CN100436450C - Novel triarylimidazoles - Google Patents
Novel triarylimidazoles Download PDFInfo
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- CN100436450C CN100436450C CNB2004800305767A CN200480030576A CN100436450C CN 100436450 C CN100436450 C CN 100436450C CN B2004800305767 A CNB2004800305767 A CN B2004800305767A CN 200480030576 A CN200480030576 A CN 200480030576A CN 100436450 C CN100436450 C CN 100436450C
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Abstract
Compounds of the general formula (I) are valuable therapeutics for the treatment of cancer and cancer related diseases.
Description
The present invention relates to novel triarylimidazoles and their pharmacologically acceptable salt.These compounds are albumen-tyrosine kinase inhibitors, and particularly therefore the c-met kinase inhibitor is the excellent therapy that is used for the treatment of cancer.The invention still further relates to and contain the pharmaceutical composition of this novel cpd as the active agent of treatment cancer and cancer relative disease.
Background of invention
The γ phosphate radical of catalysis ATP is to the enzyme of the tyrosine residues transfer of protein substrate, and albumen-Tyrosylprotein kinase (PTKs) is the key ingredient of the signal pathway of control cell proliferation and differentiation.PTKs can be subdivided into two extended familys, receptor tyrosine kinase (RTKs) and nonreceptor tyrosine kinase (NRTKs).RTKs is across plasma membrane, and contains the extracellular domain of binding partner and have catalytic activity and regulate the intracellular portion of sequence.Most of RTKs have single polypeptide chain and are monomeric forms when part does not exist as hepatocyte growth factor receptor c-met.Part is attached to the extracellular part of RTKs, makes the receptor dimerization of monomeric form, and (comment is referring to Blume-Jensen, P. and Hunter, T., Nature 411 (2001) 355-365 thereby cause the autophosphorylation of the specific tyrosine residues of kytoplasm part; Hubbard, S.R. etc., J.Biol.Chem.273 (1998) 11987-11990; Zwick, E. etc., Trends Mol.Med.8 (2002) 17-23).Usually, tyrosine autophosphorylation or costimulatory receptor inherent catalysis kinase activity, the proteic additional site of downstream signal that perhaps produces phosphoric acid tyrosine-recognition structure territory such as Src homologue 2 (SH2) structural domain or phosphoric acid tyrosine-combination (PTB) structural domain.
Protein tyrosine kinase plays a crucial role in the intracellular signal transduction approach, and described intracellular signal transduction approach causes different cellular response, for example breeds apoptosis and differentiation.Therefore these enzymes become the primary target of development of new therapy, and described novel therapies is designed for blocking-up cancer cell multiplication, transfer, vasculogenesis and promotes apoptosis.The maximum strategy of progress is to be the monoclonal antibody of target with the growth factor receptor tyrosine kinase aspect clinical development.But, use the small molecules tyrosine kinase inhibitor to have significant theoretical advantage than monoclonal antibody.Micromolecular inhibitor can have better tissue penetration, can have activity with the sudden change target site by the interior target site of pair cell, and can be designed to have oral administration biaavailability.Several lead compounds have demonstrated the activity likely to such target site, described target site such as EGFR (vascular endothelial growth factor receptor) and bcr-abl.
Hepatocyte growth factor receptor c-met is discerned as activated oncogene in people's human osteosarcoma cell clone (MUNG-HOS) that N-methyl-N '-nitrosoguanidine is handled first by its ability that transforms NIH 3T3 l cell.The albumen of two chains that the acceptor of c-met proto-oncogene (being positioned on the karyomit(e) 7) coding is made up of with the α beta composite form of 190kDa by disulfide linkage 50kDa (α) chain and 145kDa (β) chain.The α chain is exposed to cell surface, and the β chain is across cytolemma and have the intracellular tyrosine kinase domain.The existence of this intracellular tyrosine kinase domain makes c-met become a member of receptor tyrosine kinase (RTK) family of cell surface molecule.
PHGF (HGF) is also referred to as Scatter Factor (SF), is the multifunctional cytokine that causes multiple response in different cells and tissue.Because its initial discovery and sign, HGF/SF has become the object of further investigation, particularly about it cancer development and ongoing role.A large amount of evidences point out it to invade and shift effect of conditioning agent as oncogenesis, cancer, and (comment is referring to Herynk, M.H. and Radinsky, R., In Vivo 14 (2000) 587-596; Jiang, W. etc., Crit.Rev.Oncol.Hematol.29 (1999) 209-248; Longati, P. etc., Curr.DrugTargets 2 (2001) 41-55; Maulik, G. etc., Cytokine Growth Factor Rev.13 (2002) 41-59; Parr, C. and Jiang, W.G., Histol.Histopathol.16 (2001) 251-268.
HGF/SF is attached to and induces the tyrosine phosphorylation of ripe c-met acceptor β chain.It is believed that this incident has promoted to contain in the cell in src homologue (SH) zone signal protein such as PLC-γ, Ras-GAP, PI-3 kinases pp60
C-srcWith combining of GRB-2Socs mixture and activated receptor.Every kind of albumen that contains SH2 can activate the subclass of different signal phospho-peptides, thus the response of the difference in the trigger cell.
The C-met mutant has carried out abundant description in heredity and sporadic people's papillary kidney, and in hepatocellular carcinoma, transitivity head and neck squamous cell carcinoma and the cancer of the stomach report is arranged in ovarian cancer, childhood.C-met also in nonsmall-cell lung cancer and small cell lung cancer cell, crosses in chest, colon and prostate tumor and expresses.Because c-met appears to play an important role in the tumour of various tumours takes place, adopted various inhibition strategies to come this receptor tyrosine kinase of therapeutic ground target.
Shown that many arrestin-Tyrosylprotein kinase c-met for the validity of inhibition tumor growth and intrusion (for example: Abounader, R. etc., J.Natl.Cancer Inst.91 (1999) 1548-1556 in through experiment before proof clinical; Laterra, J. etc., Lab.Invest.76 (1997) 565-577; Tomioka, D., Cancer Res.61 (2001) 7518-7524; Wang, R. etc., J.Cell Biol.153 (2001) 1023-1033).
WO 96/18626 has described Tyrosylprotein kinase and the kinase whose inhibitor of c-met, and these inhibitor are derivatives (embodiment 5,6 and 55) of 2-(2, the 6-dichlorophenyl)-4-phenyl-5-(pyridin-4-yl)-1H-imidazoles.But they have unfavorable Cytochrome P450 and interact.
Discovery compound according to the present invention has been avoided this shortcoming now, and it has good solubility, is the kinase whose effective inhibitor of c-met.
Summary of the invention
The present invention relates to the compound of general formula (I),
Wherein
W is-N=; And
X is a hydrogen;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl; Phenyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Triazolyl; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base; O-A
1-NR
3R
4S-A
1-NR
3R
4The 4-carboxyl phenyl; Furans-3-base; Thiophene-2-base or 3 methyl thiophene-2-base;
N is 1 or 2; And
Z represents one or both substituting groups, and described substituting group is independently selected from: halogen; Hydroxyl; Allyloxy; Methyl; C
1-C
3-alkoxyl group, its optional pyridyl replaces; The methoxy methoxy base; (2-methoxyethoxy) methoxyl group; Methylthio group; The ethoxy methoxyl group; Methylene-dioxy; Ethynyl; Trimethylsilyl ethynyl and the optional benzyloxy that is replaced by halogen, methoxyl group, cyano group, nitro, methylene-dioxy, carboxyl or oxyethyl group;
Perhaps alternatively,
W is-CH=; And
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl; Phenyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Triazolyl; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base; O-A
1-NR
3R
4S-A
1-NR
3R
4The 4-carboxyl phenyl; Furans-3-base; Thiophene-2-base or 3 methyl thiophene-2-base;
N is 1 or 2; And
If Z n is 1, the C that its expression pyridyl replaces
1-C
3-alkoxyl group; And
If being 2, one substituting groups, n represents the C that pyridyl replaces
1-C
3-alkoxyl group, and second substituting group is independently selected from: halogen; Hydroxyl; Allyloxy; Methyl; C
1-C
3-alkoxyl group; The methoxy methoxy base; (2-methoxyethoxy) methoxyl group; Methylthio group; The ethoxy methoxyl group; Methylene-dioxy; Ethynyl; The trimethylsilyl ethynyl; With
Their pharmacologically acceptable salt.
Be surprisingly found out that: on 2-position, have 2 at imidazole ring, the 6-dichlorophenyl or-during the pyridyl residue, The compounds of this invention is because c-met restraining effect and distinguishingly have medicine and antitumorgienesis activity.
Detailed Description Of The Invention
Preferred and R
1, R
2, R
3, R
4And A
2Relevant C
1-C
6-alkyl is methyl, ethyl and propyl group.
Preferred and Q
1, the R C relevant with Z
1-C
6-alkoxyl group is methoxyl group, oxyethyl group or isopropoxy.
Preferably by R
3And R
4Together the member ring systems of Xing Chenging represent the 1-pyrrolidyl-, piperidino-(1-position only)-, morpholino-or 4-methylpiperazine-1-base.
Preferred X=A
1-Q represents-CH
2OH or-CH
2-CH
2-OH.
Preferred X=-O-A
1-Q
1Be-O-CH
2-CH
2-OH;-O-CH
2-COOH or-O-CH
2-CN.
Y=A
2The preferred group of-R is the 2-hydroxyethyl; The 3-hydroxypropyl; The 2-methoxy ethyl; The 3-methoxy-propyl; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; (R)-the 3-hydroxybutyl; (S)-the 3-hydroxybutyl; 2-morpholinyl ethyl; The morpholinyl propyl group; (CH
2)
3COOH; 2-(4-methylpiperazine-1-yl) ethyl; 3-hydroxyl-2, the 2-dimethyl propyl;
3-hydroxyl-1-phenyl propyl; 3-tert.-butoxy ethyl; The 2-amino-ethyl; The 3-aminopropyl; The amino butyl of 4-; 2-(N, N-dimethylamino) ethyl; 3-(N, N-dimethylamino) propyl group; 3-(tetramethyleneimine-1-yl) propyl group; CH
2COOH; (CH
2)
2COOH; CH (C
2H
5) COOH; (CH
2)
3COOC (CH
3)
3(CH
2)
2-N-COOC (CH
3)
3(CH
2)
3-N-COOC (CH
3)
3(CH
2)
2-O-(CH
2)
2-N (CH
3)
2(CH
2)
2-O-(CH
2)
2-NH
2(CH
2)
2-S-(CH
2)
2-N (CH
3)
2(CH
2)
2-S-(CH
2)
3-N (CH
3)
2(CH
2)
3-S-(CH
2)
2-N (CH
3)
2(CH
2)
3-S-(CH
2)
3-N (CH
3)
2(1,2, the 4-triazol-1-yl) ethyl; 3-(1,2,4-triazole-3-yl) propyl group;
Halogen is fluorine, chlorine, bromine or iodine.
Preferred n is 1, and described substituting group Z is positioned at 3-or 4-position.If Z represents the methoxyl group that pyridyl replaces; The benzyloxy of benzyloxy or replacement, then preferred Z is positioned at the 3-position.
Particularly preferably be the compound of general formula (I) and their pharmacologically acceptable salt, wherein W is-N=; Z is selected from: 3-chlorine; 4-chlorine; The 3-bromine; 3-iodine; The 3-ethynyl; 3-methoxy methoxy base; 3-(2-methoxyethoxy) methoxyl group; The 3-methylthio group; 3-ethoxy methoxyl group; 3,4-methylene radical dioxy base or the optional 3-benzyloxy that is replaced by halogen, methoxyl group, cyano group, nitro, methylene-dioxy, carboxyl or oxyethyl group.
Also particularly preferably be the compound of general formula (I), wherein
W is-N=;
X is a hydrogen;
Y represents the 2-hydroxyethyl; The 3-hydroxypropyl; The 2-methoxy ethyl; The 3-methoxy-propyl; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; (R)-the 3-hydroxybutyl; (S)-the 3-hydroxybutyl; 3-hydroxyl-2, the 2-dimethyl propyl; 2-morpholinyl ethyl;
The morpholinyl propyl group; 2-(4-methylpiperazine-1-yl) ethyl; 3-hydroxyl-1-phenyl propyl;
The 2-amino-ethyl; The 3-aminopropyl; The amino butyl of 4-; 2-(N, N-dimethylamino) ethyl;
3-(N, N-dimethylamino) propyl group; 3-(tetramethyleneimine-1-yl) propyl group; CH
2COOH; (CH
2)
2COOH; (CH
2)
3COOH; CH (C
2H
5) COOH; (CH
2)
2-O-(CH
2)
2-N (CH
3)
2(CH
2)
2-O-(CH
2)
2-NH
2(CH
2)
2-S-(CH
2)
2-N (CH
3)
2(CH
2)
2-S-(CH
2)
3-N (CH
3)
2(CH
2)
3-S-(CH
2)
2-N (CH
3)
2Or (CH
2)
3-S-(CH
2)
3-N (CH
3)
2
N is 1; And
Z is selected from: 3-chlorine; 4-chlorine; The 3-bromine; 3-iodine; The 3-ethynyl; 3-methoxy methoxy base or the optional 3-benzyloxy that is replaced by halogen, methoxyl group, cyano group, nitro, methylene-dioxy, carboxyl or oxyethyl group.
Also particularly preferably be the compound of general formula (I), wherein
W is-N=;
X is a hydrogen;
Y is the 2-hydroxyethyl; The 3-hydroxypropyl; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 2-morpholinyl ethyl; The morpholinyl propyl group; 2-(4-methylpiperazine-1-yl) ethyl; The 2-amino-ethyl; The 3-aminopropyl; 2-(N, N-dimethylamino) ethyl; 3-(N, N-dimethylamino) propyl group or 3-(tetramethyleneimine-1-yl) propyl group;
N is 1; And
Z is selected from: 3-chlorine; 4-chlorine; The 3-bromine; 3-iodine; The 3-ethynyl; 3-methoxy methoxy base or the optional 3-benzyloxy that is replaced by halogen, methoxyl group or cyano group.
Such compound is for example:
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-[3-hydroxypropyl-amino] pyrimidine-4-yl)-the N-1H-imidazoles.
Another embodiment of the present invention is the compound of formula (I), wherein
W is-CH=;
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-hydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or form 5～7 yuan saturated or unsaturated ring together, this ring are replaced and contain the heteroatoms that one or two is independently selected from N or O by methyl is optional;
Y is the 3-hydroxypropyl; And
Z is the optional 3-benzyloxy that is replaced by halogen, methoxyl group or cyano group.
An embodiment more of the present invention is the compound of formula (I), wherein
W is-CH=;
X is a hydrogen; Or OR
1
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
A
1Expression C
1-C
3-alkylidene group;
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides; C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1It is hydroxyl;
Y is the 3-hydroxypropyl; And
Z is the 3-benzyloxy.
An embodiment more of the present invention is the compound of formula (I), wherein
W is-CH=;
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl; Phenyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Triazolyl; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base; O-A
1-NR
3R
4S-A
1-NR
3R
4The 4-carboxyl phenyl; Furans-3-base; Thiophene-2-base or 3 methyl thiophene-2-base;
N is 1; And
Z represents the C that pyridyl replaces
1-C
3-alkoxyl group.
An embodiment more of the present invention is the compound of formula (I), wherein
W is-CH=;
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is the 3-hydroxypropyl;
N is 1; And
Z is pyridine-2-ylmethoxy; Pyridin-3-yl methoxyl group or pyridin-4-yl methoxyl group.
Such compound is for example:
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(4-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-the N-1H-imidazoles,
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(3-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-N-1H-imidazoles and
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(2-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-the N-1H-imidazoles.
Formula (I) expression 2-(2, the 6-dichlorophenyl)-4-phenyl-5-(4-pyrimidyl)-1H-imidazoles, these compounds are tautomers of 2-(2, the 6-dichlorophenyl)-5-phenyl-4-(4-pyrimidyl)-1H-imidazoles.Two kinds of tautomers are represented identical structure, and their name can be exchanged, and two kinds of tautomers all are parts of the present invention.Compound of the present invention can contain one or more unsymmetrical carbons, and can occur with racemic modification, racemic mixture and independent diastereomeric form, all possible isomer comprises optical isomer, is included in the scope of the present invention.
The compound of general formula (I) can pass through general formula (VI) or compound (VII) and amine Y-NH
2, wherein W, X, Y, n and Z have before this implication of definition, react under the temperature in 80～180 ℃ of scopes, separate described compound then and prepare.Preferred use described amine stoichiometric quantity or excessive.Reaction can be carried out under the situation of solvent not having, and is perhaps carrying out in the solvent of diox, glycol dimethyl ether or toluene.
The thioether group of the thioether that general formula (VI) and compound (VII) can be represented by logical formula V by oxidation obtains.In order to obtain the sulfoxide of general formula (VI), preferably use 3-chlorine peroxybenzoic acid to carry out oxidation.Sulfone for synthetic general formula (VII) preferably uses oxone
TM
The thioether of logical formula V
Can obtain by the N-deoxidation of general formula (IV) compound.This reaction preferably uses ethyl bromoacetate to carry out (Somei, M. and Tsuchiya, M., Chem.Pharm.Bull.29 (1981) 3145-3157) in the presence of triethylamine.Alternatively, this step reduction can realize by use triethyl-phosphite in dimethyl formamide.
The compound of general formula (IV) can obtain by general formula (III) compound and the reaction of general formula (II) compound, and wherein substituting group W, X and Z have the implication of definition before this.This reaction is condensation reaction, preferably uses the known method that is used for other aldehyde to carry out in the presence of ammonia.
Another embodiment of the present invention is to adopt aforesaid method, uses the compound of general formula (II), and wherein substituent X has the implication of definition before this, makes the compound of general formula (I).
2, the 6-dichlorobenzaldehyde is a useful intermediates of making general formula of the present invention (I) compound.2,6-two chloro-3-hydroxy benzaldehydes and 2,6-two chloro-4-hydroxy benzaldehydes are that prior art is known.Synthesized 2 from the 3-hydroxy benzaldehyde, 6-two chloro-3-hydroxy benzaldehyde (Gust, R. and Schoenenberg, H., Eur.J.Med.Chem.28 (1993) 103-115), but this method need be used highly toxic chlorine and owing to peroxidation produces by product.Disclosed method among the present invention (embodiment A 2) has been avoided these shortcomings.2,6-two chloro-4-hydroxy benzaldehydes can be from 3, and the 5-chlorophenesic acid is by Reimer-Tiemann reaction (Baldwin, J.J. etc., J.Med.Chem.22 (1979) 687-693) or by bromination/grignard reaction order (WO 01/44154) preparation.The Reimer-Tiemann method can not prepare economically owing to low-down productive rate (＜4%); In addition, require to use chloroform also to cause sizable ecological problem.Other known reaction by bromination/grignard reaction order required for 4 steps altogether, comprised with bromine and carried out the bromination of stoichiometric ratio and use deleterious chloromethyl methyl ether to protect phenol.In addition, overall yield has only 40%.
The invention provides and make 2,6-two chloro-3-hydroxy benzaldehydes and 2, the improving one's methods of 6-two chloro-4-hydroxy benzaldehydes.The method is characterized in that with the 2,4 dichloro phenol or 3 of lithium basic metal protection, 5-chlorophenesic acid, then ester or the acid amides with formic acid reacts, and goes protection and separate described compound.Suitable lithium alkali is lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, LDA or two trimethylsilyl acid amides lithium, preferred butyllithium.The suitable solvent is ether, tetrahydrofuran (THF) or 1,2-glycol dimethyl ether, preferred tetrahydrofuran (THF).Metallization step-100 ℃～-60 ℃, preferably carry out at-80 ℃～-70 ℃.Suitable protecting group is tri isopropyl silane base, tertiary butyl dimethylsilyl or phenyl dimethylsilyl, preferred tri isopropyl silane base.Suitable carboxylic acid derivatives is methyl-formiate, ethyl formate, dimethyl formamide or N-formylpiperidine, preferred dimethyl formamide.This method also can be used for making according to of the present invention 2,6-two chloro-3-methylol phenyl aldehydes and 2,6-two chloro-4-methylol-phenyl aldehydes.
The term of Shi Yonging " pharmaceutically useful salt " is meant conventional acid additive salt or the base addition salt that has kept formula (I) compound biopotency and character before this, and these salt are to form from suitable non-toxic organic or mineral acid or organic or inorganic alkali.The example of acid salt comprises those salt derived from mineral acid, described mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid, and derived from organic acid salt, described organic acid such as tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid etc.The example of base addition salt comprises derived from ammonium, potassium, and the salt of the oxyhydroxide of sodium and quaternary ammonium is for example derived from the salt of tetramethyl ammonium hydroxide.With medical compounds (for example medicine) chemical modification salify is the well-known technology of Pharmaceutical Chemist, physics or chemical stability with improved compound, water absorbability, flowability or solubleness are (referring to for example H.Ansel etc., Pharmaceutical Dosage Forms and DrugDelivery Systems, (the 6th edition, 1995) 196 and 1456-1457 page or leaf).
The pharmacologically acceptable salt of formula (I) compound and formula (I) compound can be used as medicine, for example be used as medicine with pharmaceutical dosage forms.Described pharmaceutical preparation can be oral, for example with tablet, coated tablet, dragee, hard and soft gelatin capsule, solution, emulsion or suspension agent form are oral.But, can also carry out rectal administration, for example with suppository form, perhaps can administered parenterally, for example with the injection liquid form.
Can be with inorganic or organic carrier machining type (I) compound of pharmacy inert useful in preparing drug formulations.For example, can use lactose, the W-Gum or derivatives thereof, talcum, stearic acid or its salt etc. are as this carrier that is used for tablet, coated tablet, dragee and hard gelatin capsule.The suitable carrier of soft gelatin capsule is, vegetables oil for example, wax, fat, semi-solid and liquid polyol etc.But according to the self property of active substance, soft gelatin capsule does not need carrier usually.Making solution or syrupy suitable carrier is, water for example, polyvalent alcohol, glycerine, plant wet goods.The suitable carrier of suppository is for example natural or winterized stearin, wax, fat, semiliquid and liquid polyol etc.
In addition, pharmaceutical preparation can also comprise sanitas, solubilizing agent, and stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, flavouring agent is used to change salt, buffer reagent, sequestering agent or the antioxidant of osmotic pressure.They can also comprise other materials that therapeutic value is arranged.
The medicine that contains formula (I) compound or pharmaceutically acceptable salt thereof and treatment inert support also is an one object of the present invention, their preparation method also is an one object of the present invention, this method comprises one or more formulas (I) compound and/or pharmacologically acceptable salt, and if desired, one or more other the material that therapeutic value is arranged, together with one or more treatment inert supports, make the Galenic form of medication.
Because they are as the activity of tyrosine kinase inhibitor, preferred c-met kinase inhibitor, the compound of general formula (I) is the valuable ingredients that is used for the treatment of the therapy of cancer and other disease relevant with c-met acceptor that improves or associated kinase expression of receptor.
Therefore, can in grace period, change according to the dosage of compound of the present invention, and must be according to the individual need adjustment in each concrete case.Under case of oral administration, the variation range of adult dosage can be from every day about 0.01mg to about 1, the respective amount of the general formula of 000mg (I) compound or pharmaceutically acceptable salt thereof.Per daily dose can in addition, when finding the sign that must treat is arranged, can surpass the upper limit with single dose or divided dose form administration.
Following examples and preparation example are for example understood the present invention, but the implication of unrestricted its scope.
Embodiment
A replace 2,6-dichlorobenzaldehyde synthetic
Embodiment A 1
2,6-two chloro-4-hydroxy benzaldehydes (A1)
Preparation 3,5-dichloro triisopropyl siloxy-benzene (A1.1)
In 0 ℃ in 1 hour to 200g 3,5-chlorophenesic acid and 330ml 2,3.0 liters of anhydrous CH of 6-lutidine
2Cl
2Add 400g triisopropyl-silyl triflate in the solution, and with mixture this temperature restir 3 hours.After with 1.0 premium on currency hydrolysis, organic layer is washed MgSO with saturated NaCl
4Drying, and be evaporated to dried (70 ℃/80 millibars).Resistates places sherwood oil, and filters by silicon-dioxide, obtains 360g (92%) A1.1 colorless oil.
1H-NMR (250MHz, CDCl
3) δ=1.03-1.15 (m, 18H, CH
3); 1.16-1.35 (m, 3H, CH); 6.73-6.80 (m, 2H, CH
Aromatics); 6.92-6.98 (m, 1H, CH
Aromatics)
13C-NMR (62.9MHz, CDCl
3) δ=12.7 (CH); 18.0 (CH
3); 119.0,121.6 (CH
Aromatics); 135.2,157.4 (C
Aromatics).
2,6-two chloro-4-hydroxy benzaldehydes (A1) and 2, the preparation of 6-two chloro-4-triisopropyl siloxy--phenyl aldehydes (A1.2)
Under nitrogen, keep below-65 ℃ temperature, in 2.6 liters of anhydrous tetrahydrofuran solutions of 360g A1.1, add 440ml n-Butyl Lithium (2.7M hexane solution).-70 ℃ stir 2 hours after, add the 120ml anhydrous dimethyl formamide keeping temperature to be lower than under-65 ℃ the situation.Mixture is warmed to ambient temperature overnight.After adding 700ml 4M HCl, with mixture room temperature vigorous stirring 1 hour.Be separated then (adding solid NaCl perhaps is necessary), and organic layer is reduced with dried over sodium sulfate and vacuum.Throw out obtains 154g (70%) A1, m.p.229-230 ℃ with toluene/tetrahydrofuran (THF) recrystallization.
1H-NMR (250MHz, DMSO-D
6) δ=6.94 (s, 2H, CH
Aromatics); 10.25 (s, 1H, CH=O), 11.46 (s (wide), 1H, OH)
13C-NMR (62.9MHz, DMSO-D
6) δ=117.0 (CH
Aromatics); 120.7,137.8,162.1 (C
Aromatics); 187.2 (CH=O).
Embodiment A 2
The preparation of (3,5-two chloro-4-formyl radical phenoxy groups) ethyl acetate (A2)
2.87g (15mmol) A1,2.76g (16.5mmol) ethyl bromoacetate and the mixture of 2.90g (21mmol) salt of wormwood in the 50ml anhydrous propanone were stirred 3 hours at 60 ℃.In filtration with except that after desolvating, resistates silica gel chromatography (ethyl acetate/methanol 100: 2).Output: 3.55g (86%) A2, colorless solid.
1H-NMR (250MHz, CDCl
3): δ=1.32 (t, 7.2Hz, 3H, CH
3); 4.30 (q, 7.2Hz, 2H, CH
2); 4.68 (s, 2H, CH
2); 6.92 (s, 2H, CH
Aromatics); 10.41 (s, 1H, CH=O).
13C-NMR (62.9MHz, CDCl
3): δ=14.3 (CH
3); 62.1,65.5 (CH
2); 116.4 (CH
Aromatics); 123.8,139.2,160.9 (C
Aromatics); 167.3 (C=O); 187.8 (CH=O).
Synthesizing of B " Weinreb "-type acid amides
Embodiment B 1
3-benzyloxy-N-methoxyl group-N-methyl-benzamide (B1)
In the benzoic 1200ml methylene dichloride of 136.8g (0.60mol) 3-benzyloxy suspension, add 60.6g (0.6mol) triethylamine in 10 ℃.Under the temperature of 10 ℃～15 ℃ of maintenances, add the 100ml dichloromethane solution of 64.8g (0.60mol) Vinyl chloroformate (ethyl chloroformiate), last 15 minutes.Stirring 40 minutes and adding 58.2g (0.60mol) N, behind the O-dimethyl hydroxylamine hydrochloride,, lasting 20 minutes in 10～15 ℃ of adding 60.6g (0.60mol) triethylamine solutions.After stirring 30 minutes in addition, add entry, and with the organic layer dried over sodium sulfate.Vacuum fractionation obtains 131.9g (81%) B1.
MS：273(API+)。
Embodiment B 2
3-hydroxy-n-methoxyl group-N-methyl-benzamide (B2)
In the 750ml tetrahydrofuran solution of 100g (0.37mol) B1, add 10g Pd/C (10%), and with mixture hydrogenation under atmospheric pressure 2 hours.Leach catalyzer,, obtain 66.0g B2 (98%) the filtrate evaporation.
MS：182(API+)，180(API-)。
Embodiment B 3
3-(2-pyridyl methoxyl group)-N-methoxyl group-N-methyl-benzamide (B3)
The 5ml anhydrous tetrahydrofuran solution that in the 30ml anhydrous tetrahydrofuran solution of 1.21g (10.0mmol) B2,2.89g (11.0mmol) triphenyl phosphine and 1.20g (11.0mmol) pyridine-2-methyl alcohol, adds 1.92g (11.0mmol) diethylazodicarboxylate, with mixture stirring at room 2 hours.Remove desolvate after, obtain 2.81g B3 light yellow oil (72% productive rate, think the triphenyl phosphine oxide impurity (measuring) of 30mol%) through silica gel column chromatography (hexane/ethyl acetate 2: 1) by NMR.Because the isolating problem of impurity in this specific examples with PS-bonded triphenyl phosphine revision test, obtains the pure B3 of 58% productive rate.
MS：M＝273(API+)
1H-NMR(400MHz，CDCl
3)δ＝3.25(s，3H，CH
3)；3.45(s，3H，OCH
3)；5.15(s，2H，OCH
2)；6.98-7.04(m，1H)；7.12-7.28(m，4H)；7.40-7.48(m，1H)；7.60-7.68(m，1H)；8.46-8.56(m，1H)。
13C-NMR (100.6MHz, CDCl
3) δ=34.3 (CH
3); 61.5 (OCH
3); 71.0 (OCH
2); 114.9,117.6,121.3,121.8,123.2,129.7,135.9
*, 137.3,149.6,157.3
*, 158.3
*(C
AromaticsH); 169.9 (C=O).(
*=quaternary carbon).
Embodiment B 4
3-(3-pyridyl methoxyl group)-N-methoxyl group-N-methyl-benzamide (B4)
With Embodiment B 3 described response class seemingly, but be to use 3-pyridyl methyl alcohol to react, obtain the B4 of 81% productive rate.
MS：M＝273(API+)
1H-NMR(400MHz，DMSO-D
6)δ＝3.24(s，3H，CH
3)；3.53(s，3H，OCH
3)；5.20(s，2H，OCH
2)；7.12-7.24(m，3H)；7.34-7.48(m，2H)；7.84-7.92(m，1H)；8.52-8.60(m，1H)；8.68-8.72(m，1H)。
13C-NMR (100.6MHz, DMSO-D
6) δ=33.7 (CH
3); 61.1 (OCH
3); 67.4 (OCH
2); 114.1,117.3,120.5,124.0,129.7,132.8,136.1,136.2,149.5,149.6,157.9 (C
AromaticsH); 169.0 (C=O).
Embodiment B 5
3-(4-pyridyl methoxyl group)-N-methoxyl group-N-methyl-benzamide (B5)
With Embodiment B 3 described response class seemingly, but be to use 4-pyridyl methyl alcohol to react, obtain the B5 of 82% productive rate.
MS：M＝273(API+)
1H-NMR(400MHz，DMSO-D
6)δ＝3.24(s，3H，CH
3)；3.51(s，3H，OCH
3)；5.24(s，2H，OCH
2)；7.12-7.22(m，3H)；7.34-7.41(m，1H)；7.42-7.48(m，2H)；8.52-8.64(m，2H)。
13C-NMR (100.6MHz, DMSO-D
6) δ=33.7 (CH
3); 61.0 (OCH
3); 67.9 (OCH
2); 114.1,117.3,120.7,122.1,129.8,136.3,146.4,150.1,157.7 (C
AromaticsH); 169.0 (C=O).
C's " ethyl ketone " is synthetic
Embodiment C 1
1-(3-(2-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-ethyl ketone (C1)
Be dissolved in 2.1ml (15mmol) diisopropylamine in the 70ml anhydrous tetrahydro furan and be cooled to-75 ℃, (1.6M 15mmol), lasts 10 minutes to add the n-butyllithium solution of 9.4ml.,, again mixture was stirred 15 minutes after 15 minutes-75 ℃ of stirrings in-75 ℃ of 5ml anhydrous tetrahydrofuran solutions that in 10 minutes, add 1.69g (12mmol) 2-methylthio group-4-methylpyrimidine.Then in-75 ℃ of 5ml anhydrous tetrahydrofuran solutions that in 10 minutes, add 2.73g (7mmol) B3 (70% purity).Mixture was stirred 1 hour at-75 ℃, make it be warming to room temperature then, be poured at last in 100ml ethyl acetate/water (1: 1).Water layer 50ml ethyl acetate extraction, and with the organic layer dried over sodium sulfate that merges.Solvent removed in vacuo obtains 1.52g (62%) C1 through silica gel column chromatography (normal heptane/ethyl acetate 3: 1).(use NMR at CDCl
3In the keto-enol ratio that records in 400MHz be about 30: 70).
MS：M＝352(API+)，350(API-)。
Embodiment C 2
1-(3-(3-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-ethyl ketone (C2)
Be similar to the reaction described in the Embodiment C 1, but start from B4, obtain the C2 of 60% productive rate.
MS：M＝352(API+)，350(API-)。
Embodiment C 3
1-(3-(4-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-ethyl ketone (C3)
Be similar to the reaction described in the Embodiment C 1, but start from B5, obtain the C3 of 55% productive rate.
MS：M＝352(API+)，350(API-)。
Embodiment C 4
1-(3-benzyloxy phenyl)-2-(2-methylthiopyrimidine-4-yl)-ethyl ketone (C4)
Reaction described in the similar sub-Embodiment C 1, but start from B1, obtain the C4 of 89% productive rate.
MS：M＝351(API+)，349(API-)。
D's " ketoxime " is synthetic
Embodiment D1
1-(3-(2-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-2-hydroxyl-imino-ethyl ketone (D1)
1.50g (4.3mmol) C1 is dissolved in the mixture of 18.6ml Glacial acetic acid (glacial acid), 15.0ml tetrahydrofuran (THF) and 2.0ml water.After being cooled to 5 ℃, under situation about maintaining the temperature between 5 ℃～10 ℃, add the 3.5ml aqueous solution of 353mg (5.1mmol) Sodium Nitrite.Remove cooling, at room temperature stirred the mixture 2 hours.After solvent removed in vacuo, add 35ml water and 240ml ethyl acetate.With 3N NaOH with pH regulator to 8.Be separated water layer 50ml ethyl acetate extraction.The organic layer dried over sodium sulfate that merges, and solvent removed in vacuo.Output: 1.61g (99%) D1.
MS：M＝381(API+)，379(API-)
1H-NMR (400MHz, DMSO-D
6) δ=2.17 (s, 3H, SCH3); 5.25 (s, 2H, OCH
2); 7.30-7.35 (m, 1H); 7.36-7.42 (m, 3H); 7.47-7.54 (m, 2H); 7.62-7.65 (m, 1H); 7.78-7.85 (m, 1H); 8.52-8.55 (m, 1H); 8.68-8.72 (m, 1H); 12.80 (wide, 1H, OH).
13C-NMR (100.6MHz, DMSO-D
6) δ=13.6 (SCH
3); 70.9 (OCH
2); 111.7,113.8,121.6,122.0,122.1,123.4,131.0,136.4
*, 137.3,149.5,154.0
*, 156.5
*, 158.7,158.9
*, 159.3
*, 171.8
*193.3
*(C=O). (
*=quaternary carbon).
Embodiment D2
1-(3-(3-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-2-hydroxyl-imino-ethyl ketone (D2)
Carry out and the similar reaction described in the Embodiment C 1, but start from C2, obtain the D2 of 92% productive rate.
MS：M＝381(API+)，379(API-)
1H-NMR(400MHz，DMSO-D
6)δ＝2.19(s，3H，SCH
3)；5.23(s，2H，OCH
2)；7.32-7.46(m，4H)；7.46-7.56(m，1H)；7.58-7.68(m，1H)；7.84-7.92(m，1H)；8.50-8.56(m，1H)；8.64-8.72(m，2H)。
Embodiment D3
1-(3-(4-pyridyl methoxyl group) phenyl)-2-(2-methylthiopyrimidine-4-yl)-2-hydroxyl-imino-ethyl ketone (D3)
Carry out and the similar reaction described in the Embodiment C 1, but start from C3, obtain the D3 of 97% productive rate.
MS：M＝381(API+)，379(API-)
1H-NMR(400MHz，DMSO-D
6)δ＝2.18(s，3H，SCH
3)；5.27(s，2H，OCH
2)；7.36-7.43(m，3H)；7.43-7.49(m，2H)；7.49-7.55(m，1H)；7.61-7.68(m，1H)；8.54-8.63(m，2H)；8.68-8.74(m，1H)；12.78(s，1H，OH)。
Embodiment D4
1-(3-benzyloxy phenyl)-2-(2-methylthiopyrimidine-4-yl)-2-oxyimino ethyl ketone (D4)
Carry out and the similar reaction described in the Embodiment C 1, but start from C4, obtain the D4 of 86% productive rate.
MS：M＝380(API+)，378(API-)
1H-NMR (250MHz, DMSO-D
6) δ=2.19 (s, 3H SCH
3); 5.17 (s, 2H, OCH
2); 7.24-7.53 (m, 9H); 7.59-7.69 (m, 1H); 8.63-8.72 (m, 1H); 12.83 (wide, 1H, OH).
13C-NMR (62.9MHz, DMSO-D
6) δ=13.6 (SCH
3); 69.9 (OCH
2); 111.7,113.7,121.6,122.1,128.1,128.3,128.8,130.9,136.5
*, 136.9
*, 154.0
*, 158.6,159.1
*, 159.4
*, 171.8
*193.5
*(C=O). (
*=quaternary carbon).
E's " N-hydroxyl imidazoles " is synthetic
Embodiment E 1
2-(2,6-two chloro-4-[ethoxycarbonyl methoxies] phenyl)-4-(3-(2-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-hydroxyl-imidazoles (E1)
1.60g (4.2mmol) D1,1.40g (5.0mrmol) A2 and the mixture of 3.25g (42mmol) ammonium acetate in 40ml acetate were stirred 3.5 hours at 105 ℃.Distillation removes and desolvates, and resistates is distributed between 40ml frozen water and 60ml ethyl acetate, and be adjusted to pH8 with strong aqua.The water layer ethyl acetate extraction is with the organic layer MgSO that merges
4Dry and be evaporated to driedly, obtain the oily matter that the 3.60g light brown is slowly solidified, this oily matter is directly used in next step (embodiment F 1) without being further purified.
MS：M＝638(API+)，636(API-)。
Embodiment E 2
2-(2,6-two chloro-4-[ethoxycarbonyl methoxies] phenyl)-4-(3-(3-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-hydroxyl-imidazoles (E2)
Carry out and the similar reaction described in the embodiment E 1, but start from D2, obtain orange buttery E2.
MS：M＝638(API+)，636(API-)。
Embodiment E 3
2-(2,6-two chloro-4-[ethoxycarbonyl methoxies] phenyl)-4-(3-(4-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-hydroxyl-imidazoles (E3)
Carry out and the similar reaction described in the embodiment E 1, but start from D3, obtain yellow solid E3.
MS：M＝638(API+)，636(API-)。
Embodiment E 4
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-hydroxyl-imidazoles (E4)
Carry out and the similar reaction described in the embodiment E 1, but start from D4 and 3,5-dichloropyridine-4-formaldehyde (J.Med.Chem.44 (2001) 997) obtains the E4 orange solids.
MS：M＝536(API+)，534(API-)。
F's " N-H imidazoles " is synthetic
Embodiment F 1
2-(2,6-two chloro-4-[methoxycarbonyl methoxyl groups] phenyl)-4-(3-(2-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F1)
3.59g (4.2mmol) E1,1.41g (8.4mmol) methyl bromoacetate and the mixture of 2.85g (28mmol) triethylamine in 80ml methyl alcohol are spent the night in 60 ℃ of stirrings.After solvent removed in vacuo, obtain the pure F1 of 2.08g (81%) (transesterify in the methyl alcohol) through silica gel column chromatography (ethyl acetate/isohexane 3: 1).
MS：M＝608(API+)，606(API-)。
Embodiment F 2
2-(2,6-two chloro-4-[methoxycarbonyl methoxyl groups] phenyl)-4-(3-(3-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F2)
Carry out and the similar reaction described in the embodiment F 1, but start from E2, obtain 65%F2.
MS：M＝608(API+)，606(API-)。
Embodiment F 3
2-(2,6-two chloro-4-[methoxycarbonyl methoxyl groups] phenyl)-4-(3-(4-pyridylmethyl-oxygen base) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F3)
Carry out and the similar reaction described in the embodiment F 1, but start from E3, obtain 66%F3.
MS：M＝608(API+)，606(API-)。
Embodiment F 4
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(2-pyridyl methoxyl group) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F4)
In the 50ml anhydrous THF solution of the 2.07g under nitrogen (3.3mmol) F1, add LiAlH in 0 ℃
4(1M THF solution) is until detecting less than F1 with HPLC.Be hydrolyzed with 0.5ml water and, resistates with silica gel chromatography (ethyl acetate/methanol 9: 1), obtained 93%F4 except that after desolvating.
MS：M＝580(API+)，578(API-)。
Embodiment F 5
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(3-pyridyl methoxyl group) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F5)
Carry out and the similar reaction described in the embodiment F 4, but start from F2, obtain 64%F5.
MS：M＝580(API+)，578(API-)。
Embodiment F 6
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(4-pyridyl methoxyl group) phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F6)
Carry out and the similar reaction described in the embodiment F 4, but start from F3, obtain 69%F6.
MS：M＝580(API+)，578(API-)。
Embodiment F 7
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-methylthiopyrimidine-4-yl)-N-H-imidazoles (F7)
Carry out and the similar reaction described in the embodiment F 1, but start from E4, obtain 66%F7.
MS：M＝520(API+)，518(API-)。
Synthesizing of G " N-H imidazoles sulfonium " and " N-H imidazoles sulfone "
Embodiment G1
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(2-pyridyl methoxyl group) phenyl)-5-(2-methylsulfinyl pyrimidine-4-yl)-N-H-imidazoles (G1)
At-40 ℃ of 20ml ethyl acetate solutions that in the solution of 1.20g (2.1mmol) F4 in 300ml ethyl acetate and 50ml methylene dichloride, add 0.70g (3.1mmol) metachloroperbenzoic acid, last 10 minutes.After under this temperature 1 hour, make mixture be warmed to room temperature and stirring is spent the night.Purging compound (saturated NaHCO
3The aqueous solution/saturated Na
2CO
3The aqueous solution 1: 1), MgSO
4Dry and be evaporated to driedly, obtain 1.21g G1 crude product, it is without being further purified direct use.
MS：M＝596(API+)，594(API-)。
Embodiment G2
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(3-pyridyl methoxyl group) phenyl)-5-(2-methylsulfinyl pyrimidine-4-yl)-N-H-imidazoles (G2)
Carry out and the similar reaction described in the embodiment G1, but start from F5, obtain G2.
MS：M＝596(API+)，594(API-)。
Embodiment G3
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(4-pyridyl methoxyl group) phenyl)-5-(2-methylsulfinyl pyrimidine-4-yl)-N-H-imidazoles (G3)
Carry out and the similar reaction described in the embodiment G1, but start from F6, obtain G3.
MS：M＝596(API+)，594(API-)。
Embodiment G4
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-methylthio group-pyrimidine-4-yl)-N-H-imidazoles (G4)
2.38g (4.6mmol) F7 is suspended in the 200ml methyl alcohol, at room temperature in 20 minutes, adds 5.62g (9.1mmol) Oxone
TMSolution.After at room temperature stirring was spent the night, vacuum was removed methyl alcohol, and resistates is placed ethyl acetate.Organic layer NaHCO
3Solution washing, Na
2SO
4Dry and be evaporated to dried.Thick G4 (47%) is without being further purified direct use.
MS：M＝552(API+)，550(API-)。
H's " N-H imidazoles aminopyrimidine " is synthetic
Embodiment H1
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(2-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-N-1H-imidazoles (H1)
With 1.21g (2.0mmol) G1 and 3.1g (40.6mmol) 3-amino-1-propyl alcohol be heated to 110 ℃ 60 minutes.Adopt preparation HPLC/MS, go up purifying, obtain 510mg (42%) H1 at RP 18 (methanol-water-gradient).
MS：M＝607(API+)，605(API-)。
Embodiment H2
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(3-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-N-1H-imidazoles (H2)
Carry out and the similar reaction described in the embodiment H1, but start from G2, obtain 50%H2.
MS：M＝607(API+)，605(API-)。
Embodiment H3
2-(2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(4-pyridyl methoxyl group) phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-N-1H-imidazoles (H3)
Carry out and the similar reaction described in the embodiment H1, but start from G3, obtain 32%H3.
MS：M＝607(API+)，605(API-)。
Embodiment H4
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-[3-hydroxypropyl-amino] pyrimidine-4-yl)-N-1H-imidazoles (H4)
Carry out and the similar reaction described in the embodiment H1, but start from G4, obtain 68%H4.
MS：M＝547(API+)，545(API-)。
Embodiment J:c-met self-activation kinase assay (AKA)
Test principle:
C-met relates to the typical Tyrosylprotein kinase of metastases, propagation/apoptosis and vasculogenesis.This test is to use phosphoric acid-tyrosine-specific antibody to measure the ELISA type test of the phosphorylation of c-met.
Known cell lysates with human colon adenocarcinoma HT29 of high c-met content (resist-hHGFR) is attached in the hole of microtiter plate (MTP) by anti--hHGF receptor antibody.Use phosphoric acid-tyrosine mouse IgG and POD labelled goat to resist-mouse IgG detection architecture,, detect the ATP-phosphorylation of c-met in the test compounds existence or not.Use traditional POD substrate TMB, use the absorption of 450nm/620nm to calculate enzymic activity.
Material:
Plate: the microtiter plate of 96 hole polystyrene plate (NUNC) chain bacterium microbiotic-coatings
Clone/lysate: HT29 (ATCC HTB-38) (converges the human colon adenocarcinoma: 2.5 * 10
5Cell/cm
2) wash with PBS, and use molten born of the same parents' damping fluid incubation 10 minutes on ice.Collect supernatant liquor, dilute with TBS.Lysate is quick-frozen in liquid nitrogen ,-80 ℃ of storages.
Reagent (unless stated otherwise, all working solution all remains on 4 ℃):
Anti--hHGFR detects liquid storage: 50 μ g/ml (R﹠amp; D Systems, Cat.No.BAF 358) the antibody ultimate density: 1 μ g/ml
P-Tyr (PY99) mouse liquid storage: 200 μ g/ml (Santa Cruz Biotechnology, mono-clonal IgG2bCat.No.SC-7020) ultimate density: 0.2 μ g/ml
Goat-anti--mouse IgG:2ml (BIO RAD, Cat.No.170-6516), (H+L)-the HRP conjugate; Ultimate density: 1: 2000
Closed reagent: be used for the Roche Diagnostics GmbH of ELISA, Cat.No.1112589 was diluted among the TBS with 1: 10
ATP: adenosine-5 '-triphosphoric acid, liquid storage 10mM, liquid storage 10mM (Roche Diagnostics GmbH, Cat.No.127531), ultimate density: 40 μ M
The TBS:Tris-buffered saline, and 50mM TRIS pH 7.5 (Roche Diagnostics GmbH, Cat.No.708976), 150mM NaCl (SIGMA, Cat.No.S-3014)
Lavation buffer solution TBS-T:Tris-buffered saline, 50mM TRIS pH 7.5150mM NaCl contains 0.5% polysorbas20
Kinase buffer liquid: Tris-buffered saline, 50mM TRIS pH 7.5,100mM NaCl, 60mMMgCl
2(SIGMA Chemical Company, Cat.No.M-1028)
Molten born of the same parents' damping fluid: 50mM TRIS pH 7.5, contain 1%Nonidet P40 (Roche DiagnosticsGmbH, Cat.No.1754599) 0.5% Septochol (SIGMA Chemical Company, Cat.No.D-6750), ultimate density: 1mM 1mM PMSF liquid storage 70mM (Roche DiagnosticsGmbH, Cat.No.83709140 μ l/ml Complete (Roche Diagnostics GmbH, Cat.No.1836145), ultimate density: 40 μ l/ml
TMB: tetramethyl benzidine (Intergen Company, Cat.No.91000)
Sample: 10mM DMSO solution (in-20 ℃ of storages), room temperature is thawed.
Program:
With 50 μ l anti--closed reagent solution that hHGFR detects antibody is added to (ultimate density 1 μ g/ml) on the test board, on the MTP vibrator in room temperature incubation test board 60 minutes.
2. remove anti--hHGFR from test board and detect antibody-solutions.
3. add 250 μ l closed reagents to the every hole of test board, 4 ℃ of incubation test boards 20 hours.
4. remove closed reagent from test board.
5. add 50 μ l HT29 lysates, on the MTP vibrator in 4 ℃ of incubation test boards 180 minutes.
6. with the amount washing test plate of every hole 2 * 200 μ l TBS damping fluids.
7. add 40 0.2%DMSOs of μ l in kinase buffer liquid to test board.
8. add 40 μ l sample solutions (be dissolved in the kinase buffer liquid-ultimate density 22.5 μ M).
9. with sample dissolution (1: 3 ratio) in MTP.
10. the ATP (200 μ M) that 10 μ l is dissolved in the kinase buffer liquid joins (ultimate density 40 μ M ATP) in the sample.Positive control: add 40 μ l kinase buffer liquid+10 μ l, 200 μ M ATP.Negative control: add 40 μ l kinase buffer liquid+10 μ l and do not contain the kinase buffer liquid of ATP.On the MTP vibrator in room temperature incubation test board 60 minutes.
11. amount washing test plate with every hole 2 * 200 μ l TBS damping fluids and 2 * 200 μ l confining liquids.
12. with 50 μ l P-Tyr (PY99) mouse monoclonal IgG
2bClosed reagent solution (ultimate density 200ng/ml) join test board, on the MTP vibrator, spend the night in 4 ℃ of incubation test boards.
13. amount washing test plate with every hole 2 * 200 μ l TBS damping fluids and 2 * 200 μ l closed reagents.
14. add 50 μ l goats anti--the closed reagent solution (1: 2000 ratio) of mouse IgG (H+L)-HRP conjugate, on the MTP vibrator in room temperature incubation test board 60 minutes.
15. amount washing test plate with every hole 6 * 200 μ l TBS-T damping fluids.
16. add 50 μ l TMB solution, on the MTP vibrator,, add 25 μ l 1M H in room temperature incubation 30 minutes
2SO
4
17. measure the optical density(OD) (E) at 450nm/620nm place.
18. following calculating % inhibiting rate:
1-[(E
Sample-E
Negative control)/(E
Positive control-E
Negative control) * 100]
When with above-mentioned experimental test, the typical IC of the kinase inhibition of reagent of the present invention
50The value scope is about 1nM～about 100nM:
| Sample | IC 50C-met[nM] |
| H4 | 23 |
| H1 | 22 |
| H2 | 32 |
| H3 | 54 |
Embodiment K: tablet formulation (wet granulation)
Project
Composition
The mg/ sheet
1. formula (I) compound 5 25 100 500
2. the anhydrous DTG 125 105 30 150 of lactose
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1111
Add up to 167 167 167 831
Manufacture method:
1, mixes 1,2,3 and 4, and use the pure water granulation.
2, at 50 ℃ of following dried particles.
3, allow particle pass through suitable abrasive dust equipment.
4, add the 5th and mixed 3 minutes; On suitable pressing machine, compress.
Embodiment L: capsule formula
Project
Composition
The mg/ capsule
1. formula (I) compound 5 25 100 500
2. lactose hydrous 159 123 148---
3. W-Gum 25 35 40 70
4. talcum 10 15 10 25
5. Magnesium Stearate 1225
Add up to 200 200 300 600
Manufacture method:
1, in suitable mixing tank, mix 1,2 and 3 30 minutes.
2, add 4 and 5 and mixed 3 minutes.
3, be filled in the examples of suitable.
Reference list
Abounader, R. etc., J.Natl.Cancer Inst.91 (1999) 1548-1556
Ansel etc., Pharmaceutical Dosage Forms and Drug Delivery Systems, sixth version, (1995), 196 and the 1456-1457 page or leaf
Baldwin, J.J. etc., J.Med.Chem.22 (1979) 687-693
Blume-Jensen, P. and Hunter, T., Nature411 (2001) 355-365
Gust, R. and Schoenenberg, H., Eur.J.Med.Chem.28 (1993) 103-115
Herynk, M.H. and Radinsky, R., In Vivo 14 (2000) 587-596
Hubbard, S.R. etc., J.Biol.Chem.273 (1998) 11987-11990
Jiang, W. etc., Crit.Rev.Oncol.Hematol.29 (1999) 209-248
J.Med.Chem.44(2001)997
Laterra, J. etc., Lab.Invest.76 (1997) 565-577
Longati, P. etc., Curr.Drug Targets 2 (2001) 41-55
Maulik, G. etc., Cytokine Growth Factor Rev.13 (2002) 41-59
Par, C. and Jiang, W.G., Histol.Histopathol.16 (2001) 251-268
Somei, M. and Tsuchiya, M., Chem.Pharm.Bull.29 (1981) 3145-3157
Tomioka，D.，Cancer Res.61(2001)7518-7524
Wang, R. etc., J.Cell Biol.153 (2001) 1023-1033
WO 01/44154
WO 96/18626
Zwick, E. etc., Trends Mol.Med.8 (2002) 17-23.
Claims (12)
1, a kind of general formula (I) compound,
Wherein
W is-N=; And
X is a hydrogen;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base;
O-A
1-NR
3R
4；S-A
1-NR
3R
4；
A
1Expression C
1-C
3-alkylidene group;
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
N is 1 or 2; And
Z represents one or both substituting groups, and described substituting group is independently selected from: halogen; Hydroxyl; Allyloxy; Methyl; C
1-C
3-alkoxyl group, its optional pyridyl replaces; The methoxy methoxy base; (2-methoxyethoxy) methoxyl group; Methylthio group; The ethoxy methoxyl group; Methylene-dioxy; Ethynyl; Trimethylsilyl ethynyl and the optional benzyloxy that is replaced by halogen, methoxyl group, cyano group, nitro, methylene-dioxy, carboxyl or oxyethyl group;
Perhaps,
W is-CH=; And
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxy ethoxy methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base; O-A
1-NR
3R
4S-A
1-NR
3R
4
N is 1 or 2; And
If Z n is 1, the C that its expression pyridyl replaces
1-C
3-alkoxyl group; And
If being 2, one substituting groups, n represents the C that pyridyl replaces
1-C
3-alkoxyl group, and second substituting group is independently selected from: halogen; Hydroxyl; Allyloxy; Methyl; C
1-C
3-alkoxyl group; The methoxy methoxy base; (2-methoxyethoxy) methoxyl group; Methylthio group; The ethoxy methoxyl group; Methylene-dioxy; Ethynyl; The trimethylsilyl ethynyl; With their pharmacologically acceptable salt.
2, the compound of claim 1, wherein
W is-N=;
X is a hydrogen;
Y represents the 2-hydroxyethyl; The 3-hydroxypropyl; The 2-methoxy ethyl; The 3-methoxy-propyl; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; (R)-the 3-hydroxybutyl; (S)-the 3-hydroxybutyl; 3-hydroxyl-2, the 2-dimethyl propyl; 2-morpholinyl ethyl; The morpholinyl propyl group; 2-(4-methylpiperazine-1-yl) ethyl; The 2-amino-ethyl; The 3-aminopropyl; The amino butyl of 4-; 2-(N, N-dimethylamino) ethyl; 3-(N, N-dimethylamino) propyl group; 3-(tetramethyleneimine-1-yl) propyl group; CH
2COOH; (CH
2)
2COOH; (CH
2)
3COOH; CH (C
2H
5) COOH; (CH
2)
2-O-(CH
2)
2-N (CH
3)
2(CH
2)
2-O-(CH
2)
2-NH
2(CH
2)
2-S-(CH
2)
2-N (CH
3)
2(CH
2)
2-S-(CH
2)
3-N (CH
3)
2(CH
2)
3-S-(CH
2)
2-N (CH
3)
2Or (CH
2)
3-S-(CH
2)
3-N (CH
3)
2
N is 1; And
Z is selected from: 3-chlorine; 4-chlorine; The 3-bromine; 3-iodine; The 3-ethynyl; 3-methoxy methoxy base or the optional 3-benzyloxy that is replaced by halogen, methoxyl group, cyano group, nitro, methylene-dioxy, carboxyl or oxyethyl group.
3, the compound of claim 1, wherein
W is-N=;
X is a hydrogen;
Y is the 2-hydroxyethyl; The 3-hydroxypropyl; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 2-morpholinyl ethyl; Morpholinyl-propyl group; 2-(4-methylpiperazine-1-yl) ethyl; The 2-amino-ethyl; The 3-aminopropyl; 2-(N, N-dimethylamino) ethyl; 3-(N, N-dimethylamino) propyl group or 3-(tetramethyleneimine-1-yl) propyl group;
N is 1; And
Z is selected from: 3-chlorine; 4-chlorine; The 3-bromine; 3-iodine; The 3-ethynyl; 3-methoxy methoxy base or the optional 3-benzyloxy that is replaced by halogen, methoxyl group or cyano group.
4, the compound of claim 3, it is:
2-(3,5-dichloropyridine-4-yl)-4-(3-benzyloxy phenyl)-5-(2-[3-hydroxypropyl-amino] pyrimidine-4-yl)-the N-1H-imidazoles.
5, the compound of claim 1, wherein
W is-CH=;
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxyl group-ethoxyl methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is hydrogen or group A
2-R;
A
2Be C
1-C
5-alkylidene group, it can be by C
1-C
6-alkyl or replaced by hydroxyl is optional;
R represents hydroxyl; Straight or branched C
1-C
6-alkoxyl group; Amino; Dimethylamino; Diethylamino; Tert-butoxycarbonyl amino; Carboxyl; C
1-C
6-carbalkoxy; Cyano group; Piperidino-(1-position only); The 1-pyrrolidyl; Morpholino; 4-methylpiperazine-1-base; O-A
1-NR
3R
4S-A
1-NR
3R
4
N is 1; And
Z represents the C that pyridyl replaces
1-C
3-alkoxyl group.
6, the compound of claim 1, wherein
W is-CH=;
X is a hydrogen; OR
1SR
2(SO) R
2(SO
2) R
2CH
2-S-CH
2-C (O)
2-CH
2-CH
3CH
2-S-(CH
2)
2-OH or group A
1-Q;
A
1Expression C
1-C
3-alkylidene group;
Q is OR
1SR
2SOR
2SO
2R
2NR
3R
4NHCH
2CH
2NR
3R
4Or halogen;
R
1Be selected from: hydrogen; C
1-C
3-alkyl; Allyl group; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; (R)-2,3-dihydroxyl-1-propyl group; (S)-2,3-dihydroxyl-1-propyl group; 1,3-dihydroxyl-2-propyl group; 3-hydroxyl-2-methylol-1-propyl group; 2-methoxyl group-ethoxyl methyl; 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or group A
1-Q
1
Q
1Expression C
1-C
2-alkoxyl group; Cyano group; Carboxyl; C
1-C
6-carbalkoxy; Acid amides;-CO-NR
3R
4C
1-C
6-alkylthio; C
1-C
6-alkyl sulphinyl; C
1-C
6-alkyl sulphonyl, and
At A
1The expression ethylene-or the situation of trimethylene under, Q
1Be hydroxyl or NR
3R
4
R
2Be C
1-C
6-alkyl; The dimethyl (phosphonomethyl); 2,3-epoxy group(ing)-1-propyl group; 2,3-dihydroxyl-1-propyl group 2,2-dimethyl-1,3-dioxolane-4-ylmethyl or A
1-Q
1
R
3, R
4Be independently selected from: hydrogen; C
1-C
6-alkyl or
Form 5～7 yuan saturated or unsaturated ring together, this ring is by the optional replacement of methyl and contain the heteroatoms that one or two is independently selected from N or O;
Y is the 3-hydroxypropyl;
N is 1; And
Z is pyridine-2-ylmethoxy; Pyridin-3-yl methoxyl group or pyridin-4-yl methoxyl group.
7, claim 6 compound, it is:
2 (2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(4-pyridyl methoxyl group)-phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-the N-1H-imidazoles,
2 (2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(3-pyridyl methoxyl group)-phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-the N-1H-imidazoles, or
2 (2,6-two chloro-4-[2-hydroxyl-oxethyls] phenyl)-4-(3-(2-pyridyl methoxyl group)-phenyl)-5-(2-[3-hydroxypropyl amino] pyrimidine-4-yl)-the N-1H-imidazoles.
8, a kind of method of making the compound of claim 1, wherein
A) compound of general formula (VI)
Or compound (VII)
The thioether group that is the thioether represented by the logical formula V of oxidation obtains,
The thioether of logical formula V is that the N-deoxidation by general formula (IV) compound obtains,
Wherein said general formula (IV) compound is the compound by general formula (II)
Obtain with the reaction of the compound of general formula (III),
With
B) with described formula (VI) or (VII) compound and formula Y-NH
2Compound reaction, obtain the compound of formula (I); And
Substituting group W, X, Y and Z and n have the given implication of claim 1.
9, a kind of composition contains one or more as a described compound and suitable adjuvant in the claim 1～7.
10, a kind of pharmaceutical composition, contain one or more as activeconstituents as a described compound and pharmaceutically acceptable adjuvant in the claim 1～7.
11, one or more are used to make the purposes of medicine as a described compound in the claim 1～7, and described medicine is used for the treatment of the kinase mediated disease by c-met.
12, one or more are used to make the purposes of treatment cancer with medicine as a described compound in the claim 1～7.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03023633 | 2003-10-16 | ||
| EP03023633.5 | 2003-10-16 | ||
| EP03026522.7 | 2003-11-18 |
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| CN102600892B (en) * | 2012-02-17 | 2013-08-21 | 北京工业大学 | Application of triarylimidazole compound serving as catalyst in electroorganic synthesis |
| JP6675986B2 (en) * | 2014-08-13 | 2020-04-08 | 日本曹達株式会社 | Diarylimidazole compounds and pesticides |
| CN107162982B (en) * | 2017-06-19 | 2020-02-11 | 广东药科大学 | Imidazole compounds with anticancer activity and derivatives thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996018626A1 (en) * | 1994-12-13 | 1996-06-20 | F. Hoffmann-La Roche Ag | Imidazole derivatives as protein kinase inhibitors in particular egf-r tyrosine kinase |
| US5656644A (en) * | 1994-07-20 | 1997-08-12 | Smithkline Beecham Corporation | Pyridyl imidazoles |
| US6610695B1 (en) * | 1997-06-19 | 2003-08-26 | Smithkline Beecham Corporation | Aryloxy substituted pyrimidine imidazole compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5656644A (en) * | 1994-07-20 | 1997-08-12 | Smithkline Beecham Corporation | Pyridyl imidazoles |
| WO1996018626A1 (en) * | 1994-12-13 | 1996-06-20 | F. Hoffmann-La Roche Ag | Imidazole derivatives as protein kinase inhibitors in particular egf-r tyrosine kinase |
| US6610695B1 (en) * | 1997-06-19 | 2003-08-26 | Smithkline Beecham Corporation | Aryloxy substituted pyrimidine imidazole compounds |
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