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 PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs 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
Description
Claims (96)
- 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。
- 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。
- 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。
- 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。
- 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。
- 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)。
- 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。
- 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。
- 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)。
- 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)。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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: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;
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 根据权利要求31所述的用途,其中所述抗肿瘤剂为化疗剂。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 药物组合,其包含:1)抗肿瘤剂;以及2)NO-NSAID化合物。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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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- 2023-01-09 WO PCT/CN2023/071255 patent/WO2023142996A1/zh active Application Filing
- 2023-01-09 KR KR1020247027416A patent/KR20240144944A/ko unknown
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