CN1902190A - 2-(hetero-)aryl substituted tetrahydroquinoline derivatives - Google Patents
2-(hetero-)aryl substituted tetrahydroquinoline derivatives Download PDFInfo
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- CN1902190A CN1902190A CNA2004800371773A CN200480037177A CN1902190A CN 1902190 A CN1902190 A CN 1902190A CN A2004800371773 A CNA2004800371773 A CN A2004800371773A CN 200480037177 A CN200480037177 A CN 200480037177A CN 1902190 A CN1902190 A CN 1902190A
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- RCEYOUJOBGOYRE-DJMKXRNQSA-N OCC(CC[C@H]12)OC1c1cc(C(F)(F)F)ccc1N[C@H]2c(cc1)ccc1F Chemical compound OCC(CC[C@H]12)OC1c1cc(C(F)(F)F)ccc1N[C@H]2c(cc1)ccc1F RCEYOUJOBGOYRE-DJMKXRNQSA-N 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
Disclosed are compounds of formula (I), wherein W, R, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, and R<7> have the meanings indicated in claim 1. Said compounds can be used for the treatment of tumors, among other things.
Description
Background of invention
The objective of the invention is to find to have the new compound of valuable character, particularly can be used in those of preparation medicine.
The present invention relates to the purposes that formula I compound and its are used for the treatment of and prevent the disease that inhibition, adjusting and/or the regulating and controlling effect of mitotic division dynein, particularly mitotic division dynein Eg5 play a role therein, also relate to the pharmaceutical composition that comprises these compounds.
Specifically, the present invention relates to formula I compound, they preferably suppress, regulate and/or regulate and control one or more mitotic division dyneins; Relate to and comprise these compound compositions; Relate to their treatment diseases and the uncomfortable method used, described disease or uncomfortable for example formation, growth and propagation, arteriosclerosis, eye disease, choroid neovascularization and diabetic retinopathy, inflammatory diseases, sacroiliitis, neurodegeneration, restenosis, wound healing or the graft-rejection of vasculogenesis, cancer, tumour.Especially, compound of the present invention is suitable for treatment or preventing cancer disease.
During mitotic division, various kinases are regulated the formation and the kinetics of spindle body, and spindle body is responsible for correctly arranging with the karyomit(e) of coordinating and separating.The specific inhibitory effect of having observed mitotic division dynein-Eg5-causes disintegrating of spindle fibre.Consequently karyomit(e) no longer can be correctly step by step in daughter cell.This causes mitotic division to stop, thereby can cause necrocytosis.Describe the incremental adjustments of dynein Eg5 is existing, for example from the incremental adjustments in the tissue of mammary gland, lung and colon tumor.Since Eg5 performance mitotic division-specific function, the cell that the Eg5 restraining effect mainly influences the cell in the rapid division and do not break up fully.In addition, Eg5 exclusively regulates mitotic division microtubule (spindle body) but not the motion of cytoskeleton.This is vital for the side effect profile of The compounds of this invention, because do not take place or only for example viewed DPN under the situation of taxol (Taxol) is taking place on the faint degree.Therefore, compound of the present invention is a kind of relevant therapy notion for the restraining effect of Eg5 to the treatment of malignant tumour.
Generally speaking, all entities and non-noumenal tumour can be used formula I compounds for treating, and for example monocytic leukemia, the cancer of the brain, genito-urinary system cancer, lymphsystem cancer, cancer of the stomach, laryngocarcinoma and lung cancer comprise adenocarcinoma of lung and small cell lung cancer.Further example comprises prostate cancer, carcinoma of the pancreas and mammary cancer.
Astoundingly, have been found that compound of the present invention has specific inhibitory effect to mitotic division dynein, particularly Eg5.Compound of the present invention preferably shows favourable biologic activity, and described activity for example can easily be detected in assay method as herein described.In this class assay method, compound of the present invention preferably shows and causes restraining effect, is often registered as IC
50Value, it is in the scope that is fit to, preferably in micro-molar range, more preferably in the nmole scope.
As discussed in this article, the effect of compound of the present invention is relevant with various diseases.Therefore, compound of the present invention can be used for preventing and/or treating the disease that the restraining effect that is subjected to one or more mitotic division dynein, particularly Eg5 influences.
Therefore, the present invention relates in described treatment of diseases and/or prevention as the compound of the present invention of medicine and/or active constituents of medicine, relate to compound of the present invention and treat and/or prevent purposes in the medicine of described disease in preparation, also relate to the method for the treatment of described disease, this method comprises the patient that this class of needs is used and uses one or more compounds of the present invention.
Can prove that compound of the present invention has advantageous effect in the xenotransplantation tumor model.
Host or patient can belong to any mammal species, for example primates, particularly people; Rodents comprises mouse, rat and hamster; Rabbit; Horse, ox, dog, cat etc.Animal model is important for experimental study, and it provides the model of human disease treatment.
Certain cell can be determined by vitro test the susceptibility of the disposal carried out with compound of the present invention.Usually, the compound of the present invention of cell culture and various concentration merged to reach is enough to for some time that activeconstituents inducing cell death or inhibition are divided a word with a hyphen at the end of a line, usually between about one hour to a week.With regard to vitro test, can use from biopsy samples through cultured cells.Count disposing the remaining viable cell in back then.
Dosage is different because of used particular compound, disease specific, patient's states etc.Usually, therapeutic dose is quite sufficient, is enough to reduce undesirable cell mass in the target tissue, keeps patient's vigor simultaneously.Treatment generally continues to a large amount of minimizings that cell load occurs, for example is reduced by at least approximately 50%, and can proceed, as long as detect less than undesirable cell substantially in body.
Summary of the invention
The present invention relates to formula I compound
Wherein
W represents CH or N,
R
1, R
2, R
3Represent independently of one another H, A, aryl, heteroaryl, Hal ,-(CY
2)
n-SA ,-(CY
2)
n-SCF
3,-(CY
2)
n-SCN ,-(CY
2)
n-CF
3,-(CY
2)
n-OCF
3, cycloalkyl ,-SCH
3,-SCN ,-CF
3,-OCF
3,-OA ,-(CY
2)
n-OH ,-(CY
2)
n-CO
2R ,-(CY
2)
n-CN ,-(CY
2)
n-Hal ,-(CY
2)
n-NR
2, (CY
2)
n-OA, (CY
2)
n-OCOA ,-SCF
3, (CY
2)
n-CONR
2,-(CY
2)
n-NHCOA ,-(CY
2)
n-NHSO
2A, SF
5, Si (CH
3)
3, CO-(CY
2)
n-CH
3,-(CY
2)
n-N-pyrrolidone, CH (CH
2)
nNRCOOR, CHNRCOOR, NCO, CH (CH
2)
nCOOR, NCOOR, CH (CH
2)
nOH, N (CH
2)
nOH, CHNH
2, CH (CH
2)
nNR
2, CH (CH
2)
nNR
2, C (OH) R, CHNCOR, CH (CH
2)
n-aryl, CH (CH
2)
n-heteroaryl, CH (CH
2)
nR
1, N (CH
2)
nCOOR, CH (CH
2)
nX (CH
2)
n-aryl, CH (CH
2)
nX (CH
2)
n-heteroaryl, N (CH
2)
nCONR
2, XCONR (CH
2)
nNR
2, N[(CH
2)
nXCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
nX-aryl, N[(CH
2)
nXR] SO
2(CH
2)
n-aryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-aryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nXR] CO (CH
2)
nX-heteroaryl, N[(CH
2)
nXR] SO
2(CH
2)
n-heteroaryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nThe NR-heteroaryl, R
1And R
2Also expression-N-C (CF together
3)=N-,-N-CR=N-,-N-N=N-,
Y represents H, A, Hal,
A represents alkyl or cycloalkyl, and wherein one or more H atoms can be replaced by Hal,
Hal represents F, Cl, Br or I,
R represents H or A, R also expression-(CH together under together with the situation of atomic group
2)
5-,-(CH
2)
4-or-(CH
2)
n-X-(CH
2)
nPerhaps-(CH
2)
n-Z-(CH
2)
n,
R
4, R
5Represent H or unsubstituted or single-or many-OR-, NO independently of one another
2-, Hal-, CF
3-, OCF
3-, CN-, NR
2-or SR-, aryl-or the N-pyrrolidone of heteroaryl-replacement ,-X-(CH
2)
2OR ,-X-CO (CH
2)
nCH
3,-X-(CH
2)
2NR
2, R
1, S-aryl, O-aryl, CH
2Si (CH
3)
3, perhaps expression-X (CR together
2)
2-,-X-(CR
2)
3-,-X-(CHCH
2OR) (CH
2)
2-,-X-(CHCH
2NR
2) (CH
2)
2-,-X (CH
2)
2NR
2,-(CR
2)
3-,-(CR
2)
4-,-CR=CR-CR=CR-,-XCHQ (CR
2)
2-,-XCHQCR
2-, R-N-(C=X)-N-R ,-XC[(CH
2) nOR]
2CH
2CH
2-,
X represents O, S or NR,
Q represents CH
2Hal, CHO, COR
a, CH
2R
a, CH
2OCOR
a, CH
2NCOR
1, CH
2N (R
1)
2, CH
2OR
1, CH
2OCON (R
1)
2, CH
2OCOOR
1, CH
2NHCON (R
1)
2, CH
2NHCOOR
1,
R
aExpression
OR, NHR
2, NR
2, OR, NHR
2, NR
2, NR (CH
2)
n-aryl, NR (CH
2)
nOR, COOR, N-pyrrolidone atomic group, OCOR, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNHCOOR] CO-aryl, R
1, N[CH
2(CH
2)
nOR]
2, NR (CH
2)
nNCOOR, X (CH
2)
nX (CH
2)
nXR, NR (CH
2)
nX (CH
2)
nOH, NR (CH
2)
nO (CH
2)
nOH, (CH
2)
nCOOR, O (CO) NR (CH
2)
nOR, O (CO) (CH
2)
nNR
2, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nR
1, N (R) (CH
2)
nN (R) COOR, XCOO (CH
2)
nNR
2, OSO
2A, OSO
2CF
3, OSO
2Ar, OCONR
2, OCH
2(CH
2)
nNR
2,
Z represents CH
2, X, CHCONH
2, CH (CH
2)
nNRCOOR, CHNRCOOR, NCO, CH (CH
2)
nCOOR, NCOOR, CH (CH
2)
nOH, N (CH
2)
nOH, CHNH
2, CH (CH
2)
nNR
2, CH (CH
2)
nNR
2, C (OH) R, CHNCOR, CH (CH
2)
n-aryl, CH (CH
2)
n-heteroaryl, CH (CH
2)
nR
1, N (CH
2)
nCOOR, CH (CH
2)
nX (CH
2)
n-aryl, CH (CH
2)
nX (CH
2)
n-heteroaryl, N (CH
2)
nCONR
2, XCONR (CH
2)
nNR
2, N[(CH
2)
nXCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
nX-aryl, N[(CH
2)
nXR] SO
2(CH
2)
n-aryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-aryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nXR] CO (CH
2)
nX-heteroaryl, N[(CH
2)
nXR] SO
2(CH
2)
n-heteroaryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-heteroaryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-heteroaryl, O (CH
2)
nNR
2, X (CH
2)
nNR
2, NCO (CH
2)
nNR
2,
R
6Expression aryl or heteroaryl, they each unsubstituted naturally or by following group list-or polysubstituted: aryl or heteroaryl, described aryl or heteroaryl substituting group separately can be by Hal, NO
2, CN, A, OR, OCOR, COR, NR
2, CF
3, OCF
3, OCH (CF
3)
2Replace, perhaps Hal, NO
2, CN, OR, A ,-(CY
2)
n-OR ,-OCOR ,-(CY
2)
n-CO
2R ,-(CY
2)
n-CN ,-NCOR ,-COR or-(CY
2)
n-NR
2,
R
7Expression (C=O)-R, (C=O)-NR
2, (C=O)-OR, H or A,
M represents 0,1 or 2,
And
N represents 0,1,2,3,4,5,6 or 7,
And their pharmaceutically useful derivatives, solvate, tautomer, salt and steric isomer, comprise the mixture of its all proportions.
The present invention also relates to optically active form, enantiomorph, racemoid, diastereomer and hydrate and the solvate of these compounds.The solvate of term compound is used for representing the adducts that inert solvent molecule and formula I compound form owing to their power of attracting each other.That solvate for example has is single-or two-hydrate or alcoholate.
The pharmaceutically useful derivative of term is used for representing for example salt and the so-called preceding drug compound of The compounds of this invention.
The term prodrug derivant is used for representing such formula I compound, they by for example alkyl or acyl group, sugar or oligopeptides by modified, and in vivo rapidly cracking generate active compound of the present invention.
They also comprise the biodegradability polymer derivant of compound of the present invention, as for example Int.J.Pharm.
115, described in the 61-67 (1995).
Similar compound for example has description in following document: Tetrahedron Lett.1988,29,5855-5858, Tetrahedron Lett.2003,44,217-219, J.Org.Chem.1997,62,4880-4882, J.Org.Chem.1999,64,6462-6467, Chem.Lett.1995,423-424, J.Org.Chem.2000,65,5009-5013, Chem.Lett.2003,32,222-223, US2003149069A1, but do not mention about cancer therapy and/or do not contain feature important among the present invention.
Wording " significant quantity " expression medicine or active constituents of medicine cause the amount of biology or medical response in tissue, system, animal or human, described reaction is researchist or the doctor looks for or need for example.
In addition, wording " treatment significant quantity " is illustrated in the amount (comparing with the curee who does not accept this amount) that causes at least a following effect in people or the Mammals: the improvement in the disposal of healing property, the healing, the preventing or eliminating of disease, syndrome, illness, discomfort, obstacle or side effect, the perhaps minimizing of disease, illness or obstacle progress.
Wording " treatment significant quantity " also comprises effective increase or strengthens the amount of normal physiological function.
The present invention also relates to the purposes of the mixture of compound of the present invention, the mixture of two kinds of diastereomers for example, for example ratio is the mixture of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000.It particularly preferably is the mixture of Stereoisomeric compounds.
The present invention relates to formula I compound and salt thereof and the formula I compound of preparation Patent right requirement and the method for pharmaceutically useful derivative, salt, solvate and steric isomer thereof, it is characterized in that making wherein R
1, R
2And R
3Formula II compound with implication as implied above
With R wherein
6Formula III compound reaction with implication as implied above,
With
With R wherein
4And R
5Formula IV compound, its double bond isomer (E isomer) or its mixture reaction with implication as implied above,
This reaction preferably protonic acid or Lewis acid for example trifluoroacetic acid, hexafluoroisopropanol, Trichlorobismuthine (III), Ytterbiumtriflate (III), trifluoromethanesulfonic acid scandium (III) or cerous nitrate (IV) ammonium in the presence of carry out and randomly introduce atomic group except that H as R by ordinary method
7
The diastereomer of the formula I compound that can be obtained by aforesaid method and the mixture of enantiomorph preferably separate by chromatography or crystallization process.
If necessary, the alkali of the formula I that will be obtained by aforesaid method and acid are converted into their salt.
Atomic group R, R in the context
1, R
2, R
3, R
4, R
5, R
6, R
7, X, Y, Q, R
a, Z, W, m and n have suc as formula the implication shown in the I, other have offer some clarification on except.If the discrete atomic group occurs repeatedly in compound, implication shown in these atomic groups have independently of one another.
A represents alkyl, preferably unbranched (straight chain) or side chain, have 1,2,3,4,5,6,7,8,9 or 10 carbon atoms.A preferably represents methyl, also has ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, also has amyl group, 1-in addition, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group, preference such as trifluoromethyl in addition.A very particularly preferably represents to have 1,2,3,4, the alkyl of 5 or 6 carbon atoms, preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1,1-trifluoroethyl.A is the representative ring alkyl also.Cycloalkyl is representative ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl or suberyl preferably, but cyclopentyl particularly.
R
1Preferably represent A, CF
3, OCF
3, SA, SCN, CH
2CN ,-OCOA, Hal, SCF
3, preferably also have the tertiary butyl ,-CH (CH
3) CH
2CH
3, sec.-propyl, ethyl or methyl.Especially, R
1The expression tertiary butyl, sec.-propyl, ethyl, CF
3, methyl, Br, Cl, SCF
3, CH (CH
3) CH
2CH
3, n-propyl, OCH
3, SCH
3, normal-butyl ,-SCN, CH
2CN.R
1Particularly preferably represent the tertiary butyl, sec.-propyl, ethyl or CF
3
R
2Preferably represent Hal, A or OA, particularly Br, cyclopropyl, OCH
3In addition, preferred especially H or F.
R
3Preferably represent H or A, particularly H.R
3Be preferably located in the 5-position.Especially, R
3Expression H or F.
In particularly preferred formula I compound, R
2And R
3The implication that has H simultaneously.In further preferred formula I compound, atomic group R
2And R
3In a implication with H, another atomic group has the implication of F.
If R
5Expression H, then R
4Preferably represent one of following groups:
Or-X-(CH
2)
2-NR
2
R
5Preferably represent H, perhaps with R
4Take one of following meanings together:
Wherein X, R and R
aHas implication as implied above.
R
4With R
5Particularly preferably take one of following meanings together:
Wherein R has implication as implied above.
R
aPreferably represent 1-piperazinyl, N-morpholinyl, NHR or NR
2
If for example more than the n appearance once, these atomic groups can be taked different values independently of one another with index for atomic group and index.At atomic group R
aIn, n preferably represents 2 or 0, m preferably represents 0.
R
6Preferably represent phenyl, 2-, 3-or 4-pyridyl, pyrimidyl, furyl or thienyl, they each unsubstituted naturally or by Hal, CN, NO
2, OH, CF
3, OCH (CF
3)
2, OCOCH
3Or the A list-or many-replace.R
6It preferably not the heteroaromatic atomic group.Especially, R
6One of expression following groups:
Wherein
X represents O, S or NR, particularly O or S, and A has implication as implied above, but excellent
Choosing ground expression methyl, Hal preferably represents F or Cl.
In addition, especially preferred R wherein
6Formula I compound with one of following meanings:
R
7Preferably represent H or A, particularly H.
Aryl is preferably represented phenyl, naphthyl or xenyl, they each unsubstituted naturally or by Hal, A, OH, OA, NH
2, NO
2, CN, COOH, COOA, CONH
2, NHCOA, NHCONH
2, NHSO
2A, CHO, COA, SO
2NH
2, SO
2A ,-CH
2-COOH or-OCH
2-COOH is single-, two-or three-replace.
Aryl is preferably represented phenyl; adjacent-; between-or right-tolyl; adjacent-; between-or right-ethylphenyl; adjacent-; between-or right-propyl group phenyl; adjacent-,-or right-isopropyl phenyl; adjacent-,-or right-tert-butyl-phenyl; adjacent-; between-or right-hydroxy phenyl; adjacent-; between-or right-p-methoxy-phenyl; adjacent-,-or right-nitrophenyl; adjacent-,-or right-aminophenyl; adjacent-; between-or right-(N-methylamino) phenyl; adjacent-; between-or right-(N-methylamino carbonyl) phenyl; adjacent-,-or right-acetylamino phenyl; adjacent-,-or right-p-methoxy-phenyl; adjacent-; between-or right-ethoxyl phenenyl; adjacent-; between-or right-ethoxy carbonyl phenyl; adjacent-,-or right-(N, N-dimethylamino) phenyl; adjacent-; between-or right-(N; N-dimethylamino carbonyl) phenyl; adjacent-,-or right-(N-ethylamino) phenyl; adjacent-,-or right-(N; the N-diethylamino) phenyl; adjacent-; between-or right-fluorophenyl; adjacent-,-or right-bromophenyl; adjacent-,-or right-chloro-phenyl-; adjacent-; between-or right-(sulfonyloxy methyl amino) phenyl; adjacent-; between-or right-(methyl sulphonyl) phenyl, preferred in addition 2,3-; 2; 4-, 2,5-; 2; 6-, 3,4-or 3; the 5-difluorophenyl; 2; 3-, 2,4-; 2; 5-, 2,6-; 3; 4-or 3, the 5-dichlorophenyl; 2,3-; 2; 4-, 2,5-; 2; 6-, 3,4-or 3; the 5-dibromo phenyl; 2; 4-or 2, the 5-dinitrophenyl; 2,5-or 3; the 4-Dimethoxyphenyl; 3-nitro-4-chloro-phenyl-; 3-amino-4-chloro-; 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chloro-phenyl-; 2-nitro-4-N; the N-dimethylamino-or 3-nitro-4-N; the N-dimethylaminophenyl; 2, the 3-diamino-phenyl; 2,3; 4-; 2,3,5-; 2; 3,6-, 2; 4; 6-or 3,4, the 5-trichlorophenyl; 2; 4; the 6-trimethoxyphenyl; 2-hydroxyl-3, the 5-dichlorophenyl; right-iodophenyl; 3,6-two chloro-4-aminophenyls; 4-fluoro-3-chloro-phenyl-; 2-fluoro-4-bromophenyl; 2; 5-two fluoro-4-bromophenyls; 3-bromo-6-p-methoxy-phenyl; 3-chloro-6-p-methoxy-phenyl; 3-chloro-4-acetylamino phenyl; 3-fluoro-4-p-methoxy-phenyl; 3-amino-6-aminomethyl phenyl; 3-chloro-4-acetylamino phenyl or 2,5-dimethyl-4-chloro-phenyl-.
Heteroaryl preferably represents to have the list of one or more N, O and/or S atom-or two-cyclophane family heterocycle, and it is unsubstituted or by Hal, A, NO
2, NHA, NA
2, OA, COOA or CN be single-, two-or three-replace.
Heteroaryl particularly preferably represents to have the saturated or aromatic heterocycle of monocycle of N, a S or O atom, and it can be unsubstituted or by Hal, A, NHA, NA
2, NO
2, COOA or benzyl list-, two-or three-replace.
Do not consider further replacement, unsubstituted heteroaryl is represented for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2,4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5- azoles base, 3-, the different azoles of 4-or 5-base, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl, preferred in addition 1,2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or 5-base, 1-or 5-tetrazyl, 1,2,3- diazole-4-or-the 5-base, 1,2,4- diazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 4-or 5-pseudoindoyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazol base, 3-, 4-, 5-, 6-or 7-benzisoxa azoles base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzo-2,1,3- di azoly, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolines base, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-phendioxin, 4- piperazine base, preferred in addition 1,3-benzo dioxole-5-base, 1,4-benzo two alkane-6-base, 2,1,3-diazosulfide-4-or-5-base or 2,1,3-benzo diazole-5-base.
Hal preferably represents F, Cl or Br, but also has I, preferred especially F or Cl.
In the present invention everywhere, to occur once above atomic group can be identical or different, that is, independent of each other.
Formula I compound can have one or more chiral centres, therefore has various stereoisomeric forms in any ratio.Formula I comprises all these forms.
Particularly preferred formula I compound is those of minor IA to ID:
Wherein
R, R
1, R
2, R
6, R
7Have implication as implied above with X,
And
R
8Expression H, CH
2OR, CH
2NR
2, CH
2R
a, COR
a
Particularly preferred formula IA compound is those of minor IA1 to IA4:
Wherein R, R
a, R
1, R
2, R
3, R
6And R
7Has implication as implied above.
In particularly preferred formula IB compound, R
8Implication with H.
Atomic group R
4And R
5Particularly preferably be in cis-position each other.Atomic group R in addition
6Preferably be in atomic group R
5Trans-position.
Here the formula A or the B compound that preferably have following array structure:
With and racemoid or other mixture of enantiomers.
Therefore, The present invention be more particularly directed to such formula I compound, wherein at least one described atomic group has one of preferred meaning as implied above.Some preferred compounds can be represented by following minor I1 to I45a:
In addition, formula I compound and the raw material for preparing them are by document (classic for example, as Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], Georg-Thieme-Verlag, Stuttgart) the own known method preparation described in, definite, known and be suitable for preparing under the reaction conditions of described reaction.Also can adopt the own known method variant of not mentioning in detail here.
If necessary, raw material also can original position form, so that do not separate them from reaction mixture, but further is converted into formula I compound immediately.
Reaction is generally in inert solvent, preferably for example carry out in the presence of TFA, HFIP, bismuth (III) salt, ytterbium (III) salt or the CAN at protonic acid or Lewis acid.According to used condition, the reaction times, temperature of reaction was between about 0 ℃ to 180 ℃, usually between 0 ℃ to 100 ℃, between 15 ℃ to 35 ℃ between several minutes to 14 day.
The inert solvent that is fit to has for example hydro carbons, as hexane, sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbon, as trieline, 1,2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Nitrile is as acetonitrile; Dithiocarbonic anhydride; Carboxylic-acid is as formic acid or acetate; Nitro-compound, as Nitromethane 99Min. or oil of mirbane, the perhaps mixture of described solvent.
R wherein
7Formula I compound with the implication except that H preferably by alkylation or acylation from R wherein
7The formula I compound of expression H.
If necessary, amino and/or the hydroxyl that can modify through the official in the formula I compound can utilize ordinary method to discharge by solvolysis or hydrogenolysis.This can for example use NaOH or KOH to carry out under the temperature between 0 ℃ to 100 ℃ in water, water/THF or water/two alkane.
Ester is undertaken by method known to those skilled in the art to the reductive action of aldehyde or amine to the reductive action or the nitrile of aldehyde or alcohol, and in standard organic chemistry works description is arranged.
Described compound of the present invention can be used with its final salt-independent shape.On the other hand, the present invention also relates to the use of these compound pharmacy acceptable salt forms, described salt can be derived from various organic and inorganic bronsted lowry acids and bases bronsted lowries by technology known in the art and be obtained.The pharmacy acceptable salt form major part of formula I compound prepares by ordinary method.If formula I compound contains carboxyl, then can generate one of its salt that is fit to by making compound and the alkali reaction that is fit to obtain corresponding base addition salt.Such alkali has for example alkali metal hydroxide, comprises potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides is as hydrated barta and calcium hydroxide; Alkali metal alcoholate, for example potassium ethylate and sodium propylate; With various organic basess, as piperidines, diethanolamine and N-methylglucosamine.The aluminium salt that comprises formula I compound equally.Under the situation of some formula I compound, can be by these compounds be generated acid salt with pharmaceutically acceptable organic and mineral acid treatment, described acid is hydrogen halide for example, as hydrogenchloride, hydrogen bromide or hydrogen iodide; Other mineral acid and corresponding salt thereof are as vitriol, nitrate or phosphoric acid salt etc.; Alkyl-and single aryl-sulfonic acid salt, as esilate, tosylate and benzene sulfonate; With other organic acid and corresponding salt thereof, as acetate, trifluoroacetate, tartrate, maleate, succinate, Citrate trianion, benzoate, salicylate, ascorbate salt etc.Therefore, the pharmaceutically-acceptable acid addition of formula I compound comprises following salt: acetate, adipate, alginate, arginic acid salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, hydrosulphite, bromide, butyrates, camphorate, camsilate, octylate, muriate, chloro benzoate, Citrate trianion, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitro-benzoate, dodecyl sulfate, esilate, fumarate, mutate (from glactaric acid), the galacturonic hydrochlorate, gluceptate, gluconate, glutaminate, glycerophosphate, hemisuccinic acid salt, Hemisulphate, enanthate, hexanoate, hippurate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, iodide, isethionate, isobutyrate, lactic acid salt, Lactobionate, malate, maleate, malonate, mandelate, metaphosphate, mesylate, tolyl acid salt, monohydric phosphate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pounce on nurse hydrochlorate (palmoate), pectinic acid salt, persulphate, phenylacetic acid salt, 3-phenylpropionic acid salt, phosphoric acid salt, phosphonate, phthalate, but this does not represent restriction.
In addition, the alkali salt of compound of the present invention comprises the salt of aluminium, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc, but this is not intended to the representative restriction.In above-mentioned salt, preferred ammonium salt; An alkali metal salt sodium and sylvite; With alkaline earth salt calcium and magnesium salts.Comprise the salt of following alkali from the derive salt of the formula I compound that obtains of pharmaceutically acceptable organic nontoxicity alkali: primary amine, secondary amine and tertiary amine, the amine (amine that also comprises naturally occurring replacement) that replaces, cyclic amine and deacidite, arginine for example, trimethyl-glycine, caffeine, chloroprocaine, choline, N, N '-dibenzyl-ethylenediamin (benzathine), dicyclohexyl amine, diethanolamine, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, hydrabamine, Isopropylamine, lignocaine, Methionin, meglumine, N-methyl D-glycosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, trolamine, triethylamine, Trimethylamine 99, tripropyl amine and three (methylol) methylamine (Trometamol), but this is not intended to the representative restriction.
The The compounds of this invention that contains alkaline nitrogen-containing group can utilize following reagent quaternized: (C for example
1-C
4) alkyl halide, for example muriate of methyl, ethyl, sec.-propyl and the tertiary butyl, bromide and iodide; Sulfuric acid two (C
1-C
4) alkyl ester, for example methyl-sulfate, diethyl ester and diamyl ester; (C
10-C
18) alkyl halide, for example muriate of decyl, dodecyl, lauryl, myristyl and stearyl, bromide and iodide; And aryl (C
1-C
4) alkyl halide, for example benzyl chloride and phenethyl bromide.Use this class salt can prepare water-soluble and oil-soluble compounds of the present invention.
Preferred above-mentioned pharmaceutical salts comprises acetate, trifluoroacetate, benzene sulfonate, Citrate trianion, fumarate, gluconate, hemisuccinic acid salt, hippurate, hydrochloride, hydrobromate, isethionate, mandelate, meglumine salt, nitrate, oleate, phosphonate, Pivalate, sodium phosphate, stearate, vitriol, sulfosalicylate, tartrate, Thiomalate, tosylate and Trometamol, but this is not intended to the representative restriction.
Thereby the acid salt of alkalescence formula I compound prepares by the required acid of free alkali form and capacity being contacted cause salt to generate.By make in a usual manner salt form contact with alkali and separated free alkali can the regeneration free alkali.Free alkali form is some physical properties difference of its corresponding salt form in some aspects, for example the solubleness in polar solvent; But for purpose of the present invention, salt is equivalent to its free alkali form separately in others.
As mentioned, the pharmaceutically acceptable base addition salt of formula I compound generates with metal or amine, for example basic metal and alkaline-earth metal or organic amine.Preferred metal is sodium, potassium, magnesium and calcium.Preferred organic amine is N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, N-methyl D-glycosamine and PROCAINE HCL, PHARMA GRADE.
Thereby the base addition salt of acidic cpd of the present invention prepares by the required alkali amine of free acid form and capacity being touched cause salt to generate.Can the regeneration free acid by making salt form contact also separated free acid in a usual manner with acid.Free acid form is some physical properties difference of its corresponding salt form in some aspects, for example the solubleness in polar solvent; But for purpose of the present invention, salt is equivalent to its free acid form separately in others.
If compound of the present invention contains the group that can generate this class pharmacy acceptable salt more than, the present invention also comprises polybasic salt.Typical polybasic salt form comprises for example bitartrate, diacetin, two fumarates, two meglumine salts, diphosphate, disodium salt and tri hydrochloride, but this is not intended to the representative restriction.
About foregoing, term herein " pharmacy acceptable salt " is used for representing activeconstituents as can be seen, the formula I compound that comprises salt form has given activeconstituents improved pharmacokinetics character if particularly compare this salt form with any other salt form of the free form of activeconstituents or previously used activeconstituents.The pharmacy acceptable salt form of activeconstituents also can be first for this activeconstituents provides the required pharmacokinetics character that is not had before it, even can have positive influence to its pharmacodynamics aspect the interior therapeutic effect of this activeconstituents.
In addition, the invention still further relates to medicine, it comprises at least a formula I compound and/or its pharmaceutically useful derivative, solvate and steric isomer, comprises the mixture of its all proportions, randomly comprises vehicle and/or auxiliary agent.
Pharmaceutical preparation can be used with the form of dosage device, and each dosage device comprises the activeconstituents of predetermined amount.This class unit can for example comprise 0.5mg to 1g, preferred 1mg to 700mg, preferred especially 5mg to 100mg compound of the present invention, this depends on illness, application process and patient's age, body weight and the situation of being treated, perhaps pharmaceutical preparation can be used with the form of dosage device, and each dosage device comprises the activeconstituents of predetermined amount.Preferred dosage unit preparation is those of activeconstituents that comprise per daily dose as implied above or part dosage or the amount suitable with it.In addition, such pharmaceutical preparation can utilize the pharmacy field known method to prepare.
Pharmaceutical preparation can be suitable for using via any required appropriate methodology, for example oral (comprise and sucking or the hypogloeeis), rectum, nose, part (comprise suck, hypogloeeis or transdermal), vagina or parenteral (comprising subcutaneous, intramuscular, intravenously or intradermal) method.This class preparation can utilize known all methods of pharmacy field to be prepared, for example by activeconstituents and one or more vehicle or one or more auxiliary agents are merged.
Be suitable for Orally administered pharmaceutical preparation and can be used as independent unit and use, for example capsule or tablet; Powder or granule; Solution in water-based or non-aqueous liquid or suspensoid; Edible foam or foam food prods; Perhaps oil-in-water liq emulsion or water-in-oil-type liquid emulsion.
Therefore, for example, under the situation Orally administered, active ingredient components and oral nontoxicity and pharmaceutically acceptable inert excipient can be merged, for example ethanol, glycerine, water etc. with tablet or Capsule form.Powder is like this preparation: compound powder is broken to suitable fine particle size, its pharmaceutical excipient with pulverizing is in a similar manner mixed, edible carbohydrate for example is as starch or N.F,USP MANNITOL.Also can there be correctives, sanitas, dispersion agent and dyestuff.
Capsule is preparation like this: prepare powdered mixture as mentioned above, be filled in the shaping gelatin shell.Can in powdered mixture, add glidant and lubricant, for example polyoxyethylene glycol of polymolecularity silicic acid, talcum powder, Magnesium Stearate, calcium stearate or solid form before the stuffing operation.Also can add disintegrating agent or solubilizing agent for example agar, lime carbonate or yellow soda ash, purpose is to improve the utilizability of medicine after using capsule.
In addition, if desired or necessary, also can in mixture, mix suitable tackiness agent, lubricant and disintegrating agent and dyestuff.The tackiness agent that is fit to comprises for example for example gum arabic, tragakanta or sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax class etc. of glucose or beta lactose, the sweeting agent of being made by corn, natural and synthetic rubber of starch, gelatin, natural sugar.Used lubricant comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc. in these formulations.Disintegrating agent comprises starch, methylcellulose gum, agar, wilkinite, xanthan gum etc. without limitation.Tablet is for example to prepare like this: the preparation powdered mixture, granulation or dry method are suppressed this mixture, add lubricant and disintegrating agent, suppress whole mixture, obtain tablet.Powdered mixture is like this preparation: will mix with above-mentioned thinner or matrix to be fit to the compound that mode pulverizes, randomly with tackiness agent for example carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone; Stripping retarding agent (dissolutionretardant) is paraffin for example; Absorption enhancer (absorption accelerator) is quaternary ammonium salt for example; And/or for example wilkinite, kaolin or Lin Suanergai mixing of absorption agent.Powdered mixture can be by for example the solution-wet and the compacting of syrup, starch paste, mucialga of arabic gummy or Mierocrystalline cellulose or polymer materials sieve granulation with tackiness agent with it.As the alternative of granulation, powdered mixture can obtain the agglomerate of inhomogeneous shape through tabletting machine processing, with its broken particle that forms.Can come lubricated granules by adding stearic acid, stearate, talcum powder or mineral oil, purpose is the adhesion that prevents tablet die.Compacting obtains tablet through lubricated mixture then.Also compound of the present invention and free-pouring inert diluent can be merged, directly compacting obtains tablet then, need not to carry out granulation or dry method pressing step.Can there be transparent or opaque protective layer, forms by shellac sealing coat, sugar or polymer material layer and waxy luster layer.Can add dyestuff in these dressings, purpose is to distinguish different dosage devices.
Liquid oral for example solution, syrup and elixir can be made into the form of dosage device, so that specified rate comprises the compound of predetermined amount.Syrup can prepare by compound being dissolved in the aqueous solution that contains suitable correctives, and elixir is to use nontoxic alcohol preparing carriers.Suspensoid can be prepared by compound is dispersed in the non-toxic carrier.Also can add for example for example spearmint oil and natural sweeteners or asccharin or other artificial sweetening agent etc. of ethoxylation isooctadecanol and polyoxyethylene sorbitol ether, sanitas, flavoring additive of solubilizing agent and emulsifying agent.
If necessary, be used for Orally administered dosage unit formulation and can be encapsulated in micro-capsule.Preparation also can be extended or the mode that postpones prepares with release, for example with the granulated material dressing or be embedded in polymkeric substance, the wax etc.
Formula I compound and salt thereof, solvate and physiological function derivative also can be used with the form of liposome delivery system, for example small-sized individual layer capsule, large-scale individual layer capsule and multilayer capsule.Liposome can for example cholesterol, stearylamine or phosphatidylcholine form by various phosphatide.
Formula I compound and salt thereof, solvate and physiological function derivative also can use monoclonal antibody to send as independent carrier, and compound molecule is coupled on the described carrier.Compound also can with the soluble polymer coupling as target medicine carrier.This base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl-Methacrylamide-phenol (polyhydroxypropyl-methacrylamidophenol), poly-hydroxyethyl-l-asparagine-phenol (polyhydroxy-ethylaspartamidophenol) or polyethylene oxide polylysine, and it is replaced by palmitoyl.In addition compound can also with the Biodegradable polymeric class coupling that is suitable for realizing the medicine sustained release, for example crosslinked or amphiphilic block copolymer of poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydroxyl pyrans, polybutylcyanoacrylate and hydrogel.
The pharmaceutical preparation that is suitable for transdermal administration can be using with the long-term independent plaster form that closely contacts of recipient's epidermis.Therefore, for example, activeconstituents can be sent from plaster by ionization, and ionization is at Pharmaceutical Research, and 3 (6), in 318 (1986) the generic term description is arranged.
The medicinal compound that is suitable for topical application can be formulated into ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol or finish.
For example mouthful and with regard to the disposal of skin, preparation is preferably with topical ointments or the application of ointment form with regard to eye or other outside organization.In the preparation that produces ointment, but can adopt paraffin class matrix or water compatibility ointment matrix preparation activeconstituents.Select as an alternative, activeconstituents can be mixed with ointment with oil-in-water-type ointment matrix or water-in-oil-type matrix.
The pharmaceutical preparation that is suitable for being applied topically to eye comprises eye drops, and wherein activeconstituents is dissolved or be suspended in suitable carrier, the particularly aqueous solvent.
The pharmaceutical preparation that is suitable for being applied topically to mouthful comprises lozenge, pastille and mouth wash shua.
The pharmaceutical preparation that is suitable for rectal administration can be used with the form of suppository or enema.
Be suitable for the wherein carrier substance that nose uses and for example be the meal of 20-500 micron for the solid pharmaceutical preparation comprises particle diameter, its mode with nasil is used, that is, the container that will contain powder sucks rapidly via nasal cavity from container near nose.Be used for comprising the activeconstituents that is in water or oil to contain the suitable preparation that liquid uses as the nasal spray or the nasal drop form of carrier substance.
Be suitable for sucking the pharmaceutical preparation of using and comprise fine granular dirt or mist, it can pass through various types of pressurised aerosol dividers, spraying gun or insufflator and produce.
The pharmaceutical preparation that is suitable for vaginal application can be used with the form of vaginal suppository, tampon, ointment, gelifying agent, paste, foam or spray agent.
The pharmaceutical preparation that is suitable for parenteral administration comprises water-based and non-aqueous aseptic injectable solution agent, and it comprises antioxidant, buffer reagent, fungistat and solute, will open with recipient's blood of being treated etc. by their preparations; With water-based and non-aqueous aseptic suspensoid, it can comprise suspension medium and thickening material.Preparation can be applied and be stored with lyophilize (freeze-drying) state in ampoule that single dose or multi-dose container for example seal and bottle, so as only to add at once before use sterile carrier liquid for example water for injection get final product.
Injection solution and suspensoid according to the prescription preparation can be from sterilized powder, particle and pharmaceutical tablet.
Self-evident, except the above component of specifically mentioning, preparation can also comprise other material that this area is usually used in the particular formulations type; Therefore, for example, be suitable for Orally administered preparation and can comprise correctives.
The treatment significant quantity of formula I compound depends on multiple factor, comprises the character and the application process of the definite illness of the age of animal for example and body weight, needs treatment and seriousness thereof, preparation, and it is finally determined by doctor in charge or animal doctor.But with regard to treatment tumor growth, for example colon or mammary cancer, the significant quantity of The compounds of this invention is generally 0.1-100mg/kg recipient (Mammals) body weight/day, particularly is generally the 1-10mg/kg body weight/day.Therefore, the actual amount of Adult Mammals every day of body weight 70kg is generally 70-700mg, this amount can be used as single dose and gives or give every day with a series of divided doses (for example 2,3,4,5 or 6 divided doses) usually every day, so that total per daily dose is identical.The significant quantity of salt or solvate or its physiological function derivative can be used as the mark of the significant quantity of The compounds of this invention itself and determines.Can think that similar dosage is suitable for treating other illness mentioned above.
In addition, the invention still further relates to medicine, it comprises at least a formula I compound and/or its pharmaceutically useful derivative, solvate and steric isomer, comprises the mixture of its all proportions, and at least a other active constituents of medicine.
The present invention also relates to overlap cartridge bag (cover medicine box), its following part by independent packing is formed:
(a) the formula I compound of significant quantity and/or its pharmaceutically useful derivative, solvate and steric isomer, comprise its all proportions mixture and
(b) the other active constituents of medicine of significant quantity.
The cover cartridge bag comprises suitable container, for example box, one bottle, sack or ampoule.The cover cartridge bag can for example comprise independent ampoule, contains the formula I compound of the dissolving or the significant quantity of lyophilized form and/or the other active constituents of medicine of its pharmaceutically useful derivative, solvate and steric isomer (mixture that comprises its all proportions) and significant quantity separately.
Medicine in the table 1 preferably but be not exclusively to make up with formula I compound.The combination of formula I compound and table 1 Chinese traditional medicine also can be made up with formula V compound.
| Table 1. | ||
| Alkylating agent | Endoxan busulfan ifosfamide melphalan Hexamethylmelamine thio-tepa Chlorambucil Dacarbazine BCNU | Lomustine procarbazine hexamethyl melamine estramustine phosphate mustargen streptozotocin Temozolomide Semustine |
| Platinum reagent | The own platinum amine of cis-platinum oxaliplatin Spiroplatin Carboxyphthalatoplatinum tetrachloro Ormiplatin iproplatin | Carboplatin ZD-0473 (AnorMED) Lobaplatin (Aetema) Satraplatin (Johnson Matthey) BBR-3464 (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) |
| Metabolic antagonist | AzGR gemcitabine capecitabine 5 FU 5 fluorouracil floxuridine 2-chlorodeoxyadenosine Ismipur 6-thioguanine cytarabine 2-fluorine deoxycytidine methotrexate (MTX) Idatrexate | Tomudex Trimetrexate deoxycoformycin fludarabine spray Tuo Tading Raltitrexed hydroxycarbamide Decitabine (SuperGen) Clofarabine (Bioenvision) irofulven (MGI Pharrna) DMDC (Hoffmann-La Roche) acetenyl cytidine (Taiho) |
| Topoisomerase enzyme inhibitor | The amsacrine pidorubicin | Rubitecan (SuperGen) methylsulfonic acid exatecan (Daiichi) |
| Etoposide Teniposide or mitoxantrone Irinotecan (CPT-11) SN38 TPT dexrazoxane (TopoTarget) Pixantrone (Novuspharrna) Rebeccamycin analog (Exelixis) BBR-3576 (Novuspharrna) | Quinamed (ChemGenex) Gimatecan (Sigma-Tau) Diflomotecan (Beaufour-Ipsen) TAS-103 (Taiho) Elsamitrucin (Spectrum) J-107088 (Merck ﹠ Co) BNP-1350 (BioNumerik) CKD-602 (Chong Kun Dang) KW-2170 (Kyowa Hakko) | |
| Antitumor antibiotics | Dactinomycin D (actinomycin D) adriamycin (Adriamycin) Deoxyrubicin valrubicin daunorubicin (daunomycin) Epi-ADM Therarubicin idarubicin zorubicin plicamycin Methylmitomycin C cyano group morpholino adriamycin mitoxantrone (Novantron) | Amonafide Azonafide anthracene pyrazoles Dup 942 Losoxantrone Bleomycin Sulphate (Blenoxan) bleomycinic acid bleomycin A bleomycin B mitomycin C MEN-10755 (Menarini) GPX-100 (Gem Pharmaceuticals) |
| Antimitotic agent | Taxol docetaxel colchicin vincaleukoblastinum vincristine vinorelbine eldisine dolastatin 10 (NCI) rhizomycin (Fujisawa) mivobulin (Warner-Lambert) | SB 408075 (GlaxoSmithKline) E7010 (Abbott) PG-TXL (Cell Therapeutics) IDN 5109 (Bayer) A 105972 (Abbott) A 204197 (Abbott) LU 223651 (BASF) D 24851 (ASTA Medica) ER-86526 (Eisai) combretastatin A4 (BMS) |
| Cemadotin, (BASF) RPR 109881A, (Aventis) TXD 258, (Aventis) epothilone B, (Novartis) T 900607, (Tularik) T 138067, (Tularik) Cryptophycin 52, (Eli Lilly) vinflunine, (Fabre) Auristatin PE, (Teikoku Hormone) BMS 247550, (BMS) BMS 184476, (BMS) BMS 188797, (BMS) Taxoprexin, (Protarga) | Isohomohalichondrin-B (PharmaMar) ZD 6126 (AstraZeneca) PEG-taxol (Enzon) AZ10992 (Asahi)! DN-5109 (Indena) AVLB (Prescient NeuroPharma) Azaepothilon B (BMS) BNP-7787 (BioNumerik) CA-4-prodrug (OXiGENE) dolastatin-10 (NrH) CA-4 (OXiGENE) | ||
| Aromatase inhibitor | Aminoglutethimide letrozole Anastrozole Formestane | Exemestane Atamestane (BioMedicines) YM-511 (Yamanouchi) | |
| Thymidylate synthetase inhibitor | Pemetrexed (Eli Lilly) ZD-9331 (BTG) | Nolatrexed (Eximias) CoFactor TM(BioKeys) | |
| The DNA antagonist | Trabectedin, (PharmaMar) glufosfamide, (Baxter International) albumin+32P, (isotope solution) Thymectacin, (NewBiotics) Edotreotid, (Novartis) | Z 7557 (Baxter International) Apaziquone (Spectrum Pharmaceuticals) O6-benzyl guanine (Paligent) | |
| Farnesyl transferase inhibitor | Arglabin(NuOncology Labs) lonafarnib(Schering-Plough) BAY-43-9006(Bayer) | Tipifarnib (Johnson ﹠ Johnson) purple perilla ethanol (DOR BioPharma) | |
| Pump inhibitor | CBT-1(CBA Pharma) | Zosuquidar trihydrochloride | |
| Tariquidar(Xenova) MS-209(Schering AG) | (Eli Lilly) two citric acid biricodars (Vertex) | ||
| The histone acetyl transferase inhibitors | Tacedinaline(Pfizer) SAHA(Aton Pharma) MS-275(Schering AG) | Butyric acid oxy acid methyl neopentyl ester (Titan) Depsipeptide (Fujisawa) | |
| Inhibitors of metalloproteinase ribonucleoside reductase inhibitor | Neovastat (Aeterna Laboratories) Marimastat (British Biotech) Gallium maltolate (Titan) Triapin (Vion) | CMT-3(CollaGenex) BMS-275291(Celltech) Tezacitabine(Aventis) Didox(Molecules for Health) | |
| TNF-alfa agonists/antagonist | Virulizin (Lorus Therapeutics) CDC-394 (Celgene) | Revimid(Celgene) | |
| The endothelin receptor A antagonist | Atrasentan (Abbot) ZD-4054 (AstraZeneca) | YM-598(Yamanouchi) | |
| The retinoic acid receptor (RAR) agonist | Fenretinide (Johnson ﹠ Johnson) LGD-1550 (Ligand) | Alitretinoin (Ligand) | |
| The immunoregulation agent | Interferon Oncophage (Antigenics) GMK (Progenics) gland cancer vaccine (Biomira) CTP-37 (AVI BioPharma) JRX-2 (Immuno-Rx) PEP-005 (Peplin Biotech) Synchrovax vaccine (CTL Immuno) Melacine (CTL Immuno) p21-RAS vaccine (GemVax) | Dexosome therapy (Anosys) Pentrix (Australian Cancer Technology) JSF-154 (Tragen) cancer vaccine (Intercell) Norelin (Biostar) BLP-25 (Biomira) MGV (Progenics)! 3-Alethin (Dovetail) CLL-Thera (Vasogen) | |
| Hormone and antihormone agent | Estrogens conjugated estrogens class ethinyloestradiol Chlorotrianisene Idenestrol hydroxyprogesterone caproate Medroxyprogesterone testosterone testosterone propionate FL methyltestosterone diethylstilbestrol megestrol acetate TAM Toremofin dexamethasone | Metacortandracin methylprednisolone prednisolone aminoglutethimide leuproside Goserelin Leuprorelin Bicalutamide Flutamide Octreotide Nilutamide Ortho-para-prism DDD P-04 (Novogen) 2ME2 (EntreMed) arzoxifene (Eli Lilly) |
| Pdt agent | Talaporfin (Light Sciences) Theralux (Theratechnologies) motexafin-gadolinium (Pharmacyclics) | Pd-bacterium ph(a)eophorbide (Yeda) lutetium-Texaphyrin (Pharmacyclics) hypericin |
| Tyrosine kinase inhibitor | Imatinib, (Novartis) leflunomide, (Sugen/Pharmacia) ZDl839, (AstraZeneca) Erlotinib, (Oncogene Science) Canertjnib, (Pfizer) squalamine, (Genaera) SU5416, (Pharmacia) SU6668, (Pharmacia) ZD4190, (AstraZeneca) ZD6474, (AstraZeneca) Vatalanib, (Novartis) PKI166, (Novartis) GW2016, (GlaxoSmithKline) | Kahalide F (PharmaMar) CEP-701 (Cephalon) CEP-751 (Cephalon) MLN518 (Millenium) PKC412 (Novartis) Phenoxodiol O trastuzumab (Genentech) C225 (ImClone) rhu-Mab (Genentech) MDX-H210 (Medarex) 2C4 (Genentech) MDX-447 (Medarex) ABX-EGF (Abgenix) |
| EKB-509(Wyeth) EKB-569(Wyeth) | IMC-1C11(ImClone) | |
| Various materials | SR-27897 (CCK-A inhibitor, Sanofi-Synthelabo) tocladesine (cyclic amp agonist, Ribapharm) Alvocidib (CDK inhibitor, Aventis) CV-247 (cox 2 inhibitor, Ivy Medical) P54 (cox 2 inhibitor, Phytopharm) CapCell TM(CYP450 stimulant, Bavarian Nordic) GCS-IOO (gal3 antagonist, GlycoGenesys) G17DT immunogen (gastrin inhibitor, Aphton) Efaproxiral (oxygenating agents, AlIos Therapeutics) PI-88 (heparanase inhibitors, Progen) Tesmilifene (histamine antagonist, YM BioSciences) histamine (histamine H2-receptor agonist, Maxim) tiazofurine (IMPDH inhibitor, Ribapharm) cilengitide (integrin antagonist, Merck KGaA) SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) CCI-779 (mTOR kinase inhibitor, Wyeth) exisulind (PDE-V inhibitor, Cell | BCX-1777 (PNP inhibitor, BioCryst) ranpirnase (rnase stimulant, Alfacell) galarubicin (rna synthesis inhibitor, Dong-A) Win-59075 (reductive agent, SRI International) N-acetylcystein (reductive agent, Zambon) R-flurbiprofen (NF-kappaB inhibitor, Encore) 3CPA (NF-kappaB inhibitor, Active Biotech) seocalcitol (Vitamin D Receptor agonist, Leo) 131-I-TM-601 (DNA antagonist, TransMolecular) Eflornithine (ODC inhibitor, ILEX Oncology) minodronic acid (osteoclast inhibitor, Yamanouchi) Indisulam (p53 stimulant, Eisai) Aplidin (PPT inhibitor, PharmaMar) Rituximab (CD20 antibody, Genentech) gemtuzumab (CD33 antibody, Wyeth Ayerst) PG2 (hemopoietic promotor, Pharmagenesis) Immunol TM(the triclosan mouth wash shua, Endo) |
| Pathways) CP-461 (PDE-V inhibitor, Cell Pathways) AG-2037 (GART inhibitor, Pfizer) WX-UK1 ( |
Triacetyluridine (uridine prodrug, WelIstat) SN-4071 (sarcoma agent, Signature BioScience) TransMID-107 TM(immunotoxin, KS Biomedix) PCK-3145 (apoptosis promoters, Procyon) Doranidazole (apoptosis promoters, Pola) CHS-828 (cytotoxic substance, Leo) trans-retinic acid (differentiation agent, NIH) MX6 (apoptosis promoters, MAXIA) Apomine (apoptosis promoters, ILEX Oncology) Urocidin (apoptosis promoters, Bioniche) Ro-31-7453 (apoptosis promoters, La Roche) Brostallicin (apoptosis promoters, Pharmacia) |
Formula I compound preferably makes up with known anticancer agents:
Compound of the present invention also is suitable for and known carcinostatic agent combination.These known carcinostatic agents comprise following material: estrogen receptor adjusting control agent, androgen receptor adjusting control agent, retinoids (retinoid) receptor modulators, cytotoxic substance, antiproliferative, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors and other angiogenesis inhibitor.Compound of the present invention is particularly suitable for using simultaneously with radiotherapy.The professional had described the synergistic effect (referring to WO00/61186) of VEGF restraining effect and radiotherapy combination.
The compound of oestrogenic hormon and receptors bind is disturbed or suppresses in " estrogen receptor adjusting control agent " expression, regardless of mechanism.The example of estrogen receptor adjusting control agent includes but not limited to tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 2,2-dimethyl-propionic acid 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl] phenylester, 4,4 '-dihydroxy benzophenone-2,4-dinitrophenylhydrazone and SH646.
The compound of male sex hormone and receptors bind is disturbed or suppresses in " androgen receptor adjusting control agent " expression, regardless of mechanism.The example of androgen receptor adjusting control agent comprises finasteride and other 5 inhibitor, Nilutamide, flutamide, bicalutamide, liarozole and acetate Abiraterone.
The compound of retinoids and receptors bind is disturbed or suppresses in " retinoid receptor adjusting control agent " expression, regardless of mechanism.The example of this class retinoid receptor adjusting control agent comprises bexarotene, vitamin A acid, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, ILX23-7553, trans-N-(4 '-hydroxy phenyl) look yellow acid amides (retinamide) and the N-4-carboxyl phenyl is looked yellow acid amides.
" cytotoxic substance " expression mainly causes the maiotic compound of necrocytosis or inhibition or interference cell by the direct effect of cellular function, comprises alkylating agent, tumour necrosis factor, intercalator, Antitubulin and topoisomerase enzyme inhibitor.The example of cytotoxic substance includes but not limited to tirapazimine; sertenef; cachectin; ifosfamide; tasonermin; lonidamine; carboplatin; hexamethyl melamine; prednimustine; mitolactol; ranomustine; fotemustine; S 254; oxaliplatin; Temozolomide; platinum in heptan (heptaplatin); estramustine; improsulfan tosilate; trofosfamide; nimustine; dibrospidium chloride; pumitepa; happy platinum; husky platinum; methylmitomycin (profiromycin); cis-platinum; irofulven; right ifosfamide (dexifosfamide); cis-amine dichloro (2-picoline) platinum; the benzyl guanidine; glufosfamide; GPX100; (trans; trans; trans) cis-μ-(hexane-1; the 6-diamines) μ-[diamines platinum (II)] two [diamines (chlorine) platinum (II)] tetrachloride; two '-aziridino spermine; ARSENIC TRI OXIDE 98; 1-(11-dodecyl amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine; zorubicin; idarubicin; daunorubicin; Bisantrene; mitoxantrone; pirarubicin; pinafide; valrubicin; amrubicin; antineoplaston; 3 '-deaminize-3 '-morpholino-13-deoxidation-10-hydroxyl Carubicin; annamycin; galarubicin; Elinafide; MEN10755 and 4-de-methoxy-3-deaminize-3-'-aziridino-4-methyl sulphonyl daunorubicin (referring to WO 00/50032).
The example of Antitubulin comprises taxol; vindesine sulfate; 3 '; 4 '-two dehydrogenations-4 '-deoxidation-8 '-navelbine; docetaxel; rhizomycin; dolastatin; the hydroxyethylsulfonic acid mivobulin; auristatin; Cemadotin; RPR109881; BMS184476; Vinflunine; cryptophycin; 2; 3; 4; 5; 6-five fluoro-N-(3-fluoro-4-p-methoxy-phenyl) benzsulfamide; F 81097; N, N-dimethyl-L-is valyl-L-is valyl-and N-methyl-L-is valyl-L-prolyl-L-proline(Pro)-tert-butylamides; TDX258 and BMS188797.
Some examples of topoisomerase enzyme inhibitor have Hycamtin; hycaptamine; irinotecan; rubitecan; 6-ethoxy-c acyl group-3 '; 4 '-the outer benzylidene chartreusin of O-; 9-methoxyl group-N; N-dimethyl-5-nitropyrazole also [3; 4; 5-kl] acridine-2-(6H) propylamine; 1-amino-9-ethyl-5-fluoro-2; 3-dihydro-9-hydroxy-4-methyl-1H; 12H-benzo [de] pyrans also [3 '; 4 ': b; 7] indolizine also [1; 2b] quinoline-10; 13 (9H; 15H) diketone; lurtotecan; 7-[2-(N-sec.-propyl amino) ethyl]-(20S) camptothecine; BNP1350; BNPI1100; BN80915; BN80942; the phosphoric acid Etoposide; teniposide; sobuzoxane; 2 '-dimethylamino-2 '-the deoxidation Etoposide; GL331; N-[2-(dimethylamino) ethyl]-9-hydroxyl-5; 6-dimethyl-6H-pyrido [4; 3-b] carbazole-1-acid amides; asulacrine; (5a; 5aB; 8aa; 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino] ethyl]-5-[4-hydroxyl-3; the 5-Dimethoxyphenyl]-5; 5a; 6; 8; 8a; the 9-hexahydro furyl also (3 '; 4 ': 6; 7) naphtho-(2; 3-d)-1; 3-dioxole-6-ketone; 2; 3-(methylene-dioxy)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c] phenanthridines ; 6; two [(2-amino-ethyl) amino] benzo [g] isoquinoline 99.9-5 of 9-; the 10-diketone; 5-(3-amino propyl amino)-7; 10-dihydroxyl-2-(2-hydroxyethyl amino methyl)-6H-pyrazolo [4; 5; 1-de] acridine-6-ketone; N-[1-[2-(diethylin) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide; N-(2-(dimethylamino) ethyl) acridine-4-acid amides; 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indeno [2,1-c] quinoline-7-ketone and dimesna.
" antiproliferative " comprises sense-rna and DNA oligonucleotide; G3139 for example; ODN698; RVASKRAS; GEM231 and INX3001; with the antimetabolic product; enocitabine for example; carmofur; Tegafur; spray Tuo Tading; doxifluridine; Trimetrexate; fludarabine; capecitabine; Galocitabine; cytosine arabinoside ocfosfate; the fosteabine sodium hydrate; Raltitrexed; paltitrexid; emitefur; tiazofurine; Decitabine; Nolatrexed; pemetrexed; nelzarabine; 2 '-deoxidation-2 '-the methylene radical cytidine; 2 '-fluorine methylene radical-2 '-Deoxyribose cytidine; N-[5-(2; the 3-dihydro benzo furyl) alkylsulfonyl]-N '-(3; the 4-dichlorophenyl) urea; N6-[4-deoxidation-4-[N2-[2 (E); 4 (E)-14 carbon two enoyl-s] glycyl amino]-L-glycerine-B-L-sweet dew pyrans in heptan glycosyl (mannoheptopyranosyl)] VITAMIN B4; aplidine; ecteinascidin (ecteinascidin); troxacitabine; 4-[2-amino-4-oxo-4; 6; 7; 8-tetrahydrochysene-3H-Mi Dingbing [5; 4-b]-1; 4-thiazine-6-base-(S)-ethyl]-2; 5-Thenoyl-L-L-glutamic acid; aminopterin; 5 FU 5 fluorouracil; alanosine; 11-acetyl-8-(carbamoyloxy group methyl)-4-formyl radical-6-methoxyl group-14-oxa--1; 11-diaza Fourth Ring (7.4.1.0.0) 14 carbon-2; 4,6-triolefin-9-yl acetate; Tridolgosir; lometrexol; dexrazoxane; methioninase; 2 '-cyano group-2 '-'-deoxy-n 4-palmitoyl-1-B-D-arbinofuranose base cytosine(Cyt) and 3-aminopyridine-2-formaldehyde amithiozone." antiproliferative " also comprises except that " angiogenesis inhibitor " the down listed monoclonal antibody at somatomedin those, trastuzumab for example, and tumor suppressor gene, p53 for example, they can (for example be sent via the transgenosis of recombinant virus-mediation, referring to U.S. Patent No. 6,069,134).
Preferred especially compound of the present invention is used for the treatment of the purposes with the prophylaxis of tumours disease.
Tumour preferably is selected from the tumour of tesselated epithelium, bladder, stomach, kidney, neck, esophagus, uterine cervix, Tiroidina, intestines, liver, brain, prostate gland, urogenital tract, lymphsystem, stomach, larynx and/or lung.
In addition, tumour also preferably is selected from adenocarcinoma of lung, small cell lung cancer, carcinoma of the pancreas, glioblastoma, colorectal carcinoma and mammary cancer.
In addition, also be preferred for treating the purposes of blood and immunity system tumour, be preferably used for treatment and be selected from acute myeloid leukaemia (myelotic leukaemia), chronic myelogenous leukemia, kemia and/or chronic lymphatic leukemia.
The present invention also comprises the method for the treatment of the patient who suffers from tumour, for example cancer, and this method is used
A) one or more formulas I compound;
B) and one or more formulas V compound or its acid salt, particularly hydrochloride:
Wherein Y ' and Z ' represent O or N, R separately independently of one another
6And R
7Represent H, OH, halogen, OC1-10-alkyl, OCF separately independently of one another
3, NO
2Or NH
2, n represents to comprise 2 to 6 integer of end value, R
8And R
9Position or contraposition between preferably being in independently of one another separately are selected from:
Wherein first kind and second kind of compound are by simultaneously or use in each other 14 days, and amount of application is the amount that is enough to suppress tumor growth.
Formula I compound and formula V combination of compounds and other pentamidine analogue are suppressing to produce synergy aspect the tumorigenesis.For example in WO 02058684, mentioned and comprised formula V combination of compounds.
As if the mechanism of action of pentamidine or derivatives thereof is not still clearly explained at present: the pentamidine or derivatives thereof has pleiotropic effects, because it causes DNA, RNA and protein synthesis to reduce.According to nearest description, pentamidine is the inhibitor of PRL-1 ,-2 and-3 Phosphoric acid esterases (Pathak etc., 2002) and tyrosine phosphatase, and its overexpression is relevant with human tumorigenesis malignant tumour.On the other hand, the existing description claims that pentamidine is a kind of and DNA ditch bonded medicine (Puckowska etc., 2004), can be via disturbing its effect of the synthetic performance of genetic expression and/or DNA.
Additional experiment shows:
-pentamidine and formula I compound all make cell maintain the G2/M cell cycle;
-pentamidine has with formula I combination of compounds on cell proliferation and adds to collaborative effect mutually.
Other suitable pentamidine analogue comprises that department (G-1) replaces crust amidine (G-2) and its indole analogs thing (for example G-3) with hydroxyl department for crust amidine (stilbamidine):
Each amidine unit can be independently of one another by as above about R
8And R
11One of defined unit replaces.As the situation of benzoglyoxaline and pentamidine, department also is suitable for method of the present invention for crust amidine, hydroxyl department for the salt of crust amidine and its indole derivatives.Preferred salt comprises for example dihydrochloride and mesylate.
Other analogue is that under the structural formula that is provided by one of following document those are provided: U.S. Patent No. 5,428,051,5,521,189,5,602,172,5,643,935,5,723,495,5,843,980,6,172,104 and 6,326,395, perhaps publication number is the U.S. Patent application of US 2002/0019437A1, and they are incorporated herein by reference separately in full.The analogue of illustrative comprises 1,5-pair (4 '-(N-hydroxyl amidino groups) phenoxy group) pentane; 1,3-pair (4 '-(N-hydroxyl amidino groups) phenoxy group) propane; 1; 3-pair (2 '-methoxyl group-4 '-(N-hydroxyl amidino groups) phenoxy group) propane; 1,4-pair (4 '-(N-hydroxyl amidino groups) phenoxy group) butane; 1,5-pair (4 '-(N-hydroxyl amidino groups) phenoxy group) pentane; 1; 4-pair (4 '-(N-hydroxyl amidino groups) phenoxy group) butane; 1,3-pair (4 '-(4-hydroxyl amidino groups) phenoxy group) propane; 1,3-pair (2 '-methoxyl group-4 '-(N-hydroxyl amidino groups) phenoxy group) propane; 2; two [the 4-amidino groups phenyl] furans of 5-; 2, two [4-amidino groups phenyl] the furans bisamide oximes of 5-; 2, two [the 4-amidino groups phenyl] furans of 5-are two-O-methyl nitrosourea oxime; 2; two [the 4-amidino groups phenyl] furans of 5-are two-O-buserelin oxime; 2,8-diamidino dibenzothiophene; 2, two (the N-sec.-propyl amidino groups) carbazoles of 8-; 2; two (the N-hydroxyl amidino groups) carbazoles of 8-; 2, two (2-imidazolinyl) dibenzothiophene of 8-; 2, two (the 2-imidazolinyls)-5 of 8-; 5-dioxo dibenzothiophene; 3,7-diamidino dibenzothiophene; 3, two (the N-sec.-propyl amidino groups) dibenzothiophene of 7-; 3; two (the N-hydroxyl amidino groups) dibenzothiophene of 7-; 3,7-diamino dibenzothiophene; 3,7-dibromo dibenzothiophene; 3; 7-dicyano dibenzothiophene; 2,8-diamidino diphenylene-oxide; 2,8-two-(2-imidazolinyl) diphenylene-oxide; 2; 8-two-(N-sec.-propyl amidino groups) diphenylene-oxide; 2,8-two-(N-hydroxyl amidino groups) diphenylene-oxide; 3,7-two-(2-imidazolinyl) diphenylene-oxide; 3; 7-two-(sec.-propyl amidino groups) diphenylene-oxide; 3,7-two-(A-hydroxyl amidino groups) diphenylene-oxide; 2,8-dicyano diphenylene-oxide; 4; 4 '-two bromo-2,2 '-dinitrobenzene biphenyl; 2-methoxyl group-2 '-nitro-4,4 '-'-dibromobiphenyl; 2-methoxyl group-2 '-amino-4; 4 '-'-dibromobiphenyl; 3,7-dibromo diphenylene-oxide; 3,7-dicyano diphenylene-oxide; 2; two (5-amidino groups-2-benzimidazolyl-) pyrroles of 5-; 2, two [5-(2-the imidazolinyl)-2-benzimidazolyl-] pyrroles of 5-; 2, two [5-(2-the imidazolinyl)-2-benzimidazolyl-] pyridines of 6-; 1-methyl-2; two (5-amidino groups-2-benzimidazolyl-) pyrroles of 5-; 1-methyl-2, two [5-(2-the imidazolyl)-2-benzimidazolyl-] pyrroles of 5-; 1-methyl-2,5-is two, and [5-(1; 4,5,6-tetrahydrochysene-2-pyrimidyl)-the 2-benzimidazolyl-] pyrroles; 2; two (5-amidino groups-2-benzimidazolyl-) pyridines of 6-; 2,6-pair-[5-(1,4; 5,6-tetrahydrochysene-2-pyrimidyl)-the 2-benzimidazolyl-] pyridine; 2, two (5-amidino groups-2-benzimidazolyl-) furans of 5-; 2; two [5-(2-the imidazolinyl)-2-benzimidazolyl-] furans of 5-; 2, two (the 5-N-sec.-propyl amidino groups-2-benzimidazolyl-) furans of 5-; 2, two (the 4-amidino groups phenyl) furans of 5-; 2; two (the 4-amidino groups phenyl)-3 of 5-, the 4-dimethyl furan; 2,5-two-right-[2-(3; 4,5, the 6-tetrahydro-pyrimidine base) phenyl] furans; 2; two [4-(2-imidazolinyl) phenyl] furans of 5-; 2, two { 4-(2-the tetrahydro-pyrimidine base) } phenyl of 5-[] right-(tolyloxy) furans; 2, two { 4-(2-imidazolinyl) } phenyl of 5-[]-3-is right-(tolyloxy) furans; 2; 5-pair 4-[5-(N-2-amino-ethyl amido) benzimidazolyl-2 radicals-yl] and phenyl } furans; 2,5-two [4-(3a, 4; 5,6,7; the phenyl of 7a-six hydrogen-1H-benzimidazolyl-2 radicals-yl)] furans; 2,5-is two, and [4-(4,5; 6,7-tetrahydrochysene-1H-1,3-diaza -2-yl) phenyl] furans; 2; two (4-N, the N-dimethyl phosphinylidyne diazanyl phenyl) furans of 5-; 2,5-pair 4-[2-(N-2-hydroxyethyl)-imidazolinyl] and phenyl } furans; 2; two [4-(the N-sec.-propyl amidino groups) phenyl] furans of 5-; 2,5-pair 4-[3-(dimethylamino-propyl) amidino groups] and phenyl } furans; 2,5-pair 4-[N-(3-aminopropyl) amidino groups] and phenyl } furans; 2; two [2-(imidazolinyl) phenyl]-3 of 5-, two (methoxymethyl) furans of 4-; 2, two [4-N-(dimethylaminoethyl) amidino groups] benzofuranes of 5-; 2; 5-pair the 4-[(N-2-hydroxyethyl) and amidino groups] phenyl } furans; 2, two [4-N-(cyclopropyl amidino groups) phenyl] furans of 5-; 2, the two [4-(N of 5-; N-diethylamino propyl group) amidino groups] benzofurane; 2,5-pair 4-[2-(N-ethyl imidazol(e) quinoline base)] and phenyl } furans; 2,5-pair 4-[N-(3-amyl group amidino groups)] } benzofurane; 2; two [4-(2-imidazolinyl) the phenyl]-3-methoxyl group furans of 5-; 2, two [4-(N-sec.-propyl amidino groups) the phenyl]-3-methyl furans of 5-; two [5-amidino groups-2-benzimidazolyl-] methane; two [5-(2-imidazolyl)-2-benzimidazolyl-] methane; 1, two [5-amidino groups-2-benzimidazolyl-] ethane of 2-; 1; two [5-(2-the imidazolyl)-2-benzimidazolyl-] ethane of 2-; 1, two [5-amidino groups-2-benzimidazolyl-] propane of 3-; 1, two [5-(2-the imidazolyl)-2-benzimidazolyl-] propane of 3-; 1; two [5-amidino groups-2-benzimidazolyl-] propane of 4-; 1, two [5-(2-the imidazolyl)-2-benzimidazolyl-] butane of 4-; 1, two [5-amidino groups-2-benzimidazolyl-] octanes of 8-; anti-form-1; two [5-amidino groups-2-benzimidazolyl-] ethene of 2-; 1, two [5-(2-imidazolyl)-2-the benzimidazolyl-]-1-butylene of 4-; 1, two [5-(2-imidazolyl)-2-the benzimidazolyl-]-2-butylene of 4-; 1; two [5-(2-imidazolyl)-2-the benzimidazolyl-]-1-methylbutanes of 4-; 1, two [5-(2-imidazolyl)-2-the benzimidazolyl-]-2-ethyl butane of 4-; 1, two [5-(2-imidazolyl)-2-the benzimidazolyl-]-1-methyl isophthalic acid-butylene of 4-; 1; two [5-(2-imidazolyl)-2-benzimidazolyl-]-2 of 4-; 3-diethyl-2-butylene; 1, two [5-(2-imidazolyl)-2-the benzimidazolyl-]-1,3-butadienes of 4-; 1; two [5-(2-imidazolyl)-2-the benzimidazolyl-]-2-methyl isophthalic acids of 4-; the 3-divinyl; two [5-(2-pyrimidyl)-2-benzimidazolyl-] methane; 1, two [5-(2-the pyrimidyl)-2-benzimidazolyl-] ethane of 2-; 1, two [5-amidino groups-2-benzimidazolyl-] propane of 3-; 1; two [5-(2-the pyrimidyl)-2-benzimidazolyl-] propane of 3-; 1; two [5-(2-the pyrimidyl)-2-benzimidazolyl-] butane of 4-; 1, two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-1-butylene of 4-; 1, two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-2-butylene of 4-; 1; two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-1-methylbutanes of 4-; 1; two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-2-ethyl butane of 4-; 1, two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-1-methyl isophthalic acid-butylene of 4-; 1, two [5-(2-pyrimidyl)-2-benzimidazolyl-]-2 of 4-; 3-diethyl-2-butylene; 1; two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-1,3-butadienes of 4-; 1, two [5-(2-pyrimidyl)-2-the benzimidazolyl-]-2-methyl isophthalic acids of 4-; the 3-divinyl; 2; two (the 4-amidino groups phenyl) pyrimidines of 4-; 2, two (4-tetrahydroglyoxaline-2-yl) pyrimidines of 4-; 2, two [(tetrahydropyrimidine-2-yl) phenyl] pyrimidines of 4-; 2-(4-[N-sec.-propyl-amidino groups] phenyl)-4-(2-methoxyl group-4-[N-sec.-propyl amidino groups] phenyl) pyrimidine; 4-(N-cyclopentyl amidino groups)-1; the 2-phenylenediamine; 2; two [2-(5-amidino groups) benzimidazolyl-] furans of 5-; 2,5-pair [2-{5-(the 2-tetrahydroglyoxaline is for base (imidazolino)) } benzimidazolyl-] furans; 2, two [2-(the 5-N-sec.-propyl amidino groups) benzimidazolyl-] furans of 5-; 2; two [2-(the 5-N-cyclopentyl amidino groups) benzimidazolyl-] furans of 5-; 2; two [2-(5-amidino groups) benzimidazolyl-] pyrroles of 5-; 2,5-pair [2-{5-(the 2-tetrahydroglyoxaline is for base) } benzimidazolyl-] pyrroles; 2,5-pair-[2-(5-N-sec.-propyl amidino groups) benzimidazolyl-] pyrroles; 2; two [2-(the 5-N-cyclopentyl amidino groups) benzimidazolyl-] pyrroles of 5-; 1-methyl-2; two [2-(5-amidino groups) benzimidazolyl-] pyrroles of 5-; 2,5-pair [2-{5-(the 2-tetrahydroglyoxaline is for base) } benzimidazolyl-]-the 1-methylpyrrole; 2, two [2-(5-N-cyclopentyl amidino groups) the benzimidazolyl-]-1-methylpyrroles of 5-; 2; two [2-(the 5-N-sec.-propyl amidino groups) benzimidazolyl-] thiophene of 5-; 2; 6-pair [2-{5-(the 2-tetrahydroglyoxaline is for base) } benzimidazolyl-] pyridine; 2, two [2-(5-amidino groups) benzimidazolyl-] pyridines of 6-; 4,4 '-two-[2-(5-N-sec.-propyl amidino groups) benzimidazolyl-]-1; the 2-diphenylethane; 4; 4 '-two [2-(5-N-cyclopentyl amidino groups) benzimidazolyl-s]-2,5-phenylbenzene furans; 2, two [2-(5-amidino groups) benzimidazolyl-] benzo [b] furans of 5-; 2; two [2-(5-N-cyclopentyl amidino groups) benzimidazolyl-] benzo [b] furans of 5-; 2; two [2-(the 5-N-sec.-propyl amidino groups) benzimidazolyl-] fluorine of 7-; 2, two [4-(3-(the N-morpholino propyl group) carbamyl) phenyl] furans of 5-; 2, the two [4-(2-N of 5-; N-dimethyl aminoethyl carbamyl) phenyl] furans; 2; two [4-(3-N, the N-dimethylaminopropyl carbamyl) phenyl] furans of 5-; 2, two [4-(3-N-methyl-3-N-phenyl amino propyl group carbamyl) phenyl] furans of 5-; 2; two [4-(the 3-N of 5-; N8, N11-trimethylammonium aminopropyl carbamyl) phenyl]-furans; 2, two [the 3-amidino groups phenyl] furans of 5-; 2; two [3-(the N-sec.-propyl amidino groups) amidino groups phenyl] furans of 5-; 2; 5-pair [3-[(N-(2-dimethyl aminoethyl) amidino groups) benzofurane; 2,5-two [4-(N-2,2; 2-trichlorine ethoxy carbonyl) amidino groups phenyl] furans; 2; two [4-(the N-thio-ethyl carbonyl) amidino groups phenyl] furans of 5-; 2, two [4-(N-benzyloxycarbonyl) amidino groups phenyl] furans of 5-; 2, two [4-(N-phenyloxycarbonyl) amidino groups phenyl] furans of 5-; 2; two [4-(N-(4-fluorine) phenyloxycarbonyl) amidino groups phenyl] furans of 5-; 2; two [4-(N-(4-methoxyl group) phenyloxycarbonyl) amidino groups phenyl] furans of 5-; 2, two [4-(the 1-acetoxyethoxy carbonyl) amidino groups phenyl] furans and 2 of 5-, two [4-(N-(3-fluorine) phenyloxycarbonyl) amidino groups phenyl] furans of 5-.The preparation method of one of above-claimed cpd has been described: U.S. Patent No. 5,428,051,5 in following document, 521,189,5,602,172,5,643,935,5,723,495,5,843,980,6,172,104 and 6,326,395, perhaps publication number is the U.S. Patent application of US 2002/0019437A1.
The pentamidine meta-bolites is fit in antiproliferative combination of the present invention equally.Pentamidine is at least seven kinds of main metabolites by rapid metabolism in body.In these meta-bolitess some have one or more effects total with pentamidine.With benzoglyoxaline or the combination of its analogue the time, the pentamidine meta-bolites has antiproliferative effect.
Seven kinds of pentamidine analogues are as follows.
The combination of formula I compound of the present invention and formula V compound or its analogue and meta-bolites thereof is suitable for treating tumour.Combination treatment can carry out separately or carry out with another kind of therapy (for example perform the operation, radiation, chemotherapy, biotherapy) combination.In addition, the personnel (people who genetic predisposition is for example arranged or suffered from tumour in the past) with tumorigenic danger can give preventive disposal, and purpose is to suppress or postpone tumour to form.
The invention still further relates to the combination of kinesin adenosine triphosphatase Eg5/KSP and formula V compound, pentamidine, its analogue and/or its meta-bolites.
The application dosage of each compound and frequency can be controlled independently in the combination.For example, a kind of compound can every day three times Orally administered, and second kind of compound intramuscular administration once a day.Compound also can be formulated together, makes that two kinds of compounds are used together.
The component that antiproliferative combination of the present invention also can be used as medicinal packaging kit is provided.Two kinds of medicines can be prepared together or individually and by dosage separately.
On the other hand, the present invention includes by using formula (I) and (V) combination of compound and the antiproliferative method for the treatment of the patient who suffers from tumour such as cancer.Those that the antiproliferative that is fit to comprises in the table 1 being provided.
In context, all temperature are all with a ℃ expression.In following examples, " conventional aftertreatment " means: if necessary add entry, if necessary with the value between pH regulator to 2 and 10, this depends on the composition of end product, with mixture with ethyl acetate or dichloromethane extraction, separate each phase, organic phase with dried over sodium sulfate and evaporation, is passed through product silica gel chromatography and/or passed through the crystallization process purifying.Rf value on silica gel; Eluent: ethyl acetate/methanol 9: 1.
Mass spectrum (MS): EI (electron impact ionization) M
+
FAB (fast atom bombardment(FAB)) (M+H)
+
ESI (electron spray ionisation) (M+H)
+
APCI-MS (atmospheric pressure chemical ionization-mass spectrum) (M+H)
+
A. the reaction in the presence of trifluoroacetic acid (TFA)
With the acetonitrile solution of the tfa salt of 4-tertiary butyl aniline (with 4-tertiary butyl aniline (0.50g, 3.35mmol) absorb with acetonitrile (4ml), be cooled to 0 ℃, slowly add TFA (0.38g 3.35mmol), stirs simultaneously) and join the 3-hydroxy benzaldehyde (0.41g that is cooled to 0 ℃ rapidly, 3.35mmol) with 3, (0.28g 3.35mmol) in the solution in acetonitrile (2ml), stirs other 60min with mixture to 4-dihydro-2H-pyrans under this temperature.Reaction soln is evaporated to dried, separates, obtain colorless solid (620mg, 1.84mmol, 55%), confirm that it is that ratio is the isomer mixture of each racemize trans/cis compound of 13: 1 by column chromatography.
In order to separate the cis/trans isomer, the aqueous isopropanol (20ml) of solid with 0.1N HCl absorbed, add ether and each 100ml of hexanaphthene, mixture is spent the night 4 ℃ of following crystallizations.Leach colorless solid, with a small amount of ether washing, drying obtains 570mg (1.52mmol) leucocompound rac-1 hydrochloride.Mother liquor is evaporated to dried in rotatory evaporator,, and is translated into hydrochloride (70mg, 0.19mmol colorless solid) by column chromatography purifying cis-isomeride.
The rac-1 and the rac-2 of relatively small amount are passed through chirality HPLC (2 * Chiralpak AD, 20 μ m, eluent: methyl alcohol) be separated into corresponding enantiomorph, be converted into hydrochloride once more.
B. the reaction in the presence of hexafluoroisopropanol (HFIP)
In order to obtain the cis-isomeride of higher yield, adopt hexafluoroisopropanol (HFIP) to replace TFA.
With 4-tertiary butyl aniline (0.50g, 3.35mmol), the 3-hydroxy benzaldehyde (0.41g, 3.35mmol) and 3, (0.28g 3.35mmol) is dissolved in acetonitrile (1ml) to 4-dihydro-2H-pyrans, drips HFIP (0.56g under RT, 3.35mmol), mixture is stirred other 18h under RT.Reaction soln is evaporated to dried, separates, obtain colorless solid (485mg, 1.44mmol, 43%), confirm that it is that ratio is the isomer mixture of each racemize trans/cis compound of 1: 1.6 by column chromatography.
As a.) carry out the separation of isomer as described in down.
C. the reaction in the presence of Trichlorobismuthine (III)
Under RT, (0.41g, 3.35mmol) (0.50g 3.35mmol) joins BiCl with 4-tertiary butyl aniline will to be dissolved in the 3-hydroxy benzaldehyde of acetonitrile (1ml) separately
3(0.21g, 0.67mmol) with the suspension of anhydrous sodium sulphate (0.40g) in acetonitrile (2ml) in, mixture is stirred 10min under RT.Drip 3 then under RT, (0.28g 3.35mmol), stirs other 30min with mixture to 4-dihydro-2H-pyrans under RT.By diatomite filtration, filtrate is evaporated to dried reaction soln,, obtains colorless solid (850mg, 2.51mmol, 75%), confirm that it is that ratio is the isomer mixture of each racemize trans/cis compound of 1: 1.1 by the column chromatography purifying.
As a.) carry out the separation of isomer as described in down.
D. the reaction in the presence of Ytterbiumtriflate (III)
Under RT, (0.41g, 3.35mmol) (0.50g 3.35mmol) joins Yb (OTf) with 4-tertiary butyl aniline will to be dissolved in the 3-hydroxy benzaldehyde of acetonitrile (1ml) separately
3(0.42g, 0.67mmol) with the suspension of anhydrous sodium sulphate (0.40g) in acetonitrile (2ml) in, mixture is stirred 10min under RT.Drip 3 then under RT, (0.28g 3.35mmol), stirs other 30min with mixture to 4-dihydro-2H-pyrans under RT.By diatomite filtration, filtrate is evaporated to dried reaction soln,, obtains colorless solid (780mg, 2.31mmol, 69%), confirm that it is that ratio is the isomer mixture of each racemize trans/cis compound of 1: 1.3 by the column chromatography purifying.
As a.) carry out the separation of isomer as described in down.
E. the reaction in the presence of trifluoromethanesulfonic acid scandium (III)
Under RT, add, will be dissolved in separately acetonitrile (1ml) the 3-hydroxy benzaldehyde (0.41g, 3.35mmol) and 4-tertiary butyl aniline (0.50g is 3.35mmol) to Sc (OTf)
3(0.33g, 0.67mmol) with the suspension of anhydrous sodium sulphate (0.40g) in acetonitrile (2ml) in, mixture is stirred 10min under RT.Drip 3 then under RT, (0.28g 3.35mmol), stirs other 30min with mixture to 4-dihydro-2H-pyrans under RT.By diatomite filtration, filtrate is evaporated to dried reaction soln,, obtains colorless solid (620mg, 1.84mmol, 55%), confirm that it is the isomer mixture of each racemize trans/cis compound by the column chromatography purifying.
As a.) carry out the separation of isomer as described in down.
F. the reaction in the presence of cerous nitrate (IV) ammonium (CAN)
Under RT, with CAN (0.37g, 0.67mmol) join 3-hydroxy benzaldehyde (0.41g, 3.35mmol), 4-tertiary butyl aniline (0.50g, 3.35mmol) with 3, (0.28g 3.35mmol) in the solution in acetonitrile (10ml), stirs other 30min with mixture to 4-dihydro-2H-pyrans under RT.Reaction mixture is evaporated to dried,, obtains colorless solid (237mg, 0.70mmol, 21%), confirm that it is that ratio is the isomer mixture of each racemize trans/cis compound of 5: 1 by the column chromatography purifying.
As a.) carry out the separation of isomer as described in down.
Embodiment 2
A. the reaction in the presence of trifluoroacetic acid (TFA)
With the acetonitrile solution of the tfa salt of 4-thiocyano aniline (with thiocyano aniline (0.46g, 3.06mmol) absorb with acetonitrile (4ml), be cooled to 0 ℃, slowly add TFA (0.35g 3.06mmol), stirs simultaneously) and join the 3-hydroxy benzaldehyde (0.37g that is cooled to 0 ℃ rapidly, 3.06mmol) and l-vinyl-2-pyrrolidone (0.34g, 3.06mmol) in the solution in acetonitrile (2ml), mixture is stirred other 60min under this temperature, under RT, stir 18h.Evaporation reaction solution absorbs with amount of ethyl acetate, uses the ether crystallization, obtains colorless solid (390mg, 1.06mmol, 35%), confirms that it is a cis-isomeride.
In order to separate the cis/trans isomer, filtrate is evaporated to dried, by the column chromatography purifying, obtain trans-isomer(ide), be colorless solid (160mg, 0.44mmol, 14%).
The rac-3 and the rac-4 of relatively small amount are passed through chirality HPLC (2 * Chiralpak AD, 20 μ m, eluent: methyl alcohol) be separated into corresponding enantiomorph, and be translated into hydrochloride.
Use corresponding precursor, obtained following compound of the present invention similarly.Shown in retention time obtain under the following conditions:
Method A:
Merck Hitachi LaChrom
Gradient 9min
Flow velocity: 1.5ml/min, from 80: 20 to 0: 100 (in 6min), 0: 100 (1min) gets back to 80: 20 (in 1min), water/acetonitrile
Water+TFA (0.1% volume)
Acetonitrile+TFA (0.1% volume)
Post: LichroCART 125-4 RP-LiChrospher 60, RP-select-B (5 μ m/60mm)
Wavelength: 220nm
Method B:
Merck Hitachi LaChrom
Gradient 9min
Flow velocity: 1.5ml/min, from 80: 20 to 0: 100 (in 6min), 0: 100 (1min) gets back to 80: 20 (in 0.8min), water/acetonitrile
Water+TFA (0.1% volume)
Acetonitrile+TFA (0.1% volume)
Post: Lichrospher RP-select-B (5 μ m/125mm)
Wavelength: 220nm
Method C:
Agilent 1100 Series
Gradient 3.5min
Flow velocity: 2ml/min, from 80: 20 to 0: 100 (in 2.3min), 0: 100 (0.5min) got back to water/acetonitrile 80: 20
Water+TFA (0.1% volume)
Acetonitrile+TFA (0.1% volume)
Post: β experimental study sample, Chromolith Performance RP-18e (3 μ m/100mm)
Wavelength: 220nm
Embodiment 3-654
The formula I compound of embodiment 562 to 654 here is particularly preferred, because they show the effect of increase according to the present invention.
Embodiment A: assay method I
The effect of compound of the present invention can for example be measured via the Eg5 atpase activity, and the latter is regenerated as ATP, measures with NADH-dependency serum lactic dehydrogenase (LDH) reaction coupling subsequently via the product A DP enzymatic that utilizes pyruvate kinase (PK) to carry out.Can come monitoring reaction by changing via the absorbancy under 340nm with NADH-dependency LDH coupling.The regeneration of ATP has guaranteed that simultaneously concentration of substrate keeps constant.On figure, analyze the variation of per time unit's absorbancy, carry out linear regression at the range estimation linear section that reacts.
Embodiment B: assay method II
In the cell proliferation test that carries out with colon carcinoma cell line HCT116, the combination of antiprotozoal pentamidine and kinesin adenosine triphosphatase Eg5/KSP inhibitor causes retarding effect to increase.
The Eg5 inhibitor influences atpase activity unfriendly, and suppresses the process of cell cycle, and this is because the explode error of spindle pole causes.
The effect mensuration of the combination of the medicine in formula I compound of the present invention and formula V compound and/or the table 1 can prove as follows in the combine measured method:
With the regulation clone (HCT116, Colo 205, MDA-MB 231 etc.) 10
3To 10
4Individual cell inoculation in each hole of 96 hole microtiter plates, overnight incubation under standard conditions.For the material that is tried to make up, the storing solution in DMSO of preparation 10-50mM.The diluent series of each material (general 3 heavy dilution step) is made up (schema that vide infra) in the mode that suction moves schema each other, and the final concentration of keeping DMSO simultaneously is 0.5% (v/v).Added substance mixture to cell the next morning, with other 48 hours of its incubation under culture condition.When cultivating end, carry out the violet staining of cell.After from the fixed cell, extracting Viola crystallina, with the optical density under the metric measurement 550nm.Can be used as the quantitative measure of the attached cell that exists.
Schema
Following result has shown the restraining effect of Compound I 12 cell cycle of the present invention with way of example.
Monasterol and pentamidine in each experiment:
-with the HCT116 cell with the compound treatment of given concentration 24 hours, processing is so that use BD-FACS scanning carrying out propidium iodide analysis, purpose is to measure the dna content of processed cell mass.The cell per-cent that is in G0/G1 phase (DNA that does not duplicate), S phase (dna replication dna phase) and G2/M phase (DNA that duplicates before the mitotic division) is as follows.10,000 incidents of each concentration counting.The considerable change of G2/M enrichment is obviously shown.
I12 (Eg5 inhibitor of the present invention):
| μM | G1 | S | G2/M |
| 0 0.0032 0.016 0.08 0.4 2 | 36 36 36 35 7 0 | 43 44 43 42 7 15 | 21 21 2l 23 86 85 |
Monastrol (from the Eg5 inhibitor of prior art):
| μM | G1 | S | G2/M |
| 0 0.08 0.4 2 10 50 | 41 35 34 33 34 14 | 38 39 38 42 39 33 | 2l 25 28 25 27 52 |
Pentamidine isethionate (Pentamidine isothionate):
| μM | G1 | S | G2/M |
| 0 0.016 0.08 0.4 2 10 | 36 36 35 33 32 32 | 42 42 44 45 44 32 | 22 22 21 22 24 32 |
Following result has shown the restraining effect of Compound I 12 of the present invention or monasterol and pentamidine cell cycle in combination experiment with way of example:
Combination treatment: I12+ pentamidine
In 96 orifice plates, the density of HCT116 cell with 2500 or 5000 cells/well is incubated overnight under 37 ℃.Second day, the pentamidine of the matrix of concentration shown in the adding and described compound were with other 48 hours of cell incubation.With the cell violet staining, measure optical density behind the extraction dyestuff then.The optical density value has reflected the cell count in the hole.
Suction moves schema:
The result:
Upper matrix: calibrated OD550nm background
Center matrix: the % of contrast (the cell subtracting background signal of 100% value representation media processes)
Lower region: suppress multiple value (that is, 100%/x% value representation propagation suppresses multiple).
Table 2
The diagrammatic representation of data:
In Fig. 1, data have been expressed as concentration curve (every line has illustrated a curve under given pentamidine concentration).
Combination treatment: monastrol+ pentamidine
Suction moves schema:
The result:
Upper matrix: calibrated OD550nm background
Center matrix: the % of contrast (the cell subtracting background signal of 100% value representation media processes)
Lower region: suppress multiple value (that is, 100%/x% value representation propagation suppresses multiple).
Table 3
The diagrammatic representation of data:
In Fig. 2, data have been expressed as concentration curve (every line has illustrated a curve under given pentamidine concentration).
The following example relates to medicament:
Embodiment C: injection vials
Activeconstituents and the solution of 5g Sodium phosphate dibasic in the 3L redistilled water of 100g formula I are transferred to pH6.5 with 2N hydrochloric acid, and sterile filtration is transferred in the injection bottle, and lyophilize under aseptic condition is in sealed under aseptic conditions.Every injection vials contains the 5mg activeconstituents.
Embodiment D: suppository
With the mixture melt of activeconstituents and 100g soybean lecithin and the 1400g theobroma oil of 20g formula I, pour in the mould, make its cooling.Every suppository contains the 20mg activeconstituents.
Embodiment E: solution
Activeconstituents, the 9.38g NaH of preparation 1g formula I
2PO
42H
2O, 28.48gNa
2HPO
412H
2O and the solution of 0.1g benzalkonium chloride in the 940ml redistilled water.Regulate pH to 6.8, solution is added to 1L, radiation sterilization.This solution can use with the form of eye drops.
Embodiment F: ointment
The activeconstituents of 500mg formula I is mixed under aseptic condition with 99.5g Vaseline.
Embodiment G: tablet
The mixture of activeconstituents, 4kg lactose, 1.2kg yam starch, 0.2kg talcum powder and the 0.1kg Magnesium Stearate of 1kg formula I is suppressed in flakes in a usual manner, so that every contains the 10mg activeconstituents.
Embodiment H: dragee
Be similar to the embodiment E compressed tablets, carry out dressing with sucrose, yam starch, talcum powder, tragakanta and dyestuff in a usual manner subsequently.
Example I: capsule
The activeconstituents of 2kg formula I is packed in the hard gelatin capsule in a usual manner, so that every capsules contains the 20mg activeconstituents.
Embodiment J: ampulla
The solution sterile filtration of activeconstituents in the 60L redistilled water with 1kg formula I is transferred in the ampoule, and lyophilize under aseptic condition is in sealed under aseptic conditions.Every ampoule contains the 10mg activeconstituents.
Description of drawings
Fig. 1
The diagrammatic representation of data in the table 2
Data are expressed as the concentration curve of formula I12 material.Every line has illustrated a curve under given pentamidine concentration.
Fig. 2
The diagrammatic representation of data in the table 3
Data are expressed as the concentration curve of material monastrol.Every line has illustrated a curve under given pentamidine concentration.
Fig. 3 to Figure 25
The NMR spectrum of representative formula I compound
Claims (29)
1. formula I compound
Wherein
W represents CH or N,
R
1, R
2, R
3Represent independently of one another H, R, A, aryl, heteroaryl, Hal ,-(CY
2)
n-SA ,-(CY
2)
n-SCF
3,-(CY
2)
n-SCN ,-(CY
2)
n-CF
3,-(CY
2)
n-OCF
3, cycloalkyl ,-SCH
3,-SCN ,-CF
3,-OCF
3,-OA ,-(CY
2)
n-OH ,-(CY
2)
n-CO
2R ,-(CY
2)
n-CN ,-(CY
2)
n-Hal ,-(CY
2)
n-NR
2, (CY
2)
n-OA, (CY
2)
n-OCOA ,-SCF
3, (CY
2)
n-CONR
2,-(CY
2)
n-NHCOA ,-(CY
2)
n-NHSO
2A, SF
5, Si (CH
3)
3, CO-(CY
2)
n-CH
3,-(CY
2)
n-N-pyrrolidone, CH (CH
2)
nNRCOOR, CHNRCOOR, NCO, CH (CH
2)
nCOOR, NCOOR, CH (CH
2)
nOH, N (CH
2)
nOH, CHNH
2, CH (CH
2)
nNR
2, CH (CH
2)
nNR
2, C (OH) R, CHNCOR, CH (CH
2)
n-aryl, CH (CH
2)
n-heteroaryl, CH (CH
2)
nR
1, N (CH
2)
nCOOR, CH (CH
2)
nX (CH
2)
n-aryl, CH (CH
2)
nX (CH
2)
n-heteroaryl, N (CH
2)
nCONR
2, XCONR (CH
2)
nNR
2, N[(CH
2)
nXCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
nX-aryl, N[(CH
2)
nXR] SO
2(CH
2)
n-aryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-aryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nXR] CO (CH
2)
nX-heteroaryl, N[(CH
2)
nXR] SO
2(CH
2)
n-heteroaryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-heteroaryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-heteroaryl, O (CH
2)
nNR
2, X (CH
2)
nNR
2, NCO (CH
2)
nNR
2, R
1And R
2Also expression-N-C (CF together
3)=N-,-N-CR=N-,-N-N=N-,
Y represents H, A, Hal,
A represents alkyl or cycloalkyl, and wherein one or more H atoms can be replaced by Hal,
Hal represents F, Cl, Br or I,
R represents H or A, R also expression-(CH together under together with the situation of atomic group
2)
5-,-(CH
2)
4-,-(CH
2)
2-X-(CH
2)
2Or-(CH
2)
2-Z-(CH
2)
n,
R
4, R
5Represent H or unsubstituted or single-or many-OR-, NO independently of one another
2-, Hal-, CF
3-, OCF
3-, CN-, NR
2-or SR-, aryl-or the N-pyrrolidone atomic group of heteroaryl-replacement ,-X-(CH
2)
2OR ,-X-CO (CH
2)
nCH
3,-X-(CH
2)
2NR
2, R
1, S-aryl, O-aryl, CH
2Si (CH
3)
3, perhaps expression-X (CR together
2)
2-,-X-(CR
2)
3-,-X-(CHCH
2OR) (CH
2)
2-,-X-(CHCH
2NR
2) (CH
2)
2-,-X (CH
2)
2NR
2,-(CR
2)
3-,-(CR
2)
4-,-CR=CR-CR=CR-,-XCHQ (CR
2)
2-,-XCHQCR
2-, R-N-(C=X)-N-R ,-XC[(CH
2) nOR]
2CH
2CH
2-,
X represents O, S or NR,
Q represents CH
2Hal, CHO, COR
a, CH
2R
a, CH
2OCOR
a, CH
2NCOR
1, CH
2N (R
1)
2, CH
2OR
1, CH
2OCON (R
1)
2, CH
2OCOOR
1, CH
2NHCON (R
1)
2, CH
2NHCOOR
1,
R
aExpression
OR, NHR
2, NR
2, NR (CH
2)
n-aryl, NR (CH
2)
nOR, COOR, N-pyrrolidone atomic group, OCOR, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNHCOOR] CO-aryl, R
1, N[CH
2(CH
2)
nOR]
2, NR (CH
2)
nNCOOR, X (CH
2)
nX (CH
2)
nXR, NR (CH
2)
nX (CH
2)
nOH, NR (CH
2)
nO (CH
2)
nOH, (CH
2)
nCOOR, O (CO) NR (CH
2)
nOR, O (CO) (CH
2)
nNR
2, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nR
1, N (R) (CH
2)
nN (R) COOR, XCOO (CH
2)
nNR
2, OSO
2A, OSO
2CF
3, OSO
2Ar, OCONR
2, OCH
2(CH
2)
nNR
2,
Z represents CH
2, X, CHCONH
2, CH (CH
2)
nNRCOOR, CHNRCOOR, NCO, CH (CH
2)
nCOOR, NCOOR, CH (CH
2)
nOH, N (CH
2)
nOH, CHNH
2, CH (CH
2)
nNR
2, CH (CH
2)
nNR
2, C (OH) R, CHNCOR, CH (CH
2)
n-aryl, CH (CH
2)
n-heteroaryl, CH (CH
2)
nR
1, N (CH
2)
nCOOR, CH (CH
2)
nX (CH
2)
n-aryl, CH (CH
2)
nX (CH
2)
n-heteroaryl, N (CH
2)
nCONR
2, XCONR (CH
2)
nNR
2, N[(CH
2)
nXCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
nX-aryl, N[(CH
2)
nXR] SO
2(CH
2)
n-aryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
n-aryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-aryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-aryl, N[(CH
2)
nXR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nXR] CO (CH
2)
nX-heteroaryl, N[(CH
2)
nXR] SO
2(CH
2)
n-heteroaryl, N[(CH
2)
nNRCOOR] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
n-heteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nNR-heteroaryl, N[(CH
2)
nNR
2] SO
2(CH
2)
n-heteroaryl, O (CH
2)
nNR
2, X (CH
2)
nNR
2, NCO (CH
2)
nNR
2,
R
6Expression aryl or heteroaryl, they each unsubstituted naturally or by following group list-or polysubstituted: aryl or heteroaryl, described aryl or heteroaryl substituting group separately can be by Hal, NO
2, CN, A, OR, OCOR, COR, NR
2, CF
3, OCF
3, OCH (CF
3)
2Replace, perhaps Hal, NO
2, CN, OR, A ,-(CY
2)
n-OR ,-OCOR ,-(CY
2)
n-CO
2R ,-(CY
2)
n-CN ,-NCOR ,-COR or-(CY
2)
n-NR
2,
R
7Expression (C=O)-R, (C=O)-NR
2, (C=O)-OR, H or A,
M represents 0,1 or 2,
And
N represents 0,1,2,3,4,5,6 or 7, and their pharmaceutically useful derivatives, solvate, tautomer, salt and steric isomer, comprises the mixture of its all proportions.
2. compound according to claim 1, wherein
R
1Expression A, CF
3, OCF
3, SA, SCN, CH
2CN ,-OCOA, Hal, SCF
3, the tertiary butyl ,-CH (CH
3) CH
2CH
3, sec.-propyl, ethyl or methyl.
3. compound according to claim 1 and 2, wherein
R
2Expression F or H.
4. according to one or multinomial described compound among the claim 1-3, wherein
R
3Expression F or H.
5. according to one or multinomial described compound among the claim 1-4, wherein
R
4Preferably represent one of following groups, condition is R
5Expression H:
6. according to one or multinomial described compound among the claim 1-5, wherein
R
5Expression H.
7. according to one or multinomial described compound among the claim 1-6, wherein
R
5With R
4Take one of following meanings together:
Wherein
X, R and R
aHas the implication shown in the claim 1.
8. according to one or multinomial described compound among the claim 1-7, wherein
R
6Expression phenyl, 2-, 3-or 4-pyridyl, pyrimidyl, furyl or thienyl, they each unsubstituted naturally or by Hal, CN, NO
2, OH, CF
3, OCH (CF
3)
2, OCOCH
3Or the A list-or many-replace.
9. according to one or multinomial described compound among the claim 1-8, wherein
R
6One of expression following groups:
10. according to one or multinomial described compound among the claim 1-9, wherein
R
7Expression H.
11. the compound of minor IA to ID:
R wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7Have the implication shown in the claim 1 with X, and
R
8Expression H, CH
2OR or CH
2NR
2
12. the compound of minor A and B:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7Have the implication shown in the claim 1, with and racemoid or other mixture of enantiomers.
13. the compound of minor I1 to I45a:
14. the formula I compound of preparation claim 1-13 and the method for pharmaceutically useful derivative, salt, solvate, tautomer and steric isomer thereof is characterized in that making wherein R
1, R
2And R
3Formula II compound with implication shown in the claim 1
With R wherein
6Formula III compound reaction with implication shown in the claim 1,
With
With R wherein
4And R
5Formula IV compound, its double bond isomer (E isomer) or its mixture reaction with implication shown in the claim 1,
If necessary, the atomic group R of H will be represented
7Be converted into atomic group R with implication except that H
7,
And/or if necessary,
Alkali or the acid of formula I are converted into one of its salt.
15. method according to claim 14, it is characterized in that reacting protonic acid or lewis acidic in the presence of carry out.
16., it is characterized in that reaction is to carry out in the presence of trifluoroacetic acid, hexafluoroisopropanol, Trichlorobismuthine (III), Ytterbiumtriflate (III), trifluoromethanesulfonic acid scandium (III) or cerous nitrate (IV) ammonium according to claim 14 or 15 described methods.
17. medicine, formula I compound and/or its pharmaceutically useful derivative, salt, solvate, tautomer and steric isomer that it comprises at least a claim 1 to 13 comprise the mixture of its all proportions randomly also comprising vehicle and/or auxiliary agent.
18. mixture, it comprises one or more formulas I compound and a certain amount of one or more formulas V compound, its analogue and/or its meta-bolites
Wherein
Y ' and Z ' represent O or N, R separately independently of one another
9And R
10Represent H, OH, halogen, OC1-10-alkyl, OCF separately independently of one another
3, NO
2Or NH
2, n represents to comprise 2 to 6 integer of end value, R
8And R
11Position or contraposition between being in independently of one another separately, and be selected from:
19. purposes according to claim 18, wherein used formula V compound are pentamidine or its salt.
20. the purposes of the mixture of the compound of claim 1 to 13 and pharmaceutically useful derivative, salt, solvate, tautomer and steric isomer, the mixture that comprises its all proportions or claim 18 in the preparation medicine, described medicine are used for the treatment of can be by the disease of the inhibition of mitotic division dynein Eg5, adjusting and/or regulating and controlling effect influence.
21. the compound of claim 1 to 13 or the mixture of claim 18 purposes in the preparation medicine, described medicine is used for the treatment of and the preventing cancer disease.
22. purposes according to claim 21, wherein said Cancerous disease is relevant with tumour, and described tumour is selected from the tumour of tesselated epithelium, bladder, stomach, kidney, neck, esophagus, uterine cervix, Tiroidina, intestines, liver, brain, prostate gland, urogenital tract, lymphsystem, stomach, larynx and/or lung.
23. purposes according to claim 22, wherein said tumour is derived from monocytic leukemia, adenocarcinoma of lung, small cell lung cancer, carcinoma of the pancreas, glioblastoma, mammary cancer and colorectal carcinoma.
24. purposes according to claim 21, wherein the Cancerous disease of being treated is blood and immune tumour.
25. purposes according to claim 24, wherein said tumour is derived from acute myeloid leukaemia, chronic myelogenous leukemia, kemia and/or chronic lymphatic leukemia.
26. acceptable salt and the solvate purposes in the preparation medicine on the formula I compound of claim 1 to 13 and/or its physiology, described medicine is used for the treatment of tumour with one or more formulas V compound, its analogue and/or the combination of its meta-bolites of treatment significant quantity:
Wherein
Y ' and Z ' represent O or N, R separately independently of one another
9And R
10Represent H, OH, halogen, OC1-10-alkyl, OCF separately independently of one another
3, NO
2Or NH
2, n represents to comprise 2 to 6 integer of end value, R
8And R
11Position or contraposition between being in independently of one another separately, and be selected from:
Wherein
Formula I compound and formula V compound, its analogue and/or its meta-bolites be by simultaneously or using in 14 days each other, and amount of application is the amount that is enough to suppress the growth of tumour or other hyper-proliferative sexual cell.
27. purposes according to claim 26, wherein used formula V compound are pentamidine or its salt.
28. acceptable salt and the solvate purposes in the preparation medicine on the formula I compound of claim 1 to 13 and/or its physiology, described medicine is used for the treatment of tumour, wherein will treat the formula I compound and the radiotherapy of significant quantity and be selected from down the compound combined administration of organizing: 1) estrogen receptor adjusting control agent, 2) androgen receptor adjusting control agent, 3) retinoid receptor adjusting control agent, 4) cytotoxic substance, 5) antiproliferative, 6) prenyl-protein transferase inhibitors, 7) HMG-CoA reductase inhibitor, 8) hiv protease inhibitor, 9) reverse transcriptase inhibitors and 10) other angiogenesis inhibitor.
29. formula I compound, wherein Q represents CH
2R
a, R
aHas one of following meanings: NHR
2, NR
2, NR (CH
2)
nAryl, NR (CH
2)
nOR, COOR, N-pyrrolidone atomic group, OCOR, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
nAryl, N[(CH
2)
nNHCOOR] CO aryl, R
1, N[CH
2(CH
2)
nOR]
2, NR (CH
2)
nNCOOR, X (CH
2)
nX (CH
2)
nXR, NR (CH
2)
nX (CH
2)
nOH, NR (CH
2)
nO (CH
2)
nOH, (CH
2)
nCOOR, O (CO) NR (CH
2)
nOR, O (CO) (CH
2)
nNR
2, NR (CH
2)
nNR
2, N[(CH
2)
nNR
2] CO (CH
2)
nAryl, N[(CH
2)
nXR] CO (CH
2)
nAryl, N[(CH
2)
nXR] CO (CH
2)
nHeteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nHeteroaryl, N[(CH
2)
nNR
2] CO (CH
2)
nR
1, N (R) (CH
2)
nN (R) COOR, XCOO (CH
2)
nNR
2, OSO
2A, OSO
2CF
3, OSO
2Ar, OCONR
2Or OCH
2(CH
2)
nNR.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10360154.6 | 2003-12-20 | ||
| DE10360154A DE10360154A1 (en) | 2003-12-20 | 2003-12-20 | New 2-(hetero)aryl-tetrahydroquinoline derivatives and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives are mitotic motor protein Eg5 inhibitors used as anticancer agents for treating carcinoma or leukemia |
| US60/539,961 | 2004-01-30 | ||
| DE102004026026.5 | 2004-05-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1902190A true CN1902190A (en) | 2007-01-24 |
| CN100567289C CN100567289C (en) | 2009-12-09 |
Family
ID=34683681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800371773A Expired - Fee Related CN100567289C (en) | 2003-12-20 | 2004-12-14 | The tetrahydroquinoline derivative of 2-(mixing) aryl-replacement |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN100567289C (en) |
| DE (1) | DE10360154A1 (en) |
| ES (1) | ES2365097T3 (en) |
| ZA (1) | ZA200605981B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964361A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Application of selective alpha2A receptor stimulants to treatment of Alzheimer disease |
| CN104817496A (en) * | 2015-04-24 | 2015-08-05 | 中国科学院化学研究所 | 1, 2, 3, 4-tetrahydroquinoline derivative and method for preparing same |
-
2003
- 2003-12-20 DE DE10360154A patent/DE10360154A1/en not_active Withdrawn
-
2004
- 2004-12-14 ES ES08014660T patent/ES2365097T3/en active Active
- 2004-12-14 CN CNB2004800371773A patent/CN100567289C/en not_active Expired - Fee Related
-
2006
- 2006-07-19 ZA ZA200605981A patent/ZA200605981B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964361A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Application of selective alpha2A receptor stimulants to treatment of Alzheimer disease |
| CN104817496A (en) * | 2015-04-24 | 2015-08-05 | 中国科学院化学研究所 | 1, 2, 3, 4-tetrahydroquinoline derivative and method for preparing same |
| CN104817496B (en) * | 2015-04-24 | 2017-06-16 | 中国科学院化学研究所 | A kind of 1,2,3,4 tetrahydroquinoline derivatives and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200605981B (en) | 2008-06-25 |
| DE10360154A1 (en) | 2005-07-21 |
| CN100567289C (en) | 2009-12-09 |
| ES2365097T3 (en) | 2011-09-22 |
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