CN100471841C - (2-carboxamido) (3-amino) thiophene compounds - Google Patents
(2-carboxamido) (3-amino) thiophene compounds Download PDFInfo
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- CN100471841C CN100471841C CNB2004800019159A CN200480001915A CN100471841C CN 100471841 C CN100471841 C CN 100471841C CN B2004800019159 A CNB2004800019159 A CN B2004800019159A CN 200480001915 A CN200480001915 A CN 200480001915A CN 100471841 C CN100471841 C CN 100471841C
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Abstract
Compounds represented by Formula (I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein R1 is Formula (II, III, IV, V or VI); R2 is Formula (VII, VIII, IX or X); and R3 is C0-4 alkyl, are useful in the treatment of cancer.
Description
Background of invention
The present invention relates to 2, the thiophene that 3-replaces.Particularly, the present invention relates to (2-formamido-) (3-amino) thiophene, it is the inhibitor of oncogene (being also referred to as Kit, CD-117, STEM CELL FACTOR acceptor, mast cell growth factor acceptor) before the c-Kit.
Oncogene it is believed that the embryo and takes place before the c-Kit, and melanogen generates, hemopoietic and Mastocytosis, gastrointestinal tumor and other solid tumors, and specific leukemia comprises in the pathogenesis of AML extremely important.Therefore, the inhibitor of developing new c-Kit acceptor will be expected.
Many treatment plans that are used for abnormality proliferation (cancer) at present adopt and suppress DNA synthetic compound.Working mechanism's pair cell of these compounds is toxic, especially to quick splitted tumour cell.Therefore, its broad spectrum toxicity is a problem for trying patient.But, suppressed the approach of other carcinostatic agents of DNA outside synthetic, thereby reduced side effect with the selectivity that strengthens antitumous effect in research.
Known cell can (i.e. the gene of generation malignant cell after activation) becomes cancer cells in the oncogene owing to its part DNA is transformed into.Many oncogene codings can make the paraprotein Tyrosylprotein kinase of cell transformation.By different approach, the overexpression of normal preceding oncogene Tyrosylprotein kinase can produce proliferative disease, produces the malignant phenotype sometimes.Perhaps, the coexpression of the connection part of receptor tyrosine kinase and same cell type also can produce vicious transformation.
Receptor tyrosine kinase is the big enzyme of cross-cell membrane, it contains i) somatomedin such as KIT part (be also referred to as STEM CELL FACTOR (SCF), the Steel factor (SLF) or mast cell growth factor (MGF)) the outer binding domains of born of the same parents, ii) membrane spaning domain, iii) born of the same parents' intracellular domain, it makes specific tyrosine residues phosphorylation in the albumen as kinases.The KIT part is attached to the KIT Tyrosylprotein kinase and produces acceptor homotype dimerization, activation KIT tyrosine kinase activity also carries out phosphorylation to the multiple protein substrate subsequently, it is effectors of signal conduction in the cell that many substrates are wherein arranged, and these incidents make enhanced cellular proliferation or promote cell survival to strengthen.For some receptor kinases, the special-shaped dimerization of acceptor also can take place.
Known these kinases are unconventionality expression in human cancer such as breast cancer, head and neck cancer, gastrointestinal cancer such as colorectal carcinoma, the rectum cancer or cancer of the stomach, leukemia and ovarian cancer, bronchogenic carcinoma, lung or carcinoma of the pancreas usually.The Kit kinase expression has record in a variety of human malignant lesions, as Mastocytosis/mast cell leukemia, gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, ovarian cancer, cystadenocarcinoma, acute myelogenous leukemia (AML), breast cancer, children's T cell acute lymphoblastic leukemia, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium, and prostate cancer.The mechanism of causing a disease of these tumours of the kinase activity and several of KIT and other tumours is relevant, comprises breast cancer, SCLC, GIST, germinoma, mast cell leukemia, neuroblastoma, AML, melanoma and ovarian cancer.
KIT activatory mechanism has had report in several tumour cells, comprises activation sudden change, and the autocrine of receptor kinase and paracrine are activated by its part, and the active disappearance of Protein-tyrosine-phosphatase and intersected by other kinases activates.Be believed to comprise dimer by shifting to new management mechanisms of causing of activation sudden change and form the active increase in inside with kinase domain, the substrate specificity that both all produce the ind kinase activation of composing type part and may change.The proteic activation sudden change of KIT above 30 is relevant with people's high malignancy tumour.
Therefore, the inhibitor of known receptor Tyrosylprotein kinase effectively is used as the selective depressant of mammalian cancer cells growth.For example, Gleevec
TM(be also referred to as imatinib mesylate (imatinibmesylate) or STI571), suppress the 2-phenyl pyrimidine tyrosine kinase inhibitor of BCR-ABL fusion gene product kinase activity, be used for the treatment of CML by U.S. food and drugs administration approved recently.Gleevec
TM, remove to suppress the BCR-ABL kinases, also suppress KIT kinases and pdgf receptor kinase, although be not very effective to the kinase whose sudden change isomer of KIT.The MO7e human leukemia cell's of Kit ligand stimulation growth is by Gleevec
TMSuppress, it also induces apoptosis under these conditions.As a comparison, the MO7e human leukemia cell's of GM-CSF stimulation growth is not subjected to Gleevec
TMInfluence.In addition, in recent clinical study, use Gleevec
TMTreatment patient GIST, GIST is the disease that a kind of KIT kinases participates in this cell transformation, many patient table reveal tangible improvement.
These studies show that the KIT kinase inhibitor is how to treat the tumour that its growth depends on the KIT kinase activity.Other kinase inhibitor shows stronger kinases selectivity.For example, 4-anilinoquinazoline compound Tarceva
TMThe only efficient EGF receptor kinase that suppresses is although it can suppress the signal conduction of other receptor kinases, such as realizing by these acceptors and the special-shaped dimerization of EGF acceptor.
Although these above-mentioned anticancer compounds have been made significant contribution to prior art, still improved cancer therapy drug there is continuous demand, exploitation has better choice or effectiveness, or has the toxicity of reduction or the new compound of side effect is desirable.
The open WO00/27820 of international monopoly has described N-aryl (sulphur) o-amino benzoyl acid amide derivatives.Open WO99/32477 of international monopoly and United States Patent (USP) 6,140,351 have been described the ortho-anthranilimide derivative.The open WO00/27819 of international monopoly has described the anthranilic acid acid amides.Open WO02/00651 of international monopoly and WO01/19798 have described factor Xa inhibitor.The open WO01/07050 of international monopoly has described nociceptin (nociceptin) receptor ORL-1-1 agonist.United States Patent (USP) 5,968,965 have described farnesyl-protein inhibitor.Open WO01/64642 of international monopoly and United States Patent (USP) 6,376,515 have described benzamide.Open WO01/05763 of international monopoly and United States Patent (USP) 6,410,561 have been described the M-ChR compound.United States Patent (USP) 6,410,561 have described amide derivatives.
The open WO02/066470 of international monopoly has described the alkylamine derivative that replaces.The open WO02/068406 of international monopoly has described the sulfonamide derivatives that replaces.The open WO02/055501 of international monopoly has described the arylamines derivative that replaces.
United States Patent (USP) 6,207,693 and 6,316,482 and European patent EP 0832061 benzamide derivatives with antidiuretic hormone antagonistic activity has been described.
Summary of the invention
The compound of general formula (I)
Or its pharmaceutical salts or N-oxide compound be effective to treat tumour, and wherein R1 is
R2 is
Or
And R3 is C
0-4Alkyl.
Detailed Description Of The Invention
The present invention relates to the compound of general formula (I):
Or its pharmaceutical salts or N-oxide compound be effective to treat tumour, wherein
R1 is
Or
R2 is
Or
And R3 is C
0-4Alkyl.
On the one hand, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound,
Wherein R2 is
And its dependent variable is as above stated the description of general formula (I).
In an embodiment aspect this, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is a hydrogen, and its dependent variable is as above stated the description of general formula (I).
In second aspect, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is C
0-4Alkyl; And its dependent variable is as above stated the description of general formula (I).
In an embodiment aspect this, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is a hydrogen; And its dependent variable is as above stated the description of general formula (I).
In the third aspect, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is C
0-4Alkyl; And its dependent variable is as above stated the description of general formula (I).
In the embodiment aspect this, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is a hydrogen; And its dependent variable is as above stated the description of general formula (I).
In fourth aspect, the present invention relates to the compound of general formula (I), or its pharmaceutical salts or N-oxide compound, wherein R2 is
R3 is C
0-4Alkyl; And its dependent variable is as above stated the description of general formula (I).
The compound or pharmaceutically acceptable salt thereof that the invention still further relates to the general formula I I by effective dosage is treated the method for abnormal hyperplasia, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer
Wherein:
R11 is optional separately by the 1-6 aryl that replaces of halogen independently, C
3-6Cycloalkyl or heterocyclic radical; Hydroxyl; Nitro; Amino; Acyl group; The acyl group that replaces; Acyl group C
1-6Alkyl sulphinyl; Acyl group C
1-6Alkyl sulphonyl; Acyloxy; C
1-6Alkylamino C
1-6Alkyl-carbamoyl oxygen base; Aryl; Cyano group; Heterocyclic radical; The optional C that is replaced by the aryl of the acyl group of acyl group, replacement, aryl or acyl substituted
2-6Thiazolinyl; The optional C that is replaced by the amido of amino, amido or replacement
2-6Alkynyl; Optional by halogen, amino, C
1-6The amido of alkylamino, amido, replacement, hydroxyl, acyloxy, alkyl C
1-6The acyl group of alkyloyl oxygen base, acyl group, replacement, acyl group C
1-6The C that the aryl of Alkoximino, aryl or acyl substituted replaces
1-6Alkyl; Optional by the C of the acyl substituted of acyl group or replacement
1-6Alkylthio-; Optional by the pyridyl of the acyl substituted of the pyridyl of the amino of the aryl of aryl, replacement, hydroxyl, acyloxy, amino, low-grade alkyl amino, protection, heterocyclic radical, acyl substituted, replacement, halogen, acyl group C
1-6The acyl group C of alkylamino, N-protected
1-6Alkylamino, N-acyl group C
1-6The acyl group of alkyl-N-low-grade alkyl amino, acyl group, replacement, amido, the amido of replacement, C
1-6Alkyl hydrazine carbonyl amino, oxyimino, acyl group C
1-6The acyl group C of Alkoximino, replacement
1-6Alkoximino, acyl group C
1-6The alkoxyl group that the guanidine radicals of alkoxyl group, guanidine radicals or N-protected replaces; Or the optional C that is replaced by the acyl substituent of acyl group or replacement
2-6Thiazolinyl oxygen base;
R21 is a hydrogen; Optional by the low alkyl group of hydroxyl, aryl or acyl substituted; Or ring (rudimentary) alkyl;
R31 is a hydrogen; Halogen; Hydroxyl; Acyloxy; The acyloxy that replaces; Optional by hydroxyl or C
1-6The C that alkoxyl group replaces
1-6Alkyl; Optional by the amino of aryl, amino, protection, acyl group, hydroxyl, cyano group or C
1-6The C of alkylthio-replacement
1-6Alkoxyl group; Nitro; Amino; Acyl group; The acyl group that replaces; Or C
3-6Cycloalkyloxy;
R41 is a hydroxyl; Halogen; Nitro; Amino; The amino of protection; C
1-6Alkylamino; Acyloxy; Amino C
1-6Alkylamino; The amino C of N-protected
1-6Alkylamino; Optional by the acyl group of the aryl of hydroxyl, aryl, replacement, acyl group, replacement, amino, C
1-6The C that the amido of alkylamino, amido, replacement, the amino of protection, heterocyclic radical or guanidine radicals replace
1-6Alkoxyl group; Optional by the acyl group of acyl group, replacement, amino, C
1-6The amido of alkylamino, amido, replacement, the amino of protection, heterocyclic radical, hydroxyl, C
1-6Alkyl sulphonyl oxygen base, aryl sulfonyl oxygen base, arC
1-6The arC of alkoxyl group or replacement
1-6The C that alkoxyl group replaces
1-6Alkylthio; By the amino of the amido of the acyl group of acyl group, replacement, amino, low-grade alkyl amino, amido, replacement, protection, heterocyclic radical, hydroxyl, C
1-6The C that alkylsulfonyloxy oxygen base or aryl-sulfonyl oxygen oxygen base replace
1-6Alkyl; Optional by the C of acyl substituted
2-6Thiazolinyl; Optional by the amino of hydroxyl, amino, protection, C
1-6The C that alkylsulfonyloxy or aryl-sulfonyl oxygen replace
2-6Alkynyl; Amino C
1-6Alkyl sulphonyl; The amino C of N-protected
1-6Alkyl sulphonyl; C
1-6Alkyl amino sulfonyl; The heterocyclic radical alkylsulfonyl; Amino C
1-6Alkyl sulphinyl; The amino C of N-protected
1-6Alkyl sulphinyl; Piperidines oxygen base; Or the piperidines oxygen base of N-protected;
R51 is hydrogen, C
1-6Alkyl, C
1-6Alkoxy or halogen;
A is a singly-bound, O or NH;
E is C
1-6Alkylidene group, C
2-6Alkenylene,
Or E is the group of general formula-G-J-, wherein
G is C
1-6Alkylidene group and
J be O or
Wherein R61 is hydrogen or N-protected group;
X is-CH=CH--C=N-or S; And
Y is CH or N.
The compound of general formula (II) is described in United States Patent (USP) 6,054,457.
On the one hand, the present invention relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula I I by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer, wherein X is S, and the description of other variable such as above-mentioned general formula I I.
In an embodiment aspect this, the present invention relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula I I by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer, and wherein X is S; R11 is optional to be replaced by aryl; And the description of other variable such as above-mentioned general formula I I.
In another embodiment aspect this, the present invention relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula I I by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer, and wherein X is S; R11 is optional to be replaced by heteroaryl; And the description of other variable such as above-mentioned general formula I I.
In the another one embodiment aspect this, the present invention relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula I I by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer, and wherein X is S; Y is N; And the description of other variable such as above-mentioned general formula I I.
The invention still further relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula III by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer
Wherein R12 is an aryl, C
3-6Cycloalkyl or heterocyclic radical, optional separately by independently halogen replacement of 1-6; Hydroxyl; Nitro; The amino of protection, amino; Acyl group; The acyl group that replaces; Acyl group C
1-6Alkyl sulphinyl; Acyl group C
1-6Alkyl sulphonyl; Acyloxy; C
1-6Alkylamino C
1-6The alkyl carbamoyloxy base; Aryl; Cyano group; Heterocyclic radical; The optional C that is replaced by the aryl of the acyl group of acyl group, replacement, aryl or acyl substituted
2-6Thiazolinyl; The optional C that is replaced by the acyl amino of amino, acyl amino or replacement
2-6Alkynyl; Optional by halogen, amino, C
1-6The amido of alkylamino, amido, replacement, hydroxyl, acyloxy, acyl group C
1-6The acyl group of alkyloyl oxygen base, acyl group, replacement, acyl group C
1-6Alkoximino, the C that the aryl of aryl or acyl substituted replaces
1-6Alkyl; Optional by the C of the acyl substituted of acyl group or replacement
1-6Alkylthio-; Optional by the pyridyl of the acyl substituted of the pyridyl of the amino of the aryl of aryl, replacement, hydroxyl, acyloxy, amino, low-grade alkyl amino, protection, heterocyclic radical, acyl substituted, replacement, halogen, acyl group C
1-6The acyl group C of alkylamino, N-protected
1-6Alkylamino, N-acyl group C
1-6The acyl group of alkyl-N-low-grade alkyl amino, acyl group, replacement, acyl amino, the acyl amino of replacement, C
1-6Alkyl hydrazine carbonyl amino, oxyimino, acyl group C
1-6The acyl group C of Alkoximino, replacement
1-6Alkoximino, acyl group C
1-6The alkoxyl group that the guanidine radicals of alkoxyl group, guanidine radicals or N-protected replaces; Or the optional C that is replaced by the acyl substituent of acyl group or replacement
2-6Thiazolinyl oxygen base;
R22 is a hydrogen; Optional by the C of hydroxyl, aryl or acyl substituted
1-6Alkyl; Or C
3-6Cycloalkyl;
R32 is a hydrogen; Halogen; Hydroxyl; Acyloxy; The acyloxy that replaces; Optional by hydroxyl or C
1-6The C that alkoxyl group replaces
1-6Alkyl; Optional by the amino of aryl, amino, protection, acyl group, hydroxyl, cyano group or C
1-6The C of alkylthio-replacement
1-6Alkoxyl group; Nitro; Amino; Acyl group; The acyl group that replaces; Or C
3-6Cycloalkyloxy;
A
1Be singly-bound, O or NH;
E
1Be C
1-6Alkylidene group, C
2-6Alkenylene,
Or E
1Be the group of general formula-G1-J1-, wherein
G1 is C
1-6Alkylidene group or
And
J1 be O or
Wherein R62 is hydrogen or N-protected group;
X
1, be-CH=CH--C=N-or S; And
Y
1Be optional by the individual independently amino C of acyl group, protection of 1-6
1-6The aryl that the amino of alkyloyl, protection and nitro, amino and nitro or diamino substituting group replace; Or Y1 is optional by 1-6 halogen, acyl group, C
1-6Alkoxyl group, hydroxyl, guanidine radicals, sulfydryl, acyl amino, amino, heterocyclic radical, cyano group amino, amino C
1-6Alkyl (C
1-6Alkyl) amino, C
1-6Alkylamino, C
1-6Alkylamino (C
1-6Alkylamino), the heterocyclic radical of Qu Daiing, C
1-6Alkyl diazanyl, aryloxy, C
1-6Alkylthio-, aryl, the amino of protection, the C of N-protected
1-6Alkylamino (C
1-6Alkyl) the amino C of amino, N-protected
1-6Alkyl (N-C
1-6Alkyl) amino, amino C
1-6Alkyl (N '-C
1-6Alkyl) amino, C
1-6Alkylamino (C
1-6Alkyl) (N-C
1-6Alkyl) amino, or C
1-6Alkoxyl group (C
1-6Alkyl) heterocyclic radical of the condensation of amino substituting group replacement; Or C
1-6Alkyl substituent is further by aryl, arC
1-6Alkoxyl group, cyano group, oxyimino, sulfydryl, C
1-6Alkylamino, acyloxy, halogen, C
1-6The hydroxyl of alkoxyl group, protection, hydroxyl, C
1-6The heterocyclic radical substituting group of the amino of alkoxy aryl, protection, amino, heterocyclic radical or replacement replaces;
Condition is, if Y
1For choosing wantonly by C
1-6The phenyl of alkyl or acyl substituted, then
A
1Be singly-bound and
E
1Be
The compound of general formula (III) is described in United States Patent (USP) 6,316,482.
On the one hand, the present invention relates to the method for the compound or pharmaceutically acceptable salt thereof treatment abnormal hyperplasia of the general formula III by effective dosage, described disease comprises breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer or carcinoma of the pancreas, sinonasal natural killer cell/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, cystadenocarcinoma, angiosarcoma, degeneration large celllymphoma, carcinoma of endometrium or prostate cancer, wherein X1 is S, and other variable description is in general formula III.
" C used herein
0-4Alkyl " be used to represent to contain the alkyl of 0-4 carbon atom, promptly 0,1,2,3, the carbon atom of 4 straight or branched conformations.The alkyl that does not have carbon atom when alkyl is the group of end is a hydrogen.When alkyl was bridging (connection) group, the alkyl that does not have carbon atom was straight key.
Unless stated otherwise, " alkyl " used herein, " thiazolinyl " and " alkynyl " comprise a straight chain and a chain conformation.Low alkyl group, thiazolinyl and alkynyl have 1-6 carbon atom.Senior alkyl, thiazolinyl, alkynyl have 6 above carbon atoms.
Unless stated otherwise, " aryl " used herein and " ar " well known to a person skilled in the art, it comprises, for example, phenyl and naphthyl, and have one or more short alkyl phenyl (tolyl, xylyl,
Base, cumenyl, two (t-butyl) phenyl).Preferred phenyl, naphthyl, tolyl, xylyl." aryl of replacement " is the aryl that replaces with suitable substituents, the piperazinyl alkylsulfonyl of the acyl group of described substituting group such as acyl group, replacement, N-protected, piperazinyl alkylsulfonyl, N-C
1-6Alkylpiperazine base alkylsulfonyl, hydroxyl C
1-6Alkyl, heterocyclic radical, halogen, nitro, amino, C
1-6Alkylamino, cyano group or C
1-6Alkoxyl group.
Unless stated otherwise, " heterocyclic radical " used herein is well known to a person skilled in the art, and comprise at least one N, S or O heterocyclic atom, and comprise saturated, undersaturated, fractional saturation, monocycle or polycyclic heterocyclic group, for example, pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazyl, pyrrolidyl, imidazolidyl, piperidyl, piperazinyl, high piperazinyl, indyl, isoindolyl, the indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, the benzotriazole base, tetrazolium-pyridazinyl, pyranyl, furyl, the 1H-THP trtrahydropyranyl, tetrahydrofuran base, thienyl oxazolyl isoxazolyl oxadiazole base, azoles quinoline base, morpholinyl, benzofuryl benzoxazolyl Ben Bing oxadiazole base, thiazolyl, thiadiazolyl group, thiazolidyl, benzothiazolyl, the diazosulfide base, benzofuryl, or benzodioxyl etc.These heterocyclic radicals are replaced suitably by low alkyl group or oxygen-containing substituents.
Unless stated otherwise, " acyl group " used herein comprise, for example the carboxyl of carboxyl, esterification, carbamyl, low-grade alkyl amino formyl, low-grade alkane acidyl, aroyl, heterocyclic radical carbonyl etc.The carboxyl of esterification comprises elementary alkoxy carbonyl replacement or unsubstituted, as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, t-butoxy carbonyl, hexyloxy carbonyl, 2-iodine ethoxy carbonyl, 2,2,2-trichlorine ethoxy carbonyl, dimethylamino propoxy carbonyl, dimethylamino ethoxy carbonyl; That replace or unsubstituted aryloxycarbonyl is as phenyloxycarbonyl, 4-nitrophenoxy carbonyl, 2-naphthyloxy carbonyl; That replace or unsubstituted ar (rudimentary) alkoxy carbonyl is as phenyloxycarbonyl, benzene ethoxy carbonyl, hexichol methoxycarbonyl, 4-oil of mirbane methoxy base carbonyl, 3-methoxyl group-4-oil of mirbane methoxy base carbonyl; With contain N heterocyclic oxy group carbonyl such as N-methyl piperidine oxygen base carbonyl etc.
Unless stated otherwise, " halogen " used herein is fluorine, chlorine, bromine or iodine.
Unless stated otherwise, " C used herein
1-6The alkyl diazanyl " can be 2-list or 2,2-two (C
1-6Alkyl) diazanyl, as 2-methyl diazanyl, 2,2-dimethyl diazanyl, 2-ethyl diazanyl, 2,2-diethyl diazanyl etc.
Unless stated otherwise, ＂ C used herein
1-6Alkylamino C
1-6Alkyl " comprise for example methylamino methyl, dimethylaminomethyl, dimethyl aminoethyl etc.
" C
1-6Alkyloyl " comprise replacement or unsubstituted alkyloyl such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, pivaloyl group, caproyl, trifluoroacetyl group etc.
" aroyl " comprises benzoyl, naphthoyl base, toluyl, two (t-butyl) benzoyl etc.
Unless stated otherwise; that " N-protected group " in " amino of protection " used herein comprises replacement or unsubstituted low-grade alkane acidyl (for example formyl radical, ethanoyl, propionyl, trifluoroacetyl group), phthaloyl, elementary alkoxy carbonyl (as t-butoxy carbonyl, t-pentyloxy carbonyl), aromatic alkoxy carbonyl replacement or unsubstituted (as benzyloxycarbonyl, p-nitro benzyloxycarbonyl), 9-fluorenyl methoxy carbonyl, replacement or unsubstituted aromatic hydrocarbons alkylsulfonyl (benzenesulfonyl, tosyl group).Preferred phthaloyl, t-butoxy carbonyl or 9-fluorenyl methoxy carbonyl.
Unless stated otherwise, " the N protectiveness group " in " guanidine radicals of protection " used herein comprises elementary alkoxy carbonyl (as t-butoxy carbonyl, t-pentyloxy carbonyl).
Unless stated otherwise, " hydroxy-protective group " used herein comprises the silyl (for example, t-butyl diphenyl silyl) of arylmethyl replacement or unsubstituted (for example benzyl, lower alkoxy benzyl), acyl group or replacement.
Above-mentioned general formula I, II and III represent with the stereochemical form of not determining at certain position.The present invention includes general formula I, all steric isomers and the pharmaceutical salts thereof of II and III.The mixture and the isolating specific steric isomer that also comprise steric isomer in addition.Be used to prepare the method for these compounds in building-up process, or the method in using racemize or epimerization is the known technology of this area, the product of these methods is mixtures of steric isomer.
The present invention also comprises the pharmaceutical composition by the compound of general formula I and pharmaceutical carrier combination.
Preferably, said composition comprises the compound (or its pharmaceutical salts or N-oxide compound) of the above-mentioned general formula I of pharmaceutical carrier and nontoxicity treatment significant quantity.
In addition, in this embodiment preferred, the present invention contains by suppressing the pharmaceutical composition of c-KIT kinases treatment disease, this kinases can be proteic wild-type or mutant, and described composition contains the compound (or its pharmaceutical salts or N-oxide compound) of the above-mentioned general formula I of pharmaceutical carrier and nontoxicity treatment significant quantity.
Compound of the present invention and composition are effective to treat Mammals, as the people.
Term " pharmaceutical salts " refers to from the medicinal nontoxic alkali or the salt of acid preparation.When compound of the present invention was acidity, its corresponding salt can comprise mineral alkali and organic bases easily from medicinal nontoxic alkali preparation.The salt that obtains from these mineral alkalis comprises salt such as aluminium, ammonium, calcium, copper and cuprous, iron, ferrous, lithium, magnesium, manganese and inferior manganese, potassium, sodium, zinc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.The salt that obtains from medicinal organic nontoxic alkali comprises the salt of primary amine, secondary amine and tertiary amine, and cyclammonium and replace amine such as natural replace amine with synthetic.Other medicinal organic nontoxic alkalis that can prepare salt comprise ion exchange resin as, arginine, trimethyl-glycine, caffeine, choline, N ', N '-diphenyl-methyl vinyl diamines, diethylamide, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, amino grape, Histidine, oxyamine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol (tromethamine) etc.
When compound of the present invention was alkalescence, its corresponding salt can prepare from medicinal non-toxic acid easily, comprises mineral acid and organic acid.These acid comprise, for example acetate, Phenylsulfonic acid, M-nitro benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, FUMARIC ACID TECH GRADE, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, p-toluenesulphonic acids etc.Particularly preferably be citric acid, Hydrogen bromide, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, methylsulfonic acid and tartrate.
Pharmaceutical composition of the present invention or the inventive method pharmaceutical compositions for use comprise the general formula I as activeconstituents, the compound of II or III representative (or its treatment salt or N-oxide compound), pharmaceutical carrier and optional other medicinal ingredientss or adjuvant.Composition comprises the composition of suitable oral cavity, rectum, part and parenteral (comprising subcutaneous, intramuscular and intravenously) administration, although most of suitable way depend on specific object and by the character of the illness of administration activeconstituents and severity under any given situation.Pharmaceutical composition can be presented with unit dosage form and prepare by any known method of pharmacy field easily.
In practice, the compound or pharmaceutically acceptable salt thereof of general formula I of the present invention or N oxide compound can closely mix with pharmaceutical carrier as activeconstituents according to the pharmacology compounding technology of routine and make up.The carrier formulation of administration as required adopts various ways.As, oral or parenteral (comprising vein) administration.Therefore, pharmaceutical composition of the present invention can be fit to oral discrete unit to be presented, as capsule, cartridge bag or the tablet of the active ingredient that contains predetermined amount separately.In addition, composition can also adopt the form of powder, particle, solution, aqueous suspensions, on-aqueous liquid, O/w emulsion or water-in-oil liquid emulsion to present.Remove the common dosage form of above-mentioned setting, the compound of general formula I representative, or its pharmaceutical salts or N oxide compound can also be by the mode administrations of sustained release and/or throwing device.Composition can be with any method preparation of pharmacology.Generally speaking, these methods comprise with active ingredient with constitute one or more steps of connecting of carrier that must component.Usually, composition by with active ingredient with liquid vehicle or finely disintegrated solid carrier or prepare the two all even closely mixing.Product can be shaped to required form easily.
Therefore, pharmaceutical composition of the present invention comprises pharmaceutical carrier and general formula I, the compound or pharmaceutically acceptable salt thereof of II or III or N oxide compound.General formula I, the compound or pharmaceutically acceptable salt thereof of II or III or N oxide compound can also be contained in the pharmaceutical composition with one or more other therapeutical active compound combinations.
Pharmaceutical composition of the present invention comprises and contains general formula I, the axunge plastid prescription of the compound or pharmaceutically acceptable salt thereof of II or III or N oxide compound.
The pharmaceutical carrier that uses can be, for example, and solid, liquid or gas.The example of solid carrier comprises lactose, anhydrite (terra alba), sucrose, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.The example of liquid vehicle has syrup, peanut oil, sweet oil and water.The example of carrier gas comprises carbonic acid gas and nitrogen.
In the composition of preparation oral dosage form, can adopt any drug media easily.For example, water, ethylene glycol, oil, ethanol, flavouring agent, sanitas, tinting material etc. can be used for the oral liquid of preparation example such as suspension, elixir and solution; And for example carriers such as starch, sugar, Microcrystalline Cellulose, thinner, one-tenth granule, lubricant, wedding agent, dispersion agent can be used to form for example oral solid formulation of powder, capsule and tablet.For the administration facility, tablet and capsule are preferred oral dosage units, adopt solid pharmaceutical carriers thus.Randomly, tablet can be by the water of standard or the technology bag quilt of non-water.
The tablet that contains the present composition can prepare by compression or casting mold, optional one or more auxiliary components or the adjuvant of having.The preparation method of compressed tablets compresses in suitable machine, and free-flowing form is powder or particulate active ingredient for example, chooses wantonly and mixes with wedding agent, lubricant, inert diluent, tensio-active agent or dispersion agent or other this class vehicle etc.Vehicle can be, for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Become granule and dispersion agent, for example W-Gum or alginic acid; Wedding agent, for example starch, gelatin or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can not wrap by or by known technology bag by postponing disintegration and the absorption in gi tract, thereby and provide the continuous action of longer time.For example, can use time-delay material as glycerol monostearate or glyceryl SUNSOFT Q-182S.
In hard gelatin capsule, active ingredient and inert solid diluent, for example lime carbonate, calcium phosphate or kaolin mix.In soft gelatin capsule, active ingredient and water or oily medium be peanut oil, whiteruss or mixed with olive oil for example.The tablet of casting mold can be by obtaining with mixture casting mold in suitable machine of the moistening powdered compounds of inert liquid diluent.Each tablet preferably contains about 0.05mg to about 5g active ingredient, and each cartridge bag or capsule preferably contain about 0.05mg to about 5g active ingredient.
For example, the preparation that is used for to human oral can contain about 0.5mg to about 5g promoting agent, its with total composition about 5 to about 95% with suitable compound with the convenient carrier substance of measuring.Unit dosage form contains about 1mg usually to about 2mg active ingredient, and the part is 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or 1000mg.
The pharmaceutical composition of the present invention that is fit to parenterai administration can be prepared into the aqueous solution or the suspension of active compound.Suitable tensio-active agent can comprise, for example, and hydroxy propyl cellulose.Dispersion agent can also prepare in the oil of glycerine, liquid macrogol and composition thereof.In addition, also can comprise the obnoxious growth that sanitas prevents microorganism.
The pharmaceutical composition of the present invention that is suitable for injecting comprises aseptic aqueous solution or suspension.In addition, composition can also take the form of sterilized powder to be used for preparing immediately these aseptic injectable solutions or suspension.Under all situations, final injection form must be aseptic and must be to be effective to the fluid of injection easily.Pharmaceutical composition must be stable under production and condition of storage, therefore, preferably stores in the mode that prevents microorganism such as bacterium and fungal contamination.Carrier can be solvent or dispersion medium, contains for example water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol), vegetables oil and suitable mixture thereof.
Be fit to the local pharmaceutical composition of the present invention that uses and adopt for example forms such as aerosol, breast frost, ointment, lotion, dusting flour.In addition, composition can adopt the form that transdermal device uses that is adapted at.The compound or pharmaceutically acceptable salt thereof N oxide compound that these preparations can use general formula I of the present invention prepares by the working method of routine.As embodiment, the preparation method of newborn frost or ointment is with hydrophilic substance and water, adds that about 5 weight % produce newborn frost or the ointment with required denseness to the compound of about 10 weight %.
It is the form that solid is fit to rectal administration that pharmaceutical composition of the present invention can adopt carrier.Preferred mixture forms unitary dose suppository.Suitable carriers comprises theobroma oil and the normally used material in other this areas.These suppositorys can be cast and formation easily by composition is pre-mixed with postcooling with in mould with carrier softening or fusing.
Except the carrier component of mentioning, above-mentioned pharmaceutical preparation can comprise, if be fit to, one or more other carrier component are as thinner, buffer reagent, seasonings, wedding agent, tensio-active agent, thickening material, lubricant, sanitas (comprising antioxidant) etc.In addition, also can comprise other adjuvant so that preparation and target receptor's blood etc. ooze.The compound that contains general formula I, or the composition of its pharmaceutical salts or N-oxide compound, the form preparation of all right powder or liquid concentration.
Usually, the above-mentioned disease of treatment, be effectively according to dosage level from the about 0.01mg of per kilogram of body weight to about 150mg, perhaps optional every patient's every day, about 0.5mg was to about 10g.For example, breast cancer, head and neck cancer and gastrointestinal cancer such as colon, rectum or cancer of the stomach can effectively be treated to this compound of about 100mg by the about 0.01mg of per kilogram of body weight administration every day, and perhaps optional every patient's every day, about 0.5mg was to about 7g.
Similarly, leukemia, ovarian cancer, bronchogenic carcinoma, lung cancer and carcinoma of the pancreas can effectively be treated to this compound of about 100mg by the about 0.01mg of per kilogram of body weight administration every day, and perhaps optional every patient's every day, about 0.5mg was to about 7g.
Mastocytosis/mast cell leukemia, gastrointestinal stromal cancer (GIST), small cell lung cancer (SCLC), sinonasal natural killer/t cell lymphoma, carcinoma of testis (spermocytoma), thyroid carcinoma, malignant melanoma, ovarian cancer, cystadenocarcinoma, acute marrow shape leukemia (AML), breast cancer, children's T cell acute lymphoblastic leukemia, angiosarcoma, the degeneration large celllymphoma, carcinoma of endometrium and prostate cancer can effectively be treated to this compound of about 100mg by the about 0.01mg of per kilogram of body weight administration every day, and perhaps optional every patient's every day, about 0.5mg was to about 7g.
Should be appreciated that, the concrete dosage level of any given patient is decided by multiple factor, comprises age, body weight, general health situation, sex, diet, administration time, route of administration, excretion rate, drug regimen and the severity of the disease specific for the treatment of.
Compound of the present invention, or its pharmaceutical salts or N-oxide compound can also effectively be used with other cancer therapy compounds.For example, cell toxicant reagent and angiogenesis inhibitor can be the favourable auxiliary agents of The compounds of this invention.Therefore, the present invention includes the compound that contains general formula I, or the composition of its pharmaceutical salts or N-oxide compound and cell toxicant reagent or blood vessel production inhibitor.Amount separately can be independent treatment significant quantity, and wherein adjection can overcome the cancer that single current system method treatment is had resistance.Amount separately can also make the minimized inferior therapeutic dose of side effect, especially to responsive patient.
Be to be understood that treatment for cancer depends on the type of cancer.For example, lung cancer is different with the treatment of colorectal carcinoma or breast cancer as a roentgenism x.Even lung cancer, for example, a roentgenism x is different with two roentgenism ies, and they are also different with three roentgenism ies.The patient of new diagnosis may be with the plus cisplatin in treatment with scheme.If two roentgenism ies such as taxane are then adopted in this therapy failure.At last, if failure again can adopt Tyrosylprotein kinase EGFR inhibitor as three roentgenism ies.In addition, the homologation process of various countries is also different.Therefore, the treatment plan of acceptance is also different in various countries.But, compound of the present invention, or its pharmaceutical salts or N-oxide compound can also advantageously be used with other cancer therapy compounds altogether.These other compound comprises, for example various kinds of cell poison reagent (alkylating agent, DNA topoisomerase enzyme inhibitor, antimetabolite, tubulin binding substances); Angiogenesis inhibitor and various other forms of therapy comprise kinase inhibitor such as Tarceva, monoclonal antibody and cancer vaccine.Other these can be advantageously comprise Zorubicin (doxorabicin), vincristine(VCR), cis-platinum, carboplatin, gemcitabine and taxanes with the compound of compound co-administered of the present invention.Therefore, composition of the present invention comprises the compound or pharmaceutically acceptable salt thereof of general formula I or N oxide compound and anti-knurl, antitumor, anti-angiogenic agent or chemotherapeutics.
Compound of the present invention, or its pharmaceutical salts or N-oxide compound can also be effectively with the other treatment compound medications beyond the cancer therapy.For example, the therapeutical agent that effectively alleviates side effect can be the favourable auxiliary agent of The compounds of this invention.
The representational embodiment of the present invention is summarized in following table 1:
Table 1
I. the desk-top analysis of activatory c-Kit kinases (bench assay)
The cDNA of encoded K it tyrosine kinase domain separates from the K562 cell and is cloned into rhabdovirus expression vector and is used at insect cell as expressing with the fusion rotein of GST (glutathione-S-transferase).Behind the purifying, the common incubation of enzyme and ATP produces the enzyme of the activated form of tyrosine phosphorylation, and it is used for kinases and analyzes detection compound inhibition external source substrate by the ability of Kit tyrosine kinase domain phosphorylation.
The proteic phosphorylation of c-Kit
The reagent that uses is as follows:
The post damping fluid
50mM?HEPES?pH7.4?125mM?NaCl
10% glycerine
1mg/mL?BSA
2mM?DTT
200μM?NaVO
3
The phosphorylation damping fluid
50mM?HEPES?pH?7.4
125mMNaCl
24mM?MgCl
2
1mM?MnCl
2
1% glycerine
200μM?NaVO
3
2mM?DTT
2mM?ATP
The GST-Kit tyrosine-kinase zymoprotein of 75 μ L purifying (about 150 μ g) and 225 μ L phosphorylation damping fluids were 30 ℃ of incubations 1 hour.In the cold house, with 25mL post damping fluid balance desalting column (as Pharmacia PD-10 post).Phosphorylated protein is applied on the post, with after-applied enough post damping fluids to total amount 2.5mL (being 2.2mL here).The Kit albumen of phosphorylation is used 3.5mL post buffer solution elution then, and is collected in (glycerine final concentration 50%) in the pipe that contains 3.5mL glycerine.After the mixing, will wait duplicate samples to be stored in-20 ℃ or-70 ℃.
The analysis of c-Kit kinase activity
Use based on the analysis of ELISA and determine kinase activity, described analysis is measured Kit and is made external source substrate (polyglutamic acid: the ability of tyrosine residues phosphorylation tyrosine) existing under the condition of ATP.Substrate phosphorylation by with the Kit incubation after the combination degree of only discerning the antibody of the tyrosine residues of phosphorylation in the substrate is carried out quantitatively monitoring.The antibody that uses have covalently bound reporter enzyme (as horseradish peroxidase, HRP) so that antibody can be by the quantitative assay with appropriate H RP substrate (as ABTS) incubation with the combining of substrate of phosphorylation.
The storage reagent that uses is as follows:
13.3 μ g/mL PGT storage liquid: add 66.7 μ L 10mg/mL PGT in 50mL PBS.
The 1X lavation buffer solution: water is diluted to 1X with 20X lavation buffer solution (KPL #50-63-00).
Analysis buffer:
50mM?Hepes，pH?7.4
125mM?NaCl
24mM?MgCl
2
1mM?MnCl
2
1% glycerine
Add before 200 μ M vanadate-uses
2mM DTT-adds before using
Analysis buffer+ATP: 5.8 μ l 75mM ATP are joined in the analysis buffer of 12mL.
Activatory GST-c-kit (TK): with analysis buffer 1:500 dilution.
The sealing damping fluid:
Contain 0.5% Tween-20, the PBS of 3% BSA
Add before 200 μ M vanadate-uses
pY20-HRP：
6.2 μ L 100g/mL pY20-HRP storage liquid are joined in the 10mL sealing damping fluid
ABTS substrate: KPL 3 50-66-06 are by providing form to use
The analysis operation flow process
, be incubated overnight by each hole of 94 hole immulon-4 microwell plates with 75 μ L, 13.3 μ g/mL PGT storage liquid bags, wash once with 250 μ L 1X lavation buffer solutions at 37 ℃.
Add 50 μ L analysis buffer (no ATP) to negative control hole, 50 μ L analysis buffer+ATP are contained in every other hole.Heliotropism and negative control hole add 10 μ L, 5% DMSO, and other holes are contained 10 μ L and are dissolved in testing compound among 5% DMSO (concentration at 10nm to 100 μ M).
Add 30 μ L activatory GST-c-kit with initial action, it adds 50 μ L/ hole 0.5M EDTA termination reactions then room temperature incubation 30 minutes.Plate is given a baby a bath on the third day after its birth time with 1 * lavation buffer solution, add then the special antibody-HRP binding substances of 75 μ L phosphoric acid-tyrosine (as pY20-HRP, store buffer liquid Calbiochem).Plate is room temperature incubation 2 hours, uses 1 * lavation buffer solution to give a baby a bath on the third day after its birth time then.Then add 100 μ L ABTS substrates,, add 100 μ L, 1% SDS termination reaction at last room temperature incubation 30 minutes.By quantitatively this reaction of OD value of on the microwell plate scanner, reading 405/490nM.
Relatively the analytical signal that obtains under compound existence and those contrasts (be with or without ATP, the do not add compound) situation is being arranged, determining the inhibition degree of kinase activity by a series of compound concentrations.These inhibiting values suppress fitting of a curve to determine IC to S shape dose response
50Value (that is, making kinase activity be reduced to 50% compound concentration of control activity).
Compound of the present invention reduces Kit and makes that poly-(L-glutamic acid: the ability of phosphorylation tyrosine) therefore shows directly inhibition c-Kit receptor tyrosine kinase activity in the above-mentioned analysis.IC in this analysis
50Value is between 9nM and 388nM.
According to above-mentioned analysis, compound of the present invention astonishing with show vigor (the The compounds of this invention IC in this analysis that better inhibition c-Kit is arranged than thiophene compound the most similar in the prior art unexpectedly
50Value is than the IC of the most similar known thiophene compound
50Be worth low).In addition, compound of the present invention astonishing and unexpectedly than its many regioisomers separately chemically more stable.
Experiment
Provide embodiments of the invention according to following method:
Scheme with reference to the embodiment 1 that shows below, 3 type aniline can be directly prepare under Weinreb amidation condition from the ester of for example compound 1, the aniline of wherein said ester and for example compound 2 reacts (Synthetic Communications at alkyllithium reagent in the presence of as (but being not limited to) trimethyl aluminium or Chlorodimethyl chlorine in neutral solvent such as toluene or dichloromethane, (1982), 12,989).
For example 3 compound has primary amine functional group, can under reductive condition, react with aldehyde and produce secondary amine, for example at the mixture of triethyl silicane and trifluoroacetic acid, or other reagent exist down as (but being not limited to) SODIUM CYANO BOROHYDRIDE, sodium triacetoxy borohydride, sodium borohydride and hydrogen as embodiment 1-.
Embodiment 1
N-(4-Trifluoromethoxyphen-l) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives
Embodiment 1 prepares through the following steps:
First part:
N-(4-Trifluoromethoxyphen-l) 3-aminothiophene-2-methane amide: under nitrogen atmosphere condition to the 4-trifluoro-methoxyaniline that stirs (add among the 7.8g, toluene solution 44.5mmol) (50mL) trimethyl aluminium toluene (2M, 26.7mL, 53.4mmol).Mixture stirred 16 hours in room temperature.Add methyl 3-amino-2-thiophene carboxylation salt (7g, 44.5mmol), the solution that the obtains stirring (oil bath temperature: 130 ℃) 24 hours that under the nitrogen atmosphere, refluxes.Behind cool to room temperature, carefully drip saturated sodium hydrogen carbonate solution (100mL), mixture was stirring at room 30 minutes.Product methylene dichloride extracting (3x100mL), organic layer is to Na
2SO
4Drying concentrates and generates thick oil, and it is pulverized with the mixture of hexane/ethyl acetate then and produces brown solid N-(4-Trifluoromethoxyphen-l) 3-aminothiophene-2-methane amide.
1H-NMR(400MHz/CD
3OD)：δ＝6.65(d，J＝5.6Hz，1H)，7.23(d，J＝8.4Hz，2H)，7.39(d，J＝5.2Hz，1H)，7.67(d，J＝9.2Hz，2H).MS(ES
+)：303[MH
+].
Second section:
N-(4-Trifluoromethoxyphen-l) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives: N-(4-Trifluoromethoxyphen-l) 3-aminothiophene-2-methane amide (1g, 3.31mmol) and quinoline-4-formaldehyde (347mg, 2.21mmol) trifluoroacetic acid: methylene dichloride (1:1, solution 30mL) reflux 2 hours under nitrogen atmosphere condition.The reaction cool to room temperature and add triethyl silicane (0.71mL, 4.42mmol).The solution that obtains refluxes under the nitrogen atmosphere and stirred 16 hours.Behind the cool to room temperature, reaction mixture reduction vaporization, residue be distributed in ethyl acetate (3 * 100mL) and saturated sodium hydrogen carbonate solution (50mL) between.Organic layer is to Na
2SO
4Dry filter and concentrated.Residuum is by the faint yellow solid of silica gel column chromatography purifying (hexane of 20-30% ethyl acetate) generation embodiment 1, fusing point 168-170 ℃.
1H-NMR(400MHz/CDCl
3)：δ＝5.01(d，J＝6.2Hz，2H)，6.56(d，J＝5.4Hz，1H)，7.12(s，1H)，7.22(d，J＝8.7Hz，2H)，7.25(s，1H)，7.44(d，J＝4.3Hz，1H)，7.58(d，J＝9.0Hz，2H)，7.62(t，J＝8.2Hz，1H)，7.76(t，J＝8.3Hz，1H)，8.02(d，J＝7.5Hz，2H)，8.17(d，J＝8.3Hz，1H)，8.86(d，J＝4.5Hz，1H).MS(ES
+)：444[MH
+].
13C-NMR (400MHz/CDCl
3): δ=45.9,101.4,117.9,118.9,119.5,121.9,122.0,122.6,126.5,127.2,129.1,129.7,130.6,136.8,144.5,145.4,148.3,150.7,155.9,163.8. is to C
22H
16F
3N
3O
2The analytical calculation value of S is: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23.
Measured value is: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
Embodiment 2
N-(4-bromo-3-aminomethyl phenyl) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives
Embodiment 2 uses 4-bromo-3-monomethylaniline to replace the preparation of 4-trifluoro-methoxyaniline according to the step of the foregoing description 1.MS(ES
+)：452，454[MH
+]
Embodiment 3
N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives
Embodiment 3 uses 6-amino-2,2,3 according to the step of the foregoing description 1, and 3-tetrafluoro benzodioxan replaces the preparation of 4-trifluoro-methoxyaniline.MS(ES
+)：490[MH
+]
Embodiment 4
N-(4-chloro-phenyl-) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives
Embodiment 4 uses the 4-chloroaniline to replace the preparation of 4-trifluoro-methoxyaniline according to the step of the foregoing description 1.MS(ES
+)：394，396[MH
+]
Embodiment 5
4-{[2-(4-bromo-3-aminomethyl phenyl carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methane amide
To the N-of 0 ℃ of stirring in uncovered flask (4-bromo-3-aminomethyl phenyl) 3-aminothiophene-2-methane amide (1 equivalent, press the foregoing description 1, the description of first part, the preparation of use 4-bromo-3-monomethylaniline replacement 4-trifluoro-methoxyaniline) THF solution, the THF and the 4M H of adding 2-(N-methyl carboxamide) Pyridine-4-Carboxaldehyde (description as the open WO 01/23375 of international monopoly prepares) (1.1 equivalent)
2SO
4(0.1 equivalent), mixture stirred 30 minutes at 0 ℃.Portions adds sodium borohydride (1 equivalent), makes mixture be warming to room temperature and stirs 2 hours.Add entry then, mixture is basified to pH12 with the 2M sodium hydroxide solution, the product that obtains ethyl acetate extracting.The extract water of combination is used the salt water washing then, dry (MgSO
4), filtering and the yellow semisolid of vacuum concentration generation, it adopts 95:5 to bring up to the hexane of 50:50 gradually: ethyl acetate mixture is the wash-out purifying on column chromatography.MS(ES
+)：459，461[MH
+]
Embodiment 6
4-{[2-(2,2,3,3-tetrafluoro benzodioxan-6-base carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methane amide
Embodiment 6 adopts the step of the foregoing description 5, uses N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) (press the foregoing description 1, the description of first part is with 6-amino 2 for 3-aminothiophene-2-methane amide, 2,3,3-tetrafluoro benzodioxan replaces the preparation of 4-trifluoro-methoxyaniline) prepare.MS(ES
+)：497[MH
+]
Embodiment 7
4-{[2-(4-chloro-phenyl-carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methane amide
Embodiment 7 uses N-(4-chloro-phenyl-) 3-aminothiophene-2-methane amide (press the foregoing description 1, the description of first part uses the 4-chloroaniline to replace the preparation of 4-trifluoro-methoxyaniline) preparation by the step of the foregoing description 5.MS(ES
+)：401，403[MH
+]
Embodiment 8
N-(4-chloro-phenyl-) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives
First part:
7-azaindole-3-formaldehyde: phosphoryl chloride (36.5mL) is added dropwise in refrigerative DMF (40mL) solution, and holding temperature is under 10 ℃.The solution that obtains further is cooled to 5 ℃, and slowly adds DMF (40mL) solution of 7-azaindole in 30-40 minute, and holding temperature is under 25 ℃.Mixture was cooled to 35 ℃ in 48 hours then 95 ℃ of heating, joined refrigerative saturated sodium bicarbonate aqueous solution (800mL) under carefully stirring in one hour.(salt solution (500mL) washing is used in 4 * 500mL) extractings, the extract water (500mL) of combination to mixture then, dry (MgSO with ethyl acetate
4), filter and vacuum concentration generation burgundy semisolid.This crude product adopts 50:50 to bring up to the ethyl acetate of 90:10 gradually: hexanes mixtures is the wash-out purifying on column chromatography.1H-NMR(400MHz/D
6-DMSO)：δ＝7.25(m，1H)，8.38(m，2H)，8.42(s，1H)，9.92(s，1H)，12.62(br.s，1H).MS(ES
+)：147[MH
+]。
Second section
N-(4-chloro-phenyl-) 3-[(1H-pyrrolo-[2,3-b] the pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives: according to the step preparation of embodiment 5, use N-(4-chloro-phenyl-) 3-aminothiophene-2-methane amide (according to embodiment 1, the description of first part, use the 4-chloroaniline to replace the preparation of 4-trifluoro-methoxyaniline) and 7-azaindole-3-formaldehyde (embodiment 8, first part) replacement 2-(N-methyl carboxamide) Pyridine-4-Carboxaldehyde.MS(ES
+)：83，385[MH
+]
Embodiment 9
N-(4-bromo-3-aminomethyl phenyl) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives
The step preparation that embodiment 9 describes according to embodiment 5, use N-(4-bromo-3-aminomethyl phenyl) 3-aminothiophene-2-methane amide (according to embodiment 1, the description preparation of first part, use 4-bromo-3-monomethylaniline to replace the 4-trifluoro-methoxyaniline) and 7-azaindole-3-formaldehyde (embodiment 8, first part) replacement 2-(N-methyl carboxamide) Pyridine-4-Carboxaldehyde.MS(ES
+)：441，443[MH
+]
Embodiment 10
N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives
The step preparation that embodiment 10 describes according to embodiment 5, use N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) 3-aminothiophene-2-methane amide is (according to embodiment 1, the description preparation of first part, use 6-amino-2,2,3,3-tetrafluoro benzodioxan replaces the 4-trifluoro-methoxyaniline) and 7-azaindole-3-formaldehyde (embodiment 8, first part) replacement 2-(N-methyl carboxamide) Pyridine-4-Carboxaldehyde.MS(ES
+)：479[MH
+]
Embodiment 11
N-{[2-(4-Trifluoromethoxyphen-l carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methane amide
Embodiment 11 uses N-(4-Trifluoromethoxyphen-l) 3-aminothiophene-2-methane amide (according to the description preparation of the foregoing description 1) according to the step preparation that embodiment 5 describes.MS(ES
+)：451[MH
+]。
Embodiment 13
N-(4-trifluoromethoxy) phenyl-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxamide derivatives
First part:
4-chloro-1H-pyrrolo-[2,3-b] pyridine: 1H-pyrrolo-[2,3-b] pyridine 7-oxide compound slowly is added to 200mL POCl
3, the mixture that obtains spends the night 80 ℃ of stirrings.Vacuum is removed unnecessary POCl then
3, residuum 500mL H
2O handles and with saturated K
2CO
3EtOAc (2 * 300mL) extractings are used in aqueous solution alkalization then.The extract water and the salt water washing of combination obtain 4-chloro-1H-pyrrolo-[2,3-b] pyridine (12.9g, 76%) to anhydrous sodium sulfate drying and vacuum concentration.MS(ES
+)：153[MH
+].
Second section:
4-iodo-1H-pyrrolo-[2,3-b] pyridine: to 4-chloro-1H-pyrrolo-[2,3-b] pyridine (12.9g, 84.3mmol) and NaI (40g, acetonitrile solution 168mmol) (150mL) slowly add Acetyl Chloride 98Min. (12.6mL, 176mmol).Mixture stirred 4 days at 80 ℃, and vacuum is removed unnecessary acetonitrile then.300mL 10% K
2CO
3The aqueous solution is added in the residuum, mixture CH
2Cl
2(3 x 100mL) extracting.Organic extract of combination obtains crude product (22.2g) with 10% aqueous solution of sodium bisulfite and salt water washing to anhydrous sodium sulfate drying and vacuum concentration.In the THF of this crude product (150mL) solution, add 1M NaOH (100mL).Vacuum-evaporation is except that desolvating again after 2 hours in stirring at room for mixture, and dilute with water is also used CH
2Cl
2Extracting.Extract salt water washing, the dry and vacuum concentration to anhydrous sulfate.The brown solid that obtains is by purification by silica gel column chromatography, and recrystallization obtains pure 4-iodo-1H-pyrrolo-[2,3-b] pyridine (9.75g, 48%) from acetonitrile.MS(ES
+)：245[MH
+].
Third part:
1H-pyrrolo-[2,3-b] pyridine-4-nitrile: (4.7g 19.3mmol) adds Pd in Tuo Qi DMF (25mL) solution to 4-iodo-1H-pyrrolo-[2,3-b] pyridine
2(dba)
3(10mg), dppf (15mg), degassing H
2O (2mL) and Zn (CN)
2(1.4g, 11.6mmol).Mixture stirred 20 hours under 90 ℃ of nitrogen atmosphere conditions, was cooled to 70 ℃ then, added the saturated NH of 75mL 4:1:4
4Cl:NH
4OH:H
2The O mixture.Mixture stirred 20 minutes at 5 ℃, removed by filter the precipitation of generation, with the saturated NH of 75mL 4:1:5
4Cl:NH
4OH:H
2The O mixture, 500mLH
2O and 100mL toluene wash, vacuum-drying obtains 2.06g (74%) 1H-pyrrolo-[2,3-b] pyridine-4-nitrile then.MS(ES
+)：143[MH
+].
1H?NMR(DMSO-d
6，400MHz)：δ6.65(d，IH，J＝3.2)，7.56(d，1H，J＝4.8Hz)，7.84(d，1H，J＝4.0Hz)，8.40(d，1H，J＝4.8Hz).
The 4th part:
1H-pyrrolo-[2,3-b] Pyridine-4-Carboxaldehyde: the 1H-pyrrolo-under-78 ℃ of nitrogen atmosphere [2,3-b] pyridine-4-nitrile (200mg, and the toluene of THF 1.4mmol) (7mL) solution adding Dibal-H (1.0M, 3.07mL, 3.07mmol).Reaction mixture stirred 1 hour at-78 ℃, was warming to 55 ℃ of restir 2 hours.(1.4mL, 1.4mmol), mixture stirred 2 hours at 55 ℃ to add normal DIBAL-H.Mixture is cooled to 5 ℃, with 2M HCl acidifying and stirred 15 minutes.Mixture is used saturated NaHCO then
3CH is used in aqueous solution neutralization
2Cl
2(to anhydrous sodium sulfate drying, vacuum-drying obtains 1H-pyrrolo-[2,3-b] Pyridine-4-Carboxaldehyde (107mg, 52%) for 5 * 25mL) extractings, salt water washing.MS(ES
+)：146[MH
+].1H?NMR(DMSO-d
6，400MHz)：δ?7.22(d，1H，J＝3.6Hz)，7.57(d，1H，J＝4.8Hz)，7.67(d，1H，J＝2.4Hz)，8.61(d，1H，J＝5.2Hz)，10.42(s，1H).
The 5th part:
3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] the thiophene-2-carboxylic acid methyl esters: (110mg is 0.701mmol) with 1H pyrrolo-[2,3-b] Pyridine-4-Carboxaldehyde (107mg, TFA/CH 0.736mmol) for 3-aminothiophene-2-carboxylate methyl ester
2Cl
2Solution (2mL/2mL) stirred 3 hours at 50 ℃.Solution be cooled to 0 ℃ and drip three silicoethanes (0.224mL, 1.40mmol).Mixture stirs at 50 ℃ and handled (to pH6) with the 2N NaOH aqueous solution then in 4 hours, uses saturated NaHCO then
3The aqueous solution is handled (to pH8).Separate organic layer, with water layer CH
2Cl
2(3 * 10mL) extractings.Make up organic extract, use the salt water washing, to anhydrous sodium sulfate drying and vacuum concentration.Residue utilization silica gel column chromatography (the 20%EtOAc/ hexane is to the gradient of 70%EtOAc/ hexane) purifying produces 3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxylic acid methyl esters (98mg, 49%).MS(ES
+)：287[MH
+].
1H?NMR(DMSO-d
6，400MHz)：δ?3.75(s，3H)，4.84(d，2H，J＝4.4Hz)，6.74(dd，1H，J＝2.8Hz?&?2.0Hz)，6.70(d，1H，J＝5.6Hz)，7.01(d，1H，J＝4.8Hz)，7.51(t，1H，J＝2.4Hz)，7.61(d，1H，J＝5.2Hz)，8.18(d，1H，J＝4.8Hz).
The 6th part:
N-(4-trifluoromethoxy) phenyl-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxamide derivatives: (0.381mL, dry toluene 1.74mmol) (5mL) solution adds AlMe to the 4-trifluoro-methoxyaniline
3Toluene (1.4mmol), solution is in stirred overnight at room temperature for 2.0M, 0.520mL.Add 3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] (100mg's thiophene-2-carboxylic acid methyl esters 0.348mmol), spends the night mixture and with the saturated NaHCO of 15mL 130 ℃ of stirrings before cool to room temperature
3Solution-treated.Stir after 1 hour, mixture is filtered, separate filtering layer is with water layer CH
2Cl
2(3 x 10mL) extracting.Isolating solid is dissolved in 15mL CH
2Cl
2, make up all organic solution (toluene and CH
2Cl
2), use the salt water washing, to anhydrous sodium sulfate drying and vacuum concentration.Residuum produces N-(4-trifluoromethoxy) phenyl-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl with silica gel column chromatography (20% EtOAc/ hexane is to the gradient of 50% EtOAc/ hexane) purifying) amino] thiophene-2-carboxamide derivatives (93mg, 62%).MS(ES
+)：432[MH
+].
1H?NMR(DMSO-d
6，400MHz)：δ?4.81(d，2H，J＝6.4Hz)，6.62(dd，1H，J＝3.6?&?1.6Hz)，6.78(d，1H，J＝5.6Hz)，6.99(d，1H，J＝4.8Hz)，7.31(d，2H，J＝8.8Hz)，7.45(dd，1H，J＝2.8?&?3.2Hz)，7.59(d，1H，J＝5.6Hz，1H)，7.79(ddd，2H，J＝8.8，3.2?&?2.0Hz)，8.08(t，1H，J＝6.4Hz)，8.15(d，1H，J＝4.8Hz)，9.54(s，1H).
Following analogue uses 3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxylic acid methyl esters (embodiment 13, the five parts) and suitable aniline, the step of describing according to the foregoing description 13, the six parts prepares.
Embodiment 14
N-(4-chloro-phenyl-)-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxamide derivatives: (5.1mg, 4%) .MS (ES
+): 383[MH
+].
Embodiment 15
3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-Ben Bing dioxin-6-yl) thiophene-2-carboxamide derivatives: (19.4mg, 16%).MS(ES
+)：479[MH
+].
Embodiment 16
4-methyl-N-(4-Trifluoromethoxyphen-l) phenyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives:
According to embodiment 13 the 5th and the described method preparation of six parts, adopt 3-amino-4-thiotolene-2-carboxylate methyl ester, quinoline-4-formaldehyde and 4-(trifluoromethoxy) aniline are as initial substance.MS(ES
+)：458[MH
+]，459[MH
2+].
1H?NMR(CDCl
3，400MHz)：δ?2.15(d，3H，J＝1.2Hz)，5.01(d，2H，J＝7.2Hz)，6.98(d，1H，J＝1.2Hz)，7.17-7.24(m，3H)，7.51-7.54(m，3H)，7.58(ddd，1H，J＝8.0，6.4，1.2Hz)，7.74(ddd，1H，J＝8.0，6.8，1.2Hz)，7.86(bs，1H)，7.97(dd，1H，J＝8.8，0.8Hz)，8.16(d，1H，J＝8.0Hz)，8.89(d，1H，J＝4.8Hz).
The following examples are similar preparations, use suitable aniline separately.
Embodiment 17
N-(4-chloro-phenyl-)-4-methyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives: MS (ES
+): 408,410[MH
+]
Embodiment 18
N-(4-bromo-3-aminomethyl phenyl)-4-methyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives: MS (ES
+): 467,469[MH
+]
Embodiment 19
4-methyl-3-[(quinolyl-4 methyl) amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-Ben Bing dioxin-6-yl) thiophene-2-carboxamide derivatives: MS (ES
+): 503[MH
+]
Embodiment 20
3-{[(1-epoxy quinolyl-4) methyl] amino }-N-[4-(trifluoromethoxy) phenyl] thiophene-2-carboxamide derivatives
First part:
Quinolyl-4 methyl alcohol
(0.50g, 3.24mmol) solution is cooled to 0 ℃ to be dissolved in the quinoline-4-formaldehyde of methyl alcohol (5mL).Then portions add sodium borohydride (0.11g, 2.91mmol).After 1 hour, drip the 2M HCl aqueous solution 0 ℃ of stirring until pH～5.Methyl alcohol is removed in vacuum-evaporation then, by adding saturated NaHCO
3The aqueous solution make aqueous phase and.Aqueous solution CH
2Cl
2(3 *) extracting, the saturated NaHCO of the organic extraction of combination
3The aqueous solution and salt water washing, organic solution is to Na
2SO
4Drying, filtration and vacuum concentration produce yellow solid quinolyl-4 methyl alcohol.
MS(ES
+)：160[MH
+].
1H?NMR(CDCl
3，400MHz)：δ?2.41(bs，1H)，5.25(bs，2H)，7.55(ddd，J＝4.4，1.2，1.2Hz，1H)，7.58(ddd，J＝8.4，7.2，1.2Hz，1H)，7.73(ddd，J＝8.4，6.8，1.6Hz，IH)，7.97(ddd，J＝8.4，1.2，0.4Hz，1H)，8.14(ddd，J＝8.0，1.2，0.4Hz，1H)，8.90(d，J＝4.4Hz，1H).
Second section:
The epoxy quinolyl-4) methyl alcohol
To the CH that is dissolved in that is cooled to 0 ℃
2Cl
2Quinolyl-4 methyl alcohol (10mL) (0.20g, 1.26mmol) solution with a part add m-chloro peroxybenzoic acid water (57-86 weight %, 0.50mg).Be reflected to stir and slowly be warming to room temperature simultaneously.17.5 after hour, the solid filtering that obtains is also used CH
2Cl
2Washing produces white solid (1-epoxy quinolyl-4) methyl alcohol.MS(ES
+)：176[MH
+].
Third part:
Quinoline-4-formaldehyde 1-oxide compound
To (1-epoxy quinolyl-4) methyl alcohol of vigorous agitation (0.10g, acetonitrile 0.57mmol) (10mL) suspension add Dess-Martin periodinane (0.47g, 0.63mmol).After 1 hour, add the 2M NaOH aqueous solution (2mL) and ethyl acetate (105mL), reaction was stirred 5 minutes.Separate each layer, use saturated NaHCO
3The aqueous solution, salt water washing organic phase is to MgSO
4Drying is filtered, and vacuum concentration produces faint yellow solid.MS(ES
+)：174[MH
+].
(this intermediate product also can be as Heterocycles (2003), 60 (4), 953 description preparation).
The 4th part:
3-{[(1-epoxy quinolyl-4) methyl] amino }-N[4-(trifluoromethoxy) phenyl] thiophene-2-carboxamide derivatives
Quinoline-4-formaldehyde 1-oxide compound (0.12g, 0.69mmol), 3-amino-N-[4-(trifluoromethoxy) phenyl] thiophene-2-carboxamide derivatives (0.21g, 0.69mmol), the solution of methylene dichloride (2ml) and trifluoroacetic acid (2ml) was 50 ℃ of heating 2 hours, and cool to room temperature is used triethyl silicane (0.22ml then, 1.38mmol) handle, and continue to stir 2 hours at 50 ℃.After this, with mixture water (40ml) dilution, with 2M NaOH aqueous solution alkalization (pH9) with ethyl acetate (3 x 20ml) extracting.Extract water (30ml) and salt solution (30ml) washing, dry then (MgSO
4), vacuum concentration produces crude product.This matter utilization 15% acetonitrile/CH
2Cl
2To silica gel column chromatography, isolating product further produces 3-{[(1-epoxy quinoline 4-yl by the acetonitrile recrystallization purifying) methyl] amino }-N-[4-(trifluoromethoxy) phenyl] thiophene-2-carboxamide derivatives.MS(ES
+)：460[MH
+].
1HNMR(DMSO-d
6，400MHz)：δ?5.00(s，2H)，6.87(d，J＝5.6Hz，1H)，7.25-7.40(m，3H)，7.65(d，J＝5.3Hz，1H)，7.73-7.91(m，4H)，8.04(t，J＝6.4Hz，1H)，8.30(d，J＝7.1Hz，1H)，8.56(d，J＝6.3Hz，1H)，8.61(d，J＝8.3Hz，1H)，9.60(s，1H).
Claims (12)
1. the compound or pharmaceutically acceptable salt thereof or the N-oxide compound of general formula (I) representative,
Wherein R1 is
Or
R2 is
Or
And
R3 is H or C
1-4Alkyl.
2. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
3. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
And R3 is a hydrogen.
4. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
5. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
And R3 is a hydrogen.
6. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
7. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
And R3 is H or C
1-4Alkyl.
8. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
And R3 is a hydrogen.
9. compound of claim 1, or its pharmaceutical salts or N-oxide compound, wherein R2 is
And R3 is H or C
1-4Alkyl.
10. pharmaceutical composition contains the compound or pharmaceutically acceptable salt thereof or the N oxide compound of claim 1 and pharmaceutical carrier.
11. the compound or pharmaceutically acceptable salt thereof of claim 1 or N oxide compound, described compound is selected from:
N-(4-Trifluoromethoxyphen-l) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-bromo-3-aminomethyl phenyl) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-chloro-phenyl-) 3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
4-{[2-(4-bromo-3-aminomethyl phenyl carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methyl nitrosourea;
4-{[2-(2,2,3,3-tetrafluoro benzodioxan-6-base carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methyl nitrosourea;
4-{[2-(4-chloro-phenyl-carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methyl nitrosourea;
N-(4-chloro-phenyl-) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-bromo-3-aminomethyl phenyl) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives;
N-(2,2,3,3-tetrafluoro benzodioxan-6-yl) 3-[(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) amino] thiophene-2-carboxamide derivatives;
N{[2-(4-Trifluoromethoxyphen-l carboxamide) thiene-3-yl-amino] methyl } the pyridine-2-carboxylic acids methyl nitrosourea;
N-(4-trifluoromethoxy) phenyl-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-chloro-phenyl-)-3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino] thiophene-2-carboxamide derivatives;
3-[(1H-pyrrolo-[2,3-b] pyridin-4-yl methyl) amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzo two oxines-6-yl) thiophene-2-carboxamide derivatives;
4-methyl-N-(4-Trifluoromethoxyphen-l) phenyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-chloro-phenyl-)-4-methyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
N-(4-bromo-3-aminomethyl phenyl)-4-methyl-3-[(quinolyl-4 methyl) amino] thiophene-2-carboxamide derivatives;
4-methyl-3-[(quinolyl-4 methyl) amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzo two oxines-6-yl) thiophene-2-carboxamide derivatives;
3-{[(1-epoxy quinolyl-4) methyl] amino }-N[4-(trifluoromethoxy) phenyl] thiophene-2-carboxamide derivatives.
12. the compound of claim 1 is used for suppressing the application of the medicine of c-Kit receptor tyrosine kinase activity in preparation.
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|---|---|---|---|
| US43815203P | 2003-01-06 | 2003-01-06 | |
| US60/438,152 | 2003-01-06 | ||
| US60/524,972 | 2003-11-25 | ||
| US60/526,358 | 2003-12-02 |
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|---|---|
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| CL (1) | CL2004000013A1 (en) |
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