向治疗(如VEGFR抑制剂和/或VEGF抑制剂)的过程中可能出现相应症状。
手足综合征(HFS)目前有多种分级方法,其中以美国国立癌症研究所(NCI)分级标准较为常用,该分级将手足综合征分为3级:1级为轻微的皮肤改变或皮炎伴感觉异常(如指纹消失、色素沉着、红斑、脱皮、感觉异常、感觉迟钝、皮肤麻木等),但不影响日常活动; 2级为皮肤改变同1级,并伴疼痛,轻度影响日常活动,皮肤表面完整;3级为溃疡性皮炎或皮肤改变伴剧烈疼痛,严重影响日常生活,具有明显的组织破坏,(如脱屑、水疱、出血、水肿等)。
此外,世界卫生组织(WHO)对HFS的分级则为4级:1级为手和脚感觉迟钝、感觉异常或刺痛感;2级为在持物和走路时的不舒适、无痛肿胀或红斑;3级为疼痛的红斑和水肿的手掌和脚底,甲周的红斑和肿胀;4级为脱皮、溃烂、起庖及剧烈的疼痛。
在本申请中,术语“红斑”通常是指真皮乳头层毛细血管网局限性或全身性扩张而产生局部的或全身性的红色斑疹。
在本申请中,术语“甲沟炎”通常是指指(趾)甲周围软组织的感染性病变,通常是细菌通过甲旁皮肤的微小破损侵袭至皮下并发生繁殖引起的,临床表现为患处红肿疼痛,伴炎性渗出及肉芽组织增生等。
在本申请中,术语“色素沉积紊乱”通常是指皮肤比正常情况下颜色更浅或更深、产生斑点或变色的病症。色素沉积不足(hypopigmentation)是由于身体无法产生足够多的色素,色素沉积过度(hyperpigmentation)是由于身体产生过多的色素。
在本申请中,术语“五官疾病或病症”通常是指耳、眉、眼、鼻、口等器官的形态、结构和/或功能发生的病理性变化。例如,所述五官疾病或病症可包括但不限于口腔溃疡(oral Mucositis)、口干(dry mouth)、鼻衄(epistaxis)、鼻咽炎和/或唇炎。
在本申请中,术语“鼻咽炎”通常是指鼻咽部黏膜、黏膜下和淋巴组织的炎症反应,可分为急性鼻咽炎和慢性鼻咽炎。症状包括但不限于鼻咽干燥不适,有黏稠分泌物不易咳出,常伴有恶心,严重者有声嘶、咽痛、头痛、头晕、乏力、消化不良、低热等局部或全身症状。鼻咽部检查见黏膜慢性充血、增生、肥厚,覆以分泌物或干痂等。
在本申请中,术语“唇炎”通常是指发生于唇部的炎症性疾病或病症。例如,其可包括口周皮肤、朱红边界、和/或唇粘膜的炎症等。根据病程可分为急性唇炎和慢性唇炎,根据临床症状特征可分为糜烂性唇炎、湿疹性唇炎、脱屑性唇炎,根据病因病理可分为慢性非特异性唇炎、腺性唇炎、良性淋巴增生性唇炎、肉芽肿性唇炎、梅-罗综合征、光化性唇炎和变态反应性唇炎等。
在本申请中,术语“胃肠道疾病或病症”通常是指胃或肠道组织(例如,从胃幽门至肛门的消化管组织)的形态、结构和/或功能发生的病理性变化。例如,所述胃肠道疾病或病症可包括但不限于腹泻(diarrhea)、呕吐(vomitting)、恶心(nausea)、厌食(anorexia)、便秘(constipation)和/或腹痛(abdominal pain)等。
在本申请中,术语“上皮组织”包括一层或多层覆盖整个身体的自由和封闭表面的细胞,包括皮肤、粘液、腔、浆液和腺体空间。所有上皮层都包含两个特殊的结构域:面向粘膜(或腔)空间的顶端结构域和面向浆膜(或深层)空间的基底外侧膜。因此,上皮组织的重要功能是提供适当的屏障功以分离和控制这两个空间之间的许多生理过程。上皮组织包括上皮细胞以及内皮细胞。
在本申请中,术语“上皮组织疾病或病症”通常是指上皮细胞和/或内皮细胞病变引起的疾病或病症。例如,所述上皮组织疾病或病症可以包括皮疹、痤疮、皮肤瘙痒、脱发、毛发改变、红斑、皮肤脱落(skin exfoliation)、疱脓疹、多毛症、色素沉着(hyper-pigmentation)、指甲疾病(nail disorders)、甲沟炎及甲裂、皮肤干燥、超敏反应、黏膜炎、鼻咽炎、鼻出血、口腔干燥、唇炎、口腔溃疡和/或胃肠道粘膜损伤。又例如,所述上皮组织疾病或病症还可以包括皮肤上皮细胞疾病或病症(例如,皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干燥、超敏反应以及牛皮癣)、口腔上皮细胞疾病或病症(例如,天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞疾病或病症(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞疾病或病症(例如,胃炎、肠化生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞疾病或病症(例如,肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)。
在本申请中,术语“一氧化氮释放部分”通常是指任何能够贡献、产生和/或释放一氧化氮产生的物质。在某些实施方式中,一氧化氮释放部分可以直接贡献、生产和/或释放一氧化氮。例如,一氧化氮释放部分可以通过刺激其他物质来贡献、生产和/或释放一氧化氮。例如,一氧化氮释放部分可以作为化学反应或酶催化反应的反应物,通过该等反应贡献、生产和/或释放一氧化氮。在某些实施方式中,一氧化氮释放部分可以作为化学反应或酶催化反应的催化剂,通过该等反应来刺激其他物质贡献、生产和/或释放一氧化氮。一氧化氮释放部分也可以包括一氧化氮本身。
在本申请中,术语“有机分子”通常是指含碳元素的化合物,且不包含碳的氧化物、碳酸、碳酸盐、氰、氰化物、氧氰、氰酸盐、硫氰、金属碳化物等。
在本申请中,术语“高分子”通常是指分子量为大于2000道尔顿、大于3000道尔顿、大于4000道尔顿、大于5000道尔顿、大于6000道尔顿、大于7000道尔顿、大于8000道尔顿、大于9000道尔顿、大于10000道尔顿、大于12000道尔顿、大于15000道尔顿或大于 20000道尔顿的任何化合物。
在本申请中,术语“小分子”通常是指分子量小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿或小于或等于100道尔顿的分子量的任何化合物。
在本申请中,所述一氧化氮释放部分可以具有下述的一个或多个基团:偶氮鎓二醇盐、羟基二氮烯磺酸、S-亚硝基硫醇、呋咱氮氧、肟、N-亚硝胺、N-羟基胍、偶氮鎓二醇盐、硝酸盐、亚硝酸盐、硝酸酯、亚硝酸酯、斯得酮亚胺、斯得酮、恶三唑-5-亚胺、恶三唑-5-酮、羟胺、二氧二氮杂环丁烯、N-羟基亚硝胺、N-亚硝亚胺、羟基脲和金属亚硝氨基络合物。
例如,所述一氧化氮释放部分可以具有选自表1的一个或多个基团:
表1
Figure PCTCN2023071255-appb-000063
Figure PCTCN2023071255-appb-000064
Figure PCTCN2023071255-appb-000065
在本申请中,术语“预防”可以与“预防性治疗”互换地使用。在本申请中“预防”通常是指通过预先采取某些措施而防止疾病或其一种或多种症状的发作,复发或扩散。在本申请中,术语”治疗”通常是指消除或改善疾病,或缓解与疾病相关的一种或多种症状。
在本申请中,术语“受试者”通常是指需要接受疾病的诊断、预后、改善、预防和/或治疗的人或非人动物(包括哺乳动物,啮齿类动物和禽类动物等)。例如,所述受试者可以为家畜动物(例如,牛、猪、羊、鸡、兔或马),或啮齿类动物(例如,大鼠和小鼠),或灵长类动物(例如,大猩猩和猴子),或家养动物(例如,狗和猫)。
在本申请中,术语“有效量”通常是指可以缓解或者消除受试者的疾病或症状,或者可以预防性地抑制或防止疾病或症状发生的药物的量。通常,可根据受试者的体重、年龄、性别、饮食、排泄速率、过往病史、现用治疗、给药时间、剂型、给药方法、给药途径、药物组合、所述受试者的健康状况和交叉感染的潜力、过敏、超敏和副作用、和/或上皮(或内皮)组织疾病发展的程度等来确定具体的有效量。本领域技术人员(例如,医生或兽医)可根据这些或其它条件或要求按比例降低或升高剂量。
本申请中,所述“基本上不影响”可以指,效果相当,或者不产生显著的劣势。例如,对任意的受试者,所导致的肿瘤体积减少的程度是相同的,或者,减少的程度不小于约5%、不小于约4%、不小于约3%、不小于约2%、不小于约1%、不小于约0.5%、不小于约0.1%、不小于约0.01%、不小于约0.001%或更小。
在本申请中,术语“易患有”通常是指受试者具备较大概率患有所述与施用抗肿瘤剂相关的疾病或病症。例如,所述较大概率可以指与健康的受试者相比,一个受试者患有所述与施 用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的概率提高了大约至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少150%、至少200%或更多。
在本申请中,术语“皮肤组织特征”通常是指能够反映皮肤疾病或病症的特征。例如,所述特征可以包括能够反映与施用所述抗肿瘤剂相关的皮肤疾病或病症的特征。例如,所述特征可以包括能够反映与施用抗肿瘤剂相关的皮疹、与施用抗肿瘤剂相关的手足综合征、与施用抗肿瘤剂相关的皮肤瘙痒、与施用抗肿瘤剂相关的皮肤红斑和/或紫癜、与施用抗肿瘤剂相关的皮肤干燥和/或皲裂、与施用抗肿瘤剂相关的脱发、与施用抗肿瘤剂相关的甲沟炎,和/或,与施用抗肿瘤剂相关的色素沉积紊乱的特征。例如,所述特征可以包括红斑面积和程度、紫癜面积和程度、丘疹数量与程度、脓疱数量与程度、结节数量与程度、皮肤肿胀范围与程度、皮肤溃疡程度、皮肤干燥程度、皮肤皲裂程度、皮肤角化程度、皮肤苔藓化程度、皮肤脱屑面积与程度、皮肤紧绷状态、皮肤瘙痒程度、真皮与皮下交界处血管炎症程度、皮肤组织的坏死程度、皮肤糜烂溃疡程度、网状青斑面积、皮肤色素沉着程度、水疱与大疱数量、毛发脱失部位/面积/程度、皮肤肉芽增生程度、皮肤脂溢程度,毛囊炎程度、甲周红肿程度、甲周脓肿程度、甲周皮肤色素沉着、甲床萎缩程度、甲板变薄或肥厚、甲板颜色异常、甲横纹、甲纵脊、甲翼状胬肉等。
在本申请中,术语“五官特征”通常是指能够反映五官疾病或病症的特征。例如,所述特征可以包括能够反映与施用所述抗肿瘤剂相关的五官疾病或病症的特征。例如,所述特征可以包括能够反映与施用抗肿瘤剂相关的口腔溃疡、与施用抗肿瘤剂相关的口干、与施用抗肿瘤剂相关的鼻衄、与施用抗肿瘤剂相关的鼻咽炎,和/或,与施用抗肿瘤剂相关的唇炎的特征。例如,所述特征可以包括口腔粘膜充血程度、口腔粘膜水肿程度、口腔黏膜疱疹程度、口腔黏膜溃疡程度、口腔粘膜下层腺周缺损程度、舌腺/舌下腺/腮腺等唾液腺体萎缩程度、口干程度、龋齿程度、舌肿胀程度、舌周齿痕程度、鼻血发生频率、鼻血量、口咽和鼻咽部黏膜水肿程度、口咽和鼻咽部黏膜疱疹程度、口咽和鼻咽部黏膜溃疡程度、口咽和鼻咽部黏膜增生程度、口咽及鼻咽部滤泡增生程度、唇及唇周肿胀程度、唇及唇周疱疹程度、唇及唇周红斑程度、唇及唇周皮肤脱屑程度、唇及唇周皮肤苔藓化程度和唇及唇周皮肤糜烂程度等。
在本申请中,术语“胃肠道特征”通常是指能够反映胃肠道疾病或病症的特征。例如,所述特征可以包括能够反映与施用所述抗肿瘤剂相关的胃肠道疾病或病症的特征。例如,所述特征可以包括能够反映与施用抗肿瘤剂相关的食管黏膜炎、与施用抗肿瘤剂相关的胃黏膜炎、与施用抗肿瘤剂相关的胃溃疡、与施用抗肿瘤剂相关的腹泻、与施用抗肿瘤剂相关的呕吐、 与施用抗肿瘤剂相关的恶心、与施用抗肿瘤剂相关的厌食、与施用抗肿瘤剂相关的便秘,和/或,与施用抗肿瘤剂相关的腹痛的特征。例如,所述特征可以包括食欲减退程度、胃脘嗳气程度、吞咽困难程度、胸骨后烧灼感程度、胸骨后疼痛程度、上腹部疼痛的时间(空腹或饱腹时)和程度、腹胀程度、腹泻程度、排便次数、排便时间、便前腹痛、里急后重、粪便异常(如黑血便、鲜血便、粘液便、粘液脓血便、稀水样便、蛋花汤样便等)、呕吐频次、呕吐物情况、呕血情况、恶心、营养不良程度、微量元素缺乏程度等。
在本申请中,术语“基本不含癌细胞的部位”通常是指受试者中癌细胞含量低至基本上被认为不含癌细胞的组织器官或部位。例如,所述基本上不含可以指所述癌细胞的数量占该部位的总细胞数量的0.01%以下,例如,0.005%以下,0.001%以下,0.0001%以下,0.00001%以下或更低。
在本申请中,术语“非癌症部位”通常是指受试者中非癌症病灶且非癌症转移区域的部位。例如,所述癌症病灶可以为癌症的原发部位。例如,所述癌症转移区域可以为与原发部位肿瘤类型相同的肿瘤的所在区域。例如,所述癌症转移区域可以经淋巴道转移、血管转移或种植性转移而形成。
在本申请中,术语“一(a)”和“一个(an)”和“所述(the)”和“至少一种”以及相似指示词的使用应理解为包括单数和复数。除非在本文中另有说明或者与上下文明显矛盾,当使用的术语”至少一种”后接一项或多项列举项(例如,“至少一种A和B”)时,应理解为表示选自所列项的一项(A或B)或者所列项中两项或多项的任意组合(A和B)。
在本申请中,除非另有注明,术语“包含”、“具有”、“包括”以及“含有”都应理解为开放性术语(即,意思是“包括,但不限于”)。然而,在本申请中,“包含”的表述应被理解为也记载了“由…组成”,“具有”或者“为”等封闭式表述。
本申请中,术语“EGFR”通常是指表皮生长因子受体(Epidermal Growth Factor Receptor),也称为ErbB1或HER1,其是由c-erbB1原癌基因编码的170kDa的跨膜糖蛋白。EGFR是受体酪氨酸激酶(RTK)的人表皮生长因子受体(HER)家族的成员,该家族还包括HER2(ErbB2)、HER3(ErbB3)和HER4(ErbB4)。EGFR信号通过配体结合引发,随后通过诱导受体与其他ErbB家族成员的构象变化、同二聚化或异二聚化、以及受体的反式自磷酸化等(参见,Ferguson等人,Annu Rev Biophys,37:353-73,2008),来启动信号转导级联,从而最终影响多种细胞功能(例如,细胞增殖和存活)。EGFR的表达或其激酶活性的增加与一系列人类癌症相关(参见,Mendelsohn等人,Oncogene 19:6550-6565,2000;GrUnwald等人,J Natl Cancer Inst 95:851-67,2003;Mendelsohn等人,Semin Oncol 33:369-85,2006)。已知在众多癌症, 如脑胶质瘤、乳腺癌、卵巢癌、子宫颈癌等中发现了EGFR的表达升高。
本申请中,术语“EGFR被抑制”包括任何原因导致的(例如,由治疗引起的或者由受试者自身身体状况造成的)EGFR活性、表达或者数量的降低。在一些实施方式中,EGFR被抑制通常是指EGFR的活性或者数量降低至少10%。在一些实施方式中,EGFR被抑制通常是指EGFR的活性或者数量降低至少20%、40%、50%、80%、90%、95%或更多。在一些实施方式中,所述的降低是与同类受试者(例如,同样的正常人或者同类型的患者)中的标准值相比较的。在一些实施方式中,所述的降低是与相同受试者一段时间之前的数值相比较的。
本申请中,术语“EGFR抑制剂”通常是指本领域中已知的或将来发现的任何EGFR抑制剂,包括任何当其被施用至受试者时,导致了受试者中与EGFR活性相关的生物活性的抑制(包括任何EGFR与其天然配体结合产生的下游生物效应的抑制)的任何物质。在一些实施方式中,EGFR抑制剂包括在治疗癌症过程中任何能够阻断EGFR活性或其任何下游生物效应的试剂。
本申请中,术语“小分子EGFR抑制剂”可以包括与EGFR可逆结合的小分子EGFR抑制剂(例如,吉非替尼、厄洛替尼、Sapitinib和埃克替尼),与EGFR不可逆结合的小分子EGFR抑制剂(例如,阿法替尼、Dacomitinib、拉帕替尼(Lapatinib,例如
Figure PCTCN2023071255-appb-000066
GW572016GlaxoSmithKline)、凡德替尼(Vandetanib,例如ZACTIMA TM,ZD6474)、乐伐替尼、卡奈替尼、伐利替尼和来那替尼)和/或特异性结合突变型EGFR的小分子EGFR抑制剂(例如,奥希替尼、那扎替尼、诺司替尼、奥木替尼(奥木替尼)、艾维替尼和EAI045)。
本申请中使用的术语“药学上可接受的”通常是指在合理的医学判断范围内适宜用于与人和动物的组织接触而无过度的毒性、刺激、过敏反应或者其他问题或并发症,具有合理的收益/风险比的那些化合物、材料、组合物和/或剂型。在一些实施方式中,药学上可接受的化合物、材料、组合物和/或剂型指由管理机构批准(如美国食品药品管理局、中国食品药品管理局或欧洲药品局)或者列于普遍认可的药典中(如美国药典、中国药典或欧洲药典)的用于动物(更特别地用于人)的那些。
发明详述
一方面,本申请提供了一种NO-NSAID化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面,本申请提供了一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的NO-NSAID化合物或其药学上可接受的盐。
另一方面,本申请提供了一种NO-NSAID化合物或其药学上可接受的盐,其用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面,本申请提供了一种药物组合,其包含:1)抗肿瘤剂;以及2)NO-NSAID化合物。
另一方面,本申请提供了NO释放剂和NSAID在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面,本申请提供了一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的NO释放剂和NSAID。
另一方面,本申请提供了一种药物组合,其包含:1)抗肿瘤剂;2)NO释放剂;以及3)NSAID。
NO-NSAID
在本申请的任一方面,所述NO-NSAID化合物可以包括一氧化氮(NO)释放部分和非甾体抗炎剂(NSAID)部分,且所述NO释放部分与所述非甾体抗炎剂部分之间可以共价直接连接或通过间隔基连接。
例如,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间可以通过可裂解连接子连接。在某些实施方式中,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间通过包含酯键和/或二硫键的连接子连接。
例如,在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间可以包含间隔基。在某些实施方式中,所述间隔基包含:一个或多个任选取代的-CH 2-,任选取代的苯基和/或它们的组合。例如,所述间隔基可以包含/可以是:一个或多个-CH 2-,一个或多个取代的-CH 2-,一个或多个苯基,一个或多个取代的苯基,或者它们的任意组合。
所述非甾体抗炎剂(NSAID)部分可包含环氧合酶(COX)抑制部分。所述(COX)抑制部分可包括与COX可逆结合的小分子COX抑制部分和/或与COX不可逆结合的小分子COX抑制部分。所述小分子COX抑制部分可以具有小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
在某些实施方式中,所述COX抑制部分包括能够减少所述COX表达的部分,和/或降低所述COX活性的部分。例如,所述COX抑制部分可直接作用于所述COX蛋白和/或编码所 述COX蛋白的核酸。例如,所述COX抑制部分能够抑制环氧合酶-1(COX-1)和/或环氧合酶-2(COX-2)。在某些实施方式中,所述COX抑制部分选择性抑制COX-2。在某些实施方式中,所述COX抑制部分能够非选择性地抑制COX-1和COX-2。
例如,所述COX抑制部分可包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:对乙酰氨基酚(acetaminophen),阿西美辛(acemetacin),醋氯,芬酸(aceclofenac),氨洛芬(alminoprofen),阿芬酸(arnfenac),bendazac,苯诺沙洛芬(benoxaprofen),溴芬酸(bromfenac),丁氯芬酸(bucloxic acid),布替布芬(butibufen),卡洛芬(carprofen),辛美辛(cinmetacin),氯吡酸(clopirac),双氯芬酸(diclofenac),依托度酸(etodolac),联苯乙酸(felbinac),芬氯苯丙酸(fenclozic acid),芬布芬(fenbufen),氟丁苯丙胺(fenoprofen),fentiazac,氟诺沙洛芬(flunoxaprofen),氟比洛芬(flurbiprofen),布芬酸(ibufenac),布洛芬(ibuprofen),吲哚美辛(indomethacin),异芬唑酸(isofezolac),isoxepac,吲哚洛芬(indoprofen),酮洛芬(ketoprofen),lonazolac,洛索洛芬(loxoprofen),甲嗪酸(metiazinic acid),莫非唑酸(mofezolac),米洛芬(miroprofen),萘普生(naproxen),恶丙嗪(oxaprozin),pirozolac,普拉洛芬(pranoprofen),普罗替尼酸(protizinic acid),水杨酰胺(salicylamide),sulindac,舒洛芬(suprofen),suxibuzone,噻洛芬酸(tiaprofenic acid),托美汀(tolmetin),xenbucin,西莫洛芬(ximoprofen),zaltoprofen,zomepirac,阿司匹林(aspirin),acemetcin,bumadizon,卡洛芬酸(carprofenac),clidanac,二氟尼柳(diflunisal),氟尼酸(enfenamic acid),芬多沙(fendosal),氟芬那酸(flufenamic acid),氟尼辛(flunixin),龙胆酸(gentisic acid),酮咯酸(ketorolac),甲氯芬那酸(meclofenamic acid),甲芬那酸(mefenamic acid)和美沙拉嗪(mesalamine)。
在某些实施方式中,所述COX抑制部分包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:萘普生(naproxen),阿司匹林(aspirin),双氯芬酸(diclofenac),酮洛芬(ketoprofen),氟比洛芬(flurbiprofen)和布洛芬(ibuprofen)。
根据本申请的任一方面,所述NO释放部分能够产生NO +、NO -、N 2O、NO、N 2O 3、NO 2、NO 3 -和NO 2 -之中的至少一种。例如,所述NO释放部分可直接或者间接产生NO。例如,所述NO释放部分可包括有机分子、无机分子和/或高分子或纳米材料。
在某些实施方式中,所述NO释放部分可包括选自下组的成分:硝酸甘油、单硝酸异山梨酯、丁二醇单硝酸酯、季戊四醇四硝酸酯、硝酸异山梨酯、三硝乙醇胺、尼可地尔、硝二羟甲丁醇、5-氨基-3-(4-吗啉基)-1,2,3-恶二唑、亚硝酸异戊酯、3,3-二(氨乙基)-1-羟基-2-羰基-1-三氮烯(NOC-18)、磺基亲核复合体二钠盐(Sulfo NONOate disodium salt)、S-亚硝基谷 胱甘肽(S-Nitrosoglutathione)、S-亚硝基-N-乙酰青霉胺(S-Nitroso-N-acetylpenicillamine)、4-苯基-3-呋腈(4-Phenyl-3-furoxancarbonitrile)、(±)-(E)-4-乙基-2-(E)-肟基-5-硝基-3-己酰胺((±)-(E)-4-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide)、链脲菌素(Streptozocin)、NG-羟基-L-精氨酸合乙酸(NG-Hydroxy-L-arginine acetate salt)、O 2-(2,4-二硝基苯基)1-[(4-乙氧基羰基)哌嗪-1-基]1,2-二醇二氮烯-1-鎓(O 2-(2,4-Dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate)、N-亚硝基二丁胺、3-吗啉-斯得酮亚胺(3-morpholinosydnonimine(SIN-1))、林西多明(Linsidomine)、吗多明(Molsidomine)、3-(4-乙酰苯基)悉尼酮(3-(4-acetylphenyl)sydnone)、二乙胺亲核复合体/AM(Diethylamine NONOate/AM)和Itramin。
例如,所述NO释放部分可包括选自下组的成分:硝酰配合物、亚硝酰配合物(Metal nitrosyl complex)、金属亚硝氨基络合物、硝酸盐和亚硝酸盐。
在某些实施方式中,所述NO释放部分包括选自下组的成分:S-亚硝基硫醇纳米硅球、S-亚硝基乙二硫醇甲壳素和寡聚丙二胺接枝壳聚糖NONOate。
在某些实施方式中,所述NO释放部分具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
例如,所述NO释放部分可具有下述的一个或多个基团:偶氮鎓二醇盐、羟基二氮烯磺酸、S-亚硝基硫醇、呋咱氮氧、肟、N-亚硝胺、N-羟基胍、硝酸盐、亚硝酸盐、硝酸酯、亚硝酸酯、斯得酮亚胺、斯得酮、恶三唑-5-亚胺、恶三唑-5-酮、羟胺、二氧二氮杂环丁烯、N-羟基亚硝胺、N-亚硝亚胺、羟基脲和金属亚硝氨基络合物。
在某些实施方式中,所述NO释放部分可包括-NO 2或-ONO 2
在某些实施方式中,所述NO-NSAID化合物还包含H 2S释放部分。例如,其可以是WO2013025790A2中记载的NO-NSAID化合物。
在某些实施方式中,所述NO-NSAID化合物包含式(1)所示的结构:
Figure PCTCN2023071255-appb-000067
其中:
Z为O或NH;R 1,R 2,R 3和R 4各自独立地为H,卤素,NO 2,N 3,C 1-C 10烷基,OR,OC(O)R,N(R) 2,NH-C(O)R,S(O)R或N═N-R,其中每个R各自独立地为C 1-C 10烷基或芳 香基;L 1包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m-O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;L 2包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m-O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;P和q各自独立地为0或1;X为所述H 2S释放部分或所述NO释放部分;Y为所述NO释放部分或所述H 2S释放部分,且所述Y与所述X不同时为所述NO释放部分且不同时为所述H 2S释放部分;所述NO释放部分为-C(O)-(CH 2) n-ONO 2或-(CH 2) n-ONO 2,其中n为1,2,3,4,5,6或7;且所述H 2S释放部分为:
Figure PCTCN2023071255-appb-000068
Figure PCTCN2023071255-appb-000069
例如,所述NO-NSAID化合物可以为US9688607B2中记载的NO-NSAID化合物。
例如,所述NO-NSAID化合物可以包含式(2)所示的结构:
Figure PCTCN2023071255-appb-000070
其中:
p和q各自独立地为0或1;L 1和L 2各自独立地包含选自下组的结构:-C(O)-,-(CH 2) m-,-(CH 2) m-O-,-(CH 2) m-C(O)-,-(CH 2) m-C(O)O-,-(CH 2) m-OC(O)O-,-C(O)-(CH 2) m-O-,-C(O)-(CH 2) m-C(O)-,-OC(O)-(CH 2) m-O-,-OC(O)-(CH 2) m-C(O)-和-OC(O)-(CH 2) m-C(O)O-,其中m为1,2,3,4,5,6或7;X为所述H 2S释放部分或所述NO释放部分;Y为所述NO释放部分或所述H 2S释放部分,且所述Y与所述X不同时为所述NO释放部分且不同时为所述H 2S释放部分;所述NO释放部分选自:-NO,-C(O)-(CH 2) n-ONO 2,-O-(CH 2) n-ONO 2,-(CH 2) n-ONO 2,-C(O)-CH 2-C(CH 3) 2-SNO,-NH-CH 2-C(CH 3) 2-SNO,-CH 2-C(CH 3) 2-SNO,
Figure PCTCN2023071255-appb-000071
Figure PCTCN2023071255-appb-000072
Figure PCTCN2023071255-appb-000073
其中n为1,2,3,4,5,6或7,
R a为H,C 1-C 10烷基,芳香基,S(O) 2-芳香基,CN或CON(R b) 2,且每个R b各自独立地为H或C 1-C 10烷基;且所述H 2S释放部分选自:
Figure PCTCN2023071255-appb-000074
Figure PCTCN2023071255-appb-000075
Figure PCTCN2023071255-appb-000076
Figure PCTCN2023071255-appb-000077
例如,所述NO-NSAID化合物可以为US10450260B2中记载的化合物。
在某些实施方式中,所述NO-NSAID化合物包含选自下组的结构:
Figure PCTCN2023071255-appb-000078
Figure PCTCN2023071255-appb-000079
其中,X为-(CH 2) n1-Z-(CH 2) n2-,n1和n2各自独立地为0,1,2,3,4或5;Z为O,N,S,C,
Figure PCTCN2023071255-appb-000080
A为O,N,S或C;且Y为
Figure PCTCN2023071255-appb-000081
在某些实施方式中,所述NO-NSAID化合物包含式(3)所示的结构:
M-X-Y-ONO 2(3),
其中M为选自下组的结构:
Figure PCTCN2023071255-appb-000082
其中R A为氢原子或-C(O)CH 3
Figure PCTCN2023071255-appb-000083
Figure PCTCN2023071255-appb-000084
Figure PCTCN2023071255-appb-000085
Figure PCTCN2023071255-appb-000086
X是-O-,-S-或-NR 1-,其中R 1是H或者是直链或支链的C 1-C 6烷基;
Y是具有如下定义的二价基团:
a)
-直链或支链的C 1-C 20亚烷基,其任选地被一个或多个选自下组的取代基取代:卤素,羟基,-ONO 2,-OC(O)(C 1-C 10烷基)-ONO 2和-O(C 1-C 10烷基)-ONO 2
-C 5-C 7亚环烷基,其任选地被直链或支链C 1-C 10烷基取代;
b)
Figure PCTCN2023071255-appb-000087
其中n为选自0-20的整数,n’为1-20的整数;
c)
Figure PCTCN2023071255-appb-000088
其中n为选自0-20的整数,n’为1-20的整数;
d)
Figure PCTCN2023071255-appb-000089
其中X 1为-OCO-或-COO-,并且R 2是H或CH 3,na是1-20的整数,n 2是0-2的整数;
e)
Figure PCTCN2023071255-appb-000090
其中Y 1是-CH 2-CH 2-(CH 2)n 2-,或-CH=CH-(CH 2)n 2-,X 1,na,n 2和R 2的定义同上;
f)
Figure PCTCN2023071255-appb-000091
其中na和R 2的定义同上,R 3是H或-COCH 3;或
g)
Figure PCTCN2023071255-appb-000092
其中X 2是-O-或-S-,n 3是1-6的整数,R 2的定义同上。
在某些实施方式中,所述NO-NSAID化合物包含式(3)所示的结构:M-X-Y-ONO 2(3),其中M选自以下结构:
Figure PCTCN2023071255-appb-000093
Figure PCTCN2023071255-appb-000094
Figure PCTCN2023071255-appb-000095
X是-O-;Y是直链或支链的C 1-C 10亚烷基。
例如,所述NO-NSAID化合物可包含式(4)所示的结构:A-(B) b0-(D) c0-NO 2(4)
其中:c0为0或1,b0为0或1,且c0与b0种至少有1个不为1;A为R-T 1-,其中R-T 1-是式R-T 1-OH的自由基或前体药物乙酰水杨酸,其中T 1=(CO),R是乙酰水杨酸的剩余基团;B为T B-X 2-T BI-,T B为X,T BI为(CO)或X,X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;X 2为选自以下的式H-X 2-H化合物的基团:羟基酸,没食子酸,阿魏酸,龙胆酸,柠檬酸,咖啡酸,对香豆酸和香草酸;D为二价基团:-T c-Y-,其中当b0为1时,T BI为X时T c为(CO),或者T BI为(CO)时T c为X,且X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;当b0为0时,T c=X,且X为O,S,N或NR 1C,R 1C为H或具有1至5个碳原子的直链或支链烷基;Y为Y p,Y O或Y Ar,Y p
Figure PCTCN2023071255-appb-000096
其中nIX为0-3中的整数,nIIX为1-3中的整数,R TIX,R TIX′,R TIIX和R TIIX′各自独立地为H或者线性或分支的C 1-C 4烷基,Y 3为含有一个或两个氮原子的饱和的,不饱和的或芳香杂环且具有6个原子;Y O选自下组:C 1-C 20线性或分支亚烷基氧基,
Figure PCTCN2023071255-appb-000097
其中nf′为1-6中的整数,且R 1f为H或CH 3,Y Ar
Figure PCTCN2023071255-appb-000098
其中n3为0-3中的整数,且n3’为1-3中的整数;且当b0为1时,c0为1且Y为Y O,或者当b0为0时,c0为1且Y为Y p或Y Ar。例如,所述NO-NSAID化合物可包含US7378437B2中加载的NO-NSAID化合物。
例如,所述NO-NSAID化合物可包含式(5)所示的结构:A-X 1-L-(W) p-NO 2(5)。其中:p为0或1;A为R-T 1,其中R为前药的残基并具有下式:
Figure PCTCN2023071255-appb-000099
其中s为0或1;R AI为H或CH 3;R 1为OCOR 3,NHCOR 3,OH,CH 2CH(CH 3) 2,苯基,苯甲酰基或4,6-二氯苯氨基,R 3为C 1-C 5线性或分支的残基;R 6为H或卤素;
或者,当R 1和R 6位于式(6)的芳香环上相邻的4位和5位时,形成式(7)的结构:
Figure PCTCN2023071255-appb-000100
或者,R具有下式的结构:
Figure PCTCN2023071255-appb-000101
T 1为(CO) t或(X) t′,其中X为O,S或NR 1c,R 1c为H或具有1-5个碳原子的直链或支链烷基,t和t’为0或1,当t’为0时t为1,且当t’为1时t为0;X 1为-T B-Y-T BI,其中T B与T BI可相同或不同,当t为0时T B为(CO),当t’为0时T B为X,X如上所述;T BI为(CO) tx或(X) txx,其中tx和txx为 0或1,当txx为0时tx为1,当txx为1时tx为0,X如上所述;Y是选自下述的二价连接基团:
Figure PCTCN2023071255-appb-000102
其中:nIX为0-3的整数,nIIX为1-3的整数,R TIX,R TIX′,R TIIX和R TIIX′各自独立地选自H和C 1-C 4直链或支链烷基;Y 3为具有5个或6个原子的饱和,不饱和或芳香杂环且含有1或2个氮原子;C 1-C 20直链或支链亚烷基,其任选地被选自下组的取代基取代:NHCOR 3,-NH 2和-OH,R 3为C 1-C 5线性或分支的残基;具有5-7个碳原子的亚环烷基,其任选地被C 1-C 20直链或支链亚烷基侧链取代,所述C 1-C 20直链或支链亚烷基任选地被选自下组的取代基取代:NHCOR 3,-NH 2和-OH,R 3为C 1-C 5线性或分支的残基,其中所述亚环烷基环中的1个或多个碳原子任选地被杂原子替代;
Figure PCTCN2023071255-appb-000103
其中n3为0-3的整数,且n3’为1-3的整数;
Figure PCTCN2023071255-appb-000104
(10),其中n3为0-3的整数,且n3’为1-3的整数;
Figure PCTCN2023071255-appb-000105
其中R 4为羟基,氢或R 5O,R 5为C 1-C 10直链或支链或环状烷基,R 2为C 2-C 10直链或支链的含有一个或多个双键的亚烯基;
Figure PCTCN2023071255-appb-000106
Figure PCTCN2023071255-appb-000107
Figure PCTCN2023071255-appb-000108
其中R 1f为H或CH 3,且nf为0-6的整数;L为共价键,CO或X,X如上所述;且W为Y TO,Y T与Y的含义相同,且式(5)的化合物中Y与Y T可相同或不同。例如,所述NO-NSAID化合物可包含US20040023933A1 中加载的NO-NSAID化合物。
例如,所述NO-NSAID化合物可包含式(5)所示的结构:A-X 1-L-(W) p-NO 2(5),其中:所述p为0或1,A为R-T 1-,其中R具有结构
Figure PCTCN2023071255-appb-000109
且T 1为(CO) t或(X) t′,t和t’为0或1,当t为1时t’为0,且当t为0时t’为1;X 1为-T B-Y-T B1-,其中T B和T B1相同或不同,当t为0时T B为(CO),当t’为0时T B为X;T B1为(CO) tx或(X) txx,其中tx和txx各自独立地为0或1,当txx为0时tx为1,且当txx为1时tx为0;X为O,S或NR 1C,R 1C为H或者具有1-5个碳原子的直链或支链烷基;Y选自
Figure PCTCN2023071255-appb-000110
Figure PCTCN2023071255-appb-000111
其中n3为0-3的整数,n3’为0-3的整数,R 4为羟基,氢或R 5O-烷氧基,其中R 5为C 1-C 10直链,支链或环状烷基,R 2为C 2-C 10直链或直链亚烯基且任选地包含一个或多个双键;L为共价键,CO或X,X为O,S或NR 1C,R 1C为H或者具有1-5个碳原子的直链或支链烷基;且W为Y TO,Y T选自
Figure PCTCN2023071255-appb-000112
其中n3为0-3的整数,n3’为0-3的整数,R 4为羟基,氢或R 5O-烷氧基,其中R 5为C 1-C 10直链,支链或环状烷基,R 2为C 2-C 10直链或直链亚烯基且任选地包含一个或多个双键。例如,所述NO-NSAID化合物可包含US7465803B2中加载的NO-NSAID化合物。
例如,所述NO-NSAID化合物可包含式(16)所示的结构:
Figure PCTCN2023071255-appb-000113
其中R m为H或低级烷基,R n为选自下组的结构:
Figure PCTCN2023071255-appb-000114
Figure PCTCN2023071255-appb-000115
s为0或1,X为-Y-(CR 4R 4’) o-C(R 4)(ONO 2)-(CR 4R 4’) q-(T) o-(W) q(T) o-(CR 4R 4’) o-R 5;,每个R 4和R 4’各自独立地为氢,低级烷基,-OH,-CH 2OH,-ONO 2,-NO 2或-CH 2ONO 2,或者R 4和R 4’与和它们相连的碳原子一起形成环烷基或杂环;W为共价键或羰基;每个T独立地为氧,(S(O) o) o或NR j;R j为氢,烷基,芳基,杂环,烷基羰基,烷基芳基,烷基亚磺酰基,烷基磺酰基,芳基亚磺酰基,芳基磺酰基,磺酰氨基,N-烷基磺酰氨基,N,N-二芳基磺酰胺基,N-芳基磺酰胺基,N-烷基-N-芳基磺酰胺基,甲酰胺基和/或羟基;每个q独立地为1,2或3;每个o独立地为0,1或2;Y为氧或硫;且R 5为氢,羟基,烷基,芳基,烷基磺酰基,芳基磺酰基,羧酸酯,烷基羰基,芳基羰基,甲酰胺基,烷氧基烷基,烷氧基芳基,环烷基和/或杂环。例如,所述NO-NSAID化合物可包含US8222277B2中加载的NO-NSAID化合物。
例如,所述NO-NSAID化合物可包含式(17)或式(18)所示的结构:
Figure PCTCN2023071255-appb-000116
Figure PCTCN2023071255-appb-000117
每个s各自独立地为1或2;k为1,2,3或4;每个m各自独立地为0,1,2,3或4;每个X各自独立地为O或S;Y为键,S,O或NR l,其中R l为氢或C 1-C 6烷基;R为氢或C 1-C 6烷基;所述Linker为连接子,其选自下组:1)-(CH 2) n,n为0,1,2,3或4;2)C 3-C 6环烷基,其任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基;3)芳基,所述芳基选自苯基和萘基,所述芳基任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO 2,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基;和4)杂芳基,所述杂芳基任选地被选自下组的基团取代:卤素,C 1-C 3烷基,C 1-C 3烷氧基,羟基,NO 2,CO 2,CF 3,CN,CH 2COOH,CH 2COO-C 1-3烷基和C 1-C 3硫代烷基。例如,所述NO-NSAID化合物可包含WO2004037798A1中加载的NO-NSAID化合物。
在某些实施方式中,所述NO-NSAID化合物包含式(19)所示的结构:
A-T-Y-ONO 2(19),其中:A为选自下组的药物:(A-OH或AH)的残基:非甾体抗炎药,镇痛药,退热药和COX-2抑制剂;T为-O-,-NH-,-S-,-CO-或-(CH 2) n1OCO-,其中n1是1至20的整数;A选自由以下组成的组:
Figure PCTCN2023071255-appb-000118
其中c和d各自独立地为0或1,R B选自:H,直链或支链C 1-C 12烷基和C 2-C 12烯基;当c为0,d为1时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000119
Figure PCTCN2023071255-appb-000120
R c选自下组:H,卤素,氨基,R ECONH-和-OCOR E,R D选自下组:H,OH,卤素,直链或支链C 1-C 4烷基,直链或支 链C 1-C 4烷氧基,三氟甲基,氨基和单-或二-(C 1-C 4)烷基氨基,R E选自H和直链或支链C 1-C 5烷基,e为0或1,M为C或N;当c为1,d为1,R B为氢时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000121
Figure PCTCN2023071255-appb-000122
其中R E1为H或CH 3,且R C1为Cl或F;
当c为1,d为1,R B为CH 3时,R A为选自下组的结构:
Figure PCTCN2023071255-appb-000123
Figure PCTCN2023071255-appb-000124
Figure PCTCN2023071255-appb-000125
当c为0,d为0,时,R A为选自 下组的结构:
Figure PCTCN2023071255-appb-000126
Figure PCTCN2023071255-appb-000127
Figure PCTCN2023071255-appb-000128
其中:R D如上所述,
R G为选自下组的结构:
Figure PCTCN2023071255-appb-000129
Figure PCTCN2023071255-appb-000130
其中R H为苯基或环己基;
Figure PCTCN2023071255-appb-000131
Y是具有以下含义的二价基团:
a)
-直链或支链C 1-C 20亚烷基;
-亚环烷基,该亚环烷基的环中有5至7个碳原子,该环任选地被侧链R 1取代,其中R 1为具有1至10个碳原子的直链或支链烷基;
b)
Figure PCTCN2023071255-appb-000132
其中n为0-20的整数,且n1为1-20的整数;
c)
Figure PCTCN2023071255-appb-000133
其中n为0-20的整数,且n1为1-20的整数;
d)
Figure PCTCN2023071255-appb-000134
n1为1-20的整数,且n2为0-2的整数,X 1为-OCO-或-COO-,且R 2为H或CH 3
e)
Figure PCTCN2023071255-appb-000135
其中n1,n2,R 2和X 1如上所述,Y 1为-CH 2-CH 2-或-CH=CH-(CH 2) n2-;
f)
Figure PCTCN2023071255-appb-000136
其中n1和R 2如上所述,R 3为H或COCH 3
g)
Figure PCTCN2023071255-appb-000137
其中X 2为-O-或-S-,n3为1-6的整数,R 2如上所述;
h)
Figure PCTCN2023071255-appb-000138
n4为0-10的整数,n5为1-10的整数,R 4,R 5,R 6,R 7各自独立地选自H以及直链或支链C 1-C 4烷基,且-ONO 2
Figure PCTCN2023071255-appb-000139
相连,n5如上所述,Y 2为5或6元饱和、不饱和或芳香环,且包含1个或多个选自下组的杂原子:氮、氧和硫。
在某些实施方式中,所述NO-NSAID化合物包含式(21)所示的结构:
Figure PCTCN2023071255-appb-000140
(21),其中X为连接子,M为选自下组的结构:
Figure PCTCN2023071255-appb-000141
Figure PCTCN2023071255-appb-000142
在某些实施方式中,所述NO-NSAID化合物包括选自下组的化合物:
Figure PCTCN2023071255-appb-000143
Figure PCTCN2023071255-appb-000144
在本申请所述的NO-NSAID化合物中,所述NO释放部分与所述NSAID部分的摩尔比可以为约10:1至约1:10。例如,所述NO释放部分与所述NSAID部分的摩尔比可以为约9:1至约1:1,约8:1至约1:1,约7:1至约1:1,约6:1至约1:1,约5:1至约1:1,约4:1至约1:1,约3:1至约1:1,约2:1至约1:1。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约1:1至约1:8,约1:1至约1:7,约1:1至约1:6,约1:1至约1:5,约1:1至约1:4,约1:1至约1:3,约1:1至约1:2。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约3:1。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约2:1。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约1:1。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约1:2。在某些实施方式中,所述NO释放部分与所述NSAID部分的摩尔比为约1:3。
抗肿瘤剂
根据本申请的任一方面,所述抗肿瘤剂可包括小分子化合物,小分子偶联物,蛋白质和/或多核苷酸。
例如,所述抗肿瘤剂可包括化疗剂,靶向治疗剂和/或免疫治疗剂。
在某些实施方式中,所述抗肿瘤剂为靶向治疗剂。所述靶向治疗剂可包括小分子化合物和/或抗体或其抗原结合片段。所述抗体可包括单克隆抗体,多特异性抗体,嵌合抗体,人源化抗体,全人源抗体和/或抗体药物偶联物。所述抗原结合片段可包括Fab,Fab’,F(ab )2,Fv片段,F(ab’) 2,scFv,di-scFv和/或dAb。
在某些实施方式中,所述靶向治疗剂靶向肿瘤细胞内部,肿瘤细胞表面和/或肿瘤微环境中的分子。例如,所述靶向治疗剂可靶向蛋白质和/或核酸分子。例如,所述靶向治疗剂可靶向肿瘤相关抗原。
在某些实施方式中,所述靶向治疗剂靶向选自下组的一个或多个靶标:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2, VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
例如,所述靶向治疗剂可抑制选自下组的一个或多个靶标的活性:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
例如,所述靶向治疗剂可降低选自下组的一个或多个靶标的表达:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
例如,所述靶向治疗剂可包括激素,信号转导抑制剂,基因表达调节剂,细胞凋亡诱导剂,血管生成抑制剂和/或毒素递送分子。
在某些实施方式中,所述靶向治疗剂为酪氨酸酶抑制剂。
在某些实施方式中,所述靶向治疗剂为VEGFR抑制剂和/或VEGF抑制剂。例如,所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。在某些实施方式中,所述靶向治疗剂为EGFR抑制剂。在某些实施方式中,所述靶向治疗剂为BRAF抑制剂。在某些实施方式中,所述靶向治疗剂为PDGFR抑制剂。在某些实施方式中,所述靶向治疗剂为FGFR抑制剂。在某些实施方式中,所述靶向治疗剂为mTOR抑制剂。在某些实施方式中,所述靶向治疗剂为HER2抑制剂。
例如,在本申请任一方面的实施方式中,所述EGFR(e.g.,Her2)抑制剂可选自下述化合物及其可药用盐:阿法替尼,奥木替尼,拉帕替尼,吉非替尼和达克替尼。
例如,在本申请任一方面的实施方式中,所述VEGFR抑制剂和/或VEGF抑制剂可选自下述化合物及其可药用盐:雷莫芦单抗,贝伐珠单抗,安罗替尼,瑞戈非尼,卡博替尼,乐伐替尼,索拉非尼,呋喹替尼,法米替尼,阿帕替尼,阿昔替尼和尼达尼布。
例如,在本申请任一方面的实施方式中,所述BRAF抑制剂可选自下述化合物及其可药用盐:威罗非尼,恩科拉非尼,司美替尼和达拉非尼。
例如,在本申请任一方面的实施方式中,所述PDGFR抑制剂可选自下述化合物及其可药用盐:舒尼替尼和尼达尼布。
例如,在本申请任一方面的实施方式中,所述FGFR抑制剂可选自下述化合物及其可药用盐:厄达替尼和英菲格拉替尼。
例如,在本申请任一方面的实施方式中,所述mTOR抑制剂可选自下述化合物及其可药用盐:依维莫司。
例如,本申请所述的靶向治疗剂可选自下组中的一种或多种:阿法替尼,达克替尼,奥希替尼,EAI045,吉非替尼,阿莫替尼,吡罗替尼,布加替尼,来那替尼,奥木替尼,博舒替尼,埃克替尼,凡德他尼,拉帕替尼,阿氟替尼,BPI-7711,莫波替尼,多维替尼,佐立替尼,瓦利替尼,奥布替尼,拉布替尼,布鲁替尼依鲁替尼,达沙替尼,pirtobrutinib,tolebrutinib,rilzabrutinib,fenebrutinib,evobrutinib,selumetinib,tivozanib,dovitinib,索凡替尼,binimetinib,cobimetinib,trametinib,瑞戈非尼,GSK-1120212,alpelisib,duvelisib,copanlisib,idelalisib,去甲替林,inavolisib,dactolisib,apitolisib,parsaclisib,buparlisib,rigosertib,enzastaurin,paxalisib,leniolisib,ipatasertib,zotarolimus,sirolimus,依维莫司,temsirolimus,索拉非尼,阿帕替尼,乐伐替尼,舒尼替尼,卡博替尼,阿昔替尼,尼达尼布,brivanib,vatalanib,呋喹替尼,达拉非尼,威罗非尼,恩科拉非尼,pazopanib,crizotinib,panobinostat,erlotinib,rituximab,panitumumab,cetuximab,erfonrilimab,efactinib,cadonilimab,ramucirumab,bevacizumab,安罗替尼,ponatinib,法米替尼,厄达替尼,AZD4547,英菲格拉替尼,BCD-217,amivantamab,MCLA-129,EMB-01,LY3164530,JNJ-61186372,抗EGFR及cMet双特异性抗体,GB263,它们的可药用盐以及它们的任意组合。其中,所述EGFR及cMet双特异性抗体可以如WO2010115551A1,WO2014081954A1,或WO2015016559A1所描述的。
根据本申请的任一方面,所述靶向治疗剂可与一种或多种其它疗法联合施用。
在某些实施方式中,所述抗肿瘤剂为化疗剂。例如,所述化疗剂可包括嘧啶核苷类似物和/或其前药。
在某些实施方式中,所述化疗剂包括选自下组中的一种或多种:卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
在某些实施方式中,所述化疗剂包括选自下组中的一种或多种:喃氟啶、5’-脱氧氟尿苷、 氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物、2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和3-脱氮杂尿苷。
例如,所述的化疗剂可与一种或多种其它疗法联合施用。在某些实施方式中,所述一种或多种其它疗法包括一种或多种其它本申请所述的抗肿瘤疗法(e.g.,抗肿瘤剂)。
例如,所述抗肿瘤剂(例如细胞毒抗癌剂)可以包括烷基化剂如氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替派、异硫氰酸酯、白消安、盐酸尼莫司汀、米托溴铵、美法仑、达卡巴嗪、雷莫司汀、丙米酚磷酸钠、亚乙基三胺、卡莫司汀、洛莫司汀、链脲佐菌素、哌泊溴烷(pipobroman)、依托格鲁(ethoglucid)、卡铂、顺铂、米铂、奈达铂、替奈特胺、奥莫司汀、二氯吡啶、氟匹司坦、泼尼匹昔汀、嘌嘧替派(pumitepa)、盐酸苯达莫司汀(Ribomustin)、替莫唑胺、双氯芬酸、曲伐沙星、津诺他汀、辛伐他汀、青霉烯素、半胱胺亚硝脲(cystemustine)和比折来新(bizelesin);抗代谢药物如巯嘌呤、6-巯基嘌呤核糖苷、硫代肌苷、甲氨蝶呤、培美曲塞、恩替西汀、阿糖胞苷、奥沙利铂、盐酸替沙巴汀、5-FU及其衍生物(例如,氟尿嘧啶、替加氟、UFT、多西葫芦、卡莫氟、卡培他滨等)、氨基喋呤、奈唑硫胺、甲酰四氢叶酸钙、小叶菌、叶酸钙、左派芬酸钙、克拉屈滨、埃米特福尔、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛(piritrexim)、碘尿苷、米托胍酮、噻唑呋喃、维马司他和苯达莫司汀;抗肿瘤抗生素如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、博来霉素盐酸盐、硫酸博莱霉素、盐酸西替霉素、盐酸柔比星、盐酸米托蒽醌和盐酸伊达比星;和/或,依托泊苷、依托泊甙磷酸盐、硫酸长春碱、硫酸长春新碱、替尼泊苷、紫杉醇、多西他赛和长春瑞滨等植物来源的细胞毒抗肿瘤剂物;VEGF抑制剂如贝伐珠单抗、以及在PCT专利申请WO 2005/012359、WO 2005/044853、WO 98/45332、WO 96/30046、WO 94/10202、美国专利US7,060,269、US6,582,959、US6,703,020、US6,054,297、美国专利申请US2006/009360、US2005/0186208、US2003/0206899、US2003/0190317、US2003/0203409和US2005/0112126中公开的那些VEGF抑制剂。
在某些实施方式中,所述抗肿瘤剂可以为免疫治疗抗肿瘤剂,其可以包括,例如:布比奈尼、克雷司汀、依托呋喃、香菇多糖、乌苯美辛、干扰素、白细胞介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、红细胞生成素、淋巴毒素、BCG疫苗、小棒状杆菌、依维莫司、左旋咪唑、多糖K、丙考达唑(procodazole)和/或免疫检查点抑制剂(例如,CTLA4抑制剂、TIM-3抑制剂、PD-1抑制剂(例如,Nivolumab(纳武单抗)、Pembrolizumab(派姆单抗)、Pidilizumab、AMP514(Amplimmune)、AMP-224、以及在PCT专利申请WO2006/121168、WO2009/114335、WO2009/101611、美国专利US 8609089、美国专利申请US2010/028330、 US2012/0114649中公开的其它PD-1抑制剂)、PD-L1抑制剂(例如,YW243.55.S70、MPDL3280A、MEDI-4736、MSB-0010718C、MDX-1105、以及在PCT专利申请WO2010/077634和美国专利US7,943,743中公开的其它PD-L1抑制剂))。
在某些实施方式中,所述抗肿瘤剂可以包括激素治疗抗肿瘤剂。例如,可以包括夫司他丁、己烯雌酚、氯代木香烯、醋酸甲羟孕酮、乙酸甲地孕酮、乙酸环丙孕酮、醋酸环丙孕酮、丹那唑、烯丙雌醇、孕酮、美帕曲星(mepartricin)、雷洛昔芬或美洛昔芬、左旋氧氟沙星、抗雌激素(例如,他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐等)、避孕药、前列环烷烷、睾酮内酯、氨基丁二酰亚胺、LH-RH激动剂(例如,醋酸戈舍瑞林、布舍瑞林、亮丙瑞林等)、屈洛昔芬、表雄甾烷醇、炔雌醇磺酸酯、盐酸呋苯唑、阿那曲唑、来曲唑、依西美坦、伏罗唑、抗雄激素(例如,氟他胺、比卡鲁胺、尼鲁他胺等)、5α-还原酶抑制剂(例如,非那雄胺、爱普列特(Epristeride))、皮质类固醇(例如,地塞米松、泼尼松龙、倍他米松、曲安奈德等)和/或雄激素合成抑制剂(例如,阿比特龙等)。
与抗肿瘤剂相关的疾病或病症
根据本申请的任一方面,与施用所述抗肿瘤剂相关的疾病或病症可以是由所述抗肿瘤单独引起的,也可以是由多种治疗方案引起的,但是其中包括所述抗肿瘤剂。
在某些实施方式中,所述疾病或病症是由施用所述抗肿瘤剂引起的。例如,所述疾病或病症可在施用所述抗肿瘤剂之后出现或加重。
在某些实施方式中,在施用所述抗肿瘤剂之前,所述受试者未患有所述疾病或病症。
例如,所述疾病或病症可包括上皮组织疾病或病症。所述上皮组织疾病或病症可包括与内皮细胞病变相关的疾病或病症,和/或与上皮细胞病变相关的疾病或病症。例如,所述上皮细胞可包括皮肤上皮细胞,口腔上皮细胞,鼻腔上皮细胞,胃上皮细胞和/或肠上皮细胞。
在某些实施方式中,所述内皮细胞包括血管内皮细胞。血管内皮细胞的病变可包括内皮功能障碍。例如,所述血管内皮细胞病变可以包括退行性变性血管疾病(例如,动脉粥样硬化、动脉中层硬化以及小动脉硬化(例如,透明变性型小动脉硬化和增生型小动脉硬化))、炎症性血管疾病(例如,感染性动脉炎、梅毒性动脉炎、巨细胞性动脉炎、血栓闭塞性脉管炎以及风湿性动脉炎)、功能性血管疾病(例如,雷诺氏病、手足发绀以及红斑肢痛症)和/或先天性血管疾病(例如,先天性动静脉瘘)等。
在本申请中,所述上皮细胞可包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。例如,所述上皮细胞病变可以包括皮肤上皮细胞病变(例如,皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、 黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干燥、超敏反应以及牛皮癣)、口腔上皮细胞病变(例如,天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞病变(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞病变(例如,胃炎、肠化生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞病变(例如,肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)等。
本申请的发明人发现,抗肿瘤剂会导致内皮细胞、内皮组织受损,从而引起皮肤组织、口腔组织、鼻腔组织和/或胃肠道组织的疾病或病症。在这些疾病或病症的发生及发展过程中,通常从内皮细胞、内皮组织的受损/病变开始发展病程,而上皮细胞也会有病变表现,并最终以与施用抗肿瘤剂相关的内皮细胞病变,和/或与施用抗肿瘤剂相关的上皮细胞病变的形式表现于患者。
例如,所述疾病或病症可包括皮肤疾病或病症,五官疾病或病症和/或胃肠道疾病或病症。
在某些实施方式中,所述皮肤疾病或病症包括脱发症,体臭,大疱性皮炎,皮肤干燥,湿疹,多形性红斑,红皮病,脂肪萎缩症,发色改变,毛发质地异常,多毛症(hirsutism),多汗症(hyperhidrosis),角化过度症,肥大症(hypertrichosis),少汗症(hypohidrosis),脂肥大,指甲改变,指甲变色,指甲丢失,指甲隆起,皮肤疼痛,手足综合征,光敏感性,瘙痒症,紫癜,痤疮样皮疹,斑丘疹,头皮疼痛,皮肤萎缩,皮肤色素沉着过多(skin hyperpigmentation),皮肤色素减退(skin hypopigmentation),皮肤硬结,皮肤溃疡,Stevens-Johnson综合征,皮下气肿,毛细血管扩张,中毒性表皮坏死,皮疹和/或荨麻疹。
在某些实施方式中,所述皮肤疾病或病症为手足综合征。
在某些实施方式中,本申请涉及使用所述NO-NSAID化合物来预防,缓解和/或治疗受试者中与施用所述抗肿瘤剂(例如,VEGFR抑制剂和/或VEGF抑制剂)相关的疾病或病症(例如,手足综合征)。
在某些实施方式中,本申请涉及使用所述NO-NSAID来预防,缓解和/或治疗受试者中与施用所述抗肿瘤剂(例如,EGFR抑制剂)相关的疾病或病症(例如,皮疹)。
在某些实施方式中,所述皮肤疾病或病症的严重程度为依据NCI-CTCAE中的第1级或其以上,第2级或其以上,第3级或其以上,第4级或其以上,或者第5级。
在某些实施方式中,所述受试者包括癌症患者。在某些实施方式中,所述皮肤疾病或病症的患处与癌症的患处不同。
在本申请中,所述与施用抗肿瘤剂相关的疾病或病症可以与抗肿瘤剂存在统计学上显著 的相关性。在某些实施方式中,所述与施用抗肿瘤剂相关的疾病或病症可以是由抗肿瘤剂引起的。例如,所述与施用抗肿瘤剂相关的疾病或病症可包括与施用抗肿瘤剂相关的皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症。例如,所述与施用抗肿瘤剂相关的皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症可以包括所述皮肤组织、五官和/或胃肠道中与施用抗肿瘤剂相关的上皮组织疾病或病症。在某些实施方式中,所述与施用抗肿瘤剂相关的疾病或病症可包括因施用抗肿瘤剂而引起的副作用或不良反应。
在本申请中,所述与施用抗肿瘤剂相关的疾病或病症可以为一种新的适应症,其可以不同于以往的任意一种其他的疾病或病症。例如,所述与施用抗肿瘤剂相关的疾病或病症的诊断方式、治疗方式和/或症状均是独特的。例如,红霉素软膏可以治疗皮疹,但是对与施用抗肿瘤剂相关的皮疹没有治疗作用。
在某些实施方式中,所述与施用抗肿瘤剂相关的疾病或病症可以包括与施用抗肿瘤剂相关的皮疹、与施用抗肿瘤剂相关的手足综合征、与施用抗肿瘤剂相关的瘙痒、与施用抗肿瘤剂相关的红斑、与施用抗肿瘤剂相关的皮肤干燥、与施用抗肿瘤剂相关的脱发、与施用抗肿瘤剂相关的甲沟炎、与施用抗肿瘤剂相关的色素沉积紊乱、与施用抗肿瘤剂相关的口腔溃疡、与施用抗肿瘤剂相关的口干、与施用抗肿瘤剂相关的鼻衄、与施用抗肿瘤剂相关的鼻咽炎、与施用抗肿瘤剂相关的唇炎、与施用抗肿瘤剂相关的食管黏膜炎、与施用抗肿瘤剂相关的胃黏膜炎、与施用抗肿瘤剂相关的胃溃疡、与施用抗肿瘤剂相关的腹泻、与施用抗肿瘤剂相关的呕吐、与施用抗肿瘤剂相关的恶心、与施用抗肿瘤剂相关的厌食、与施用抗肿瘤剂相关的便秘,和/或,与施用抗肿瘤剂相关的腹痛。例如,所述与施用抗肿瘤剂相关的疾病或病症包括与施用抗肿瘤剂相关的手足综合征。例如,所述与施用抗肿瘤剂相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上,和/或第5级。
在某些实施方式中,所述疾病或病症可以包括皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱、口腔溃疡、口干、鼻衄、鼻咽炎、唇炎、食管黏膜炎、胃黏膜炎、胃溃疡、腹泻、呕吐、恶心、厌食、便秘和/或腹痛。例如,所述疾病或病症包括手足综合征。
在某些实施方式中,所述与抗肿瘤剂相关的疾病或病症基本上无法通过施用选自下组的药剂而被治疗或缓解:1%西地那非、尿素霜、凡士林软膏、尿素软膏、溴莫尼定软膏、维生素B6软膏、尼古丁软膏、地塞米松软膏、氢化可的松软膏、维生素K1软膏(0.1%)、红霉素软膏和曲安奈德软膏。
在本申请中,所述疾病或病症的严重程度可以在所述施用抗肿瘤剂之后增加。例如,所述疾病或病症的严重程度可以增加约5%或以上,约10%或以上,约15%或以上,约20%或以上,约25%或以上,约30%或以上,约35%或以上,约40%或以上,约45%或以上,约50%或以上,约60%或以上,约70%或以上,约80%或以上,约90%或以上,约100%或以上,约200%或以上或更多。
在本申请中,在所述施用抗肿瘤剂之前,所述受试者可以未患有所述疾病或病症。在本申请中,术语“所述受试者未患有所述疾病或病症”通常是指受试者没有涉及所述与施用抗肿瘤剂相关的疾病或病症的既往病史。例如,在所述施用抗肿瘤剂之前1天以上、1周以上、1个月以上、1年以上、10年以上或所述受试者出生以来,未患有本申请所述与施用抗肿瘤剂相关的疾病或病症。
药物组合及药物组合物
根据本申请的任何方面,所述药物基本上不影响所述抗肿瘤剂的治疗效果。
在本申请中,所述“基本上不影响”可以指,与单独使用所述抗肿瘤剂的治疗效果相比,使用所述NO-NSAID化合物和所述抗肿瘤剂的治疗效果相当,或者不产生显著的劣势。例如,对任意的受试者,与单独使用所述抗肿瘤剂的治疗效果相比,使用所述NO-NSAID化合物和所述抗肿瘤剂所导致的肿瘤体积减少的程度是相同的,或者,减少的程度不小于约5%、不小于约4%、不小于约3%、不小于约2%、不小于约1%、不小于约0.5%、不小于约0.1%、不小于约0.01%、不小于约0.001%或更小。
在某些实施方式中,所述药物或所述NO-NSAID化合物被制备为适用于局部给药。例如,所述药物或所述NO-NSAID化合物可被制备为适用于透皮给药。在一些实施方式中,所述药物或所述NO-NSAID化合物被制备为用于局部皮肤施用。在某些实施方式中,所述药物被制备为乳膏,洗液,凝胶,软膏,油膏,喷剂,脂质体制剂,擦剂和/或气雾剂。在某些实施方式中,所述药物或所述NO-NSAID化合物可以被制备为软膏剂。
在一些实施方式中,所述药物或所述NO-NSAID化合物为口服制剂。在一些实施方式中,所述药物或所述NO-NSAID化合物可以为注射制剂。在一些实施方式中,所述药物或所述NO-NSAID化合物可以用于口腔局部施用。
在某些实施方式中,所述药物的给药部位和所述抗肿瘤剂的给药部位不同。在某些实施方式中,所述药物的给药部位不为癌症的发生部位或癌症的潜在转移部位。
在某些实施方式中,所述药物的给药方式和所述抗肿瘤剂的给药方式不同。
在所述药物中,所述NO-NSAID化合物的浓度可以为约0.0001%至约50%。例如,所述NO-NSAID化合物的浓度可以为约0.0001%(w/w)至约40%(w/w),例如,可以在约0.0001%(w/w)至约10%(w/w)、约0.0001%(w/w)至约9.5%(w/w)、约0.0001%(w/w)至约9%(w/w)、约0.0001%(w/w)至约8.5%(w/w)、约0.0001%(w/w)至约8%(w/w)、约0.0001%(w/w)至约7.5%(w/w)、约0.0001%(w/w)至约7%(w/w)、约0.0001%(w/w)至约6.5%(w/w)、约0.0001%(w/w)至约6%(w/w)、约0.0001%(w/w)至约5.5%(w/w)、约0.0001%(w/w)至约5%(w/w)、约0.0001%(w/w)至约4.5%(w/w)、约0.0001%(w/w)至约4%(w/w)、约0.0001%(w/w)至约3.5%(w/w)、约0.0001%(w/w)至约3%(w/w)、约0.0001%(w/w)至约2.5%(w/w)、约0.0001%(w/w)至约2%(w/w)、约0.0001%(w/w)至约1.5%(w/w)、约0.0001%(w/w)至约1%(w/w)、约0.0001%(w/w)至约0.5%(w/w)、约0.0001%(w/w)至约0.01%(w/w)或更小的范围内变动。在本申请的所述药物中,所述NO-NSAID化合物的浓度可以为约0.0001%(w/w)至约1%(w/w)、约0.0001%(w/w)至约0.9%(w/w)、约0.0001%(w/w)至约0.6%(w/w)、约0.05%(w/w)至约0.5%(w/w)、约0.05%(w/w)至约0.4%(w/w)、约0.05%(w/w)至约0.3%(w/w)、约0.05%(w/w)至约0.2%(w/w)、约0.1%(w/w)至约0.2%(w/w)或更小的范围内变动。例如,所述NO-NSAID化合物的浓度可以为约0.5%至约10%。在某些实施方式中,所述NO-NSAID化合物的浓度为约5%(w/w)。在某些实施方式中,所述NO-NSAID化合物的浓度为约2.5%(w/w)。在某些实施方式中,所述NO-NSAID化合物的浓度为约1%(w/w)。
在本申请中,所述药物中还可以包括一种或多种其他活性成分。例如,所述活性成分可以指具有医疗效用或者生理活性的单体化合物。例如,所述其他活性成分可以选自下组:抗炎剂、止痛剂、局部麻醉剂、抗生素、抗组胺剂、防腐剂、免疫抑制剂和抗出血剂。
在本申请中,所述药物还可以包括药学上可接受的载体。例如,所述药学上可接受的载体可以选自下组:填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂和乳化剂。
在本申请的药物组合和/或试剂盒中,在某些实施方式中,所述抗肿瘤剂与所述NO-NSAID化合物彼此不混合。
在某些实施方式中,所述抗肿瘤剂与所述NO-NSAID化合物各自独立地存在于单独的容器中。例如,所述药物组合中可以包括2种或更多种彼此独立包装的药物,其中至少一种所述药物包含本申请所述的抗肿瘤剂,且其中至少一种另外的药物包含本申请所述的NO-NSAID化合物。
在某些实施方式中,在所述药物组合中,其中2)中的所述NO-NSAID化合物能够预防,缓解和/或治疗与1)中的所述抗肿瘤剂相关的疾病或病症。
在某些实施方式中,2)中的所述NO-NSAID化合物基本上不影响1)中的所述抗肿瘤剂的治疗效果。
在某些实施方式中,在本申请的药物组合中,在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的所述NO-NSAID化合物。
预防和/或治疗方法
在本申请中,所述受试者可以包括人或非人动物。例如,所述非人动物可以选自下组:猴、鸡、鹅、猫、狗、小鼠和大鼠。此外,非人动物也可以包括任何除人以外的动物物种,例如家畜动物,或啮齿类动物,或灵长类动物,或家养动物,或家禽动物。所述人可以是高加索人、非洲人、亚洲人、闪族人,或其他种族,或各种种族的杂合体。又例如,所述人可以是老年、成年、青少年、儿童或者婴儿。
可以根据在实验动物中的有效量推测在人类中的有效量。例如,Freireich等人描述了动物和人的剂量的相互关系(基于每平方米身体表面的毫克数)(Freireich et al.,Cancer Chemother.Rep.50,219(1966))。身体表面积可以从患者的身高和体重近似确定。参见例如Scientific Tables,Geigy Pharmaceuticals,Ardsley,N.Y.,537(1970)。
在本申请的所述方法中,所述抗肿瘤剂可以由向所述受试者施用抗肿瘤剂引起。
例如,可以在向所述受试者施用所述抗肿瘤剂之前、同时或者之后施用所述NO-NSAID化合物。当本申请所述的抗肿瘤剂与所述NO-NSAID化合物同时施用时,所述NO-NSAID化合物以相对于总剂量约0.0001-10%(例如约0.005-10%、约0.01-10%、约0.05-10%、约0.1-10%、约0.2-10%、约0.3-10%、约0.4-10%、约0.5-10%、约0.6-10%、约0.7-10%、约0.8-10%、约0.9-10%、约0.95-10%、约1-10%、约2-10%、约3-10%、约5-10%、约6-10%、约8-10%或更小范围)的剂量水平施用。在所述NO-NSAID化合物与所述抗肿瘤剂间隔给药的实施方式中,所述NO-NSAID化合物可以在施用所述抗肿瘤剂之前或之后间隔给药。所述间隔的时间可以为1分钟、2分钟、5分钟、10分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、18小时、1天、2天、3天、1周、2周、3周、1个月、2个月、3个月或更长。
本申请还提供一种方法,其包括向受试者施用NO-NSAID化合物,其中所述受试者曾经、正在和/或将来被施用抗肿瘤剂且患有或易患有与施用抗肿瘤剂相关的疾病或病症。
本申请还提供一种用于预防或治疗疾病或病症的方法,包括向易患有或患有所述疾病或 病症的受试者施用NO-NSAID化合物,其中所述受试者曾经、正在和/或将来被施用抗肿瘤剂。
在本申请中,所述受试者可以已经患有与施用抗肿瘤剂相关的疾病或病症,或者,所述受试者可具备较大概率患有与施用抗肿瘤剂相关的疾病或病症。
本申请还提供一种方法,其包括下述步骤:1)监测被施用抗肿瘤剂的受试者的一种或多种副作用,例如皮肤组织、五官和/或胃肠道特征;2)当所述监测显示所述受试者出现与施用所述抗肿瘤剂相关的副作用,例如皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症时,向所述受试者施用NO-NSAID化合物。
在本申请中,所述方法还可包括继续监控所述皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症,以及任选地减少或停用所述抗肿瘤剂。例如,所述继续监控可以指在施用所述抗肿瘤剂之后约至少1天、至少1周、至少10天、至少2周、至少3周、至少1个月、至少3个月或更长时间进行监控。例如,所述减少或停用可以指向所述受试者施用所述抗肿瘤剂的剂量较所述方法步骤1)中所述抗肿瘤剂的剂量相比,减少约至少5%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少99%或100%。
在本申请中,所述与施用抗肿瘤剂相关的疾病或病症的严重程度可以在所述施用抗肿瘤剂之后增加。例如,所述严重程度可以为增加至少5%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或更多。
在本申请中,在所述施用抗肿瘤剂之前,所述受试者可以未患有所述疾病或病症。
在本申请中,可以向所述受试者局部施用所述NO-NSAID化合物。例如,可以向所述受试者中基本不含癌细胞的部位局部施用所述NO-NSAID化合物。又例如,可以向所述受试者中的非癌症部位施用所述NO-NSAID化合物。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的NO-NSAID化合物,制备方法和用途等,而不用于限制本申请发明的范围。
实施例
NO-NSAID化合物列表
在以下实施例中,所使用的本申请的NO-NSAID化合物如表2-1所示:
Figure PCTCN2023071255-appb-000145
Figure PCTCN2023071255-appb-000146
Figure PCTCN2023071255-appb-000147
表2-1
NO-NSAID能够在体内预防/治疗抗肿瘤剂引起的手足综合征
构建大鼠动物模型,通过每日灌胃的方式向8周雌性的SD大鼠分别施用表2-2中所示的抗肿瘤剂,若干天后,大鼠的爪子出现手足综合征症状(如图1所示)。与在人体上类似,大鼠在服用所述抗肿瘤剂之后会出现手足综合征症状,且症状非常相似。因此,大鼠是很好的用于模拟抗肿瘤剂引起的副作用(例如手足综合征)的动物模型。
将所述大鼠(约200g)饲养适应一周后,将其分为NO-NSAID组和对照组,每组10只,进行灌胃给药试验。将各种抗肿瘤剂溶解在蓖麻油:乙醇=1:1的混合溶液中,灌胃前用PBS将所述抗肿瘤剂药物溶液稀释至所需浓度(用PBS溶液稀释约3倍),每次灌胃量不超过2mL,给药剂量如表2-2所示。灌胃后,对大鼠后爪涂抹包含NO-NSAID的药膏,同时对照组涂空白制剂,涂药后将大鼠置于固定筒内固定4小时,4小时后放出大鼠,并用清水擦去涂药部位残留药物,放鼠回笼。抑制剂的灌胃频率如表2-2所示,NO-NSAID每天只涂药一次。每日重复灌胃和涂抹操作,直到试验结束。统计涂药15-18天后,将涂药组保持正常或明显轻于空白对照组手足综合征的大鼠只数统计为有效抑制手足综合征大鼠的只数。
表2-2列出了各抗肿瘤剂和NO-NSAID药膏的动物实验组合,以及相应的实验结果(其中,控制率栏的数值=空白组手足综合征出模率-涂药组手足综合征出模率)。
表2-2实施例1-14的实验条件和实验结果
Figure PCTCN2023071255-appb-000148
Figure PCTCN2023071255-appb-000149
Figure PCTCN2023071255-appb-000150
Figure PCTCN2023071255-appb-000151
Figure PCTCN2023071255-appb-000152
从表2-2的结果可以看出:所述NO-NSAID软膏能够有效地防治抗肿瘤剂引起的手足综合征。同时,图2的结果也表明所述NO-NSAID能够有效地防治抗肿瘤剂引起的手足综合征。实验结束后,对不同组别大鼠的爪子取材,对不同组进行组织学观察(图3),结果发现,本申请的NO-NSAID能够有效缓解抗肿瘤剂引起手足综合征,改善毛细血管,减轻角质形成细胞坏死、表皮分离、炎症等现象。此外,在本申请的NO-NSAID化合物中,当NSAID与NO的摩尔比为约1:1时,对与施用抗肿瘤剂相关的手足综合征的控制率更优。
NO-NSAID能够在体内预防/治疗蛋白质大分子抑制剂引起的手足综合征
将雷莫芦单抗(Ramucirumab)或贝伐珠单抗(Bevacizumab)用生理盐水稀释至所需浓度。将所述大鼠(约200g)饲养适应一周后,将其分组,每组10只,进行注射给药试验。静脉输注稀释后的雷莫芦单抗,输注60分钟,施用剂量为40mg/kg,每周施用1次,同时联用紫杉醇(10mg/kg)。实验组涂抹NO-NSAID药膏,对照组涂抹空白制剂,具体操作同上,实验持续2-4周,观察实验现象。
表3列出了施用各大分子抗肿瘤剂和NO-NSAID药膏的动物实验,以及相应的实验结果(其中,控制率栏的数值=空白组手足综合征出模率-涂药组手足综合征出模率)。
表3实施例15-16的实验条件和实验结果
Figure PCTCN2023071255-appb-000153
Figure PCTCN2023071255-appb-000154
由以上实验结果可知,本申请的NO-NSAID药膏对大分子抗肿瘤剂引起的手足综合征具有一定的预防作用。
NO-NSAID软膏缓解抗肿瘤剂引起的手足综合征的疼痛
在进行上述预防给药试验(涉及预防部分的实施例1-14)的实验一段时间后,对大鼠进行疼痛分析,疼痛评估模型为大鼠的机械敏感性(von Frey);实验步骤如下:首先让大鼠在房间内适应1小时,然后将大鼠放入带有金属网地板的观察箱中,让小鼠在箱中待20分钟,以适应实验平台的环境。然后用von Frey设备来检测爪子的疼痛情况,用特制的纤毛刺激大鼠掌心表面,以检测动物的机械敏感性,其力度为0.4克、0.8克、1.5克、2.5克、4克、8克、10克和20克(IITC Life Science,Woodland Hills,2390系列)。在被施以特定的压力后,大鼠立即抽出爪子或舔舐被定义为有反应,而在6秒内没有撤回爪子被定义为无反应。大鼠移动反应被认为是一种模糊的反应,在这种情况下会重复刺激实验。
结果如图4-图10所示,可见NO-NSAID对抗肿瘤剂引起的手足综合征的疼痛具有明显的缓解作用。
NO-NSAID软膏能够治疗抗肿瘤剂引起的手足综合征
将所述大鼠(约200g)饲养适应一周后,将大鼠分成每组10只,进行灌胃给药试验。将抗肿瘤剂溶解在蓖麻油:乙醇=1:1的混合溶液中,灌胃前用PBS稀释至所需浓度(用PBS溶液稀释约3倍),灌胃量不超过2mL,给药剂量如表4所示。每天持续灌胃抗肿瘤剂,直至大鼠出现手足综合征,此时开始对大鼠进行治疗实验。具体实验操作见预防试验。涂药5-13天后,将涂药恢复正常或明显轻于涂药前的大鼠只数统计为有效治疗手足综合征大鼠的只数。
表4列出了施用各抗肿瘤剂和NO-NSAID药膏的动物实验,以及相应的实验结果(其中,控制率栏的数值=空白组手足综合征出模率-涂药组手足综合征出模率)。
表4实施例17-26的实验条件和实验结果
Figure PCTCN2023071255-appb-000155
Figure PCTCN2023071255-appb-000156
从结果可以看出,本申请的NO-NSAID可以治抗肿瘤剂引起的手足综合征。此外,对部分实验组的疼痛缓解情况进行评估,如图11所示,结果表明NO-NSAID软膏在治疗抗肿瘤剂引起手足综合征的同时,对疼痛也有一定的缓解。
NO-NSAID药膏能够在大鼠模型上预防/治疗化疗药物引起的手足综合征
构建大鼠动物模型。通过每日灌胃的方式给予6周雌性SD大鼠化疗药(给药剂量及药物,见表5),若干天后,大鼠的爪部出现手足综合征。
SD大鼠饲养适应一周(约200g)后,将大鼠分成每组10只,然后进行灌胃给药试验。化疗药溶解,每只鼠灌胃量1mL/100g,给药剂量如表5所示。灌胃后,用固定筒将大鼠固定,对涂药组大鼠的爪子涂NO-NSAID药膏,空白组涂抹空白药膏(做空白对照)。每日重复灌胃和涂抹试验,直到空白组出现明显的手足综合征,此时将涂药组爪部皮肤保持正常或症状明显轻于空白组手足综合征的大鼠只数计算为有效抑制手足综合征大鼠的只数。
表5列出了化疗药和NO-NSAID药膏的动物实验组合,以及相应的实验结果(其中,控制率栏的数值=空白组手足综合征出模率-涂药组手足综合征出模率)。
表5实施例27-30的实验条件和实验结果
Figure PCTCN2023071255-appb-000157
Figure PCTCN2023071255-appb-000158
从以上结果可以看出,本申请的NO-NSAID药膏对化疗药引起的手足综合征也有一定的预防作用,同时对疼痛及炎症有明显的缓解(图12)。
在预防抗肿瘤剂产生手足综合征的实验中,不同机制化合物实验结果对比
将大鼠(约200g)饲养适应一周后,将大鼠分成每组10只,然后进行灌胃给药试验。抗肿瘤剂(以索拉非尼为建模的抗肿瘤剂)溶解在蓖麻油:乙醇=1:1的混合溶液中,灌胃前用PBS稀释至所需浓度(用PBS溶液稀释约3倍),每次灌胃量不超过2mL,给药剂量如表6所示。灌胃后,对大鼠后爪涂抹不同机制药膏(NO释放剂组、NO释放剂与临床药物联用组、NSAID组)的药膏,同时对照组涂空白制剂,涂药后将大鼠置于固定筒内固定4小时,4小时后放出大鼠,并用清水擦去涂药部位残留药物,放鼠回笼。抑制剂的灌胃频率如表6所示,不同实验组每天只涂药一次。每日重复灌胃和涂抹操作,直到试验结束。统计涂药15-18天后,将涂药组保持正常或明显轻于空白对照组手足综合征的大鼠只数统计为有效抑制手足综合征大鼠的只数。
表6列出了各抗肿瘤剂和不同实验组药膏的动物实验组合,以及相应的实验结果(其中,控制率栏的数值=空白组手足综合征出模率-涂药组手足综合征出模率)。
Figure PCTCN2023071255-appb-000159
Figure PCTCN2023071255-appb-000160
从以上结果可以看出,NSAID软膏对抗肿瘤剂引起的手足综合征基本无效或有效率很低,且在缓解的大鼠中,症状缓解较轻;从硝酸甘油和临床药物联用的结果看,NO释放剂与临床其他药物机制联用,相较于硝酸甘油对手足综合征的效果并没有明显的改善。
在疼痛评分上可以看出,NO-NSAID同浓度与NSAID比较,疼痛缓解更为明显;同时,相较硝酸甘油+其他药物机制联用,NO-NSAID缓解疼痛效果更加明显。
NO-NSAID缓解抗肿瘤剂对HUVEC细胞增殖毒性的效果
消化悬浮经培养的HUVEC细胞,对细胞进行计数,并接种到96孔板中,每孔种植5000-10000个细胞。将各孔分成:空白对照组、抗肿瘤剂组、抗肿瘤剂+NO-NSAID组、抗肿瘤剂溶剂组、NO-NSAID对照组,各组的每个孔中均含有基础培养基,每个孔最终含有的液体体积约为100μL。具体分组情况如下:
1)空白对照组:除正常更换培养基以外不额外加入任何溶液;
2)抗肿瘤剂组:加入抗肿瘤剂溶液(最终浓度如表7-1和表7-2所示,抗肿瘤剂溶液的溶剂为DMSO);
3)抗肿瘤剂+NO-NSAID组:加入抗肿瘤剂溶液以及NO-NSAID溶液(抗肿瘤剂和NO-NSAID的最终浓度如表7-1和表7-2所示,并根据NO-NSAID的溶解性,选择NO-NSAID溶液的溶剂为乙醇或无菌水,各分组的总体积细微差异通过加入所选择的相应溶剂补齐);
4)抗肿瘤剂溶剂组:加入与组2)中对应所述抗肿瘤剂溶液中所含有的、等体积的DMSO;
5)NO-NSAID对照组:加入与组3)中对应所述NO-NSAID所含有的、同体积同种类的溶剂(例如,乙醇或无菌水)。
抗肿瘤剂溶剂组不参与数据处理,仅作为评价实验系统误差的参考。NO-NSAID溶剂对照组用于数据校正,从而排除溶剂对结果的影响。
继续培养24-48小时后,使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037,上海碧云天生物科技有限公司,Beyotime Biotechnology)测定细胞的存活率,从而计算抗肿瘤剂对细胞的增殖毒性以及NO-NSAID对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检 验对结果进行统计分析和画图。
表7-1和表7-2列出了各种抗肿瘤剂和NO-NSAID的组合,以及相应的实验结果(其中,细胞存活率栏的数据标识是与抗肿瘤剂相比,相应的抗肿瘤剂和NO-NSAID组所增加的存活细胞的百分比)。图14-图21分别表示向HUVEC细胞给予抗肿瘤剂和NO-NSAID的24小时后,通过CCK-8法测定的细胞增殖毒性的示例性结果。其中,横坐标表示不同的实验组和对照组;纵坐标表示细胞的存活率(以空白对照组的细胞存活率为100%计算其他实验组或溶剂对照组中细胞的存活百分率)。*表示P<0.05,与相应的抗肿瘤剂单独给药组相比具有显著差异;利用t-test统计检验。
表7-1实施例32-的实验条件和实验结果
Figure PCTCN2023071255-appb-000161
Figure PCTCN2023071255-appb-000162
Figure PCTCN2023071255-appb-000163
Figure PCTCN2023071255-appb-000164
Figure PCTCN2023071255-appb-000165
Figure PCTCN2023071255-appb-000166
Figure PCTCN2023071255-appb-000167
Figure PCTCN2023071255-appb-000168
Figure PCTCN2023071255-appb-000169
从以上结果和图14-16的结果可以看出,抗肿瘤剂对HUVEC细胞具有一定的毒性,而加入NO-NSAID后,细胞存活率增加,说明NO-NSAID对抗肿瘤剂引起的增殖毒性有明显的缓解作用。
表7-2不同NO-NSAID化合物浓度对抗肿瘤剂缓解率
Figure PCTCN2023071255-appb-000170
Figure PCTCN2023071255-appb-000171
Figure PCTCN2023071255-appb-000172
从表7-2和图17-图21的结果可知,相同的NO-NSAID在不同浓度下,均能够不同程度上缓解抗肿瘤剂对HUVEC细胞的增殖毒性。
NO-NSAID缓解抗肿瘤剂对人永生化表皮细胞(HaCaT)、人口腔黏膜上皮角质细胞(HOK)、人小肠上皮细胞(FHs 74Int)、胃上皮细胞(GES-1)的细胞增殖毒性的效果
培养多种上皮细胞用于实验,其中:实施例47-51使用人永生化表皮细胞(HaCaT),结果对应表8-1;实施例52-56使用人口腔黏膜上皮角质细胞(HOK),结果对应表8-2;实施例57-61使用胃上皮细胞(GES-1),结果对应表8-3;实施例62-66使用人小肠上皮细胞(FHs74Int),结果对应表8-4。
消化悬浮经培养的细胞,对细胞进行计数,接种到96孔板中,每孔种植5000-10000个细胞。将各孔分成:空白对照组、抗肿瘤剂组、抗肿瘤剂+NO-NSAID组、抗肿瘤剂组、NO-NSAID溶剂对照组,各组的每个孔中均含有基础培养基,每个孔最终含有的液体体积约为100μL。具体分组情况如下:
1)空白对照组:除正常更换培养基以外不额外加入任何溶液;
2)抗肿瘤剂组:加入抗肿瘤剂溶液(最终浓度如表8-1至表8-4所示,抗肿瘤剂溶液的溶剂为DMSO);
3)抗肿瘤剂+NO-NSAID组:加入抗肿瘤剂溶液以及NO-NSAID溶液(抗肿瘤剂和NO-NSAID的最终浓度如表8-1至表8-4所示,并根据NO-NSAID的溶解性,选择NO-NSAID溶液的溶剂为乙醇或无菌水,各分组的总体积细微差异通过加入所选择的相应溶剂补齐);
4)抗肿瘤剂溶剂组:加入与组2)中对应所述抗肿瘤剂溶液中所含有的、等体积的DMSO;
5)NO-NSAID溶剂对照组:加入与组3)中对应所述NO-NSAID所中所含有的、同体积同种类的溶剂(例如,乙醇或无菌水)。
抗肿瘤剂溶剂组不参与数据处理,仅作为评价实验系统误差的参考。NO-NSAID溶剂对照组用于数据校正,从而排除溶剂对结果的影响。
继续培养24-48小时后,使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037,上海碧云天生物科技有限公司,Beyotime Biotechnology)测定细胞的存活率,从而计算抗肿瘤剂对细胞的增殖毒性以及NO-NSAID对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。
表8-1至表8-4列出了各种抗肿瘤剂和NO-NSAID的组合,以及相应的实验结果(其中,细胞存活率栏的数据标识是与抗肿瘤剂组相比,相应的抗肿瘤剂+NO-NSAID组所增加的存活细胞的百分比)。图22表示HaCaT细胞上的实验结果,图23表示HOK细胞上的实验结果,图24表示GES-1细胞上的实验结果,图25表示FHs 74 Int细胞上的实验结果。其中,横坐标表示不同的实验组和对照组;纵坐标表细胞的存活率(以空白对照组的细胞存活率为 100%计算其他实验组或溶剂对照组中细胞的存活百分率)。其中*表示P<0.05,与相应的抗肿瘤剂单独给药组相比具有显著差异;利用t-test统计检验。
表8-1实施例47-51的实验条件和实验结果
Figure PCTCN2023071255-appb-000173
Figure PCTCN2023071255-appb-000174
Figure PCTCN2023071255-appb-000175
从表8-1和图22中的结果可以看出:抗肿瘤剂对皮肤细胞(HaCaT)有增殖毒性,而NO-NSAID对抗肿瘤剂引起的增殖毒性有明显的缓解作用。
表8-2实施例52-56的实验条件和实验结果
Figure PCTCN2023071255-appb-000176
Figure PCTCN2023071255-appb-000177
Figure PCTCN2023071255-appb-000178
从表8-2和图23的结果中可以看出:抗肿瘤剂对人口腔黏膜上皮角质细胞(HOK)有增殖毒性,而NO-NSAID对抗肿瘤剂引起的增殖毒性有明显的缓解作用。
表8-3实施例57-61的实验条件和实验结果
Figure PCTCN2023071255-appb-000179
Figure PCTCN2023071255-appb-000180
Figure PCTCN2023071255-appb-000181
从表8-3和图24中的结果可以看出:抗肿瘤剂对人小肠上皮细胞(FHs 74Int)有增殖毒性,而NO-NSAID对抗肿瘤剂引起的增殖毒性有明显的缓解作用。
表8-4实施例62-66的实验条件和实验结果
Figure PCTCN2023071255-appb-000182
Figure PCTCN2023071255-appb-000183
Figure PCTCN2023071255-appb-000184
从表8-4和图25中的结果可以看出:抗肿瘤剂对人胃上皮细胞(GES-1)有增殖毒性,而NO-NSAID对抗肿瘤剂引起的增殖毒性有明显的缓解作用。

Claims (96)

  1. NO-NSAID化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
  2. 根据权利要求1所述的用途,其中所述NO-NSAID化合物包括一氧化氮(NO)释放部分和非甾体抗炎剂(NSAID)部分,且所述NO释放部分与所述非甾体抗炎剂部分之间共价直接连接或通过间隔基连接。
  3. 根据权利要求2所述的用途,其中所述非甾体抗炎剂部分包含环氧合酶(COX)抑制部分。
  4. 根据权利要求3所述的用途,其中所述COX抑制部分包括能够减少COX表达的部分,和/或降低COX活性的部分。
  5. 根据权利要求3-4中任一项所述的用途,其中所述COX抑制部分直接作用于COX蛋白和/或编码COX蛋白的核酸。
  6. 根据权利要求3-5中任一项所述的用途,其中所述COX抑制部分能够抑制环氧合酶-1(COX-1)和/或环氧合酶-2(COX-2)。
  7. 根据权利要求3-6中任一项所述的用途,其中所述COX抑制部分能够选择性抑制COX-2。
  8. 根据权利要求3-6中任一项所述的用途,其中所述COX抑制部分能够非选择性地抑制COX-1和COX-2。
  9. 根据权利要求3-8中任一项所述的用途,其中所述COX抑制部分包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:对乙酰氨基酚(acetaminophen),阿西美辛(acemetacin),醋氯,芬酸(aceclofenac),氨洛芬(alminoprofen),阿芬酸(arnfenac),bendazac,苯诺沙洛芬(benoxaprofen),溴芬酸(bromfenac),丁氯芬酸(bucloxic acid),布替布芬(butibufen),卡洛芬(carprofen),辛美辛(cinmetacin),氯吡酸(clopirac),双氯芬酸(diclofenac),依托度酸(etodolac),联苯乙酸(felbinac),芬氯苯丙酸(fenclozic acid),芬布芬(fenbufen),氟丁苯丙胺(fenoprofen),fentiazac,氟诺沙洛芬(flunoxaprofen),氟比洛芬(flurbiprofen),布芬酸(ibufenac),布洛芬(ibuprofen),吲哚美辛(indomethacin),异芬唑酸(isofezolac),isoxepac,吲哚洛芬(indoprofen),酮洛芬(ketoprofen),lonazolac,洛索洛芬(loxoprofen),甲嗪酸(metiazinic acid),莫非唑酸(mofezolac),米洛芬(miroprofen),萘普生(naproxen),恶丙嗪(oxaprozin),pirozolac,普拉洛芬(pranoprofen),普罗替尼酸(protizinic acid),水杨酰胺(salicylamide),sulindac,舒 洛芬(suprofen),suxibuzone,噻洛芬酸(tiaprofenic acid),托美汀(tolmetin),xenbucin,西莫洛芬(ximoprofen),zaltoprofen,zomepirac,阿司匹林(aspirin),acemetcin,bumadizon,卡洛芬酸(carprofenac),clidanac,二氟尼柳(diflunisal),氟尼酸(enfenamic acid),芬多沙(fendosal),氟芬那酸(flufenamic acid),氟尼辛(flunixin),龙胆酸(gentisic acid),酮咯酸(ketorolac),甲氯芬那酸(meclofenamic acid),甲芬那酸(mefenamic acid)和美沙拉嗪(mesalamine)。
  10. 根据权利要求3-9中任一项所述的用途,其中所述COX抑制部分包含选自下组的一种或多种分子,其前药,其活性衍生物和/或其活性代谢产物:萘普生(naproxen),阿司匹林(aspirin),双氯芬酸(diclofenac),酮洛芬(ketoprofen),氟比洛芬(flurbiprofen)和布洛芬(ibuprofen)。
  11. 根据权利要求2-10中任一项所述的用途,其中所述NO释放部分能够产生NO +、NO -、N 2O、NO、N 2O 3、NO 2、NO 3 -和NO 2 -之中的至少一种。
  12. 根据权利要求2-11中任一项所述的用途,其中所述NO释放部分能够直接或者间接产生NO。
  13. 根据权利要求2-12中任一项所述的用途,其中所述NO释放部分包括有机分子、无机分子和/或高分子或纳米材料。
  14. 根据权利要求2-13中任一项所述的用途,其中所述NO释放部分包括选自下组的成分:硝酸甘油、单硝酸异山梨酯、丁二醇单硝酸酯、季戊四醇四硝酸酯、硝酸异山梨酯、三硝乙醇胺、尼可地尔、硝二羟甲丁醇、5-氨基-3-(4-吗啉基)-1,2,3-恶二唑、亚硝酸异戊酯、3,3-二(氨乙基)-1-羟基-2-羰基-1-三氮烯(NOC-18)、磺基亲核复合体二钠盐(Sulfo NONOate disodium salt)、S-亚硝基谷胱甘肽(S-Nitrosoglutathione)、S-亚硝基-N-乙酰青霉胺(S-Nitroso-N-acetylpenicillamine)、4-苯基-3-呋腈(4-Phenyl-3-furoxancarbonitrile)、(±)-(E)-4-乙基-2-(E)-肟基-5-硝基-3-己酰胺((±)-(E)-4-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide)、链脲菌素(Streptozocin)、NG-羟基-L-精氨酸合乙酸(NG-Hydroxy-L-arginine acetate salt)、O 2-(2,4-二硝基苯基)1-[(4-乙氧基羰基)哌嗪-1-基]1,2-二醇二氮烯-1-鎓(O 2-(2,4-Dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate)、N-亚硝基二丁胺、3-吗啉-斯得酮亚胺(3-morpholinosydnonimine(SIN-1))、林西多明(Linsidomine)、吗多明(Molsidomine)、3-(4-乙酰苯基)悉尼酮(3-(4-acetylphenyl)sydnone)、二乙胺亲核复合体/AM(Diethylamine NONOate/AM)和Itramin。
  15. 根据权利要求2-14中任一项所述的用途,其中所述NO释放部分包括选自下组的成分:硝酰配合物、亚硝酰配合物(Metal nitrosyl complex)、金属亚硝氨基络合物、硝酸盐和亚硝酸盐。
  16. 根据权利要求2-15中任一项所述的用途,其中所述NO释放部分包括选自下组的成分:S-亚硝基硫醇纳米硅球、S-亚硝基乙二硫醇甲壳素和寡聚丙二胺接枝壳聚糖NONOate。
  17. 根据权利要求2-16中任一项所述的用途,其中所述NO释放部分具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
  18. 根据权利要求2-17中任一项所述的用途,其中所述NO释放部分具有下述的一个或多个基团:偶氮鎓二醇盐、羟基二氮烯磺酸、S-亚硝基硫醇、呋咱氮氧、肟、N-亚硝胺、N-羟基胍、硝酸盐、亚硝酸盐、硝酸酯、亚硝酸酯、斯得酮亚胺、斯得酮、恶三唑-5-亚胺、恶三唑-5-酮、羟胺、二氧二氮杂环丁烯、N-羟基亚硝胺、N-亚硝亚胺、羟基脲和金属亚硝氨基络合物。
  19. 根据权利要求2-18中任一项所述的用途,其中所述NO释放部分包括-NO 2或-ONO 2
  20. 根据权利要求2-19中任一项所述的用途,其中在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间通过可裂解连接子连接。
  21. 根据权利要求2-20中任一项所述的用途,其中在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间通过包含酯键和/或二硫键的连接子连接。
  22. 根据权利要求2-21中任一项所述的用途,其中在所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分之间包含间隔基。
  23. 根据权利要求22所述的用途,其中所述间隔基包含:一个或多个任选取代的-CH 2-,任选取代的苯基和/或它们的组合。
  24. 根据权利要求1-23中任一项所述的用途,其中所述NO-NSAID化合物还包含H 2S释放部分。
  25. 根据权利要求1-24中任一项所述的用途,其中所述NO-NSAID化合物包含式(3)所示的结构:
    M-X-Y-ONO 2(3),
    其中M为选自下组的结构:
    Figure PCTCN2023071255-appb-100001
    其中R A为氢原子或-C(O)CH 3
    Figure PCTCN2023071255-appb-100002
    Figure PCTCN2023071255-appb-100003
    Figure PCTCN2023071255-appb-100004
    X是-O-,-S-或-NR 1-,其中R 1是H或者是直链或支链的C 1-C 6烷基;
    Y是具有如下定义的二价基团:
    a)
    -直链或支链的C 1-C 20亚烷基,其任选地被一个或多个选自下组的取代基取代:卤素,羟基,-ONO 2,-OC(O)(C 1-C 10烷基)-ONO 2和-O(C 1-C 10烷基)-ONO 2
    -C 5-C 7亚环烷基,其任选地被直链或支链C 1-C 10烷基取代;
    b)
    Figure PCTCN2023071255-appb-100005
    其中n为选自0-20的整数,n’为1-20的整数;
    c)
    Figure PCTCN2023071255-appb-100006
    其中n为选自0-20的整数,n’为1-20的整数;
    d)
    Figure PCTCN2023071255-appb-100007
    其中X 1为-OCO-或-COO-,并且R 2是H或CH 3,na是1-20的整数,n 2是0-2的整数;
    e)
    Figure PCTCN2023071255-appb-100008
    其中Y 1是-CH 2-CH 2-(CH 2)n 2-,或-CH=CH-(CH 2)n 2-,X 1,na,n 2和R 2的定义同上;
    f)
    Figure PCTCN2023071255-appb-100009
    其中na和R 2的定义同上,R 3是H或-COCH 3;或
    g)
    Figure PCTCN2023071255-appb-100010
    其中X 2是-O-或-S-,n 3是1-6的整数,R 2的定义同上。
  26. 根据权利要求1-24中任一项所述的用途,其中所述NO-NSAID化合物包含式(3)所示的结构:
    M-X-Y-ONO 2(3),
    其中M选自以下结构:
    Figure PCTCN2023071255-appb-100011
    Figure PCTCN2023071255-appb-100012
    X是-O-;Y是直链或支链的C 1-C 10亚烷基。
  27. 根据权利要求1-24中任一项所述的用途,其中所述NO-NSAID化合物包含式(21)所示的结构:
    Figure PCTCN2023071255-appb-100013
    其中
    X为连接子,M为选自下组的结构:
    Figure PCTCN2023071255-appb-100014
  28. 根据权利要求1-24中任一项所述的用途,其中所述NO-NSAID化合物包括选自下组的化合物:
    Figure PCTCN2023071255-appb-100015
    Figure PCTCN2023071255-appb-100016
  29. 根据权利要求1-28中任一项所述的用途,其中所述NO-NSAID化合物中,所述NO释放部分与所述NSAID部分的摩尔比为约2:1至约1:2。
  30. 根据权利要求1-29中任一项所述的用途,其中所述抗肿瘤剂包括小分子化合物,小分子偶联物,蛋白质和/或多核苷酸。
  31. 根据权利要求1-30中任一项所述的用途,其中所述抗肿瘤剂包括化疗剂,靶向治疗剂和/或免疫治疗剂。
  32. 根据权利要求31述的用途,其中所述抗肿瘤剂为靶向治疗剂。
  33. 根据权利要求31-32中任一项所述的用途,其中所述靶向治疗剂包括小分子化合物和/或抗体或其抗原结合片段。
  34. 根据权利要求33所述的用途,其中所述抗体包括单克隆抗体,多特异性抗体,嵌合抗体,人源化抗体,全人源抗体和/或抗体药物偶联物。
  35. 根据权利要求34所述的用途,其中所述抗原结合片段包括Fab,Fab’,F(ab )2,Fv片段,F(ab’) 2,scFv,di-scFv和/或dAb。
  36. 根据权利要求31-35中任一项所述的用途,其中所述靶向治疗剂靶向肿瘤细胞内部,肿瘤细胞表面和/或肿瘤微环境中的分子。
  37. 根据权利要求31-36中任一项所述的用途,其中所述靶向治疗剂靶向蛋白质和/或核酸分子。
  38. 根据权利要求31-37中任一项所述的用途,其中所述靶向治疗剂靶向肿瘤相关抗原。
  39. 根据权利要求31-38中任一项所述的用途,其中所述靶向治疗剂靶向选自下组的一个或多个靶标:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
  40. 根据权利要求31-39中任一项所述的用途,其中所述靶向治疗剂抑制选自下组的一个或多个靶标的活性:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
  41. 根据权利要求31-40中任一项所述的用途,其中所述靶向治疗剂降低选自下组的一个或多个靶标的表达:VEGF,EGFR,EGFR1,EGFR2,EGFR3,EGFR4,HER2,HER3,HER4,VEGFR,VEGFR1,VEGFR2,VEGFR3,VEGFR4,PDGFR,PDGFRα,PDGFRβ,KIT,c-Kit,Ret,Raf,Raf-1,Abl,FGFR,FGFR1,MET,c-MET,Tie2,Src,c-Src,AXL,Ret,BCR-ABL,CSF-1R,FGFR,FGFR1,FGFR2,FGFR3,FGFR4,mTOR,TORC,BRaf,MEK,MEK1,MEK2,ALK,ABL,CDK,JAK,PI3K,NTRK,MSI,HDAC,FAK,PYK2,以及它们的突变体。
  42. 根据权利要求31-41中任一项所述的用途,其中所述靶向治疗剂包括激素,信号转导抑制剂,基因表达调节剂,细胞凋亡诱导剂,血管生成抑制剂和/或毒素递送分子。
  43. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为酪氨酸酶抑制剂。
  44. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为VEGFR抑制剂和/或VEGF抑制剂。
  45. 根据权利要求44所述的用途,其中所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。
  46. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为EGFR抑制剂。
  47. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为BRAF抑制剂。
  48. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为PDGFR抑制剂。
  49. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为FGFR抑制剂。
  50. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为mTOR抑制剂。
  51. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂为HER2抑制剂。
  52. 根据权利要求31-42中任一项所述的用途,其中所述靶向治疗剂选自下组中的一种或多种:阿法替尼,达克替尼,奥希替尼,EAI045,吉非替尼,阿莫替尼,吡罗替尼,布加替尼,来那替尼,奥木替尼,博舒替尼,埃克替尼,凡德他尼,拉帕替尼,阿氟替尼,BPI-7711,莫波替尼,多维替尼,佐立替尼,瓦利替尼,奥布替尼,拉布替尼,布鲁替尼依鲁替尼,达沙替尼,pirtobrutinib,tolebrutinib,rilzabrutinib,fenebrutinib,evobrutinib,司美替尼,tivozanib,dovitinib,索凡替尼,binimetinib,cobimetinib,trametinib,瑞戈非尼,GSK-1120212,alpelisib,duvelisib,copanlisib,idelalisib,去甲替林,inavolisib,dactolisib,apitolisib,parsaclisib,buparlisib,rigosertib,enzastaurin,paxalisib,leniolisib,ipatasertib,zotarolimus,sirolimus,依维莫司,temsirolimus,索拉非尼,阿帕替尼,乐伐替尼,舒尼替尼,卡博替尼,阿昔替尼,尼达尼布,brivanib,vatalanib,呋喹替尼,达拉非尼,威罗非尼,恩科拉非尼,pazopanib,crizotinib,panobinostat,erlotinib,rituximab,panitumumab,cetuximab,erfonrilimab,efactinib,cadonilimab,ramucirumab,bevacizumab,安罗替尼,ponatinib,法米替尼,厄达替尼,AZD4547,英菲格拉替尼,BCD-217,amivantamab,MCLA-129,EMB-01,LY3164530,JNJ-61186372,抗EGFR及cMet双特异性抗体,GB263,它们的可药用盐以及它们的任意组合。
  53. 根据权利要求31-52中任一项所述的用途,其中所述靶向治疗剂与一种或多种其它疗法联合施用。
  54. 根据权利要求31所述的用途,其中所述抗肿瘤剂为化疗剂。
  55. 根据权利要求54所述的用途,其中所述化疗剂包括嘧啶核苷类似物和/或其前药。
  56. 根据权利要求54-55中任一项所述的用途,其中所述化疗剂包括选自下组中的一种或多种:卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
  57. 根据权利要求56所述的用途,其中所述5-FU药物前体包括喃氟啶、5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物、2’-脱氧氟尿苷的药物前体衍生物、三 氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和/或3-脱氮杂尿苷。
  58. 根据权利要求56-57中任一项所述的用途,其中所述化疗剂与一种或多种其它疗法联合施用。
  59. 根据权利要求58所述的用途,其中所述一种或多种其它疗法包括一种或多种其它抗肿瘤疗法。
  60. 根据权利要求1-59中任一项所述的用途,其中所述疾病或病症是由施用所述抗肿瘤剂引起的。
  61. 根据权利要求1-60中任一项所述的用途,其中所述疾病或病症在施用所述抗肿瘤剂之后出现或加重。
  62. 根据权利要求1-61中任一项所述的用途,其中在施用所述抗肿瘤剂之前,所述受试者未患有所述疾病或病症。
  63. 根据权利要求1-62中任一项所述的用途,其中所述疾病或病症包括上皮组织疾病或病症。
  64. 根据权利要求1-63中任一项所述的用途,其中所述上皮组织疾病或病症包括与内皮细胞病变相关的疾病或病症,和/或与上皮细胞病变相关的疾病或病症。
  65. 根据权利要求64所述的用途,其中所述内皮细胞包括血管内皮细胞。
  66. 根据权利要求64-65中任一项所述的用途,其中所述上皮细胞包括皮肤上皮细胞,口腔上皮细胞,鼻腔上皮细胞,胃上皮细胞和/或肠上皮细胞。
  67. 根据权利要求1-66中任一项所述的用途,其中所述疾病或病症包括皮肤疾病或病症,五官疾病或病症和/或胃肠道疾病或病症。
  68. 根据权利要求67所述的用途,其中所述皮肤疾病或病症包括脱发症,体臭,大疱性皮炎,皮肤干燥,湿疹,多形性红斑,红皮病,脂肪萎缩症,发色改变,毛发质地异常,多毛症(hirsutism),多汗症(hyperhidrosis),角化过度症,肥大症(hypertrichosis),少汗症(hypohidrosis),脂肥大,指甲改变,指甲变色,指甲丢失,指甲隆起,皮肤疼痛,手足综合征,光敏感性,瘙痒症,紫癜,痤疮样皮疹,斑丘疹,头皮疼痛,皮肤萎缩,皮肤色素沉着过多(skinhyperpigmentation),皮肤色素减退(skinhypopigmentation),皮肤硬结,皮肤溃疡,Stevens-Johnson综合征,皮下气肿,毛细血管扩张,中毒性表皮坏死,皮疹和/或荨麻疹。
  69. 根据权利要求67-68中任一项所述的用途,其中所述皮肤疾病或病症为手足综合征。
  70. 根据权利要求67-69中任一项所述的用途,其中所述皮肤疾病或病症的严重程度为依据 NCI-CTCAE中的第1级或其以上,第2级或其以上,第3级或其以上,第4级或其以上,或者第5级。
  71. 根据权利要求1-70中任一项所述的用途,其中所述受试者包括癌症患者。
  72. 根据权利要求71所述的用途,其中所述疾病或病症的患处与癌症的患处不同。
  73. 根据权利要求1-72中任一项所述的用途,其中所述药物基本上不影响所述抗肿瘤剂的治疗效果。
  74. 根据权利要求1-73中任一项所述的用途,其中所述药物被制备为适用于局部给药。
  75. 根据权利要求1-74中任一项所述的用途,其中所述药物被制备为适用于透皮给药。
  76. 根据权利要求1-75中任一项所述的用途,其中所述药物被制备为乳膏,洗液,凝胶,软膏,油膏,喷剂,脂质体制剂,擦剂和/或气雾剂。
  77. 根据权利要求1-76中任一项所述的用途,其中所述药物的给药部位和所述抗肿瘤剂的给药部位不同。
  78. 根据权利要求77所述的用途,其中所述药物的给药部位不为癌症的发生部位或癌症的潜在转移部位。
  79. 根据权利要求1-78中任一项所述的用途,其中所述药物的给药方式和所述抗肿瘤剂的给药方式不同。
  80. 根据权利要求1-79中任一项所述的用途,其中所述药物中,所述NO-NSAID化合物的浓度为约0.005%w/w至约40%w/w。
  81. 根据权利要求1-80中任一项所述的用途,其中所述药物中,所述NO-NSAID化合物的浓度为约0.5%w/w至约10%w/w。
  82. 一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的NO-NSAID化合物或其药学上可接受的盐。
  83. NO-NSAID化合物或其药学上可接受的盐,其用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
  84. 药物组合,其包含:1)抗肿瘤剂;以及2)NO-NSAID化合物。
  85. 根据权利要求84所述的药物组合,其中所述抗肿瘤剂与所述NO-NSAID化合物彼此不混合。
  86. 根据权利要求84-85中任一项所述的药物组合,其中所述抗肿瘤剂与所述NO-NSAID化合物各自独立地存在于单独的容器中。
  87. 根据权利要求84-86中任一项所述的药物组合,其中所述NO-NSAID化合物被制备为适 用于透皮给药。
  88. 根据权利要求84-87中任一项所述的药物组合,其中所述NO-NSAID化合物被制备为软膏剂。
  89. 根据权利要求84-88中任一项所述的药物组合,其中所述NO-NSAID化合物的浓度为约0.005%w/w至约40%w/w。
  90. 根据权利要求84-89中任一项所述的药物组合,其中所述NO-NSAID化合物的浓度为约0.5%w/w至约10%w/w。
  91. 根据权利要求84-90中任一项所述的药物组合,其中2)中的所述NO-NSAID化合物能够预防,缓解和/或治疗与1)中的所述抗肿瘤剂相关的疾病或病症。
  92. 根据权利要求84-91中任一项所述的药物组合,其中2)中的所述NO-NSAID化合物基本上不影响1)中的所述抗肿瘤剂的治疗效果。
  93. 根据权利要求84-92中任一项所述的药物组合,其中在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的所述NO-NSAID化合物。
  94. NO释放剂和NSAID在制备药物中的用途,所述药物用于预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
  95. 一种预防,缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的NO释放剂和NSAID。
  96. 药物组合,其包含:1)抗肿瘤剂;2)NO释放剂;以及3)NSAID。
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