CN101993415B - Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof - Google Patents

Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof Download PDF

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CN101993415B
CN101993415B CN2010102818562A CN201010281856A CN101993415B CN 101993415 B CN101993415 B CN 101993415B CN 2010102818562 A CN2010102818562 A CN 2010102818562A CN 201010281856 A CN201010281856 A CN 201010281856A CN 101993415 B CN101993415 B CN 101993415B
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phenyl
methyl
niacinamide
trifluoromethoxy
trifluoromethyl
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CN101993415A (en
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文圣焕
张波
杨军
金孟燮
许树森
毕学智
李建华
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Beijing Hanmi Pharmaceutical Co Ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention provides a compound of general formula I as an inhibitor and a preparation method thereof. The compound is used for inhibiting a Hedgehog signal path and can provide a new medicine for clinic effective cancer resistance. The invention also provides a medicine composition as an inhibitor, which contains the compound I as an effective ingredient and can be used for inhibiting the Hedgehog signal path so as to resist cancer. In addition, the invention also provides an application of the compound in the preparation of the medicine for inhibiting the Hedgehog signal path.

Description

As the compound of Hedgehog pathway inhibitor and pharmaceutical composition and the application thereof that comprises this compound
Technical field
The present invention relates to a kind of compound, relate in particular to a kind of compound as inhibitor and comprise this compound compositions (C07D 521/00).
Background technology
The hedgehog signal path of finding in fruit bat in 1980 forms at animal embryo and plays important regulatory role in the processes such as propagation, differentiation and decision cell fate to cell period.Normally functioning Hedgehog signal path is to form the necessary condition of vitals (Ingham PW ﹠amp such as brain, four limbs, lung, skin, prostate gland; McMahon AP (2001) Genes ﹠amp; Development 15,3059-3087).Although the level of Hedgehog signal path in becoming human body be far below embryo period, this path still plays crucial effects in the propagation of adult's tissue and renewal process.Stem cell is the multipotential cell that a class has the self ability, and namely stem cell keeps not directed differentiation state and has multiplication capacity, and in appropriate condition or give appropriate signal, it can be divided into multiple functioning cell or histoorgan.The Hedgehog path is the important setter of stem cell activity, and it can stimulate self and propagation (Beachy PA, the Karhadkar SS ， ﹠amp of stem cell in the multiple tissue; Berman DM (2004) Nature 432,324-331).
Comprise existence three kinds of Hedgehog albumen: Sonic hedgehog (Shh) in the Mammals vertebrates, Desert hedgehog (Dhh) and Indian hedgehog (Ihh). owing in multiple tissue expression is arranged, Shh albumen has obtained maximum concerns.The part of these secretions is by being combined to activate the Hedgehog signal path with 12 transmembrane protein Ptch1.When not with part for example during the Shh protein binding, Ptch1 suppresses the activity of another kind of transmembrane protein (7 transmembrane proteins) Smoothend (Smo), but when when part is combined, Ptch1 albumen is activated and discharges it to the inhibition of Smo, thereby cause Smo to move to cytolemma, cause signal conduction (Varjosalo M ﹠amp in a series of cell; Taipale J (2007) Journal of Cell Science 120,3-6).The signal transduction cascade that is caused by the Smo that activates causes the activation of Gli transcription factor, and the transposition of Gli transcription factor enters in the nucleus, and their control target genes transcribes there.In vertebrates, the Gli transcription factor of three kinds of zinc finger protein families is arranged, be respectively Gli1, Gli2 and Gli3.Wherein Gli1 and Gli2 mainly as the incitant Gli3 that transcribes then mainly as suppressor.Because lasting mistake of Gli2 gene expressed, it is identified as the main target spot after Smo albumen activates usually.The activation height correlation of the expression of Gli1 and Hedgehog path, so it indicates the state of activation of Hedgehog path through being often used as reading.The activation of Gli transcription factor can cause (Ferretti E, De Smaele E, Di Marcotullio L, the ScrepantiI ， ﹠amp of transcribing of Hedgehog target genes such as Gli1, Ptch1, Myc, Bcl-2; Gulino A (2005) Trends in Molecular Medicine 11,537-545).
Recent studies show that the abnormal activation of cancer and Hedgehog path is closely related.In most of sporadic rodent cancer, the researchist finds that the Hedgehog path that the variation of Ptch1 and Smo has caused not relying on part activates (Gailani MR, StahleBackdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, et al. (1996) Nature Genetics 14,78-81; Xie JW, Murone M, Luoh SM, Ryan A, Gu QM, Zhang CH, Bonifas JM, Lam CW, Hynes M, Goddard A, et al. (1998) Nature 391,90-92), and the activation of the Hedgehog path that the variation of Ptch1 and Sufu causes also is found and closely related (the Rubin LL ﹠amp of medulloblastoma and rhabdomyoma; De Sauvage FJ (2006) Nature Reviews Drug Discovery 5,1026-1033; Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R ， ﹠amp; Unden AB (2006) Journal of Pathology 208,17-25).The cancer of the activation of Hedgehog path and other organ is also relevant.These cancers include but not limited to prostate cancer (Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM ， ﹠amp; Beachy PA (2004) Nature 431,707-712; Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S ， ﹠amp; Altaba ARI (2004) Proceedings of the National Academy of Sciences of the United States ofAmerica 101,12561-12566); Mammary cancer (Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S ， ﹠amp; Katano M (2004) Cancer Research 64,6071-6074); Carcinoma of the pancreas (Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo CF, Yajnik V, et al. (2003) Nature 425,851-856); Digestive tract tumor (Berman DM, Karhadkar SS, Maitra A, de Oca RM, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, et al. (2003) Nature425,846-851); Small cell lung cancer (Watkins DN, Berman DM, Burkholder SG, Wang BL, Beachy PA ， ﹠amp; Baylin SB (2003) Nature 422,313-317); Nonsmall-cell lung cancer (Yuan Z, Goetz JA, Singh S, Ogden SK, Petty WJ, Black CC, Memoli VA, Dmitrovsky E ， ﹠amp; Robbins DJ (2007) Oncogene 26,1046-1055) etc.
More and more evidences show the Hedgehog path may with tumor stem cell tight association (Parisi MJ ﹠amp; Lin H (1998) Cell Res 8,15-21; Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, et al. (2007) Proceedings of the National Academy of Sciences of the United States of America 104,4048-4053).Tumor stem cell may play crucial effects to growth of tumor and propagation.Discover, for example in brain and pancreas, have the ability a large amount of propagation and become new tumour (Clarke MF, Dick JE in vivo of sub-fraction cancer cells are arranged at leukemia and some solid tumors, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer Res 66,9339-9344).The hypothesis that tumor stem cell exists will have great influence to the antitumor drug design, needs targeting ground to eliminate all tumor stem cells because thoroughly eradicate tumour.
Part pancreatic cancer cell has the characteristics of tumor stem cell, character (the Li CW that possesses self and differentiation, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Cancer Research 67,1030-1037).People such as Feldmann utilize animal model to prove, Hedgehog inhibitor and gemcitabine coupling can suppress the growth of carcinoma of the pancreas, and the independent result for the treatment of of gemcitabine and hedgehog inhibitor is all not obvious.This studies show that and suppresses self and propagation (the Feldmann G that the Hedgehog path may suppress tumor stem cell, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra JBM, Habbe N, Karikari C, Mullendore M, et al. (2008) Molecular Cancer Therapeutics 7,2725-2735).In this research, people such as Feldmann also find, suppress the Hedgehog path and can prevent cancer metastasis effectively.
Differentiation except regulate tumor cell, propagation and transfer, Hedgehog path forward is regulated the expression of drug transporter, cause cancer cells to resistance (the Sims-Mourtada J of cell toxicant cancer therapy drug, Izzo JG, Ajani J, Chao KSC (2007) Oncogene 26,5674-5679).The Hedgehog path can also be regulated vasculogenesis (Klagsbrun M (1991) Annual Review of Physiology 53, the 217-239 of tumour; Cherrington JM, Strawn LM, Shawver LK (2000) Advances in Cancer Research, 79,1-38).In sum, the compound that suppresses the Hedgehog signal path with and medicinal compositions will have extraordinary anticancer potential applicability in clinical practice.
Summary of the invention
The object of the present invention is to provide a kind of compound as inhibitor, it is used for suppressing the Hedgehog signal path, can be clinical effective antitumor new medicine is provided.
Another object of the present invention is to be provided as the pharmaceutical composition of inhibitor, and the described compound I that it comprises as effective constituent can be used for suppressing the Hedgehog signal path with anticancer.
One object of the present invention is to provide described compound for the preparation of the application in the medicine that suppresses the Hedgehog signal path.
Another object of the present invention is to provide the preparation method of described compound.
According to an aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt or solvate:
Figure BSA00000270012700041
Formula I
Wherein:
The A representative:
Figure BSA00000270012700042
Or
Figure BSA00000270012700043
X represents S, S=O, S (O) 2, O, CHR 11Perhaps NR 12
R 11Represent hydrogen, cyano group, halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-C (O) 2R 14Perhaps-NR 13AR 13B, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens or hydroxyl;
R 12Represent hydrogen, C 1-6Alkyl, C 3-8Heterocyclylalkyl-C 1-6Alkyl, C 3-8Heterocyclylalkyl, C 6-10Aryl, C 5-10Heteroaryl, C 6-10Aryl-C 1-6Alkyl, C 5-10Heteroaryl-C 1-6Alkyl ,-C (O) 2R 14,-C (O) R 14Perhaps-S (O) 2R 14
R 13aAnd R 13bThe C that represents hydrogen independently, is not substituted or replaced by one or more halogens 1-6Alkyl, C 1-6Alkoxy-C 1-6Alkyl ,-C (O) 2R 14,-S (O) 2R 14, C 6-10Aryl-C 1-6Alkyl or C 5-10Heteroaryl-C 1-6Alkyl;
R 14The C that representative is not substituted or is replaced by one or more halogens 1-6Alkyl;
M and 1 represents 1 or 2 independently; N represents 0,1 or 2;
R 1And R 2Represent hydrogen or C independently 1-6Alkyl; Wherein alkyl is not substituted or is replaced by one or more halogens or hydroxyl;
Y, Z and U represent nitrogen or CR independently 11
W and V represent nitrogen or CR independently 15
R 15Represent hydrogen, C 1-6Alkyl or C 1-6Alkoxyl group, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens;
R 3Represent hydrogen, halogen, cyano group, C 1-6Alkyl or C 1-6Alkoxyl group, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens;
R 4And R 5Represent hydrogen, halogen, C independently 1-6Alkyl or C 1-6Alkoxyl group, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens, and R 4And R 5Be not hydrogen simultaneously;
R 6And R 7Represent hydrogen, halogen, C independently 1-6Alkyl or C 1-6Alkoxyl group, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens;
R 8And R 9Represent hydrogen, halogen, C independently 1-6Alkyl or C 1-6Alkoxyl group, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens; ,
R 10Represent hydrogen, halogen, cyano group, C 1-6Alkyl, C 1-6Alkoxyl group, C 6-10Aryl, C 5-10Heteroaryl, C 3-8Cycloalkyl, C 3-8Heterocyclylalkyl ,-C (O) R 14,-C (O) 2R 14,-SR 14,-S (O) 2R 14Perhaps-NR 13aR 13b, wherein alkyl or alkoxyl group are not substituted or are replaced by one or more halogens, and C wherein 3-8Heterocyclylalkyl is not substituted or by 1 or 2 C 1-6Alkyl replaces.
According to a further aspect in the invention, the invention provides a kind of pharmaceutical composition, it comprises formula I compound or its pharmacy acceptable salt or solvent thing and an amount of pharmaceutically acceptable carrier for the treatment of significant quantity.
According to a further aspect in the invention, the invention provides formula I compound for the preparation of the application in the medicine that suppresses the Hedgehog path.
The present invention also provides formula I compound for the preparation of the application in the medicine of the treatment cancer relevant with Hedgehog path abnormal activation, and wherein cancer is selected from rodent cancer, medulloblastoma, rhabdosarcoma, carcinoma of the pancreas, mammary cancer, spinal meningioma, glioblastoma, melanoma, cancer of the stomach, esophagus cancer, cholangiocarcinoma, prostate cancer, colorectal carcinoma, small cell lung cancer, nonsmall-cell lung cancer, neurogliocyte cancer, multiple myeloma and leukemia.
According to another aspect of the present invention, the invention provides the preparation method of described compound, wherein, reaction scheme is:
Figure BSA00000270012700061
Wherein, said method comprising the steps of:
1) compound of the compound of through type 1d and formula 1c carries out the compound that the Suzuki linked reaction prepares formula 1b;
2) compound of through type 1b and substituted heterocycle carboxylic acid carry out the compound that condensation reaction prepares formula 1a; And
3) obtain the compound of formula I from the compound of formula 1a.
Perhaps reaction scheme is:
Figure BSA00000270012700062
Wherein, said method comprising the steps of:
1) compound of through type 1c and substituted heterocycle carboxylic acid carry out the compound that condensation reaction prepares formula 1b; And
2) compound of through type 1b and nucleophilic reagent (A) prepared in reaction obtains the compound of formula 1a;
3) phenylo boric acid of the compound of formula 1a and replacement carries out the compound that the Suzuki linked reaction prepares formula I.
Method among the present invention and compound can be used for the Hedgehog signal path that suppresses to activate, that is to say and can suppress because the misgrowth state that the Hedgehog abnormal activation causes.Use method described in the invention, the formula I compound of q.s or formula I compound and the formed pharmaceutical composition of pharmaceutical carrier and cells contacting, thereby can suppress the Hedgehog path control of abnormal activation or reverse unusual growth conditions, thereby can treat the cancer relevant with the Hedgehog path of abnormal activation clinically effectively.
Embodiment
As follows to part term definition related among the present invention:
" alkyl " as group or the part of other groups, for example alkyl that replaces of halogen, the alkyl that hydroxyl replaces, can be straight chain or side chain.For example, C 1-6Alkyl is represented the alkyl of 1 to 6 carbon, includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl;
" alkoxyl group " refers to the generation group after alkyl and Sauerstoffatom link, and includes but not limited to methoxyl group, oxyethyl group, isopropoxy, ring propoxy-etc.
" aryl " refers to comprise the monocycle of six to ten carbon atoms or the aromatic ring that condenses.Specific aryl comprises phenyl and naphthyl, wherein preferred phenyl.
" heteroaryl " refers to any condensing or the aromatic ring system of non-condensed, wherein at least one ring be contain 1-4 be selected from nitrogen, oxygen and sulphur heteroatomic five to octatomic ring, preferably at least one heteroatoms is selected from nitrogen.Heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl etc.
" cycloalkyl " refers to comprise saturated or the undersaturated monocycle of part, condensed ring or the bridged ring of the carbon atom that specifies number.For example, C 3-8Cycloalkyl refers to the cycloalkyl of three to eight carbon, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" Heterocyclylalkyl " refers to defined cycloalkyl among the present invention, the carbon atom on wherein one or more rings by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-or-S (O) 2Replace Deng group; Heterocyclylalkyl includes but not limited to morpholinyl, piperazinyl, piperidyl, thio-morpholinyl etc.
" pharmacy acceptable salt " refers to acid salt in the present invention." pharmaceutically-acceptable acid addition " refers to keep the biological effectiveness of free alkali and do not have other side effects, with mineral acid or the formed salt of organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, vitriol, phosphoric acid salt etc.; Organic acid salt includes but not limited to formate, acetate, propionic salt, glycollate, gluconate, lactic acid salt, oxalate, maleate, succinate, fumarate, tartrate, Citrate trianion, glutaminate, aspartate, benzoate, mesylate, tosilate and salicylate etc.
" solvate " mentioned among the present invention refers to the title complex that compound of the present invention and solvent form.They or in solvent the reaction or from solvent the precipitation separate out or crystallize out.For example, a title complex that forms with water is called " hydrate ".The solvate of formula I compound belongs within the scope of the invention.
In preferred implementation of the present invention, in the compound of formula I,
X represents S, O, S=O, S (O) 2Perhaps NR 12
Y, Z and U are for representing nitrogen or CR independently 11, R wherein 11Represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
W and V are for representing nitrogen or CH independently;
R 3Represent hydrogen, fluorine, chlorine, bromine, cyano group, methyl, trifluoromethyl, methoxyl group, oxyethyl group or trifluoromethoxy;
R 4And R 5Represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group, oxyethyl group or trifluoromethoxy independently, wherein R 4Perhaps R 5Be not hydrogen simultaneously.
Wherein:
R 6, R 7, R 8Perhaps R 9Represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy independently;
R 10Represent fluorine, chlorine, cyano group, methyl, ethyl, sec.-propyl, trifluoromethyl, methoxyl group, isopropoxy, difluoro-methoxy, trifluoromethoxy, cyclopropyl, methylsulfonyl, dimethylin, NHS (O) 2Me, morpholinyl or piperazinyl, wherein morpholinyl or piperazinyl are not substituted or by 1 or 2 methyl substituted.
Wherein:
R 1Perhaps R 2Represent the methyl that hydrogen, methyl or hydroxyl replace independently.
Wherein:
R 4And R 5Represent hydrogen, chlorine or methyl independently, wherein R 4And R 5Be not hydrogen simultaneously.
Wherein:
X represents S, O, S=O, S (O) 2Perhaps NR 12, R wherein 12Represent methylidene, ethyl, ethanoyl, methylsulfonyl, benzyl, picolyl or thiazole methyl;
Y, Z and U represent nitrogen, CH or CHF independently.
Wherein:
M and 1 represents 1; When n represents 0 or 2, R 1And R 2Be hydrogen simultaneously;
R 6And R 7Represent hydrogen or chlorine independently;
R 8And R 9Be independently selected from hydrogen, methyl, fluorine or chlorine;
R 10Representation methoxy, trifluoromethoxy, trifluoromethyl, difluoro-methoxy or cyano group.
According to the present invention, preferred formula I examples for compounds is:
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-methylpiperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-ethyl piperazidine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-ethanoyl piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3R, 5S)-3, and 5-lupetazin-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-dimethylated morpholinyl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(3,5-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-dimethylated morpholinyl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza
Figure DEST_PATH_GSB00000765903700011
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(3,4-methylpiperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
5-{5-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] phenyl-formamyl }-pyridine-2-yl }-(1S, 4S)-2, the 5-diaza
Figure DEST_PATH_GSB00000765903700012
Assorted dicyclo [2.2.1] heptane base-2-t-butyl formate;
5-{5-{2-methyl-[4 '-(trifluoromethyl) phenyl] phenyl-formamyl }-pyridine-2-yl }-1, the 4-diaza
Figure DEST_PATH_GSB00000765903700013
-1-t-butyl formate;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(ethanoyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza
Figure DEST_PATH_GSB00000765903700014
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,4-diaza
Figure DEST_PATH_GSB00000765903700015
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(2,5-diaza
Figure DEST_PATH_GSB00000765903700016
Dicyclo [2.21] heptane base-2-yl)] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza
Figure DEST_PATH_GSB00000765903700021
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(3,5-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(3,4-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(2,5-diaza
Figure DEST_PATH_GSB00000765903700022
Dicyclo [2.2.1] heptane base-2-yl)] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,4-diaza
Figure DEST_PATH_GSB00000765903700023
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(difluoro-methoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] pyridazine-3 acid amides;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(phenyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide;
N-{2-methyl-3-[4 '-(difluoro-methoxy) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{4-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide;
Compound of Formula I synthetic method of the present invention can be prepared according to the step shown in following reaction scheme I or the II:
Reaction scheme I
Figure BSA00000270012700121
The synthetic logical method of the compound I among the reaction scheme I is described in detail in the route map of reaction scheme I.
The bromo aniline of the polysubstituted or mono-substituted phenylo boric acid starting raw material of step 1: formula 1d and the replacement of formula 1c is by the intermediate of Suzuki linked reaction preparation formula 1b.
Wherein, the method for Suzuki linked reaction can reference (Kotha, S.; Lahiri, K and Kashinath, D.Tetrahedron 2002,48,9633-9695) method in; The palladium catalyst that uses can be selected from bi triphenyl phosphorus palladium chloride (Pd (PPh 3) 2Cl 2), tetrakis triphenylphosphine palladium (Pd (PPh 3) 4), acid chloride (Pd (OAc) 2), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (Pd (dppf) Cl 2) and Palladous chloride (PdCl 2); Temperature of reaction is at 80 ℃ to 160 ℃; Reaction solvent can be selected from 1,4-dioxane, toluene, ethanol and water; Mineral alkali can be selected yellow soda ash, salt of wormwood etc.
For example, the amino bromobenzene of phenylo boric acid and 2-is tetrakis triphenylphosphine palladium (Pd (PPh at catalyzer 3) 4), mineral alkali is yellow soda ash, reaction solvent is in the mixing solutions of toluene, ethanol and water, is heated to 100 ℃-130 ℃, reacts to obtain corresponding product in 12 hours.
Step 2: the substituted heterocycle carboxylic acid particularly replaces the amide compound of the corresponding formula 1a of intermediate condensation prepared of nicotinic acid and formula 1b.
Wherein, the reaction of preparation acid amides can select to replace the corresponding nicotinoyl chlorine that replaces of method preparation of nicotinic acid and sulfur oxychloride or oxalyl chloride reaction, prepares the compound of corresponding formula 1a subsequently with the compound condensation of formula 1b; Also can select DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-front three aminopropyl) carbodiimide), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester), TBTU (O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester), DIC condensing agents such as (N, N '-DIC) prepares the acid amides of corresponding formula 1a; Also can select to replace nicotinic acid and CDI (N, N '-carbonyl dimidazoles) and wait the corresponding active acid amides of some reagent react preparations, the corresponding formula 1a acid amides of preparation then.
Wherein, selected alkali can be selected from triethylamine, diisopropylethylamine (DIPEA), pyridine, Dimethylamino pyridine (DMAP) etc.; Reaction solvent can be selected from methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, N, dinethylformamide (DMF) equal solvent; Temperature of reaction can be selected 0 ℃ to room temperature.
Step 3: can select corresponding formula 1a compound to react production I compound with corresponding amine or other reagent with nucleophilic substitution activity.
Wherein, reaction solvent can be selected from dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF), N-Methyl pyrrolidone, ethanol and Virahol equal solvent; Under the effect that is selected from alkali such as triethylamine, diisopropyl ethyl amine (DIPEA), salt of wormwood, cesium carbonate or yellow soda ash, temperature of reaction is at 80 ℃-240 ℃, the formula I compound corresponding with corresponding formula 1a compound prepared in reaction.
Reaction scheme II
Figure BSA00000270012700131
The synthetic logical method of the compound I among the reaction scheme II is described in detail in the route map of reaction scheme II.
Step 1: the substituted heterocycle carboxylic acid particularly replaces the amide compound that nicotinic acid and formula 1c compound condensation prepare corresponding formula 1b.
Wherein, the reaction of preparation acid amides can select to replace the corresponding nicotinoyl chlorine that replaces of method preparation of nicotinic acid and sulfur oxychloride or oxalyl chloride reaction, prepares the compound of corresponding formula 1b subsequently with the compound condensation of formula 1c; Also can select DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-front three aminopropyl) carbodiimide), HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester), TBTU (O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester), DIC condensing agents such as (N, N '-DIC) prepares the acid amides of corresponding formula 1b; Also can select to replace nicotinic acid and CDI (N, N '-carbonyl dimidazoles) and wait the corresponding active acid amides of some reagent react preparations, the corresponding formula 1b acid amides of preparation then.
Wherein, selected alkali can be selected from triethylamine, diisopropylethylamine (DIPEA), pyridine, Dimethylamino pyridine (DMAP) etc.; Reaction solvent can be selected from methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, N, dinethylformamide (DMF) equal solvent; Temperature of reaction can be selected 0 ℃ to room temperature.
Step 2: can select corresponding formula 1b compound to react production 1a compound with corresponding amine or other reagent with nucleophilic substitution activity (A).
Wherein, reaction solvent can be selected from dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF), N-Methyl pyrrolidone, ethanol and Virahol equal solvent; Under the effect of the alkali that is selected from triethylamine, diisopropyl ethyl amine (DIPEA), salt of wormwood, cesium carbonate and yellow soda ash etc., temperature of reaction is at 80 ℃-240 ℃, the formula 1a compound corresponding with corresponding formula 1b compound prepared in reaction.
Step 3: the intermediate of polysubstituted or mono-substituted phenylo boric acid and formula 1a is by Suzuki linked reaction preparation I compound.
Wherein, the method for Suzuki linked reaction can reference (Kotha, S.; Lahiri, K and Kashinath, D.Tetrahedron 2002,48,9633-9695) method in; The palladium catalyst that uses can be selected from bi triphenyl phosphorus palladium chloride (Pd (PPh3) 2Cl 2), tetrakis triphenylphosphine palladium (Pd (PPh 3) 4), acid chloride (Pd (OAc) 2), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (Pd (dppf) Cl 2) and Palladous chloride (PdCl 2); Temperature of reaction is at 80 ℃-160 ℃; Reaction solvent can be selected from 1,4-dioxane, toluene, ethanol and water; Mineral alkali can be selected yellow soda ash, salt of wormwood etc.
For example, the amino bromobenzene of phenylo boric acid and 2-is tetrakis triphenylphosphine palladium (Pd (pph at catalyzer 3) 4), mineral alkali is yellow soda ash, reaction solvent is in the mixing solutions of toluene, ethanol and water, is heated to 100 ℃-130 ℃, reacts to obtain corresponding product in 12 hours.
Compound of the present invention may contain one or more chiral carbon atoms, and therefore, compound can be used as enantiomer, diastereomer or their mixture and exists.Above-claimed cpd can select racemic modification, diastereomer or enantiomer as raw material or intermediate.Non-mapping compound can be separated by crystallization or chromatography.Enantiomer also can be separated via crystallization, chiral chromatography or other currently known methodss.Each unsymmetrical carbon can be R or S configuration, and two kinds of configurations are all within the scope of the invention.
The present invention includes the prodrug of above-claimed cpd.Prodrug comprises known amino protecting group and carboxyl-protecting group, is hydrolyzed or discharges via enzyme reaction to obtain parent compound under physiological condition; Prodrug of the present invention refers in particular to the prodrug that forms with amino, is got by the acyl compounds prepared in reaction of the active nitrogen-atoms in the The compounds of this invention and activation usually.Concrete preceding medicament preparation can be with reference to (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4,1985-1990.Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J.Med.Chem.2000,43,475.).
Usually, The compounds of this invention can form suitable formulation with one or more pharmaceutical carriers and uses.That these formulations are applicable to is oral, rectal administration, topical, mouthful in administration and other parenteral routes use (for example, subcutaneous, muscle, vein etc.).For example, the formulation of suitable oral administration comprises capsule, tablet, granule and syrup etc.The compound of the present invention that comprises in these preparations can be pressed powder or particle; Solution in water-based or the non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be made via general practice of pharmacy by active compound and one or more carriers or auxiliary material.Above-mentioned carrier need with active compound or other auxiliary material compatibilities.For solid preparation, non-toxic carrier commonly used includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.The carrier that is used for liquid preparation includes but not limited to water, physiological saline, D/W, ethylene glycol and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.
Concrete administering mode and formulation depend on the physico-chemical property of compound itself and the severity of the disease of using etc.
On the one hand, compound of the present invention or formulation are applicable to warm-blooded animal; On the other hand, compound of the present invention and formulation are applicable to Mammals, such as the mankind.
Compound of the present invention can suppress the hedgehog signal transduction, therefore is used for the treatment of the relevant cancer of Hedgehog path unusual when ptch1 can not or can not fully suppress Smo (Ptch1 loses the function phenotype) and/or when Smo still has activity (Smo obtains the function phenotype) under the situation that Ptch1 suppresses.
The compounds of this invention can be applied to tumours such as rodent cancer and medulloblastoma separately, also can with the other drug combined administration in (but being not limited to) carcinoma of the pancreas, mammary cancer, spinal meningioma, glioblastoma, melanoma, cancer of the stomach, esophagus cancer, cholangiocarcinoma, prostate cancer, colorectal carcinoma, small cell lung cancer, nonsmall-cell lung cancer, neurogliocyte cancer and multiple myeloma etc.
Can include but not limited to gemcitabine, cis-platinum, carboplatin, imatinib mesylate, Temozolomide, Zorubicin, Dacarbazine, Te Luokai, Etoposide, daunorubicin and cytosine arabinoside etc. with the medicine of this compound coupling.
Composition of the present invention is prepared in the mode that meets the medical practice standard, quantitative and administration.The factors such as the target spot of cause, medicine of " significant quantity " of compound individuality by the concrete illness that will treat, treatment, illness and administering mode that give determine.Usually, general dosage through the gi tract external administration is 1-200mg/kg.The formulation of oral administration can contain 1-1000mg/kg compound of the present invention.
Embodiment
Hereinafter described experiment, synthetic method and related intermediate are to illustrate of the present invention, do not limit the scope of the invention.
Among the present invention the employed starting raw material of experiment or buy from reagent suppliers or via standard method by known feedstock production.Except as otherwise noted, the embodiment of this paper uses following condition:
1) unit of temperature be degree centigrade (℃); The definition of room temperature is 18-25 ℃;
2) organic solvent uses anhydrous magnesium sulfate or anhydrous sodium sulfate drying; Use Rotary Evaporators under decompression intensification condition, to be spin-dried for (for example: 15mmHg, 30 ℃);
3) use during column chromatography for separation silica gel as carrier, TLC represents silica gel thin-layer plate;
4) generally, the progress of reaction is by TLC or LC-MS monitoring;
5) evaluation of the finished product by nucleus magnetic resonance (Bruker AVANCE 300,300MHz) and LC-MS (Bruker esquine 6000, Agilent 1200series) finish.
Preparation embodiment 1: N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-morpholine niacinamideSynthetic
Figure BSA00000270012700161
1) 3-amino-2-methyl-the 4 '-trifluoromethyl-biphenyl of preparation formula 3:
Take by weighing 3-bromo-2-aminotoluene (1.0g; 5.4mmol; formula 1 compound), 4-trifluoromethyl phenylo boric acid (1.3g; 6.8mmol; formula 2 compounds), bi triphenyl phosphorus palladium chloride (0.4g, 0.54mmol) and yellow soda ash (1.7g 16.0mmol) places microwave building-up reactions pipe; nitrogen protection, microwave heating to 120 ℃ reaction 30min.React the after-filtration that finishes and remove insolubles, filtrate water dilution, ethyl acetate extraction, organic phase salt water washing, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, crude product is through column chromatography purification (normal hexane: ethyl acetate 8: 1), get yellow solid (1.3g, 90.0%, formula 3 compounds).
1H-NMR(300MHz，DMSO-d 6)δ：7.65(d，2H，J＝8.1Hz)，7.42(d，2H，J＝8.1Hz)，7.09(t，1H，J＝7.8Hz)，6.75(d，1H，J＝7.8Hz)，6.67(d，1H，J＝7.5Hz)，3.86(br，2H)，2.04(s，3H).
MS(ESI，m/z)：[M+H] +251.9
2) the 6-chloro-N-of preparation formula 5 (2-methyl-4 '-trifluoromethyl-biphenyl base) niacinamide:
With 3-amino-2-methyl-4 '-trifluoromethyl-biphenyl (1.3g, 5.2mmol, formula 3 compounds), 6-chloro-nicotinic acid (1.06g, 6.73mmol, formula 4 compounds) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 1.5g 7.83mmol) mixing is dissolved in the 15mL pyridine, in stirring at room reaction 20h.The TLC detection reaction, after reaction finishes, desolventizing, oily matter is dissolved in ethyl acetate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.The crude product of desolventizing is through purification by silica gel column chromatography (normal hexane: ethyl acetate 10: 1～3: 1), get white solid (1.4g, 69.2%, formula 5 compounds).
1H-NMR(300MHz，DMSO-d 6)δ：8.90(d，1H，J＝2.1Hz)，8.21(dd，1H，J＝2.1Hz，J＝8.1Hz)，7.82(d，1H，J＝7.8Hz)，7.69(d，3H，J＝8.1Hz)，7.50(d，1H，J＝8.4Hz)，7.43(d，2H，J＝8.1Hz)，7.35(t，1H，J＝7.8Hz)，7.15(d，1H，J＝7.5Hz)，2.20(s，3H).
MS(ESI，m/z)：[M+H] +391.1
3) the N-[(2-methyl-4 of preparation formula 7 '-the trifluoromethyl-biphenyl base)] nicotinoyl amido morpholine:
Take by weighing 6-chloro-N-(2-methyl-4 '-trifluoromethyl-biphenyl base) niacinamide (50mg, 0.13mmol, the compound of formula 5), morpholine (55mg, 0.64mmol) and salt of wormwood (37mg, 0.27mmol) place microwave building-up reactions pipe, the DMSO that adds 1～2mL, microwave heating to 180 ℃ reaction 30min.After reaction finishes reactant is dropped in the 10mL water, collect the solid of separating out, water, normal hexane washing, drying gets crude product.Through thin-layer chromatography preparation of silica gel plate purifying, get off-white color solid (37mg, 64.5%, formula 7 compounds).
1H-NMR(300MHz，DMSO-d 6)δ：9.81(s，1H)，8.78(d，1H，J＝2.4Hz)，8.11?(dd，1H，J＝2.1Hz，J＝9.0Hz)，7.83(d，2H，J＝8.1Hz)，7.56(d，2H，J＝8.1Hz)，7.40(d，1H，J＝6.9Hz)，7.32(t，1H，J＝7.5Hz)，7.16(dd，1H，J＝7.5Hz)，6.93(d，1H，J＝9.0Hz)，3.71(t，4H，J＝4.2Hz)，3.59(t，4H，J＝5.1Hz)，2.09(s，3H).
MS(ESI，m/z)：[M+H] +442.2
Preparation embodiment 2:N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2,6-thebaine] pyridazine-3-acid amides synthetic
Figure BSA00000270012700181
1) N-of preparation formula 3 (3-bromo-2-aminomethyl phenyl)-6-chlorine pyridazine-3-acid amides:
Under the ice bath, with 3-bromo-2-aminotoluene (372.1mg, 2.0mmol, formula 1 compound), 6-chlorine pyridazine-3-acid (317.1mg, 2.0mmol, formula 2 compounds), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 766.8mg, 4.0mmol) mix and to be dissolved in the 10mL pyridine, stirred overnight at room temperature, pyridine, residue acetic acid ethyl dissolution are removed in decompression, organic phase wash with water (3 * 5mL), use anhydrous sodium sulfate drying.Filter, concentrate purification by silica gel column chromatography (normal hexane: ethyl acetate 5: 1), get white solid (265.0mg, 40.6%, formula 3 compounds).
1H-NMR(300MHz，CDCl 3)δ：9.95(s，1H)，8.48(d，1H，J＝8.7Hz)，8.05(d，1H，J＝8.1Hz)，7.77(d，1H，J＝8.7Hz)，7.47(d，1H，J＝8.1Hz)，7.16(t，1H，J＝8.1Hz)，2.51(s，3H).
MS(ESI，m/z)：[M+H] +327.9
2) N-of preparation formula 5 (3-bromo-2-aminomethyl phenyl)-6-[(2R, 6S)-2, the 6-thebaine] pyridazine-3-acid amides:
With N-(3-bromo-2-aminomethyl phenyl)-6-chlorine pyridazine-3-acid amides (100mg, 0.31mmol, formula 3 compounds), (2R, 6S)-2,6-thebaine (0.19mL, 1.5mmol, formula 4 compounds) and salt of wormwood (126.7mg 0.92mmol) mixes and to be dissolved in 4mL N, in the dinethylformamide, at 130 ℃ of reactions of microwave synthesizer 10min, cooling, reaction solution is poured in the frozen water, separate out white solid, suction filtration, drying, get white solid (122mg, 98.4%, formula 5 compounds).
1H-NMR(300MHz，CDCl 3)δ：9.81(s，1H)，8.12(t，2H，J＝3.3Hz)，7.41(d，1H，J＝8.1Hz)，7.12(t，1H，J＝8.1Hz)，7.02(d，1H，J＝9.6Hz)，4.30(d，2H，J＝13.2Hz)，3.75(m，2H)，2.77(dd，2H，J＝10.8Hz，J＝12.9Hz)，2.50(s，3H)，1.30(d，6H，J＝6.3Hz).
MS(ESI，m/z)：[M+H] +405.2
3) the N-{2-methyl-3-[4 ' of preparation formula 7-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] pyridazine-3-acid amides:
Under nitrogen protection; with N-(3-bromo-2-aminomethyl phenyl)-6-[(2R; 6S)-2; the 6-thebaine] pyridazine-3-acid amides (100mg; 0.20mmol, formula 5 compounds); 4-trifluoromethoxy phenylo boric acid (61.4mg, 0.30mmol; formula 6 compounds); bi triphenyl phosphorus palladium chloride (27.9mg; 0.04mmol) and yellow soda ash (63.3mg 0.60mmol) joins 4mL 1, in the mixed solvent of 4-dioxane and water (3: 1); at 130 ℃ of reactions of microwave synthesizer 60min; suction filtration, silica gel column chromatography (normal hexane: ethyl acetate 1: 4), get white solid (50.0mg; 51.6%, formula 7 compounds).
1H-NMR(300MHz，CDCl 3)δ：9.85(s，1H)，8.23(m，2H)，7.30(m，5H)，7.06(m，2H)，4.30(d，2H，J＝12.3Hz)，3.76(br，2H)，2.78(t，2H，J＝11.4Hz)，2.25(s，3H)，1.30(m，6H).
MS(ESI，m/z)：[M+H] +487.3
Preparation embodiment 3:N-{4-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2,6-thebaine] niacinamide synthetic
Figure BSA00000270012700201
1) N-of preparation formula 3 (3-bromo-4-aminomethyl phenyl)-6-chloro-niacinamide:
With 3-bromo-4 monomethylanilines (169mg, 1.07mmol, formula 1 compound), 6-chloro-nicotinic acid compound (200mg, 1.07mmol, formula 2 compounds) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) mixes and is dissolved in the 15mL pyridine, in stirring at room reaction 20h.The TLC detection reaction, after reaction finishes, desolventizing, oily matter is dissolved in ethyl acetate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Desolventizing gets yellow solid (300mg, 85.8%, formula 3 compounds).
1H-NMR(300MHz，CDCl 3)δ：8.96(s，1H)，8.49(s，1H)，8.31(d，1H，J＝8.1Hz)，8.21(dd，1H，J＝2.1Hz，J＝8.4Hz)，7.50(d，1H?J＝8.4Hz)，7.30(d，3H，J＝7.8Hz)，7.09(d，1H，J＝7.5Hz)，2.46(s，3H).
LC-MS(m/z)：[M+H] +326.9
2) N-of preparation formula 5 (3-bromo-4-aminomethyl phenyl)-6-[(2R, 6S)-2, the 6-thebaine] niacinamide:
Take by weighing N-(3-bromo-4-aminomethyl phenyl)-6-chloro-niacinamide (100mg, 0.31mmol, formula 3 compounds), (2R, 6S)-2,6-thebaine (180mg, 1.54mmol, formula 4 compounds) and salt of wormwood (85mg 0.61mmol) places microwave tube, the DMF that adds 1～2mL, microwave heating to 150 ℃ reaction 30min.After reaction finishes reactant is dropped in the 10mL water, collect the solid of separating out, water, normal hexane washing, drying gets crude product.Through the prefabricated slave board purifying of thin-layer chromatography silica gel, get yellow solid (67mg, 53.5%, formula 5 compounds), need not purifying, be directly used in next step.
LC-MS(m/z)：[M+H] +406.0
3) the N-{4-methyl-3-[4 ' of preparation formula 7-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide:
Take by weighing N-(3-bromo-4-aminomethyl phenyl)-6-[(2R, 6S)-2, the 6-thebaine] niacinamide (67mg; 0.16mmol, formula 5 compounds), 4-trifluoromethoxy phenylo boric acid (51mg; 0.25mmol, formula 6 compounds), bi triphenyl phosphorus palladium chloride (11mg; 0.016mmol) and yellow soda ash (53mg; 0.5mmol) place the microwave composite tube, add 4mL 1, the mixed solvent of 4-dioxane and water (3: 1); add nitrogen protection, in the microwave synthesizer, be heated to 120 ℃ of reaction 30min.React the after-filtration that finishes and remove insolubles, filtrate water dilution, ethyl acetate extraction, organic phase salt water washing, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, crude product is through column chromatography purification (normal hexane: ethyl acetate=8: 1), get white solid (15mg, 19.3%, formula 7 compounds).
1H-NMR(300MHz，CDCl 3)δ：8.31(d，1H，J＝8.1Hz)，8.20(d，1H，J＝2.4Hz，)，7.57(dd，1H，J＝2.1Hz，J＝9.0Hz)，7.37(m，5H)，7.08(d，1H，J＝7.8Hz)，6.51(d，1H，J＝9.3Hz)，4.13(m，2H)，3.66(m，2H)，2.58(t，2H，J＝10.8Hz)，2.07(s，3H)，1.23(s，6H).
LC-MS(m/z)：[M+H] +486.3
The embodiment compound:
Following compounds (table one) utilizes similar starting raw material to prepare by being similar to aforesaid method:
Table one
Figure BSA00000270012700211
Figure BSA00000270012700221
Figure BSA00000270012700231
Figure BSA00000270012700241
Figure BSA00000270012700251
Figure BSA00000270012700261
Figure BSA00000270012700271
Figure BSA00000270012700281
Figure BSA00000270012700291
EXPERIMENTAL EXAMPLE 1
Below, compound of the present invention is tested to estimate it for the inhibition ability of Hedgehog signal transduction path.
1. Bioactivity screening test: (test of Hedghog signal transduction pathway Gli-luciferrase reporter gene)
The two luciferase reporter gene test experience materials of Gli and method
1. material
1.1 cell strain: shhLightII, (ATCC:CRL-2795)
1.296 orifice plate: Corning, Cat#3610
1.3 cell growth medium: DMEM (Gibco, 11995) adds 10%NCS (Gibco), adds 0.4mG/mL G418 (invitrogen, 10031035), add 0.15mg/mL zeocin (invitrogen, R25001)
1.4 cell induction substratum: DMEM (Gibco, 11995) adds 0.5%NCS, adds 5mMHEPES, pH 7.4
1.5 inductor: A:20a-hydroxycholesterol (sigma, Cat.H6378), S:22 (s)-hydroxycholesterol (Sigma, Cat.H5884); Inductive condition: A: S=1: 1 mixes, and makes its final concentration be respectively 5uM.
1.6 two reporter gene test kits: Dual-Glo luciferase assay kit:promega (E2920)
1.7 multichannel pipettor
1.8 microwell plate vibrator
1.9 microplate reader: Tecan IF200
2. method
2.1 cell inoculation: the ShhlightII cell in the vegetative period of taking the logarithm is inoculated in 96 orifice plates, 30,000cells/ hole/100uL, 37 ℃, 5%CO 2Grew two days, and made cell reach maximum growth density
2.2 cell induction and administration: will take out from incubator in two days cell of 96 orifice plates growth.Old substratum is removed in suction, adds the cell induction substratum contain inductor (A: S=1: 1, each 10uM, 2 times of final concentrations), the 100uL/ hole.Then, add the cell induction substratum (2 times of final concentrations to be measured) that contains the different concns testing sample, the 100uL/ hole.96 orifice plates that administration is finished place 37 ℃, contain 5%CO 2Incubator, hatch 40h.
2.3 reporter gene detects: before the experiment beginning, with 96 orifice plates, and the test kit balance is to room temperature.Suction removes to contain the substratum of inductor and medicine to be measured, adds the cell induction substratum 50ul/ hole of equilibrium at room temperature.Then to specifications, add
Figure BSA00000270012700301
Reagent, the 50ul/ hole.96 orifice plates are placed microwell plate vibrator, room temperature 10min.According to the TecanIF200 explanation, measure luciferase reporter gene.After mensuration was finished, adding newly prepared
Figure BSA00000270012700302
Reagent, the 50ul/ hole.96 orifice plates are placed the microwell plate vibrator, behind the room temperature 10min, measure the renilla luciferase reporter gene.
2.4 calculate inhibiting rate according to the test kit specification sheets, the match of origin8 software logarithm obtains the IC of testing compound 50Value.IC 50More low, expression testing compound activity is more high.
Table oneIn compound for the inhibition ability reference of Hedgehog signal transduction path Table two(the two luciferase reporter genes of Gli detect) down:
* represent IC 50=0.1nM-10nM
* represents IC 50=10nM-100nM
* * represents IC 50=100nM-1000nM
* * * represents IC 50=1000nM-10000nM
Table two
Figure BSA00000270012700303
Figure BSA00000270012700311
As can be seen, compound of the present invention can show extraordinary in-vitro suppression capacity for the Hedgehog signal transduction path from table two, thereby can be used for the treatment for cancer relevant with Hedgehog signal transduction path abnormal activation.

Claims (5)

1. formula I compound or its pharmacy acceptable salt:
Wherein said compound is selected from:
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-methylpiperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-ethyl piperazidine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-ethanoyl piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3R, 5S)-3, and 5-lupetazin-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-dimethylated morpholinyl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-morpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(piperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(3,5-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-dimethylated morpholinyl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza -1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(3,4-methylpiperazine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
5-{5-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] phenyl-formamyl }-pyridine-2-yl }-(1S, 4S)-2, the 5-diaza Assorted dicyclo [2.2.1] heptane base-2-t-butyl formate;
5-{5-{2-methyl-[4 '-(trifluoromethyl) phenyl] phenyl-formamyl }-pyridine-2-yl }-1, the 4-diaza
Figure FDA00002847825200023
-1-t-butyl formate;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(ethanoyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza
Figure FDA00002847825200024
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,4-diaza
Figure FDA00002847825200025
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(2,5-diaza
Figure FDA00002847825200026
Dicyclo [2.21] heptane base-2-yl)] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(4-methyl isophthalic acid, 4-diaza
Figure FDA00002847825200027
-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-{[(3S)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-{[(3R)-and 3-N, the N-dimethylamino] Pyrrolidine-1-yl } niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(3S)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[(3R)-and 3-methylpiperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(4-benzyl diethylenediamine-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(3,5-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-thiomorpholine niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(3,4-lupetazin-1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-(2,5-diaza
Figure FDA00002847825200031
Dicyclo [2.2.1] heptane base-2-yl)] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-(1,4-diaza -1-yl) niacinamide;
N-{2-methyl-3-[4 '-(cyano group) phenyl] } phenyl-6-[4-(methylsulfonyl) piperazine-1-yl] niacinamide;
N-{2-methyl-3-[4 '-(difluoro-methoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] pyridazine-3 acid amides;
N-{2-methyl-3-[4 '-(trifluoromethyl) phenyl] } phenyl-6-[4-(phenyl) piperazine-1 base] niacinamide;
N-{2-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide;
N-{2-methyl-3-[4 '-(difluoro-methoxy) phenyl] } phenyl-6-(1,1-dioxo-thiomorpholine) niacinamide;
N-{4-methyl-3-[4 '-(trifluoromethoxy) phenyl] } phenyl-6-[(2R, 6S)-2, and the 6-thebaine] niacinamide.
2. pharmaceutical composition as inhibitor, it comprises the described formula I compound of the claim 1 for the treatment of significant quantity or its pharmacy acceptable salt and an amount of pharmaceutically acceptable carrier.
3. the described formula I compound of claim 1 is for the preparation of the application in the medicine that suppresses the Hedgehog path.
4. the described formula I compound of claim 1 is for the preparation of the application in the medicine of the treatment cancer relevant with Hedgehog path abnormal activation, and wherein cancer is selected from rodent cancer, medulloblastoma, rhabdosarcoma, carcinoma of the pancreas, mammary cancer, spinal meningioma, glioblastoma, melanoma, cancer of the stomach, esophagus cancer, cholangiocarcinoma, prostate cancer, colorectal carcinoma, small cell lung cancer, nonsmall-cell lung cancer, multiple myeloma and leukemia.
5. the described formula I compound of claim 1 is for the preparation of the application in the medicine of the treatment cancer relevant with Hedgehog path abnormal activation, and wherein cancer is the neurogliocyte cancer.
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