CN101106992A - Novel quinolinium salts and derivatives - Google Patents

Novel quinolinium salts and derivatives Download PDF

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CN101106992A
CN101106992A CNA2006800025905A CN200680002590A CN101106992A CN 101106992 A CN101106992 A CN 101106992A CN A2006800025905 A CNA2006800025905 A CN A2006800025905A CN 200680002590 A CN200680002590 A CN 200680002590A CN 101106992 A CN101106992 A CN 101106992A
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alkyl
cancer
replacement
phenyl
carcinoma
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詹姆士·E·麦克唐纳
米歇尔·K·哈斯欧
喻德华
李其翔
黄以静
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Immusol Inc
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Abstract

The present invention relates generally to the synthesis of novel quinolinium salts and derivative compounds. Such salts and compounds are useful for inhibiting the growth of cancer cells.

Description

Novel quinolinium and derivant
Invention field
The present invention relates in general to the synthetic of novel salt and derivative compound.Described salt and chemical compound can anticancer growth.Particularly, the invention provides novel quinolinium and novel quinoline derivatives chemical compound.
Background technology
Some patents provide 1-alkyl-2-(2-replaces-vinyl) preparation, physical property and the purposes of quinolinium.Brooker has described (1-methyl-2-quinoline)-1-Laurel-2,5-dimethyl-3-pyrroles) preparation of two methine cyanine tosilate and as the purposes of photosensitizer 1Other 2-vinylquinoline has been described as photosensitizer, comprise iodate 6-dimethylamino-1-methyl-2-[(1-phenyl-4-pyrazolyl) vinyl] quinoline, iodate-6-dimethylamino-1-methyl-2-[(3,5-dimethyl-1-phenyl-4-pyrazolyl) vinyl] quinoline, iodate-1-ethyl-2-[(3,5-dimethyl-1-phenyl-4-pyrazolyl) vinyl]-the 6-nitroquinoline 2And iodate-1-methyl-2-2 '-3 "-the pyridine radicals vinylquinoline 3Describing the effective anthelmintic of some such chemical compounds infects and they is listed in the table 1 4
Table 1: quinoline nematicidal compound
Figure A20068000259000121
R R’ R2 R3 X
Me Me Me Ph Toluene fulfonate
Me Me Me Et Iodide
Me Me Me Et Chloride
Me Me Me Lauryl (dodecyl) Iodide
Me Me Me Lauryl (dodecyl) Chloride
Et Me Me Ph Chloride
Me Me Me Heptyl Chloride
Me Me Me Me Chloride
Me Me Me Cetyl Chloride
Heptyl Me Me Ph Chloride
Dodecyl Me Me Ph Chloride
The 2-ethoxyethyl group Me Me Ph Chloride
Me Me Me Ch2 Ph Iodide
Me Me Me Amyl group Iodide
Me Me Me Amyl group Chloride
The 2-ethoxy Me Me Ph Iodide
The 2-ethoxy Me Me Ph Chloride
Me Me Me The 2-methoxy ethyl Iodide
Me Me Me The 2-methoxy ethyl Chloride
Me Dimethylamino Me Ph Iodide
Me Dimethylamino Me Ph Chloride
Me Me Me 4-ClPh Chloride
Me Me Me 4-EtOPh Chloride
Amyl group Me Me Amyl group Iodide
Me Me Me Butyl Iodide
Me Me Me Decyl Iodide
Me Me Me Isopropyl Iodide
Me Cl Me Ph Iodide
Me Cl Me Ph Chloride
Et Me Me Amyl group Iodide
Et Me Me Amyl group Chloride
Propyl group Me Me Amyl group Iodide
Propyl group Me Me Amyl group Chloride
Me Me Me Cyclohexyl Iodide
Me Me Me Cyclohexyl Chloride
Me Me Me Propyl group Iodide
Me Me Me Propyl group Chloride
Me MeO Me Amyl group Chloride
Me MeO Me Amyl group Iodide
Me Heptan amino Me Ph Iodide
Me Heptan amino Me Ph Iodide
Me Ph Me Ph Iodide
Me Ph Me Ph Chloride
Chemistry Literature also relates to preparation and their physics and the spectral quality of 1-alkyl-2-(2-aryl or 2-heteroaryl replace-vinyl) quinolinium.For example, Wizinger has reported N-methyl-2-[2-[2-hydroxyl naphthyl-1-yl] vinyl] preparation of quinoline perchlorate, its be orange colour spicule, mp266 ℃ and when adding alkali its color change 5
Lugowkin in acetic anhydride by quinoline and caffeine-8-aldehyde prepared iodate-1-methyl-2-[(E)-2-(1,3,7-trimethyl-2,6-dioxy-2,3,6,7-tetrahydrochysene-1H-purine-8-yl)-vinyl]-quinoline and iodate-1-ethyl-2-[(E)-2-(1,3,7-trimethyl-2,6-dioxy-2,3,6,7-tetrahydrochysene-1H-purine-8-yl)-vinyl]-quinoline, and reported the physical property of described dyestuff 6
Lugowkin also in acetic anhydride by quinoline and different caffeine-8-aldehyde prepared iodate-1-methyl-2-[(E)-2-(1,3,9-trimethyl-2,6-dioxy-2,3,6,9-tetrahydrochysene-1H-purine-8-yl)-vinyl]-quinoline and iodate-1-ethyl-2-[(E)-2-(1,3,9-trimethyl-2,6-dioxy-2,3,6,9-tetrahydrochysene-1H-purine-8-yl)-vinyl]-quinoline, and reported the physical property of described noval chemical compound 7
Zhmurova has reported 2-[(E)-2-(phenyl)-vinyl]-1-ethyl-quinoline perchlorate, 2-[(E)-2-(4-methyl-phenyl)-vinyl]-1-ethyl-quinoline perchlorate, 2-[(E)-2-(4-hydroxyl-phenyl)-vinyl]-1-ethyl-quinoline perchlorate, 2-[(E)-2-(4-amino-phenyl)-vinyl]-1-ethyl-quinoline perchlorate, 2-[(E)-2-(4-(dimethylamino)-phenyl)-vinyl]-1-ethyl-quinoline perchlorate and 2-[(E)-2-(4-(triphen phosphoranediyl-phenyl)-vinyl]-preparation of 1-ethyl-quinoline perchlorate, physical property and dyestuff absorb maximum 8
Pilyugin has reported 2-[(E)-2-(2-hydroxyl-phenyl)-vinyl]-1-methyl-quinoline perchlorate, 2-[(E)-2-(2-hydroxyl-phenyl)-vinyl]-1-phenyl-quinoline perchlorate, the 1-decyl-2-[(E)-2-(2-hydroxyl-phenyl)-vinyl]-the quinoline perchlorate, the 1-decyl-2-[(E)-2-(2-hydroxyl-phenyl)-vinyl]-6-methoxy yl-quinoline perchlorate, 2-[(E)-2-(2-hydroxyl-phenyl)-vinyl]-1-methyl-quinoline perchlorate, 2-[(E)-2-(2-hydroxyl-3-nitro-phenyl)-vinyl]-1-phenyl-quinoline perchlorate, the 1-decyl-2-[(E)-2-(2-hydroxyl-3-nitro-phenyl)-vinyl]-the quinoline perchlorate, the 1-decyl-2-[(E)-2-(2-hydroxyl-3-nitro-phenyl)-vinyl]-6-methoxy yl-quinoline perchlorate, 2-[(E)-2-(2-hydroxyl-1-naphthyl)-vinyl]-1-methyl-quinoline perchlorate, 2-[(E)-2-(2-hydroxyl-1-naphthyl)-vinyl]-1-phenyl-quinoline perchlorate, 1-decyl-2-[(E)-2-(2-hydroxyl-1-naphthyl)-vinyl]-quinoline perchlorate and 1-decyl-2-[(E)-2-(2-hydroxyl-1-naphthyl)-vinyl]-the dyestuff acid salt of 6-methoxy yl-quinoline perchlorate and the preparation of free alkali, physical property and absorption spectrum 9
Stepanov has reported 2-[(E)-2-(2,3-dimethyl-indolizine-1-yl)-vinyl]-1-methyl-quinoline perchlorate, 2-[(E)-2-(2,3-dimethyl-indolizine-1-yl)-vinyl]-1-ethyl-quinoline perchlorate and 2-[(E)-2-(2,3-dimethyl-indolizine-3-yl)-vinyl]-preparation and the UV spectrum of 1-methyl-quinoline perchlorate 10
Chernyuk has reported use 2-(San Ben Phosphonium) methyl isophthalic acid-methylquinoline two perchlorate prepare 2-[[4-(dimethylamino) phenyl] vinyl]-1-methylquinoline perchlorate 11Buttgereit and Scheibe have reported the phenyl with 2-[[4-(dimethylamino)] vinyl]-spectral shift of the pyrrolidine of 1-methylquinoline perchlorate reaction 12
Mal ' tseva has reported 2-[(E)-2-(1,3-dimethyl-1H-pyrazoles-4-yl)-vinyl]-1-methyl-quinoline perchlorate and 2-[(E)-2-(1,5-dimethyl-1H-pyrazoles-4-yl)-vinyl]-preparation, mp elementary analysis and the spectral absorption maximum of 1-methyl-quinoline perchlorate 13
Rout prepares and has measured the optical property of pyrazolone quinoline two methine dyestuffs 14
Boyer has reported that cyanine and merocyanine dyes are in solution and the spectral shift in the AgBr precipitation 15
Osman has reported the preparation and the absorption spectrum of iodate-2-((E)-2-benzoxazole-2-base-vinyl)-1-ethyl-quinoline and two iodate-2-((E)-3-ethyl-2-benzoxazole-2-base-vinyl)-1-ethyl-quinoline 16Wainright has reported the faint antibacterial activity of 2-(4-dimethylamino the styryl)-1-methylquinoline class that is replaced by hydrogen, methoxyl group, amino and caproamide in 6 in quinoline 17Malina has reported that 6-(amino carbonyl oxygen base)-2-(2-(8-hydroxy-5-methyl base quinoline-7-yl) vinyl)-1-methylquinoline (NSC 86372) suppresses the protein synthesis in the eukaryotic translation system.
Pyrrole dimension ammonium (pyrvinium) is the chemical compound that has with those chemical compound similar structures discussed above.Particularly, it has following structure:
Shown that it has anti-tumor activity.More specifically, Esumi has shown that the multiple cancerous cell line between its pamoic acid salt pair glucose hunger period has first-selected toxicity.In addition, to the pamoic acid pyrrole dimension ammonium of the water slurry form of the nude mouse orally give 2%DMSO that has cancer of pancreas.Although some effects are arranged, said preparation has shown the saturated of reaction, because limited dissolubility obtains identical result 100 μ g/ mices with 200 μ g/ mices.
In the broader sense, the present form of pyrrole dimension ammonium is not the optimised form that is used for treatment of cancer.For example, pyrvinium chloride salt has dense bitterness 19In addition, its iodide form is not preferred drug salts and can causes such as erythra and headache even toxic symptom.Other unaccommodated salt of pyrrole dimension ammonium comprises Methylsulfate 21And phenolphthalein (Phenolphthalein) 22Existing methyl sodium sulphate is the report of mutagenic agent.Phenolphthalein is listed in carcinogen in the California 24
At last, as mentioned above, the limited solubility of embonate produces the dose limitation effect.Therefore need better pyrrole dimension ammonium salt of exploitation and novel pyrrole dimension ammonium derivative compound badly.
Described another quinoline derivatives chemical compound, Eastman no. 1361 (describing hereinafter) has active anticancer.More specifically, existing its report as the transformed cell growth inhibitor 25
Eastman no. 1361
Figure A20068000259000162
Therefore, also need badly preparation other, also have a quinoline derivatives chemical compound of the novelty of anti-tumor activity.The present invention has satisfied these needs and associated advantages is provided.
Summary of the invention
The invention provides the salt of the novelty of chemical compound pyrrole dimension ammonium, known pyrrole dimension ammonium has anti-tumor activity.According to first aspect, the invention provides the salt of described chemical compound, it has the water solublity of improvement.According on the other hand, the invention provides the described chemical compound that is mixed with acid compound, it has anti-tumor activity.Others the invention provides the form that the pyrrole with acid ion exchange polymer is tieed up ammonium, and it is used for oral administration.On the other hand, The compounds of this invention and another chemotherapeutics associating.
The present invention also provides the derivant of the novel quinoline compounds with following formula:
Figure A20068000259000171
The implication of each variable is described hereinafter.
The present invention also provides the derivant of the novel quinoline compounds with following formula:
Figure A20068000259000172
The implication of each variable is described hereinafter.
Brief Description Of Drawings
Fig. 1 shows the chemical compound that uses embodiment 1, the decline of colon cancer cell tumor growth (compared with the control).
Fig. 2 shows the chemical compound that uses embodiment 57, the decline of non-small cell lung cancer cell tumor growth (compared with the control).
Fig. 3 shows the effect of the conjoint therapy of the chemical compound of embodiment 1 and amycin to PC3 xenotransplantation in mid-term tumor.
Fig. 4 shows the effect of the conjoint therapy of the chemical compound of embodiment 1 and paclitaxel to PC3 xenotransplantation in mid-term tumor.
The detailed description of invention
The present invention relates to the salt of the novelty of compound pyrrole dimension ammonium, its chemistry 6-(dimethylamino) by name-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl) vinyl]-1-methyl-quinoline, have following structure:
Figure A20068000259000181
more specifically, the invention provides the salt of this compound, it improves the water-soluble of this compound. therefore, the salt of pyrrole dimension ammonium comprises following salt: acetate, trifluoroacetate, carbonate, bicarbonate, benzoate, salicylate, glucuronic acid salt, lactate, tartrate, mucate, gluconate, succinate, glutamate, aspartate, maleate, citrate, glutarate, phosphate, sulfate, mesylate, TFMS salt, toluene fulfonate, benzene sulfonate, 1, the 2-ethanedisulphonate, the 2-isethionate, the 2-naphthalene sulfonate, esilate, camsilate, sulfamate and cyclohexyl-n-sulfonate. preferred salt form is sulfate and phosphate. referring to embodiment 1 and 2.
The present invention also provides the salt of the novelty of the pyrrole dimension ammonium that is mixed with acid compound, and it has extra useful anticancer activity. The example of these salt includes but not limited to pyrithione [CAS Reg.No.1121-31-9], Ciclopirox [CAS Reg.No.29342-05-0], acetyl group-11-ketone-beta boswellic acid, celastrol, dihydro celastrol, glycyrrhizic acid [CAS Reg. No.53956-04-0], malol [CAS Reg.No.77-52-1] and β glycyrrhetinic acid [C AS Reg.No.471-53-4]. In addition, the invention provides pyrrole dimension ammonium salt for the novelty of oral administration. Use these forms that prepare pyrrole dimension ammonium salt such as strong acid fluoropolymer resin plasma exchange polymer to obtain stable salt, shelter the bitter taste of pyrrole dimension ammonium, and controlled release or the slowly-releasing of pyrrole dimension ammonium cation are provided. Referring to, for example: http://www.rohmhaas.com/ionexchan ge/Pharmaceuticals/Formulations_doc/us_english/Irp69.PDF.
The example of described resin is the polystyrene Amberlite IRP-69 of sulfonation. Perhaps, can also prepare with strong acid fluoropolymer resin Dowex-50X8 or Dowex-50X2 the salt of the novelty of pyrrole dimension ammonium. Can also use other acid non-poly styrene polymer resin, for example acrylate or acrylamide polymer. Controlled release or the slowly-releasing of dextromethorphan are provided with Amberlite IRP69 in addition.
Can be by prepare described new salt with acid treatment povan corresponding to new salt in solvent. Then can collect the precipitation of described new salt.
Perhaps, can process chlorination or iodate pyrrole dimension ammonium by use silver salt corresponding to new salt in solvent, the silver halide that then removes precipitation prepares described new salt.
Perhaps, can handle pyrvinium chloride, and collect described new salt and prepare described new salt by the acid salt, sodium salt or the potassium salt that in solvent, use new salt correspondence.
Perhaps, can be with the pyrrole dimension ammonium and the strong acid ion exchange resin exchange of acid salt, ammonium salt, sodium salt or potassium salt form, so that the pyrrole dimension ammonium of resin-bonded to be provided.Can use with this form, perhaps can be subsequently by using another acid solution to handle, with its acid, ammonium salt, sodium salt or potassium salt form pyrrole is tieed up ammonium from the resin and removes.
The invention still further relates to following formula: compound:
Figure A20068000259000191
Wherein:
R is C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl or C 7-C 18The phenylalkyl that replaces;
Perhaps R and R 6Can form the heterocycle of heterocycle or replacement;
Perhaps R and R 4Can form the heterocycle of heterocycle or replacement;
R 1Be hydrogen, alkyl, alkoxyl, halogen, cyano group, nitro, CO 2R 7, C (O) NR 7R 8,-CH=NR 7, C=NR 9-NR 7R 8Or-NR 7R 8, R wherein 7And R 8Be C independently 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl or C 7-C 18The phenylalkyl that replaces; Perhaps-NR 7R 8Be heterocycle, the ring-type C of heterocycle, replacement 2-C 7The ring-type C of assorted alkylidene or replacement 2-C 7Assorted alkylidene, the heterocycle of wherein said replacement and the ring-type C of replacement 2-C 7Assorted alkylidene defines hereinafter and comprises oxo and formula=NR 9Replacement, R wherein 9Be hydrogen, C 1-C 12Alkyl or C 1-C 12The alkyl that replaces;
R 2, R 3, R 4And R 6Be hydrogen, C independently 1-C 12Alkyl, C 1-C 12The alkyl that replaces, halogen or following one of various: a)-(CH 2) nCO 2R 10B)-(CH 2) nCON (R 10) 2C)-(CH 2) nCN; Or d) (CH 2) nSO 2R 10R wherein 10Be hydrogen, C 1-C 12Alkyl or C 1-C 12The alkyl and the n that replace are 0 to 4; And
R 5Be C 1-C 12Alkyl, C 1-C 12The alkyl, phenyl, the phenyl of replacement, naphthyl, the naphthyl of replacement, heterocycle, the heterocycle of replacement, the ring-type C that replace 2-C 7The ring-type C of assorted alkylidene or replacement 2-C 7Assorted alkylidene.
In preferred embodiments, R is C 1-C 6Alkyl or C 7-C 18Phenylalkyl.In another preferred embodiment, R 2, R 3, R 4And R 6Be hydrogen, C independently 1-C 6Alkyl or halogen.
In another preferred embodiment, R 7And R 8Be C independently 1-C 6Alkyl, C 1-C 6The alkyl or the C that replace 7-C 18Phenylalkyl.Perhaps, in another preferred embodiment, NR 7R 8Form the heterocycle of 4 to 8 atoms, it contains 0 to 3 other hetero atom and group C=O or C=NR that is selected from N, O or S 9, and described heterocycle can be substituted, and perhaps has extra condensed ring.Heterocycle NR 7R 8Preferred embodiment include but not limited to morpholine-4-base, piperazine-1-base, 3-oxo piperazine-1-base, high piperazine-1-base, imidazoles-1-base, 2-oxo-imidazole alkane-1-base, 2-oxoimidazolinium-1-base and 2-iminoimidazoline-1-base.
In another preferred embodiment, R 5Be C 1-C 12Alkyl, C 1-C 12The heteroaryl of naphthyl, heteroaryl or the replacement of the phenyl of the alkyl that replaces, phenyl, replacement, naphthyl, replacement.In another preferred embodiment, R 9And R 10Be hydrogen or C independently 1-C 6Alkyl.
Be to be understood that these above-mentioned novel chemical compounds can the salt form preparation with novelty as described herein.
Can be according to United States Patent (USP) the 2nd, 515, No. 912 and the 2nd, 925, the examples preparation The compounds of this invention (" chemical compound 1 " vide infra) in No. 417.Perhaps, can prepare The compounds of this invention to obtain chemical compound 1 by alkylated compound 2.
Figure A20068000259000211
Chemical compound 2 chemical compounds 1
Can replace or the known method of three substituted olefines prepares chemical compound 2 by being used to prepare two.
For example, the coupling of the vinyl stannane by Pd mediation has prepared the 2-vinylquinoline 26Paper at AG Montalban 27In can find by aldehyde and quinaldine in acetic anhydride, react, the reaction of the reaction of quinoline-2-ylmethyl phosphine and aldehyde or quinoline-2-ylmethyl phosphonate ester and aldehyde produces other example of 2-vinylquinoline.
The present invention also provides the derivant of the novel quinoline compounds with following formula:
Figure A20068000259000212
Wherein:
A is the heteroaryl of phenyl, heteroaryl or the replacement of phenyl, replacement, and wherein the replacement on phenyl or the heteroaryl can also comprise-OR 3,-CHO ,-CN ,-SO 2NR 3R 4,-NR 5CONR 3R 4,-OCONR 3R 4,-CONR 3R 4CO 2R 3,-R 5,-OR 5,-SR 5
R is C 1-C 12Alkyl, C 1-C 12The alkyl, phenyl, the phenyl of replacement, the C that replace 7-C 18Phenylalkyl or C 7-C 18The phenylalkyl that replaces;
R 1And R 2Be hydrogen, C independently 1-C 12Alkyl, C 1-C 12The alkyl, heterocycle, the heterocycle of replacement, the ring-type C that replace 2-C 7The ring-type C of assorted alkylidene or replacement 2-C 7The bicyclic heterocycle of assorted alkylidene, bicyclic heterocycle, replacement, halogen ,-CHO or cyano group, perhaps one of following formula :-OR 3,-NR 3R 4,-SO 2NR 3R 4,-NR 5CONR 3R 4,-OCONR 3R 4,-C (O) NR 3R 4With-CO 2R 3And
R 3And R 4Be hydrogen, C independently 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl or C 7-C 18The phenylalkyl that replaces; And
R 5It is the miscellaneous alkyl aryl of alkyl phenyl, miscellaneous alkyl aryl or replacement of heteroaryl, alkyl phenyl, the replacement of phenyl, heteroaryl or the replacement of phenyl, replacement.
Preferably, when A was substituted, it had the heteroaryl of phenyl, heteroaryl or the replacement of phenyl, replacement.More preferably, these phenyl or heteroaryl are by C 1-C 12Alkyl, C 1-C 12The alkyl, the OR that replace 3, OR 5, SR 5, halogen ,-CHO ,-CN ,-CONR 3R 4Or-CO 2R 3Replace.In addition, these replacements can have 1 to 4 extra group, preferably, and C 1-C 12Alkyl, C 1-C 12The alkyl, the OR that replace 3, OR 5, SR 5, halogen ,-CHO ,-CN ,-CONR 3R 4Or-CO 2R 3
In embodiment of the present invention, comprise above-claimed cpd, but getting rid of R is C 1-C 4Those chemical compounds of alkyl or ethoxy.More preferably, C 1-C 6Alkyl and hydroxy alkyl also are excluded.
In another embodiment, comprise above-claimed cpd, but get rid of R 1Be methyl, dimethylamino, methoxyl group or heptan amino those chemical compounds.In another embodiment, get rid of ethyl, and more preferably, get rid of C 1-C 4Alkyl.Other-embodiment in, get rid of lignocaine, and more preferably, get rid of dialkylamino.In another embodiment, get rid of ethyoxyl, and more preferably, get rid of alkoxyl.In another embodiment, get rid of alkylamino.Preferably, any one or a plurality of these eliminatings are positioned at 7 of described quinoline basic ring.
In another embodiment, A is not trisubstituted pyrroles, and wherein the replacement on the pyrroles's 2 and 5 is a methyl, perhaps more preferably, and C 1-C 4Alkyl, and wherein 1 of pyrroles is phenyl, alkyl-cyclohexyl or methoxy ethyl.More preferably, 1 is not alkoxyethyl.
In the method for Miao Shuing, all chemical compounds all belong to scope of the present invention hereinafter, and belong to above-mentioned subclass.Preferably, A is the pyrroles of pyrroles or replacement.Preferred pyrroles replaces and comprises C 1-C 12Alkyl, preferable methyl, and preferably 2 or 5 of pyrroles; C 1-C 12Alkyl, preferred butyl, perhaps phenyl, perhaps heteroaryl, preferred pyridine radicals, more preferably 3-pyridine radicals, all preferably 1 of pyrroles, and preferred-CHO ,-CO 2R 3,-CONR 3R 4Or-CN, all preferably 4 of pyrroles.
Also preferably, R 1Be dialkyl amido, preferred dimethylamino, perhaps halogen, preferred bromine or chlorine, perhaps alkoxyl, preferred methoxyl group, perhaps alkyl, preferable methyl, all preferably 6 or 7 of quinolyl; R 2Hydrogen preferably; And R is alkyl preferably, is more preferably methyl or ethyl.
In addition, in claimed the compositions and methods of the invention, preferably, phenyl, sulfur phenenyl, furyl, indyl, imidazole radicals He isoxazolyl that A replaces arbitrarily.The preferred replacement, comprise C 1-C 12Alkyl, preferable methyl or butyl, perhaps phenyl or benzyl, perhaps-phenoxy group, perhaps dialkyl amido, preferred dimethylamino, perhaps alkoxyl, preferred butoxy.Preferably, these chemical compounds are at R 1The place has the amino of amino or replacement, more preferably, has alkyl amino or dialkyl amido, and, even more preferably, have dimethylamino.Also preferably, these chemical compounds have alkyl at the R place, more preferably, have methyl.
Also preferably, R 1Be dialkyl amido, preferred dimethylamino, perhaps halogen, preferred bromine or chlorine, perhaps alkoxyl, preferred methoxyl group, perhaps alkyl, preferable methyl, all preferably 6 or 7 of quinolyl; R 2Hydrogen preferably; And R is alkyl preferably, is more preferably methyl or ethyl.
Chemical compound of the present invention can be used to reduce growth of cancer cells.For example, the chemical compound of embodiment 1 has reduced the growth of cancerous cell in the various kinds of cell in liquid culture that does not add glucose and soft agar cultivation.Referring to embodiment 61 and table 4 and embodiment 62 and table 5.In addition, the chemical compound of embodiment 25 to 60 (except chemical compound 53) has also reduced the growth of cancerous cell in various kinds of cell system.Referring to embodiment 61 and table 3.
In addition, chemical compound of the present invention can be used to reduce the size of in-vivo tumour.For example, the chemical compound of embodiment 1 has reduced the size of colon cancer tumor in the mice xenotransplantation model in late period.Referring to embodiment 63 and table 1.In addition, the chemical compound of embodiment 57 has reduced the size of non-small cell lung tumor in the early stage model of mice xenotransplantation.Referring to embodiment 64 and table 2.
The present invention also provides a) chemical compound of the present invention and b) associating of one or more extra active chemotherapeutics.Preferred extra active chemotherapeutics includes but not limited to paclitaxel or amycin.As shown in Figure 3 and embodiment 65A and table 6 described, the chemical compound of embodiment 1 and the associating of amycin suppress the growth of tumor of prostate in the mice heteroplastic transplantation model very effectively.In addition, as shown in Figure 4 and embodiment 65B and table 6 described, the chemical compound of embodiment 1 and the associating of paclitaxel suppress the growth of tumor of prostate in the mice heteroplastic transplantation model very effectively.
Preventative or the therapeutic of other that can use with The compounds of this invention includes but not limited to for anticancer dose: acivicin, aklavine, the hydrochloric acid acodazole, acronine, adozelesin, general staying only, altretamine, ambomycin, the acetic acid ametantrone, aminoglutethimide, amsacrine, Anastrozole, antramycin, asparaginase, asperlin, azacitidine, azatepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, two methanesulfonic acid bisnafides, bizelesin, Bleomycin Sulphate, brequinar sodium, bropirimine, busulfan, actinomycin C, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, the methanesulfonic acid crisnatol, cyclophosphamide, cytosine arabinoside, dacarbazine, actinomycin D, daunorubicin hydrochloride, dacarbazine, decitabine, dexormaplatin, the J Dezaguanine, the methanesulfonic acid Dezaguanine, diaziquone, the polyenoid taxol, amycin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, Eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, the phosphoric acid etoposide, etoprine, CGS-16949A, fazarabine, fenretinide, azauridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin-22 (comprising recombinant interleukin 2 or rIL2), Intederon Alpha-2a, Interferon Alpha-2b, interferon alfa-n1, Alferon N, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, the acetic acid letrozole, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mustine hydrochlcride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine (metoprine), meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nitroso ureas, nocodazole, nogalamycin, ormaplatin, oxisuran, Paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, the hydrochloric acid piroxantrone, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, Rogletimide, Safingol, the hydrochloric acid Safingol, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, rufocromomycin, streptozocin, sulofenur, talisomycin, tecogalan sodium, ftorafur, teloxandrone hydrochloride, temoporfin, teniposide, teroxirone, keto lactone clonorchis, ITG, thioguanine, thiotepa, tiazofurine, tirapazamine, FC-1157a, trestolone acetate, the phosphoric acid triciribine, trimetrexate, trimetrexate glucuronic acid fat, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, Verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, the sulphuric acid vinepidine, the sulphuric acid vinglycinate, the sulphuric acid vinleurosine, vinorelbine tartrate, the sulphuric acid vinrosidine, the sulphuric acid vinzolidine, vorozole, zeniplatin, zinostatin and hydrochloric acid zinostatin.
The preferred anticarcinogen of one class that can use with The compounds of this invention is an inhibitors of kinases.Operable inhibitors of kinases includes but not limited to ABL, ACK, AFK, AKT (AKT-1 for example, AKT-2 and AKT-3), ALK, AMP-PK, ATM, Aurora1, Aurora2, bARK1, bArk2, BLK, BMX, BTK, CAK, the CaM kinases, CDC2, CDK, CK, COT, CTD, DNA-PK, EGF-R, ErbB-1, ErbB-2, ErbB-3, ErbB-4, ERK (ERK1 for example, ERK2, ERK3, ERK4, ERK5, ERK6, ERK7), ERT-PK, FAK, FGR (FGF1R for example, FGF2R), FLT (FLT-I for example, FLT-2, FLT-3, FLT-4), FRK, FYN, GSK (GSK1 for example, GSK2, GSK3-α, GSK3-β, GSK4, GSK5), G-G-protein linked receptor kinases (GRKs), HCK, HER2, HKII, JAK (JAK1 for example, JAK2, JAK3, JAK4), JNK (JNK1 for example, JNK2, JNK3), KDR, KIT, the IGF-1 receptor, IKK-1, IKK-2, INSR (Insulin receptor INSR), IRAKI, IRAK2, IRK, ITK, LCK, LOK, LYN, MAPK, MAPKAPK-1, MAPKAPK-2, MEK, MET, MFPK, MHCK, MLCK, MLK3, NEU, NIK, pdgf receptor α, pdgf receptor β, PHK, the PI-3 kinases, PKA, PKB, PKC, PKG, PRK1, PYK2, the p38 kinases, P135tyk2, P34cdc2, p42cdc2, p42mapk, p44mpk, RAF, RET, RIP, RIP-2, RK, RON, the RS kinases, SRC, SYK, S6K, TAK1, TEC, TIE1, TIE2, TRKA, TXK, TYK2, UL13, VEGFR1, VEGFR2, YES, YRK, the inhibitor of ZAP-70 and these kinase whose all hypotypes (referring to, for example, Hardie and Hanks (1995) The Protein KinaseFacts Book (protein kinase practical work volume), I and II, Academic Press, San Diego, Calif.).
Chemical compound of the present invention can also use with one or more angiogenesis inhibitors, such as but not limited to: angiostatin (plasminogen fragment), the angiogenesis inhibitor Antithrombin III, Angiozyme, ABT-627, Bay 12-9566, Benefin, bevacizumab, BMS-275291, the cartilage inhibitor (CDI) of deriving, CAI, the complementary fragment of CD59, CEP-7055, Col3, combretastatin A-4, Endostatin (collagen XVIII fragment), CH-296, Gro-β, halofuginone hydrobromide, heparitinase, heparin hexose fragment, HMV833, human chorionic gonadotropin (hCG), IM-862, interferon-ALPHA/β/γ, interferon-induced albumen (IP-IO), il-1 2, Kringle 5 (plasminogen fragment), marimastat, inhibitors of metalloproteinase (TIMPs), the 2-methoxyestradiol, MMI 270 (CGS 27023A), MoAbIMC-1 C11, Neovastat, NM-3, Panzem, PI-88, placental ribonuclease inhibitor, plasminogen activator, PF4 (PF4), the prinomastat, prolactin antagonist 16kD fragment, proliferin associated protein (PRP), PTK 787/ZK 222594, retinoid, solimastat, Squalamine, SS 3304, SU 5416, SU6668, SU11248, tetrahydrocortisol-S, tetrathiomolybdate, Thalidomide, thrombospondin-1 (TSP-1), TNP-470, transforming growth factor-beta (TGF-), angiostatin (Vasculostatin), blood vessel inhibitive factor (Vasostatin) (calprotectin fragment), ZD6126, ZD 6474, farnesyl transferase inhibitor (FTI) and diphosphate.
The present invention has also designed pharmaceutical composition, and it comprises drug acceptable salt and as the compound or its salt of the novelty of the present invention as mentioned above of active component.Preferably, in described pharmaceutical composition, described active component is carried with any acceptable tablet or capsule form, perhaps is dissolved in aqueous or the lipid carrier.In addition, according to the preferred embodiments of the invention, described compositions also comprises at least a other chemotherapeutics.
The present invention also provides the method that reduces the mammalian cancer cells growth in addition, comprises compounds described herein of the present invention or its salt to cancerous cell application of treatment effective dose.
In addition, the invention provides the method for treatment mammalian cancer, comprise giving pharmaceutical composition that this pharmaceutical composition contains as the compounds described herein of the present invention of the treatment effective dose of active component or its salt mammalian subject.
About cancerous cell, term " growth reduces " refers to the reduction of at least a following situation in the present invention: compared with the control, cell number (because cell death, this death can be downright bad, apoptosis or the cell death of any other type or their combination); The reduction of the cell speed of growth, promptly total cellular score can increase, but compared with the control, increases with low-level or low rate; The invasive reduction of cell compared with the control (for example determining) by soft agar mensuration, even their sum does not change; From the cell type of differentiation more to the progress of the lower cell type of differentiation degree; The deceleration of tumour progression; Perhaps show cancerous cell slowing down from downward stage progress of a stage.
Growth of cancer cells reduces can be used for treating cancer, by the individuality of the described treatment of needs being treated the The compounds of this invention described herein of effective dose.
The invention also discloses the purposes of compositions of the present invention as mentioned above in the medicine of preparation treatment mammalian cancer.
Term " treatment for cancer " comprises at least a following situation in the present invention: the reduction of growth of cancers speed (be that cancer is still grown, but to grow than low rate); The growth of cancerous growths stops, i.e. the stagnation of tumor growth, and in preferable case, tumor diminishes or size reduces.The decreased number, cancer that this term also comprises the minimizing of metastatic tumor number, the new metastatic tumor that forms from a stage to another stage advance slow down and by the minimizing of the inductive angiogenesis of cancer.In most preferred situation, tumor is removed fully.This term also comprises the survival period that prolongs the individuality of receiving treatment.This term comprises that also prevention situation or those are easy to the prevention of the individuality of infected tumor.The administration of The compounds of this invention will reduce the described individual probability that infects described disease.In preferred situation, the individuality of accepting described compound administration does not infect described disease.
Term " cancer " comprises all types of tumors in all sources in the present invention, and no matter its form is entity tumor or non-entity tumor, and comprises virulent and benign morbid state and their transfer.Particularly, this term refers to: cancer, sarcoma, adenoma, hepatocarcinoma, hepatoblastoma, rhabdomyoblastoma, esophageal carcinoma, thyroid carcinoma, the neuroganglion blastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, ewing's tumor, leiomyosarcoma, rhabdotheliosarcoma, colon cancer, cancer of pancreas, breast carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hematoma, cancer of biliary duct, melanoma, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, neck cancer, testicular tumor, pulmonary carcinoma, minicell and nonsmall-cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, multiple myeloma, rectal cancer, thyroid cancer, head and neck cancer, the brain cancer, the cancer of peripheral nervous system, central nervous system's cancer, nerve metrocyte carcinoma, endometrial cancer, the bone marrow lymphoma, leukemia, lymphoma, the lymphocytic hyperplasia disease, acute myelocytic leukemia, chronic leukemia, Hodgkin lymphoma, the metastatic tumor of non-Hodgkin lymphoma and above-mentioned all tumors.
More preferably, described cancer is selected from carcinoma of prostate, breast carcinoma, skin carcinoma, colon cancer, pulmonary carcinoma and cancer of pancreas.
In other embodiment of preparation medicinal usage, described medicine also comprises at least a active chemotherapeutics except that The compounds of this invention.In certain embodiments, the chemical compound of novelty of the present invention can be with effectively but traditional chemotherapeutics administration of suitable side effect is arranged.Therefore uniting of The compounds of this invention and conventional medicament makes it possible to give more a spot of conventional medicament, and the side effect of object experience can significantly reduce and still reaches enough chemotherapy effects.Preferred other active chemotherapeutics includes but not limited to paclitaxel or amycin.
The invention also discloses the method for treatment mammalian cancer, it comprises treats the effective dose of medicine compositions to mammal, and it comprises the invention described above chemical compound as active component.In addition, in the preferred embodiment of this method, described chemical compound is with the dosed administration of 1 μ g-1000mg/kg body weight.
The present invention also provides the pharmaceutical composition that is used for the treatment of mammalian cancer, and it comprises the invention described above chemical compound as active component for the treatment of effective dose.
The present invention also provides the pharmaceutical composition that is used for the treatment of mammalian cancer, and it comprises the The compounds of this invention and the drug acceptable salt of the treatment effective dose as active component as described herein.
Term " medicine is acceptable " refers to by the administrative organization of federation or state government approval or is listed in the American Pharmacopeia or other is generally acknowledged and can be used in animal, and more specifically, can be used in the people.
Term " carrier " refers to diluent, adjuvant, excipient or the carrier with the administration of treatment chemical compound.Such pharmaceutical carrier can be a sterilized liquid, and for example water and oil comprise those oil in oil, animal, plant or synthetic source, for example Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods, Polyethylene Glycol, glycerol, propylene glycol or other synthetic.When intravenous gave pharmaceutical composition, water was preferred carrier.Saline solution and D/W and glycerite also can be used as liquid-carrier, especially for injection solution.The drug excipient that is fit to comprises starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Talcum, sodium chloride, drying defatted breast, glycerol, propylene glycol, water, ethanol, cyclodextrin etc.
If desired, described compositions can also contain a spot of wetting agent or emulsifying agent, or such as pH buffer agents such as acetic acid, citric acid or phosphoric acid.Also considered antibacterial agent, for example benzylalcohol or methyl parahydroxybenzoate; Antioxidant, for example ascorbic acid or sodium bisulfate; Chelating agen is ethylenediaminetetraacetic acid for example; And the reagent of adjustment of tonicity, for example sodium chloride or glucose.
Described compositions can adopt forms such as solution, suspensoid, Emulsion, tablet, pill, capsule, powder, slow releasing preparation.Use traditional binding agent and carrier, for example triglyceride, avicel cellulose, Tragacanth or gelatin can be suppository with described chemical compound prescription.Oral formulations can comprise standard vector, for example the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate etc.The example of the pharmaceutical carrier that is fit to has been described in " Remington ' sPharmaceutical Sciences (Lei Mingdun pharmacopedics) " of E.W.Martin.Such compositions contains the The compounds of this invention for the treatment of effective dose and the carrier of proper content, so that the form to the suitable administration of individuality is provided, and the preferred pure basically form of described The compounds of this invention.
Sometimes can select carrier according to the needs form of preparation.Sometimes carrier can also have and improves described active component and carry or the effect of infiltration to target tissue, is used to improve stability of drug, the clearance rate that is used to slow down, the character that is used to give slowly to discharge, is used to reduce undesirable side effect etc.Carrier can also be the material (for example antiseptic) of stabilization formulations, so that provide edible taste etc. for preparation.
Carrier can be any conventional those that use, and only is subjected to the restriction of chemicophysical Consideration and route of administration, and described chemicophysical Consideration is the reactivity of dissolubility and shortage and The compounds of this invention for example.Determine the selection of carrier according to the ad hoc approach that is used for giving described pharmaceutical composition.Therefore, carrier can comprise the carrier that additive, coloring agent, diluent, buffer agent, disintegrating agent, wetting agent, antiseptic, correctives and pharmacy are compatible.In addition, carrier can be an adjuvant, and according to definition, adjuvant is the material that influences the active component effect in measurable mode.
The method that introducing comprises the pharmaceutical composition of The compounds of this invention includes but not limited to part, Intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, eye and oral route.Can give described chemical compound by any approach easily,, absorb (for example oral mucosa, rectum and intestinal mucosa etc.) by last leather sheet for example by infusion or inject, and can be with other therapeutic activity agent administration.Topical is preferred, but administration can be a whole body.In addition, can expect to introduce pharmaceutical composition of the present invention by any suitable approach to the central nervous system, described suitable approach comprises in the ventricle and intrathecal injection; Can help injection, for example conduit that is connected with liquid reservoir in the ventricle by the ventricle inner catheter.Can also carry out pulmonary administration, for example by use inhaler or aerosol apparatus, and the preparation that has the aerosolization agent.
Can expect to give pharmaceutical composition of the present invention partly to the zone of needs treatment; This can pass through such as but not limited to perioperative local infusion, topical application, for example with postoperative wound dressing, by injection, by conduit, realize that by suppository or by implant described implant is porous, non-porous or gelatinous material.According to some preferred embodiment, can carry out administration by tissue place direct injection before tumor or tumor tissue or tumor.
Suitable pharmaceutical composition for oral administration can be made up of following: (a) liquid solution, and wherein the active substance of effective dose is dissolved in such as in the diluent such as water, saline, natural fruit juice, alcoholic drink, syrup; (b) solid dosage forms, for example capsule (for example containing common duricrust or soft-shelled gelatin such as surfactant, lubricant and inert filler), tablet, lozenge (wherein for example use sucrose and Radix Acaciae senegalis or Tragacanth with the active substance flavoring, perhaps active substance is arranged in inert base, for example gelatin and glycerol) and dragee, each all contains the solid or the graininess active component of predetermined close; (c) powder agent; (d) suspensoid in the suitable liquid; (e) suitable Emulsion; (f) Liposomal formulation; And other preparation.
In another embodiment, prepare compositions to be used for topical, for example, as ointment, gel, drop or ointment.For example ointment, gel, drop, ointment etc. are to the body surface topical in order to use, and can and be applied in the physiology that contains or do not contain pharmaceutical carrier with the The compounds of this invention preparation can accept in the diluent.Can the part or transdermal use the present invention to treat cancer, melanoma for example.The adjuvant that is used for part or gel-type vehicle form can comprise for example sodium carboxymethyl cellulose, polyacrylate, polyethylene glycol oxide-polypropylene oxide block polymer, Polyethylene Glycol and haze tallow alcohols (wood wax alcohols).
For direct inner topical application, described pharmaceutical composition can be the form of tablet or capsule, and it can contain the chemical compound of any following ingredients or similar quality: binding agent, for example avicel cellulose, Tragacanth or gelatin; Excipient, for example starch or lactose; Disintegrating agent, for example alginic acid, Primogel or corn starch; Lubricant, for example magnesium stearate or Sterotes; Or fluidizer, for example silica sol.When dosage unit form was capsule, except that the material of the above-mentioned type, it can contain liquid-carrier, for example fatty oil.In addition, dosage unit form can contain the various other materials of the physical form of the dosage unit that changes, for example, and the coating of sugar, lac or other enteric agents.
Can in controlled release system, carry The compounds of this invention.In one embodiment, can use infusion pump to give The compounds of this invention, for example a kind of being used for carries the infusion pump of insulin or chemotherapy (referring to Buchwald et al., 1980, Surgery 88:507 to certain organs or tumor; Saudek et al., 1989, N.Engl, J.Med.321:574).In a preferred form, with The compounds of this invention and polymeric implants administration together biodegradable, bio-compatible, this implant discharges described chemical compound in the period of control in selected site.The example of preferred polymer materials comprises that poly-anhydride, poe, polyglycolic acid, polylactic acid, plastic of poly vinyl acetate, their copolymer and mixture are (referring to Medical applications of controlled release (medical applications of controlled release), Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, FIa.).In another embodiment, controlled release system can be placed on therapeutic goal near, therefore only require the part of whole-body dose.
Sometimes, described reactive compound can be made into aerosol formulations to pass through inhalation.These aerosol formulations can be placed in the acceptable propellant of compression, for example propane, butane, nitrogen etc.They can also be formulated into the medicine that is used for non-compressed preparation, for example are used in aerosol apparatus or the nebulizer.
In addition, sometimes, described pharmaceutical composition can be formulated into and be used for parenteral (subcutaneous, intravenous, intra-arterial or intramuscular injection) and can comprise aqueous and nonaqueous, isoosmotic aseptic injectable solution and aqueous and nonaqueous aseptic suspensoid, described aseptic injectable solution can contain antioxidant, buffer, antibacterial and give said preparation and the isoosmotic solute of the blood of intended recipient, and described aseptic suspensoid comprises suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic.Such as oil, animal oil, vegetable oil or synthetic wet goods oil with such as soaps such as fatty alkali metal, ammonium and triethanolamine salts, and suitable detergent also can be used to parenteral.Above-mentioned preparation can also be used to injection in the direct tumor.In addition, in order to minimize or eliminate the stimulation of injection site, described compositions can contain one or more non-ionic surface active agents.The surfactant that is fit to comprises the polyethylene sorbitan fatty ester, and dehydrating sorbitol monooleate and have the high molecular ethylene oxide adduct of hydrophobic group for example, this adduct are that the condensation by propylene oxide and propylene glycol forms.
Described parenteral administration can be contained in the sealed container of single dose or multiple dose, and for example ampoule and bottle, and can be stored under lyophilization (lyophilizing) condition are only required for example to add immediately before use that the sterile liquid carrier of water is used for injection.Can previously described and known tablet type prepare instant injection solution and suspension from sterilized powder, granule and this area.
The content that can effectively treat the The compounds of this invention of the particular disorder that comprises cancer or morbid state depends on the character of this disease or morbid state, and can determine by standard clinical techniques.In addition, can randomly use external test to help determine the optimal dose scope.The exact dose that is used in the preparation also depends on the order of severity of route of administration and described disease or disease, and should decide according to practitioner's judgement and each patient's situation.Preferred dose in the scope of 0.01-1000mg/kg body weight, more preferably 0.1mg/kg to 100mg/kg, and even more preferably 1mg/kg to 10mg/kg.Can obtain effective agent dose from the dose-effect curve extrapolation that is derived from external or animal model test bioanalysis or system.
" therapeutic " treatment is in order to reduce or to eliminate the pathology sign, the treatment that the individuality with those diseases is given." the treatment effective dose " of The compounds of this invention is the dosage that is enough to provide to the individuality that is given described chemical compound the chemical compound of beneficial effect.
Need the patient of described treatment may suffer from for example disease of cancer, perhaps may be determined these diseases of easier trouble.Therefore, Therapeutic Method according to the present invention comprises treatment and prophylactic applications.
Can measure the expectation treatment or the prophylactic activity of The compounds of this invention and determine the treatment effective dose in the body.For example, can test these chemical compounds in suitable animal model system before the human test, described animal model system includes but not limited to rat, mice, chicken, cow, monkey, rabbit etc.For to the body build-in test before the human administration, can use any animal model system known in the art.
When above-claimed cpd comprised one or more chiral centre, the spatial chemistry of these chiral centres can be R or S conformation independently, or the mixture of the two.Described chiral centre can further be named as R or S or R, S or d, D, 1, L or d, 1, D, L.
About chemical compound as herein described, the suffix " ene " that adds any described term to refers to that substituent two parts link to each other (unless this substituent group only contains a carbon with two other parts in the chemical compound respectively, in the case, this carbon links to each other with two other parts in the chemical compound, for example, methylene).
Term " C 1-C 12Alkyl " be expressed as follows group: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, tertiary pentyl, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.Preferred " C 1-C 12Alkyl " group is methyl, ethyl, isobutyl group, sec-butyl and isopropyl.Similarly, " C 1-C 12Alkylidene " group of 1 to 12 carbon linking to each other with two other parts in the chemical compound of expression.
Term " C 2-C 12Thiazolinyl " be expressed as follows group: the diene and the triolefin of vinyl, pi-allyl, crotyl, 3-cyclobutenyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, (and being connected to octenyl, nonene base, decene base, hendecene base, laurylene base of any suitable carbon location etc.) and straight chain and side chain.
Term " C 1-C 12Alkynyl " be expressed as follows group: the diine and three alkynes of acetenyl, propinyl, 2-butyne base, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, (and being connected to octyne base, n-heptylacetylene base, decynyl, undecyne base, dodecyne base of any suitable carbon location etc.) and straight chain and side chain.
Term " C 1-C 12The alkyl that replaces ", " C 1-C 12The thiazolinyl that replaces " " C 1-C 12The alkynyl that replaces ", " C 1-C 12The alkylidene that replaces ", " C 2-C 12The alkenylene that replaces " and C 2-C 12The alkynylene that replaces " expression is by one or more, and the preferred group that replaces of one or two following group: the oxo of the hydroxyl of halogen, hydroxyl, protection, oxo, protection, C 3-C 7(mono-substituted) amino, (dibasic) amino, guanidine radicals, the guanidine radicals of protection, heterocycle, the heterocycle of replacement, imidazole radicals, indyl, pyrrolidinyl, the C of the amino of cycloalkyl, phenyl, naphthyl, amino, protection, (mono-substituted) amino, protection 1-C 12Alkoxyl, C 1-C 12Acyl group, C 1-C 12The Methanamide of the carboxyl of acyloxy, nitro, carboxyl, protection, carbamoyl, Methanamide, protection, N-(C 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, cyano group, mesyl amino, thiol, C 1-C 10Alkylthio or C 1-C 10The alkyl sulphonyl group.The alkyl group of described replacement can one or many, and is preferably replaced by identical or different substituent groups once or twice.The preferred replacement is halogen.
The carbon atom of term " oxo of protection " expression and two other carbon atom bonding that is replaced by two alkoxyls or with the carbon atom of the glycol moiety secondary bond that replaces, form acyclic or cyclic ketal part thus.
Term " C used herein 1-C 12Alkoxyl " the expression following groups: groups such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy for example.Preferred alkoxyl is a methoxyl group.Term " C 1-C 12The alkoxyl that replaces " refer to described alkoxyl moieties can with C 1-C 12The identical mode of alkyl that replaces is substituted.The preferred replacement is halogen.Similarly, term " C used herein 1-C 12The phenyl alkoxyl " refer to " C with the phenyl group bonding 1-C 12Alkoxyl ".
Term " C 1-C 12Acyloxy " represent in this article such as formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy, new pentane acyloxy, penta acyloxy, hexylyloxy, heptan acyloxy, hot acyloxy, the ninth of the ten Heavenly Stems acyloxy, last of the ten Heavenly stems group such as acyloxy, undecanoyl oxygen base, lauroyl oxygen base.
Similarly, term " C 1-C 12Acyl group " comprise such as groups such as formoxyl, acetyl group, propiono, bytyry, valeryl, valeryl, caproyl, heptanoyl group, caprylyl, pelargonyl group, capryl, undecanoyl, dodecanoyl, benzoyls.Preferred carboxyl groups is acetyl group and benzoyl.
Term " C 1-C 12The acyl group that replaces " expression is by one or more, and the preferred carboxyl groups that replaces of one or two following group: the amino of the oxo of the hydroxyl of halogen, hydroxyl, protection, oxo, protection, cyclohexyl, naphthyl, amino, protection, (mono-substituted) are amino, (mono-substituted) amino, (dibasic) amino, guanidine radicals, heterocycle, the heterocycle of replacement, imidazole radicals, indyl, pyrrolidinyl, the C of protection 1-C 12Alkoxyl, C 1-C 12Acyl group, C 1-C 12Acyloxy, nitro, C 1-C 12The Methanamide of the carboxyl of Arrcostab, carboxyl, protection, carbamoyl, Methanamide, protection, N-(C 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, cyano group, mesyl amino, thiol, C 1-C 10Alkylthio or C 1-C 10The alkyl sulphonyl group.The carboxyl groups of described replacement can one or repeatedly, and preferably replaced by identical or different substituent groups once or twice.
Substituent group term " C 3-C 7Cycloalkyl " comprise cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl ring.Similarly, can be " C 3-C 7Cycloalkyl " substituent group also can be " C 5-C 7Cycloalkyl ", it comprises cyclopenta, cyclohexyl or suberyl ring.
Substituent group term " C 3-C 7The cycloalkyl that replaces " or " C 5-C 7The cycloalkyl that replaces " show by the above-mentioned cycloalkyl ring of one or two following group replacement: the hydroxyl of halogen, hydroxyl, protection, C 1-C 10Alkylthio, C 1-C 10Alkyl sulfoxide, C 1-C 10Alkyl sulphonyl, C 1-C 10The alkylthio, the C that replace 1-C 10The alkyl sulfoxide, the C that replace 1-C 10The alkyl sulphonyl, the C that replace 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkyl, the C that replace 1-C 12The amino group of the phenyl of the carboxyl of the oxo of alkoxyl, oxo, protection, (mono-substituted) amino, (dibasic) amino, trifluoromethyl, carboxyl, protection, phenyl, replacement, phenyl sulfo-, phenyl sulfoxide, phenyl sulfonyl, amino or protection.
Term " ring alkylidene " refers to cycloalkyl as defined above, and wherein this group of naphthene base connects two other independent groups at two position bondings.Similarly, term " the ring alkylidene of replacement " finger ring alkylidene, wherein this group of naphthene base connects two other independent groups and has at least one other substituent group at two position bondings.
Term " C 5-C 7Cycloalkenyl group " expression 1-, 2-or 3-cyclopentenes basic ring, 1-, 2-, 3-or 4-cyclohexene basic ring or 1-, 2-, 3-, 4-or 5-cycloheptene basic ring, and the term " C of replacement 5-C 7Cycloalkenyl group " represent by C 1-C 12The hydroxyl of alkyl group, halogen, hydroxyl, protection, C 1-C 12The above-mentioned C that amino replaced of phenyl, amino or the protection of (mono-substituted) amino of the oxo of the carboxyl of alkoxyl, trifluoromethyl, carboxyl, protection, oxo, protection, (mono-substituted) amino, protection, (dibasic) amino, phenyl, replacement 5-C 7The cyclenes basic ring.Term " C 5-C 7Inferior cycloalkenyl group " be cyclenes basic ring as defined above, wherein this cycloalkenyl groups connects two other independent groups at two position bondings.C 5-C 7The example of ring alkenylene comprises 1,3-cyclopentylene and 1,2-cyclohexylidene.
Similarly, the term " C of replacement 5-C 7Inferior cycloalkenyl group " refer to that inferior cycloalkenyl group is further by the hydroxyl of halogen, hydroxyl, protection, C 1-C 10Alkylthio, C 1-C 10Alkyl sulfoxide, C 1-C 10Alkyl sulphonyl, C 1-C 10The alkylthio, the C that replace 1-C 10The alkyl sulfoxide, the C that replace 1-C 10The alkyl sulphonyl, the C that replace 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkyl, the C that replace 1-C 12The amino group of the phenyl of the carboxyl of the oxo of alkoxyl, oxo, protection, (mono-substituted) amino, (dibasic) amino, trifluoromethyl, carboxyl, protection, phenyl, replacement, phenyl sulfo-, phenyl sulfoxide, phenyl sulfonyl, amino or protection replaces.
Term " heterocycle (heterocycle) " or " heterocycle (heterocyclic ring) " expression has five yuan of 1 to 4 heteroatomic any replacement to octatomic ring, described hetero atom is oxygen, sulfur and/or nitrogen for example, nitrogen particularly, itself or independent or with sulfur or the associating of oxygen annular atoms.Term " bicyclic heterocycle " refers to two mutual condensed rings.These five yuan to octatomic ring can be saturated, fully undersaturated or part is undersaturated, and saturated ring is preferred fully.Preferred heterocycle comprises morpholinyl, piperidyl, piperazinyl, 2-amino-imidazole radicals, tetrahydrofuran base, pyrrole radicals, tetrahydrochysene thiophenyl, hexyl methylene imine base and heptyl methylene imine base.
Term " heterocycle of replacement (substituted heterocycle) " or " heterocycle of replacement (substituted heterocyclic ring) " refer to that above-mentioned heterocycle or condensed pair of heterocycle are by for example one or more; and preferably one or two identical or different substituent groups replace, and described substituent group can be hydroxyl, cyano group, nitro, the C of halogen, hydroxyl, protection 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) heterocyclic group of amino, N-(phenyl sulfonyl) amino, heterocycle or replacement sulfonyl).
Term " heteroaryl " refers to the heteroaromatic derivant, and it is for having 1 to 4 heteroatomic five yuan or hexatomic ring system, and described hetero atom is oxygen, sulfur and/or nitrogen, particularly nitrogen for example, itself or independent or with sulfur or the associating of oxygen annular atoms.The example of heteroaryl comprises pyridine radicals, pyrimidine radicals and pyrazinyl, pyridazinyl, pyrrole radicals, furyl, oxazolyl, isoxazolyl, phthalimido, thiazolyl etc.
Term " heteroaryl of replacement " refers to above-mentioned heteroaryl by for example one or more, and preferably one or two identical or different substituent groups replace, and described substituent group can be hydroxyl, cyano group, nitro, the C of halogen, hydroxyl, protection 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12The acyl group, the C that replace 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) amino or N-(phenyl sulfonyl) amino group sulfonyl).
Term " C 7-C 18Phenylalkyl " be illustrated in the C that the optional position of alkane chain inside is replaced by phenyl 1-C 12Alkyl group.This definition comprises the group of following formula :-phenyl-alkyl ,-alkyl-phenyl and-alkyl-phenyl-alkyl.This class examples of groups comprises benzyl, 2-phenethyl, 3-phenyl (n-pro-pyl), 4-benzene hexyl, 3-phenyl (n-pentyl), 3-phenyl (sec-butyl) etc.Preferred C 7-C 18The phenylalkyl group is and the bonded arbitrary preferred alkyl group as herein described of phenyl group.
Similarly, term " C 1-C 12Heterocyclylalkyl " be illustrated in the optional position of alkane chain inside by the C of " heterocycle " replacement defined herein 1-C 12Alkyl group.This definition comprises the group of following formula :-heterocycle-alkyl ,-alkyl-heterocycle and-alkyl-heterocycle-alkyl.Preferred C 1-C 12Heterocycloalkyl is and the bonded arbitrary preferred alkyl group as herein described of arbitrary preferred heterocyclic group as herein described.
Term " C 7-C 18The phenylalkyl that replaces " and " C 1-C 12The Heterocyclylalkyl that replaces " refer to by one or more, and preferably one or two is selected from the C that following group replaces 7-C 18Phenylalkyl group or C 1-C 12Heterocyclylalkyl is (on alkyl; perhaps when suitable, on phenyl or heterocyclic moiety, replace): (mono-substituted) amino, (dibasic) amino, guanidine radicals, the guanidine radicals of protection, heterocycle, the heterocycle of replacement, the C of the amino of the oxo of the hydroxyl of halogen, hydroxyl, protection, oxo, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl, C 1-C 12The alkyl, the C that replace 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12The acyl group, the C that replace 1-C 12The Methanamide of the carboxyl of acyloxy, nitro, carboxyl, protection, carbamoyl, Methanamide, protection, N-(C 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Dialkyl group) Methanamide, cyano group, N-(C 1-C 12Alkyl sulphonyl) amino, thiol, C 1-C 10Alkylthio, C 1-C 10The alkyl sulphonyl group; And/or phenyl group can be by one or more, and preferably one or two is selected from following substituent group and replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 12Alkyl, C 1-C 12The alkyl, the C that replace 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12The acyl group, the C that replace 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) sulfonyl) amino, amino, the ring-type C of N-(phenyl sulfonyl) 2-C 12Alkylidene or phenyl group, wherein said phenyl are that replace or unsubstituted, thereby for example produce biphenyl.Alkyl, phenyl or the heterocyclic group that replaces can be by one or more, and preferably one or two, can be that identical or different substituent groups replaces.
Term " C 7-C 18The phenyl alkylidene " refer to C as defined above 7-C 18Phenylalkyl, wherein this phenylalkyl group connects two other independent groups at two diverse location bondings.Described definition comprises the group of following formula :-phenyl-alkyl-,-alkyl-phenyl-and-alkyl-phenyl-alkyl-.Replacement on the phenyl ring can be 1,2,1,3 or 1,4.C 7-C 18The phenyl alkylidene for example comprises 1,4-benzal and 1,3-xylylene.
Similarly, term " C 1-C 12Inferior Heterocyclylalkyl " refer to C as defined above 1-C 12Heterocyclylalkyl, wherein this heterocycloalkyl connects two other independent groups at two diverse location bondings.Described definition comprises the group of following formula :-heterocycle-alkyl-,-alkyl-heterocycle and-alkyl-heterocycle-alkyl-.
Term " C 7-C 18The phenyl alkylidene that replaces " and " C 1-C 12The inferior Heterocyclylalkyl that replaces " refer on the phenyl ring or the C as defined above that is further replaced by following groups on the alkyl group 7-C 18Phenyl alkylidene or C 1-C 12Inferior Heterocyclylalkyl: the hydroxyl of halogen, hydroxyl, protection, C 1-C 10Alkylthio, C 1-C 10Alkyl sulfoxide, C 1-C 10Alkyl sulphonyl, C 1-C 10The alkylthio, the C that replace 1-C 10The alkyl sulfoxide, the C that replace 1-C 10The alkyl sulphonyl, the C that replace 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkyl, the C that replace 1-C 12The amino group of the phenyl of the carboxyl of the oxo of alkoxyl, oxo, protection, (mono-substituted) amino, (dibasic) amino, trifluoromethyl, carboxyl, protection, phenyl, replacement, phenyl sulfo-, phenyl sulfoxide, phenyl sulphonyl, amino or protection.
Term " phenyl of replacement " refers to by one or more, and preferably one or two is selected from the phenyl group that following groups replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 12Alkyl, C 1-C 12The alkyl, the C that replace 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12The acyl group, the C that replace 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) sulfonyl) amino, N-(phenyl sulfonyl) amino or phenyl, wherein said phenyl are that replace or unsubstituted, thereby for example produce biphenyl.
The phenyl of term " phenoxy group " expression and oxygen atom bonding is wherein by the bonding of this oxygen atom realization with these molecule other parts.Term " phenoxy group of replacement " refers to by one or more, and preferably one or two is selected from the phenoxy group group that following groups replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) amino and N-(phenyl sulfonyl) amino sulfonyl).
Term " aryl " refers to have the aromatic group of at least one carbocyclic ring aromatic group or heteroaromatic group, and it can be unsubstituted or is selected from following group and replace by one or more: halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amide groups, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkyl amino, dialkyl amido, carboxyl or sulfo-or alkylthio.The limiting examples of aromatic ring is phenyl, naphthyl, pyranose, pyrrole radicals, pyrazinyl, pyrimidine radicals, pyrazolyl, pyridine radicals, furyl, sulfur phenenyl, thiazolyl, imidazole radicals, isoxazolyl etc.Term " aryloxy group " refers to " aryl " group with the oxygen atom bonding, wherein by the bonding of this oxygen atom realization with these molecule other parts.
Term " C 7-C 18The phenyl alkoxyl that replaces " C of other parts by the oxygen atom bonding of expression and this molecule 7-C 18The phenyl alkoxy base; wherein phenylalkyl part is by one or more, and preferably one or two is selected from following group and replaces: the amino of the oxo of the hydroxyl of halogen, hydroxyl, protection, oxo, protection, amino, protection, (mono-substituted) are amino, (mono-substituted) amino, (dibasic) amino, guanidine radicals, heterocycle, the heterocycle of replacement, the C of protection 1-C 12Alkoxyl, C 1-C 12Acyl group, C 1-C 12The Methanamide of the carboxyl of acyloxy, nitro, carboxyl, protection, carbamoyl, Methanamide, protection, N-(C 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-(C 1-C 12Dialkyl group) Methanamide, cyano group, N-(C 1-C 12Alkyl sulphonyl) amino, thiol, C 1-C 10Alkylthio, C 1-C 10The alkyl sulphonyl group; And/or described phenyl group can be by one or more, and preferably one or two is selected from following substituent group and replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12Acyl group, C 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methyl of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) sulfonyl) amino, N-(phenyl sulfonyl) amino or phenyl group, wherein said phenyl are that replace or unsubstituted, thereby for example produce xenyl.The alkyl or phenyl group that replaces can be by one or more, and preferably one or two can be that identical or different substituent groups replaces.
Term " phthalimide " refers to by phthalic acid, is also referred to as 1, the ring-type imidodicarbonic diamide of 2-phthalic acid preparation.Term " phthalimide of replacement " refers to by one or more, and preferably one or two is selected from the phthalimidyl group that following groups replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkoxyl, the C that replace 1-C 12Acyl group, C 1-C 12(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) amino and N-(phenyl sulfonyl) amino sulfonyl).
Term " naphthyl of replacement " refers on identical or different rings by one or more, and preferably one or two is selected from the naphthyl group that following groups replaces: the hydroxyl of halogen, hydroxyl, protection, cyano group, nitro, C 1-C 6Alkyl, C 1-C 7Alkoxyl, C 1-C 7Acyl group, C 1-C 7(mono-substituted) amino, (dibasic) amino, Methanamide, the Methanamide of protection, the N-(C of the amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (mono-substituted) amino, protection 1-C 12Alkyl) N-(C of Methanamide, protection 1-C 12Alkyl) Methanamide, N, N-two (C 1-C 12Alkyl) Methanamide, trifluoromethyl, N-((C 1-C 12Alkyl) amino or N-(phenyl sulfonyl) amino sulfonyl).And dibasic naphthyl group represented in term " naphthyl of replacement ", and wherein said substituent group is different.
Term " naphthylene " refers to naphthyl group at two position bondings, connects two other independent groups.Similarly, term " naphthylene of replacement " refers to by the further naphthylene group that replaces of following groups: the hydroxyl of halogen, hydroxyl, protection, C 1-C 10Alkylthio, C 1-C 10Alkyl sulfoxide, C 1-C 10Alkyl sulphonyl, C 1-C 10The alkylthio, the C that replace 1-C 10The alkyl sulfoxide, the C that replace 1-C 10The alkyl sulphonyl, the C that replace 1-C 12Alkyl, C 1-C 12Alkoxyl, C 1-C 12The alkyl, the C that replace 1-C 12The amino of the phenyl of the carboxyl of the oxo of alkoxyl, oxo, protection, (mono-substituted) amino, (dibasic) amino, trifluoromethyl, carboxyl, protection, phenyl, replacement, phenyl sulfo-, phenyl sulfoxide, phenyl sulfonyl, amino or protection.
Term " halogen (halo) " and " halogen (halogen) " refer to fluorine, chlorine, bromine or iodine atom.One or more identical or different halogens can be arranged.
Term " (mono-substituted) amino " refers to have one and is selected from following substituent amino group: the phenyl of phenyl, replacement, C 1-C 12Alkyl, C 1-C 12The alkyl, the C that replace 1-C 12Acyl group, C 1-C 12The acyl group, the C that replace 2-C 12Thiazolinyl, C 2-C 12The thiazolinyl, the C that replace 2-C 12Alkynyl, C 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl, C 7-C 18The phenylalkyl, heterocycle, the heterocycle of replacement, the C that replace 1-C 12Heterocyclylalkyl and C 1-C 12The Heterocyclylalkyl that replaces.(mono-substituted) amino can have other amido protecting group, as term " (mono-substituted) amino of protection " is included.
Term " (dibasic) amino " refers to have two and is selected from following substituent amino group: the phenyl of phenyl, replacement, C 1-C 12Alkyl, C 1-C 12The alkyl, the C that replace 1-C 12Acyl group, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 7-C 18Phenylalkyl, C 7-C 18The phenylalkyl, the C that replace 1-C 12Heterocyclylalkyl and C 1-C 12The Heterocyclylalkyl that replaces.Described two substituent groups can be identical or different.
Term used herein " amino protecting group " refers to be commonly used to stop or protect the substituent group of the amino group of amido functional group when with other functional group reactions of this molecule.Term " (mono-substituted) amino of protection " refers on the nitrogen-atoms of mono-substituted amino amino protecting group is arranged.In addition, term " Methanamide of protection " refers on the nitrogen-atoms of Methanamide amino protecting group is arranged.Similarly, the term " N-(C of protection 1-C 12Alkyl) Methanamide " refer on the nitrogen-atoms of Methanamide, amino protecting group is arranged.
The kind of employed amino protecting group is unimportant, as long as deutero-amino group is stable for the subsequent reaction condition and can be removed in due course and destroy the other parts of this chemical compound.Preferred amino protecting group is Boc, Cbz and Fmoc.Other example of the amino protecting group that above-mentioned definition comprises is known in organic synthesis and peptide field; and at for example T.W.Greene and RGM.Wuts, " Protective Groups in OrganicSynthesis (protecting group in the organic synthesis), " 2nd ed.; John Wiley and Sons; NewYork, NY, 1991; the 7th chapter; M.Bodanzsky, " Principles of Peptide Synthesis (peptide composition principle), " 1st and 2nd revised ed.; Springer-Verlag; New York, NY, 1984 and 1993; and Stewart and Young; " Solid Phase Peptide Synthesis (solid-phase peptide is synthetic), " 2nd ed., Pierce Chemical Co.; Rockford; IL has description in 1984, incorporates its full content in this mode by reference.Relational language " amino of protection " has defined the amino group that is replaced by above-mentioned amino protecting group.
Term used herein " guanidine radicals of protection " refers to " amino protecting group " on one or two guanidine radicals nitrogen-atoms.Above-mentioned TW.Greene and RGM.Wuts; M.Bodanzsky and Stewart and Young have described " guanidine radicals of protection " examples of groups.
Term " epimino " refers to-NH-.Term " epimino of replacement " refer to-N (R)-, wherein R be listed in " (mono-substituted) amino " definition in substituted radical.
Term " C 1-C 5The alkylidene epimino " refer on any point of chain, have the alkylidene chain with 1 to 5 carbon of epimino.Term " C 1-C 5The alkylidene epimino that replaces " refer to C 1-C 5Alkylidene epimino group a) in the epimino position (with above-mentioned " epimino of replacement " identical mode); And/or b) in one or more alkylidenes position (with above-mentioned " alkylidene of replacement " identical mode) be substituted.
Term " sulfo-" refers to-SH, if perhaps between two other groups, refers to-S-.Term " C 1-C 10The alkylidene sulfo-" refer on any point of chain, have the alkylidene chain with 1 to 10 carbon of sulfo-.Term " C 1-C 10The alkylidene sulfo-that replaces " refer to be substituted in one or more alkylidenes position (with above-mentioned " alkylidene of replacement " identical mode) C 1-C 10The alkylidene thio group.
Term " sulfonyl " refers to-S (O) 2-.Term " C 1-C 10The alkylidene sulfonyl " refer on any point of chain, have the alkylidene chain with 1 to 10 carbon of sulfonyl.Term " C 1-C 10The alkylidene sulfonyl that replaces " refer to be substituted in one or more alkylidenes position (with above-mentioned " alkylidene of replacement " identical mode) C 1-C 10Alkylidene sulfonyl group.
Term " sulfinyl " refers to-S (O)-.Term " C 1-C 10The alkylidene sulfinyl " refer on any point of chain, have the alkylidene chain with 1 to 10 carbon of sulfinyl.Term " C 1-C 10The alkylidene sulfinyl that replaces " refer to be substituted in one or more alkylidenes position (with above-mentioned " alkylidene of replacement " identical mode) C 1-C 10Alkylidene sulfinyl group.
Term " oxygen base " refers to-O-.Term " C 1-C 10Alkylidene oxygen base ", " C 1-C 10Alkylenedioxy group " and " C 1-C 10Alkylidene three oxygen bases " refer on any point of chain, to have respectively the alkylidene chain of 1,2 or 3-O-with 1 to 10 carbon, condition be do not have two oxygen atoms be successive and any two oxygen atoms all separately by at least two carbon.Term " C 1-C 10The alkylidene oxygen base that replaces ", " C 1-C 10The alkylenedioxy group that replaces " and " C 1-C 10The alkylidene three oxygen bases that replace " refer to respectively to be substituted in one or more alkylidenes position (with above-mentioned " alkylidene of replacement " identical mode) " C 1-C 10Alkylidene oxygen base ", " C 1-C 10Alkylenedioxy group " and " C 1-C 10Alkylidene three oxygen bases ".
Term " thiocarbonyl " refers to-C (S) H, if perhaps between two other groups, refer to-C (S)-.Term " monothioester " refers to-C (O) SH, if perhaps between two other groups, refers to-C (O) S-.
Term used herein " carboxyl-protecting group " refers to one of ester derivant of hydroxy-acid group, is used for usually stoping when reacting in other functional group at this chemical compound or the protection hydroxy-acid group.The example of these groups can be at E.Haslam; " Protective Groups in OrganicChemistry (protecting group in the organic chemistry); " J.G.W.McOmie; Ed., Plenum Press, New York; NY; 1973, the 5 chapters, and T.W.Greene and P.G.M.Wuts; " Protective Groups in Organic Synthesis (protecting group in the organic synthesis); " 2nded., John Wiley and Sons, New York; NY; find in 1991, the 5 chapters, incorporate its full content in this mode by reference.Relational language is " carboxyl of protection ", the carboxylic group that its expression is replaced by an above-mentioned carboxyl-protecting group.
Term " hydroxyl protecting group " refers to the group that is easy to slough with the oh group bonding.The kind of hydroxyl protecting group is inessential, as long as deutero-oh group is stable for the subsequent reaction condition and can be removed in due course and destroy the other parts of this molecule.CB.Reese and E.Haslam; " Protective Groups in Organic Chemistry (protecting group in the organic chemistry); " J.G.W.McOmie; Ed.; Plenum Press, New York, NY; 1973; the 3rd Zhanghe the 4th chapter, and T.W.Greene and P.G.M.Wuts, " ProtectiveGroups in Organic Synthesis (protecting group in the organic synthesis); " 2nd ed.; JohnWiley and Sons, New York, NY; 1991, the 2 Zhanghe the 3rd chapter has been described the example of hydroxyl protecting group respectively.Relational language is " hydroxyl of protection " and " methylol of protection ", hydroxyl or methylol that its expression is replaced by an above-mentioned hydroxyl protecting group.
Term " C 1-C 10Alkylthio " refer to sulfide group, groups such as methyl mercapto, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, uncle's butylthio for example.
Term " C 1-C 10Alkyl sulfoxide " expression sulfoxide radicals, for example methyl sulfoxide, ethyl-sulfoxide, n-pro-pyl sulfoxide, isopropyl sulfoxide, butyl sulphoxide, sec-butyl sulfoxide etc.Term " C 1-C 10Alkyl sulphonyl " comprise such as groups such as methyl sulphonyl, ethylsulfonyl, n-pro-pyl sulfonyl, isopropyl sulfonyl, normal-butyl sulfonyl, tert-butyl group sulfonyls; it should also be understood that above-mentioned sulfo-, sulfoxide or sulfonyl group can be positioned at any point of alkyl chain (for example, 2-methyl mercapto ethyl).
Term " C 1-C 10The alkylthio that replaces ", C 1-C 10The alkyl sulfoxide that replaces " and " C 1-C 10The alkyl sulphonyl that replaces " represent that the moieties of these groups can be as being substituted as described in " alkyl of replacement ".
Term " phenyl sulfo-", " phenyl sulfoxide " and " phenyl sulfonyl " are specified thiol, sulfoxide or the sulfone that contains phenyl group respectively.Term " the phenyl sulfo-of replacement ", " the phenyl sulfoxide of replacement " and " phenyl sulfonyl of replacement " refer to that the phenyl of these groups can be as being substituted as described in " phenyl of replacement ".
Term " C 1-C 12The alkyl formamides base " refer to the C that links to each other with the nitrogen of formamido group 1-C 12Alkyl.C 1-C 12The example of alkyl formamides base comprises methylformamide base, ethyl-formamide base, propyl group formamido and butyl formamido.Term " C 1-C 12The alkyl formamides base that replaces " alkyl of expression and the replacement of the nitrogen bonding of formamido group, this alkyl can be as " C 1-C 12The alkyl that replaces " described being substituted.
Term " C 1-C 12Alkoxy carbonyl " refer to be connected to " the C of carbonyl group 1-C 12Alkoxyl " group.Term " C 1-C 12The alkoxy carbonyl that replaces " refer to and the substituted alkoxy of carbonyl group bonding that this alkoxyl can be as " C 1-C 12The alkyl that replaces " described being substituted.
Term " phenyl formamide base " refers to the phenyl that links to each other with the nitrogen of formamido group.The substituted alkyl of the nitrogen bonding of term " the phenyl formamide base of replacement " expression and formamido group, this phenyl can be substituted as described in " phenyl of replacement ".
Term " C 1-C 12Thio-alkyl amino-carbonyl " refer to the C that links to each other with amino thiocarbonyl group 1-C 12Alkyl, wherein said alkyl have the implication identical with above-mentioned definition.
Term " C 1-C 12The thio-alkyl amino-carbonyl that replaces " refer to and the substituted alkyl of amino thiocarbonyl group bonding that wherein said alkyl can be as " C 1-C 12The alkyl that replaces " described being substituted.
Term " phenyl amino thiocarbonyl " refers to the phenyl that links to each other with amino thiocarbonyl group, and wherein said phenyl has the implication identical with above-mentioned definition.
Term " the phenyl amino thiocarbonyl of replacement " refers to and the substituted-phenyl of amino thiocarbonyl group bonding that wherein said phenyl can be substituted as described in " phenyl of replacement ".
Term " phenylene " refers to phenyl group, and wherein this phenyl connects two other independent groups at two position bondings.
Term " phenylene of replacement " refers to phenyl group, and wherein this phenyl group connects two other independent groups at two position bondings, and wherein this phenyl is substituted as described in " phenyl of replacement ".
Term " the C of replacement 1-C 12Alkylidene " refer to C 1-C 12Alkyl group, wherein this alkyl group connects two other independent groups, and has other substituent group at two position bondings.
Term " ring-type C 2-C 7Alkylidene ", " the ring-type C of replacement 2-C 7Alkylidene ", " ring-type C 2-C 7Assorted alkylidene " and " the ring-type C of replacement 2-C 7Assorted alkylidene " definition and phenyl group bonding (" condensing ") produce the cyclic group of bicyclic system.Described cyclic group can be saturated or contain one or two pair key.In addition, this cyclic group can have one or two methylene or the methine that is replaced by one or two oxygen, nitrogen or sulphur atom, and it is ring-type C 2-C 7Assorted alkylidene.
The assorted alkylidene group of cyclic alkylidene or ring-type can be replaced once or twice by identical or different substituent groups; if suitably; described substituent group can be connected to another part (for example alkylidene) of this chemical compound, and described substituent group is selected from by following part: the oxo of the carboxyl of the hydroxyl of hydroxyl, protection, carboxyl, protection, oxo, protection, C 1-C 4Acyloxy, formoxyl, C 1-C 12Acyl group, C 1-C 12Alkyl, C 1-C 7Alkoxyl, C 1-C 10Alkylthio, C 1-C 10Alkyl sulfoxide, C 1-C 10The methylol of (mono-substituted) amino of the amino of alkyl sulphonyl, halogen, amino, protection, (mono-substituted) amino, protection, (dibasic) amino, methylol or protection.
The cyclic alkylidene or the assorted alkylidene group of ring-type that are fused on the phenyl can contain 2 to 10 ring memberses, but it may contain 3 to 6 members.The example of the cyclic group that these are saturated is that the bicyclic system that ought obtain is 2, when 3-indanyl and 1,2,3,4-tetralin ring.When described cyclic group was unsaturated, example occurred in when the bicyclic system that obtains is naphthyl ring or indyl.Each condensed cyclic group contains a nitrogen-atoms and one or more pairs of keys, preferably the example of the condensed cyclic group of one or two pair key be when phenyl be fused to pyrido, pyrans also, pyrrolo-, pyridine radicals, pyrrolin and or during the dihydropyridine basic ring.The example that each condensed cyclic group contains the condensed cyclic group of an oxygen atom and one or two pair key be when phenyl be fused to furo, pyrans also, dihydrofuran also or dihydropyran and when encircling.The example that each condensed cyclic group contains the condensed cyclic group of a sulphur atom and one or two pair key be when phenyl be fused to thieno, sulfo-pyrans also, dihydro-thiophene also or dihydrogen phosphorothioate pyrans and when encircling.The example that contains the cyclic group of two hetero atoms that are selected from sulfur and nitrogen and one or two pair key be when phenyl be fused to thiazole also, isothiazole also, thiazoline also or dihydro isothiazole and when encircling.The example that contains the cyclic group of two hetero atoms that are selected from oxygen and nitrogen and one or two pair key be when phenyl condense oxazole and, isoxazole also, dihydro-oxazole also or dihydro-isoxazole and when encircling.The example that contains the cyclic group of two nitrogen heteroatoms and one or two pair key occurs in when phenyl is fused to pyrazolo, imidazo, dihydro-pyrazolo or glyoxalidine and ring or pyrazinyl..
Term " carbamoyl " refers to-NC (O)-group that wherein this group connects two other independent groups at two position bondings.
Term " organic or inorganic cation " refers to the counter ion of the carboxylate anion of carboxylate.This counter ion is selected from alkali metal and alkaline-earth metal (for example lithium, sodium, potassium, barium, aluminum and calcium); Ammonium and monoalkylamine, dialkylamine and trialkylamine, for example triethylamine, cyclohexylamine; And organic cation, for example cationes such as hexichol first ammonium, benzene first ammonium, 2-hydroxyl second ammonium, two (2-ethoxy) ammonium, phenethyl benzyl ammonium, two inferior phenethyl diammonium.Referring to, for example, " PharmaceuticalSalts (drug salts), " Berge et al., J.Pharm.Sci., 66:1-19 (1977) incorporates its full content in this mode by reference.Other cation that is comprised by above-mentioned term comprises protonated form, quinine and the N-methylglucosamine of procaine, and such as the protonated form of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.In addition, this term refers to the The compounds of this invention of any zwitterionic form of being formed by carboxylic acid and amino group.For example, when a part is replaced by (quaternary ammonium) methyl group, will there be the cation of carboxylate anion.The cation of preferred carboxylate anion is a sodium cation.
The compounds of this invention can also exist as solvate and hydrate.Therefore, these chemical compounds can with the water crystallization of for example hydration, perhaps with one or more any molecular crystalline of parent solution solvents.The solvate of these chemical compounds and hydrate are included in the scope of the present invention.
One or more The compounds of this invention can be bioactive ester-formins, ester-formin for example nontoxic, that easy metabolism is decomposed.These ester-formins are induced the blood levels of increase and are prolonged the usefulness of the corresponding non-esterified form of described chemical compound.The ester group that can use comprises the lower alkoxy methyl group, for example, and methoxy, ethoxyl methyl, isopropoxy methyl etc.;-(C 1-C 12) alkoxyethyl group, for example methoxy ethyl, ethoxyethyl group, propoxyl group ethyl, isopropoxy ethyl etc.; 2-oxygen-1,3-dioxole-4-ylmethyl group, 5-methyl-2-oxygen-1 for example, 3-dioxole-4-ylmethyl, 5-phenyl-2-oxygen-1,3-dioxole-4-ylmethyl etc.; C 1-C 10Alkylthiomethyl group, for example methylthiomethyl, ethylenebis dithiocarbamate methyl, isopropylthio methyl etc.; Acyloxy methyl group, for example oxy acid methyl neopentyl, new pentane acyloxy ethyl, acetoxy-methyl etc.; Ethoxy carbonyl-1-methyl group; The acetoxyl group ethyl; 1-(C 1-C 12Alkoxy-carbonyl oxy) ethyl group, for example 1-(ethoxy carbonyl oxygen base) ethyl group; And 1-(C 1-C 12Alkyl amino carbonyl oxy) ethyl group, for example 1-(amino-carbonyl oxygen base) ethyl group.
Term " aminoacid " comprises any one 20 kinds of naturally occurring aminoacid or any one described natural amino acid whose D type that exists.In addition, term " aminoacid " also comprises the aminoacid that other non-natural exists except that D-aminoacid, and it is the natural amino acid whose functional equivalent that exists.The aminoacid that these non-naturals exist comprises, for example, nor-leucine (" NIe "), norvaline (" Nva "), L-or D-naphthalanine alanine, ornithine (" Orn "), homoarginine (homoArg) and other peptide field are known, M.Bodanzsky for example, " Principlesof Peptide Synthesis (peptide composition principle); " 1st and 2nd revised ed., Springer-Verlag, New York, NY, 1984 and 1993, and Stewar and Young, " Solid PhasePeptide Synthesis (solid-phase peptide is synthetic), " 2nd ed., Pierce Chemical Co., Rockford, IL, those that describe in 1984 are incorporated the full content of above-mentioned document in this mode by reference.Aminoacid and amino acid analogue can be purchased (Sigma Chemical Co.; AdvancedChemtech) or use methods known in the art synthetic.
Any position that is to be understood that claimed invention all has nearly 3 series " replacement ".For example, " alkyl of replacement " that replaced by " phenyl of replacement " can be replaced and no longer further be replaced by another group again, wherein should " phenyl of replacement " be replaced by " alkyl of replacement " again.Yet, it is also understood that if suitably, the present invention relates to parallel replacement more than 3.For example, if suitably, can be comprised that more than 3 hydrogen any one or a plurality of multiple group of halogen and hydroxyl replace on the moieties.
The general of quinoline synthesized
Shown in scheme 1, finish the synthetic of exemplary compounds.In dichloromethane, chloroform or toluene, use alkyl triflate, alkyl sulfate, alkyl methanesulfonates or alkyl toluene sulphonic acid ester to finish the alkylation of different quinoline so that the quinolinium of expectation to be provided.Purification by be evaporated to that drying or simple filtration are formed and yield one to higher.Use catalytic iodine or catalytic acetic acid by primary amine and 2, the pyrroles that N-replaces is synthesized in the condensation of 5-acetyl butyryl.Use this pyrroles of Vilsmeier-Haack condition formylated.Catalytic piperidines condensation between aldehyde and the quinolinium provides the final quinoline of expectation.
Figure A20068000259000521
Synthesizing of scheme 1. quinoline analog
The alkylation quinoline is to provide the general process of intermediate A.(Tetrahedron 2003，59，4911-4921)：
Figure A20068000259000522
Form the pyrroles so that the general process of intermediate B to be provided.(J.Org.Chem.2004，69，213-216)：
Formylated is to form the general process of intermediate C.(J.Org.Chem.1959，24，372-374)：
Figure A20068000259000531
The general process of condensation:
In methanol (1mL) solution of 2-methylquinoline salt (0.571mmol) and aldehyde (0.571mmol), add piperidines (1-2 drips), and refluxed 4 to 16 hours.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation to obtain solid.
Embodiment
The preparation of intermediate
Be prepared as follows intermediate 1:(2,5-dimethyl-1-phenyl-1H-pyrroles-3,4-dicarbaldehyde):
Figure A20068000259000532
To well-beaten 2, and 5-dimethyl-1-phenylpyrrole (Banik J.Org.Chem.2004,69,213-216) drip POCl in dry toluene (9mL) solution of (12mmol) and DMF (10.2 equivalent) 3(8.2 equivalent).Solution is heated to 110 ℃ to be kept 6 hours.This mixture is cooled to room temperature.Add (100mL) vigorous stirring 20 minutes then of NaOAc (saturated).The K that adds dichloromethane (500mL) and 5g 2CO 3(solid).This mixture that vibrates disappears from water layer until all colors.Use NaHCO 3Also evaporate with salt water washing organic layer to provide 2,5-dimethyl-1-phenyl-1H-pyrroles-3,4-dicarbaldehyde.
： 1HNMR(CDCl 3)：d 10.29(s，2H)，3.83(t，J＝7.8Hz，2H)，2.54(s，6H)，1.66-1.62(m，2H)，1.43(m，2H)，0.98(t，J＝7.4Hz，3H)。
Be prepared as follows intermediate 2:(4 '-formoxyl-xenyl-3-carboxylate methyl ester):
Figure A20068000259000541
To 4 '-formoxyl-xenyl-3-carboxylic acid and potassium carbonate (0.305g, drip in dichloromethane 2.21mmol) (10mL) solution trifluoromethanesulfonic acid methyl ester (0.26mL, 2.32mmol).At room temperature stirred this solution 16 hours.Filtering-depositing also concentrates organic layer so that white solid (0.395g, 74%) to be provided. 1H NMR (CDCl 3) 10 1 (s, 1H) 8.33 (t, J=1.8Hz, 1H), 8.09 (dd, J=9.1Hz, 1H), 7.99-7.97 (m, 2H), 7.84-7.80 (m, 1H), 7.80 (dd, J=6.6,1.8Hz, 2H), 7.57 (t, J=7.9Hz, 1H), 3.97 (s, 3H).
Intermediate 3:
1,2-dimethyl quinoline fluoroform sulphonate
At room temperature in stirring dichloromethane (7mL) solution of quinoline (1.34mmol), drip trifluoromethanesulfonic acid methyl ester (1.47mmol).Stir this solution and produced precipitation in 16 hours, collect this precipitation to provide 1,2-dimethyl quinoline fluoroform sulphonate by vacuum filtration.
1H NMR(DMSO)d 8.71(d，J＝8.5Hz，1H)，8.34(d，J＝9.8Hz，1H)，7.85(d，J＝8.6Hz，1H)，7.76(d，J＝9.7，3.0Hz，1H)，7.28-7.25(m，1H)，4.34(s，3H)，3.77(s，3H)，3.11(s，6H)。
Intermediate 4:
6-bromo-1,2-dimethyl quinoline fluoroform sulphonate
Use the method for intermediate 3:
1H NMR(DMSO)d 8.99(d，J＝8.6Hz，1H)，8.71(d，J＝2.3Hz，1H)，8.53(d，J＝9.5Hz，1H)，8.36(dd，J＝9.5，2.4Hz，1H)，8.15(d，J＝8.6Hz，2H)，3.03(s，3H)，3.05(s，3H)。
Use HPLC to characterize residual compounds.Use the flow velocity of Zorbax-SB C-18 analytical column (5mm) and 1.5mL/ minute, the eluent that uses is the aqueous solution of the 0.05%TFA CH to 0.05%TFA 3CN solution (0-100% in 15 minutes).
Retention time (the R of table 2. quinolinium t)
Intermediate R 1 R 2 R 3 R t Alkylating reagent
3 H H Me 4.2 MeOTf
4 Cl H Me 5.1 MeOTf
5 Br H Me 5.4 MeOTf
6 Ome H Me 6.5 MeOTf
7 Me 2N H Me 6.1 MeOTf MeSO3Me MeOSO2Tos
8 H Cl Me 4.9 MeOTf MeSO3Me
9 Br H Et 5.9 EtOTf
10 Me 2N H Et 6.4 EtOTf，Et 2SO4
11 Me H Me MeSO3Me MeOSO2Tos
Intermediate 12:
2,5-dimethyl-1-phenylpyrrole
At room temperature, add iodine (0.1mmol) in the agitating solution of 5-acetyl butyryl (1.2mmol) and aniline (1mmol) to 2.Stirred this solution 16 hours.Use dichloromethane (20mL) to dilute this solution and use 5%NaSSO then successively 3, NaHCO 3And saline (each 5mL) washing.Use MgSO 4Dry organic layer and vacuum concentration are to provide 2,5-dimethyl-1-phenylpyrrole.
1HNMR consistent with literature value (J.Org.Chem.1959,24,372-374).
Intermediate 13:
2,5-dimethyl-1-(3-pyridine radicals) pyrroles
Method such as intermediate 12.
1HNMR(CDCl 3)：d 8.60(dd，J＝4.7，1.7Hz，1H)，7.81(td，J＝7.8，1.9Hz，1H)，7.29(dd，J＝7.2，5.0Hz，1H)，7.22(d，J＝7.9Hz，1H)，5.89(s，2H)，2.18(s，6H)。
Intermediate 14:
1-butyl-2, the 5-dimethyl pyrrole
Method such as intermediate 12.
1HNMR(CDCl 3)：d 5.76(s，2H)，3.72(t，J＝3.6Hz，2H)，2.22(s，6H)，1.63-1.57(m，2H)，1.39-1.35(m，2H)，0.96(t，J＝7.4Hz，3H)。
Other method of intermediate 14:
Use 1 of 9.6g, the 5-acetyl butyryl is handled the butylamine sample of 6.3g, adds the acetic acid of 2 μ l then.With this mixture heated to tangibly temperature and place ice bath.Ice bath melts after 4 hours, and isolates the water layer of 3ml.Use 30ml hexane and this mixture of 10ml water treatment and storage under-20 ℃.Second day decant organic layer from the water layer that freezes, this organic layer of vacuum evaporation is to provide the light yellow oily 1-butyl-2 of 12.24g, 5-dimethyl pyrrole then.
Intermediate 15:
2,5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde
To 2, drip POCl in well-beaten dry toluene (9mL) solution of 5-dimethyl-1-phenylpyrrole (12mmol) and DMF (10.2 equivalent) 3(12mmol).Solution is heated to 110 ℃ to be kept 6 hours.This mixture is cooled to room temperature.Add NaOAc (saturated) (100 mL) vigorous stirring 20 minutes then.The K that adds dichloromethane (500mL) and 5g 2CO 3(solid).This mixture that vibrates disappears from water layer until all colors.Use NaHCO 3Also evaporate with salt water washing organic layer to provide 2,5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde.
1HNMR(CDCl 3)：d 9.87(s，1H)，7.54-7.48(m，3H)，7.21-7.19(m，2H)，6.38(s，1H)，2.27(s，3H)，1.98(s，3H)。
Intermediate 16:
2,5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-formaldehyde
Method such as intermediate 15.
1HNMR(CDCl 3)：d 9.89(s，1H)，8.75-8.74(m，1H)，8.54(m，1H)，7.61-7.58(m，1H)，7.52-7.49(m，1H)，6.42(s，1h)，2.30(s，3H)，2.00(s，3H)。
Intermediate 17:
2,5-dimethyl-1-butyl-1H-pyrroles-3-formaldehyde
Preparation method such as intermediate 15, silica gel tlc, Rf=0.3 uses 1: 1 EtOAc and hexane.
1HNMR(CDCl 3)δ10.30(s，2H)，3.83-3.80(m，2H)，3.15(s，6H)，1.65-1.62(m，2H)，1.43-1.38(m，2H)，0.99(t，J＝7.4，3H)。
Intermediate 18:
4-benzyloxy-3-chlorobenzaldehyde
The 3-chloro-4-hydroxy benzaldehyde sample of 0.156g is placed the 13 * 100mm test tube that has splash bar.The Anhydrous potassium carbonate that adds 0.33g then adds the dry acetone of 0.5ml subsequently again.The benzyl bromide a-bromotoluene that adds 0.12ml then, and at room temperature stir this mixture overnight.Stir after 22 hours, add the dichloromethane of 2ml, solids removed by filtration.The TLC of filtrate is presented at and produces new point on the silica gel tlc that uses dichloromethane, and RF 0.7, and do not contain starting material, and RF 0.2.Evaporation obtains white solid.
Intermediate 19:
3,4-diformyl-2,5-dimethyl-1-(2-phenethyl) pyrroles
A:2,5-dimethyl-1-(2-phenethyl) pyrroles
With 1.67g oneself-2, the 5-diketone places the 20ml bottle that has splash bar.The phenethylamine that adds 1.67ml then adds the acetic acid of 0.1ml subsequently again.Along with the adding of acetic acid, it is muddy that mixture heats up rapidly and becomes.Stir this mixture 2 hours, and added the hexane of 10ml and the water of 2ml then.Stir this mixture overnight.Separate organic layer, and evaporate to obtain the light yellow oil of 2.5g, it stores down at-20 ℃ becomes solid.
NMR DMSO 7.27-7.11，M，5H，5.58，S，2H，3.90，T，2H，2.80，T，2H。
B:3,4-diformyl-2,5-dimethyl-1-(2-phenethyl) pyrroles
With 2 of 1.0g, 5-dimethyl-1-(2-phenethyl) pyrroles places the 20 * 150ml test tube that has splash bar, and adds the dry DMF of 5ml.In 5 minutes, drip the POCl of 1.8ml then 3Handle this mixture.With this mixture heat release be heated to 85 ℃, then 100 ℃ the heating 1 hour.Use the CH of 10% acetone 2Cl 2The TLC of solution shows new some RF 0.5, and does not contain starting material, and RF 0.8.Reactant is poured on 90g ice and the 8g sodium acetate.Handle this mixture with the ethyl acetate of 30ml, and vigorous stirring 5 minutes.Separate this mixture then, use the dried over mgso upper strata, vacuum evaporation is to provide the dark oil thing then.Use 1 * 2.5 inch silicagel column that this grease is carried out chromatography.This grease is dissolved in the dichloromethane of 40ml and is adsorbed on the post.Use the dichloromethane solution eluting of 5% ethyl acetate of 2 * 40ml then.TLC is defined as pure partially mixed and vacuum evaporation solidified yellow oil when obtaining leaving standstill.
NMR DMSO 10.16，S，2H，7.31-7.24，M，3H，7.15-7.14，M，2H，4.14，T，2H，2.93，T，2H，2.37，S，6H。
Intermediate 20
1-butyl-3,4-diformyl-2,5-dimethyl pyrrole
The intermediate 14 of 12.24g is placed the 250ml round-bottomed flask that has magnetic force splash bar and thermometer.The dimethyl formamide that adds 60ml then.This flask of cooling is handled this mixture with the phosphoryl chloride phosphorus oxychloride of 19ml with every part of 1ml then in ice bath.For the 8ml of first, the very exothermic that each 1ml causes makes this solution be warming up to 20 ℃ from 10 ℃.After the 8ml of first, more phosphoryl chloride phosphorus oxychloride causes intensification hardly.After adding phosphoryl chloride phosphorus oxychloride, remove ice bath, and the flask that will contain light orange color solution places oil bath, oil bath is heated to 100 ℃ then.Solution reached 90 ℃ after 45 minutes, in ensuing 45 minutes solution is cooled to 85 ℃.Heat after 2 hours, remove oil bath and solution cooling 15 minutes.Then solution is poured on the mixture of 600g ice and 100g sodium acetate, and stirs.Form the suspension of gray solid after 25 minutes, filter this mixture, with 2 * 100ml water washing solid, and air drying is to provide the 1-butyl-3 of 9.8g, 4-diformyl-2,5-dimethyl pyrrole.Solid is presented on the silica gel tlc of the dichloromethane solution that uses 10% ethyl acetate and forms a point, and RF 0.3.
1HNMR(DMSO，500MH)：10.18(s，2H)，3.90(dd，2H)，2.51(s，6H)，1.56(m，2H)，1.34(m，2H)，0.92(t，3H)。
Intermediate 21
1,2-dimethyl quinoline toluene fulfonate
To 6-dimethylamino quinaldine (5.0g, 4mL CHCl 26.8mmol) 3Add the 4.0mL methyl tosylate in the solution and be heated to reflux and continue 12 hours.The product of concentration response thing to obtain expecting.
1HNMR(DMSO-d 6)δ8.67(d，J＝9.2，1H)，8.28(d，J＝9.8，1H)，7.80(d，J＝8.7，1H)，7.69-7.66(m，1H)，7.48(d，J＝8.0，2H)，4.31(s，3H)，3.07(s，6H)，2.98(s，3H)，2.25(s，3H)。
Embodiment 1: the phosphoric acid pyrrole is tieed up the synthetic of ammonium
With the pamoic acid pyrrole dimension ammonium sample of 0.51g, ICN#156475, lot 8256B places the 250ml conical flask that has the magnetic force splash bar.Add the 40ml chloroform then, FischerBP1145-1, lot 982393, add 95% ethanol of 20ml more then, and 0204092 batch of 02102-15 of PhamacoACS/USP level lot obtains dark red solution.
With this mixture heated to 50 ℃ and stirred 10 minutes.Use 95% alcoholic solution of the phosphoric acid (85%) of 10ml 2% to handle this mixture then, produce precipitation.After 2 minutes, add the 30ml ethyl acetate, and stirred this mixture 20 minutes.Solid collected by filtration wash with 20ml 2/1/1 ethyl acetate/chloroform/ethanol, and air drying is to provide 0.45g brick-red powder then.Two cell means of CNH obtain C 50.75 H 6.11 N 6.70, and the value of calculation of C26H28N3.H2PO4.H3PO4.2H2O is C 50.90 H 6.08 N 6.85.
Embodiment 1 phosphatic sample is soluble in water under the concentration of 1mg/ml, obtains orange-red solution.This low-solubility with pamoic acid pyrrole dimension ammonium is opposite, at room temperature stirs in water with the concentration of 1mg/ml and filters then in 16 hours, and pamoic acid pyrrole dimension ammonium forms colourless solution, and pyrrole dimension ammonium concentration is under the detectability that HPLC analyzes.
Embodiment 2: the sulphuric acid pyrrole is tieed up the synthetic of ammonium
The pamoic acid pyrrole dimension ammonium sample of 0.51g is placed the 250ml conical flask of the magnetic force splash bar that has 1.5 * 3/8 inches.Add 40ml chloroform (ethanol is stable) and 20ml 95% ethanol then, stir this mixture, obtain dark red solution.Drip 0.11ml 95% vitriolic 4ml 95% alcoholic solution after 10 minutes, obtain dark red solution.Stir and once pour the 50ml ethyl acetate into after 5 minutes.The gained solid suspension was stirred 20 minutes, then solid collected by filtration.Use 2 * 5ml ethyl acetate washing solid, and air drying is to provide 0.4035g fine-powdered dark red solid.CHN obtains C 61.09, H, and 6.08, N 8.07, and S 6.53, and KF 5.40, and the value of calculation of C26H28N3+.HSO4-.4H2O is 61.656.378.30, S 6.32 KF 5.33.
Sulphuric acid pyrrole dimension ammonium is solvable to 1mg/ml in the aqueous solution of 1.5%DMSO and 5% glucose.
Embodiment 3:6-dimethylamino-2-[(E)-2-(4-dimethylamino-phenyl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000601
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 4-(dimethylamino) benzaldehyde (85mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that purple solid (102mg, 37%) to be provided. 1H NMR(DMSO-d 6)δ 8.55(d，J＝9.4Hz，1H)，8.31(d，J＝9.3Hz，1H)，8.25(d，J＝9.8Hz，1H)，8.01(d，J＝15.6Hz，1H)，7.78(d，J＝9.0Hz，2H)，7.63(dd，J＝9.8，3.0Hz，1H)，7.50(d，J＝15.6Hz，1H)，7.23(d，J＝3.0Hz，1H)，6.81(d，J＝9.0Hz，2H)，4.40(s，3H)，3.11(s，6H)，3.06(s，6H)；HPLC R t＝10.0。
Embodiment 4:6-dimethylamino-2-[(E)-2-(4-methoxyl group-phenyl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000611
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and p-anisaldehyde (69uL adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that aubergine solid (121mg, 45%) to be provided. 1H NMR(DMSO-d 6)δ 8.67(d，J＝9.1Hz，1H)，8.34-8.31(m，2H)，7.99(d，J＝15.9Hz，1H)，7.89(d，J＝8.8Hz，2H)，7.72-7.69(m，2H)，7.26(d，J＝3.0Hz，1H)，7.09(d，J＝7.0Hz，2H)，4.47(s，3H)，3.20(s，3H)，3.13(s，6H)；HPLC R t＝10.0。
Synthesizing of embodiment 5:2-((E)-2-xenyl-4-base-vinyl)-6-dimethylamino-1-methyl-quinoline fluoroform sulphonate
Figure A20068000259000612
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 4-xenyl formaldehyde (104mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (150mg, 51%) to be provided. 1H NMR(DMSO-d 6)δ 8.73(d，J＝9.1Hz，1H)，8.39-8.35(m，2H)，8.08-7.90(m，3H)，7.92(d，J＝15.9Hz，1H)，7.85(d，J＝8.4Hz，2H)，7.78(dd，J＝7.4，1.8Hz，2H)，7.74(dd，J＝9.3，3.0Hz，1H)，7.52(t，J＝7.4Hz，2H)，7.43(td，J＝7.1，1.2Hz，1H)，7.28(d，J＝3.1Hz，1H)，4.53(s，3H)，3.15(s，6H)；HPLC R t＝11.7。
Embodiment 6:6-dimethylamino-1-methyl-2-[(E)-2-(5-(4-aminomethyl phenyl)-isoxazole-3-bases)-vinyl]-quinoline fluoroform sulphonate synthetic
Figure A20068000259000621
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 5-(4-aminomethyl phenyl)-isoxazoles-3-formaldehyde (99mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (126mg, 43%) to be provided. 1H NMR(DMSO-d 6)δ 8.78(d，J＝9.1Hz，1H)，8.44(d，J＝9.0Hz，1H)，8.41(d，J＝10.0Hz，1H)，8.04(d，J＝16.0Hz，1H)，7.95(d，J＝16.0Hz，1H)，7.83-7.81(m，3H)，7.76(s，1H)7.42(d，J＝8.0Hz，2H)，7.30(d，J＝3.0Hz，1H)，4.54(s，3H)，3.17(s，6H)，2.40(s，3H)；HPLC R t＝11.2。
Embodiment 7:6-dimethylamino-1-methyl-2-[(E)-2-(4-phenyl-thiophene-2-yl)-vinyl]-quinoline fluoroform sulphonate synthetic
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 4-phenyl-thiophene-2-formaldehyde (107mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (142mg, 48%) to be provided. 1H NMR(DMSO-d 6)δ 8.69(d，J＝9.2，1H)，8.34(d，J＝9.9Hz，1H)，8.32(d，J＝9.2Hz，1H)，8.23(s，1H)，8.21(s，1H)，8.19(d，J＝15.7Hz，1H)，7.78(dd，J＝8.4，1.2Hz，2H)，7.73(dd，J＝9.8，3.0Hz，1H)，7.66(d，J＝15.6，1H)，7.48(td，J＝9.2，2H)，7.38-7.35(m，1H)，7.26(d，J＝3.0，1H)，4.48(s，3H)，3.14(s，6H)；HPLCR t＝11.7。
Embodiment 8:6-dimethylamino-2-[(E)-2-(1H-indol-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000631
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.mmol) and indole-3-formaldehyde (83mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that kermesinus solid (95mg, 35%) to be provided. 1H NMR(DMSO-d 6)δ 12.1(s，1H)，8.57(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.38(d，J＝15.6Hz，1H)，8.27(d，J＝9.3Hz，1H)，8.24(s，1H)8.18-8.16(m，1H)，7.63(dd，J＝9.8，3.0Hz，1H)，7.53-7.50(m，2H)，7.29-7.24(m，3H)，4.42(s，3H)，3.12(s，6H)；HPLC R t＝10.0。
Embodiment 9:6-dimethylamino-1-methyl-2-[(E)-2-(5-phenyl-furan-2-yl)-vinyl]-quinoline fluoroform sulphonate synthetic
Figure A20068000259000632
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 5-phenyl-2-furfural (98mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (142mg, 49%) to be provided. 1H NMR(DMSO-d 6)δ 8.65(d，J＝9.1Hz，1H)，8.35(d，J＝9.8Hz，1H)，8.32(d，J＝9.2Hz，1H)，7.99-7.97(m，2H)，7.95(d，J＝15.6Hz，1H)，7.71(dd，J＝9.8，3.0Hz，1H)，7.65(d，J＝15.6Hz，1H)，7.52(t，J＝7.6Hz，2H)，7.44-7.40(m，1H)，7.29(d，J＝3.8Hz，1H)，7.26(d，J＝3.0Hz，1H)，7.21(d，J＝3.6Hz，1H)，4.49(s，3H)，3.14(s，6H)；HPLC R t＝11.4。
Embodiment 10:6-dimethylamino-2-[(E)-2-(4-formoxyl-2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000641
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.111g, 0.318mmol) with 2,5-dimethyl-1-phenyl-1H-pyrroles-3, (132mg adds piperidines (1 to 2) and refluxed 4 hours the 4-dicarbaldehyde in MeOH 0.636mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (49mg, 29%) to be provided. 1HNMR(DMSO-d 6)δ 10.0(s，1H)，8.60(d，J＝9.2Hz，1H)，8.42(d，J＝9.3Hz，1H)，8.34(d，J＝15.4Hz，1H)，8.25(d，J＝9.8Hz，1H)，7.99(d，J＝15.4Hz，1H)，7.66(dd，J＝9.8，3.1Hz，1H)，7.25(d，J＝3.0Hz，1H)，4.40(s，3H)，3.98(t，J＝7.8Hz，2H)，3.12(s，6H)，2.59(s，3H)，2.53(s，3H)，1.62-1.59(m，2H)，1.39-1.34(m，2H)，0.95(t，J＝7.4Hz，3H)。
Embodiment 11:6-dimethylamino-2-[(E)-2-(3 '-methoxycarbonyl group-xenyl-4-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000651
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and intermediate 2 (mg adds piperidines (1 to 2) and refluxed 4 hours in MeOH 0.571mmol) (1mL) solution.Solution is cooled to room temperature and use the vacuum filtration collecting precipitation with provide coloured solid (mg, %). 1H NMR(DMSOd 6)δ 8.72(d，J＝9.0Hz，1H)，8.37-8.27(m，2H)，8.27-8.26(m，1H)，8.07-8.01(m，5H)，7.93-7.83(m，3H)，7.73(dd，J＝9.8，3.1Hz，1H)，7.68(t，J＝7.8Hz，1H)，7.26(d，J＝3.0Hz，1H)，4.52(s，3H)，3.91(s，3H)，3.14(s，3H)；HPLC R t＝11.4。
Embodiment 12:6-dimethylamino-2-[(E)-2-(2,5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000652
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 2, (114mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-formaldehyde in MeOH 0.571mmol) (1.3mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (131mg, 43%) to be provided. 1HNMR(DMSO-d 6)δ 8.73(dd，J＝4.8，1.5Hz，1H)，8.63(d，J＝2.4Hz，1H)，8.54(d，J＝9.2Hz，1H)，8.46(d，J＝9.3Hz，1H)，8.24(d，J＝9.7Hz，1H)，8.09(d，J＝15.2Hz，1H)，7.92-7.90(m，1H)，7.65-7.60(m，2H)，7.27(d，J＝15.2Hz，1H)，7.23(d，J＝3.0Hz，1H)，6.78(s，1H)，4.37(s，3H)，3.11(s，6H)，2.26(s，3H)，2.03(s，3H)；HPLC R t＝9.3。
Embodiment 13:6-dimethylamino-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles 3-yl)-vinyl]-1-ethyl-quinoline sulfovinate synthetic
Figure A20068000259000661
To 6-dimethylamino-2-methyl isophthalic acid-ethyl quinoline sulfovinate (0.120g, 0.352mmol) and 2, (70mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde in the solution of MeOH 0.352mmol) (1mL).Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (78mg, 44%) to be provided. 1HNMR(DMSO-d 6)δ 8.53-8.47(m，2H)，8.23(d，J＝9.8Hz，1H)，8.15(d，J＝15.0Hz，1H)，7.62-7.58(m，3H)，7.56-7.54(m，1H)，7.37(dd，J＝3.5，1.4Hz，2H)，7.24(d，J＝3.0Hz，1H)，7.16(d，J＝15.1Hz，1H)，6.77(s，1H)，4.96(q，J＝7.1Hz，2H)，3.73(q，J＝7.0Hz，2H)，3.11(s，6H)，2.23(s，3H)，2.01(s，3H)，1.50(t，J＝7.1Hz，3H)，1.10(t，J＝6.9Hz，3H)；HPLC R t＝12.8。
Embodiment 14:6-bromo-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles 3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000662
To 6-bromo-1, (0.200g, 0.517mmol) and 2, (103mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.517mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (99mg, 34%) to be provided. 1H NMR(DMSO-d 6)δ 8.70(d，J＝9.4Hz，1H)，8.64(d，J＝9.3Hz，1H)，8.49(d，J＝2.3Hz，1H)，8.38(d，J＝14.8Hz，2H)，8.33(d，J＝9.4Hz，1H)，8.18(dd，J＝9.3，2.3Hz，1H)，7.62-7.59(m，2H)，7.57-7.54(m，1H)，7.39(dd，J＝3.5，1.4Hz，1H)，7.28(d，J＝15.0Hz，1H)，6.84(s，1H)，4.37(s，3H)，2.29(s，3H)，2.02(s，3H)；HPLC R t＝11.9。
Embodiment 15:6-dimethylamino-2-[(E)-2-(2,5-dimethyl-1-butyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000671
To 6-dimethylamino-1,2-dimethyl quinoline fluoroform sulphonate (0.200g, 0.571mmol) and 1-butyl-2, (300mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1H-pyrroles-3-formaldehyde in the solution of MeOH 0.571mmol) (1mL).Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid to be provided.Use the SiO of the chloroformic solution of 10% acetone 2Column chromatography is further purified solid (57mg, 20%). 1H NMR(DMSO-d 6)δ 8.46(d，J＝9.2Hz，1H)，8.41(d，J＝9.4Hz，1H)，8.18(d，J＝2.3Hz，1H)，8.04(d，J＝15.0Hz，1H)，7.57(dd，J＝9.7，3.1Hz，1H)，7.21(J＝3.0Hz，1H)，7.08(d，J＝15.0Hz，1H)，6.54(s，1H)，4.30(s，3H)，3.83(t，J＝7.8Hz，2H)，3.09(s，6H)，2.49(s，3H)，2.23(s，3H)，1.58-1.55(m，2H)，1.36-1.31(m，2H)，0.92(t，J＝4.0Hz，3H)；HPLC R t＝12.6。
Embodiment 16:6-bromo-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-ethyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000672
(0.200g, 0.0.499mmol) and 2, (100mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde in MeOH 0.499mmol) (1mL) solution to 6-bromo-1-ethyl-2-methylquinoline fluoroform sulphonate.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (50mg, 17%) to be provided. 1H NMR(DMSOd 6)δ 8.72(d，J＝11.2Hz，1H)，8.64(d，J＝9.3Hz，1H)，8.50(d，J＝2.3Hz，1H)，8.43(d，J＝14.8，1H)，8.34(d，J＝9.5Hz，1H)，8.18(dd，J＝9.4，2.3Hz，1H)，7.63-7.60(m，3H)，7.39-7.38(m，2H)，7.20(d，J＝14.9Hz，1H)，6.87(s，1H)，4.97(q，J＝7.1Hz，2H)，2.29(s，3H)，2.02(s，3H)，1.50(t，J＝7.1Hz，3H)；HPLC R t＝12.9。
Embodiment 17:6-dimethylamino-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-ethyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000681
To 6-dimethylamino-1-ethyl-2-methylquinoline fluoroform sulphonate (0.125g, 0.343mmol) and 2, (68mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde in MeOH 0.343mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that red solid (30mg, 16%) to be provided. 1H NMR(DMSO-d 6)δ 8.52-8.47(m，2H)，8.23(d，J＝9.9Hz，1H)，8.14(d，J＝15.1Hz，1H)，7.62-7.52(m，4H)，7.37-7.35(m，2H)，7.24(d，J＝3.0Hz，1H)，7.16(d，J＝15.1Hz，1H)，6.77(s，1H)，4.96(q，J＝7.5Hz，2H)，3.11(s，6H)，2.24(s，3H)，2.12(s，3H)，1.50(t，J＝7.1Hz，1H)；HPLC Rt＝12.9。
Embodiment 18:2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000691
To 1, (0.200g, 0.651mmol) and 2, (130mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.651mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that black solid (113mg, 36%) to be provided. 1H NMR(DMSO-d 6)δ8.75(d，J＝9.2Hz，1H)，8.66(d，J＝9.0Hz，1H)，8.40(d，J＝9.0Hz，1H)，8.34(d，J＝15.0Hz，1H)，8.22(dd，J＝8.0，1.5Hz，1H)，8.08-8.05(m，1H)，7.83(t，J＝7.8Hz，1H)，7.62-7.54(m，3H)，7.39-7.37(m，2H)，7.30(d，J＝15.0Hz，1H)，6.83(s，1H)，4.40(s，3H)，2.28(s，3H)，2.02(2，3H)；HPLC R t 11.2。
Embodiment 19:6-bromo-2-[(E)-2-(2,5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000692
To 6-bromo-1, (0.200g, 0.518mmol) and 2, (104mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.518mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that mulberry solid (34mg, 12%) to be provided. 1H NMR(DMSOd 6)δ.8.76-8.66(m，4H)，8.51(d，J＝2.3Hz，1H)，8.39(s，1H)，8.35(d，J＝10.0Hz，1H)，8.20(dd，J＝9.4，2.4Hz，1H)，7.95-7.93(m，1H)，7.67-7.65(m，1H)，7.32(d，J＝14.9Hz，1H)，6.83(s，1H)，4.39(s，3H)，2.31(s，3H)，2.04(s，3H)；HPLC R t＝9.0。
Embodiment 20:6-methyl-2-[(E)-2-(2,5-dimethyl-1-pyridin-3-yl-1H-pyrroles-3-yl)-vinyl]-1-ethyl-quinoline iodide synthetic
Figure A20068000259000701
To 1-ethyl-2, (0.025g, 0.080mmol) and 2, (16mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 6-dimethyl quinoline iodide in MeOH 0.080mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that coloured solid (5mg, 13%) to be provided.HPLC R t＝12.0。
Embodiment 21:6-chloro-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000702
To 6-chloro-1, (0.200g, 0.585mmol) and 2, (117mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.585mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that solid (85mg, 28%) to be provided. 1H NMR(DMSO-d 6)δ8.71(d，J＝9.5Hz，1H)，8.65(d，J＝9.3Hz，1H)，8.40(m，J＝9.4Hz，2H)，8.36-8.35(m，1H)，8.08(dd，J＝9.4，2.5，1H)，7.63-7.54(m，3H)，7.40-7.38(m，2H)，7.28(d，J＝14.9Hz，1H)，6.84(s，1H)，4.38(s，3H)，2.29(s，3H)，2.01(s，3H)；HPLC R t＝11.7。
Embodiment 22:7-chloro-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000711
To 7-chloro-1, (0.200g, 0.585mmol) and 2, (117mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.585mmol) (1niL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that solid (99mg, 32%) to be provided. 1H NMR(DMSOd 6)δ8.73(d，J＝9.3Hz，1H)，8.67(d，J＝9.4Hz，1H)，8.53(d，J＝1.6Hz，1H)，8.38(d，J＝14.9Hz，1H)，8.23(d，J＝8.6Hz，1H)，7.87(dd，J＝8.3，1.7Hz，1H)，7.63-7.53(m，3H)，7.40-7.38(m，2H)，7.28(d，J＝14.9Hz，1H)，6.86(s，1H)，4.37(s，3H)，2.29(s，3H)，2.01(s，3H)；HPLC R t＝11.8。
Embodiment 23:6-methoxyl group-2-[(E)-2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-yl)-vinyl]-1-methyl-quinoline fluoroform sulphonate synthetic
Figure A20068000259000712
To 6-methoxyl group-1, (0.200g, 0.593mmol) and 2, (118mg adds piperidines (1 to 2) and refluxed 4 hours 5-dimethyl-1-phenyl-1H-pyrroles-3-formaldehyde 2-dimethyl quinoline fluoroform sulphonate in MeOH 0.593mmol) (1mL) solution.Solution is cooled to room temperature and uses the vacuum filtration collecting precipitation so that purple solid (114mg, 37%) to be provided. 1H NMR(DMSO-d 6)δ 8.66(d，J＝9.2Hz，1H)，8.61(d，J＝9.3Hz，1H)，8.35(d，J＝9.5Hz，1H)，8.23(d，J＝15.0Hz，1H)，7.72-7.68(m，2H)，7.62-7.53(m，3H)，7.38(m，2H)，7.27(d，J＝15.0Hz，1H)，6.78(s，1H)，4.40(s，3H)，3.03(s，3H)，2.26(s，3H)，2.01(s，3H)；HPLC R t＝11.5。
Synthesizing of embodiment 24:2-(2-(4-benzyloxy-3-chlorphenyl) vinyl)-6-dimethylamino-1-methylquinoline mesylate
Figure A20068000259000721
With the 6-(dimethylamino)-1 of 10 μ l piperidines processing 120mg, the 1ml butanol solution of 4-benzyloxy-3-chlorobenzaldehyde of 2-dimethyl quinoline mesylate sample and 180mg, and be heated to 100 ℃ and lasting 1 hour.Mixture is cooled to-20 ℃ and spends the night precipitated solid.Along with being heated to room temperature, the solid dissolving.Handle this solution with the 2ml ethyl acetate, be cooled to-20 ℃ then.By filter collecting the solid of gained, with the washing of 2ml ethyl acetate also air drying to obtain the 68mg solid, HPLC method 0100CD R t12.118 minute, purity 99%.NMR D6DMSO 500 MH 8.70 J＝9 D 1H，8.34 J＝9.9 D 1H，8.29 J＝9.15D 1H，8.18 J＝2.1 D 1H，7.94 J＝15.9 D 1H，7.81 J＝8.7，2.2 DD 1H，7.79J＝16 D 1H，7.73 J＝9.8，3.0 DD 1H，7.50 J＝7.4 D 2H，7.45-7.35 M 4H，7.26 J＝3 D，1H，5.33 S 2H，4.49 S 3H，3.14 S 6H，2.28 S 3H。
Embodiment 25 to 58:
Use the method for embodiment 23 to prepare the following example chemical compound:
Figure A20068000259000722
Table 3: embodiment 25 to 59
R2=H, it is a fluoroform sulphonate
Embodiment R1 R A EC50 μM
25 6-Me2N- Me 4-formoxyl-2,5-dimethyl-1-(2-methoxyethyl)-pyrroles-3-base ＜1
26 6-(4-morpholinyl) Me 2,5-dimethyl-1-phenylpyrrole-3-base 1
27 6-(4-morpholinyl) Me 2,5-dimethyl-1-butyl-4-formoxyl pyrroles-3-base ＞1
28 6-Me2N- Me 2,5-dimethyl-1-phenyl-4-formylpyrrole-3-base ＜1
29 6-(piperidines-1-yl) Me 2,5-dimethyl-1-phenylpyrrole-3-base 1
30 6-(4-methyl piperidine-1-yl) Me 2,5-dimethyl-1-phenylpyrrole-3-base 1
31 6-Me2N- Me 6-(thiophene-2-yl) pyridine-2-base 1
32 6-Me2N- Me 5-phenyl thiophene-2-base 1
33 6-Me2N- Me 4,5-dimethyl furan-2-base 1
34 6-Me2N- Me The 3-Phenoxyphenyl 1
35 6-Me2N- Me The 4-Phenoxyphenyl ＜1
36 6-Me2N- Me The 4-butoxy phenyl ＜1
37 6-Me2N- Me The 4-butoxy phenyl ＜1
38 6-Me2N- Me 5-(2-methyl-5-trifluoromethyl-2H-pyrazole-3-yl) thiophene-2-base 1
39 6-Me2N- Me 5-(1-methyl-4-Trifluoromethyl-1 H-pyrazole-3-yl) thiophene-2-base 1
40 6-Me2N- Me 2-butyl-5-chloro-imidazol-4 yl ＞1
41 6-Me2N- Me .alpha.-5:6-benzopyran-4-ketone-3-base 1
42 6-Me2N- Me 1-benzenesulfonyl-indol-3-yl 1
43 6-Me2N- Me 2-(4-chlorphenyl) carbonyl-benzo furan 1
Mutter-the 5-base
44 6-Me2N- Me 4-(2-cyano thiophene-3-base-methoxyl group) phenyl ＜1
45 6-Me2N- Me 4-trifluoromethoxy-phenyl 1
46 6-Me2N- Me 4-benzyloxy-3-methoxyl group-phenyl ＜1
47 6-Me2N- Me 4-benzyloxy phenyl ＜1
48 6-Me2N- Me 4-benzyloxy-3, the 5-3,5-dimethylphenyl ＜1
49 6-Me2N- Me 5-methyl isophthalic acid-Phenylpyrazole-4-base ＞1
50 6-Me2N- Me 2-phenoxy group thiophene-2-base ＜1
51 6-Me2N- Me 5-(2-phenylacetylene)-thiophene-2-base ＜1
52 6-Me2N- Me 9-ethyl carbazole-3-base ＜1
53 6-Me2N- Me 4-(4-fluoro benzoyl)-1-methylpyrrole-2-base IA
Following compounds is a mesylate
54 6-Me2N- Me 1-cyclopropyl-2,5-dimethyl-4-carbethoxyl group pyrroles-3-base ＜1
55 6-Me2N- Me 2,5-dimethyl-1-phenyl-4-carbethoxyl group pyrroles-3-base ＜1
56 6-Me2N- Me 2,5-dimethyl-1-(thiophene-2-yl) methyl-4-carbethoxyl group pyrroles-3-base ＜1
57 6-Me2N- Me 3-formoxyl-2,5-dimethyl-1-butyl pyrroles-4-base ＜1
58 6-Me Me 3-formoxyl-2,5-dimethyl-1-butyl pyrroles-4-base ＜1
59 6-Cl Me 3-formoxyl-2,5-dimethyl-1-butyl pyrroles-4-base ＜1
Embodiment 60:3-formoxyl-2,5-dimethyl-1-(2-phenethyl) pyrroles-4-base synthetic
Figure A20068000259000751
To 1, (4.08g 10.9mmol) with 2, adds 1 piperidines to 2-dimethyl quinaldine in the 4mL alcoholic solution of 5-dimethyl pyrrole (2.25g), be heated to then and refluxed 16 hours.Cooling solution and filtering-depositing are to obtain not pure products of 1.8g.Use this pure products (response rate 60%) not of anhydrous EtOH recrystallization.
1H NMR(DMSO-d 6)δ 10.00(s，1H)，8.59(d，J＝9.2，1H)，8.41(d，J＝9.2，1H)，8.34(d，J＝15.0，1H)，8.25(d，J＝9.8，1H)，8.00(d，J＝15.4，1H)，7.67-7.65(m，1H)，7.46(dd，J＝6.4，1.8，2H)，7.25(d，J＝3.0，1H)，7.11(d，J＝8，2H)，4.41(s，3H)，3.99-3.97(m，2H)，3.12(s，6H)，2.59(s，3H)，2.53(s，3H)，2.28(s，3H)，1.62-1.59(m，2H)，1.39-1.43(m，2H)，0.95(t，J＝7.3，1H)。
Embodiment 61: the reduction of the anchorage dependence growth (normal liquid cell culture) of cancerous cell.
Test implementation example 1 chemical compound reduces the effect of growth of cancer cells to determine it in the liquid culture that adds or do not add glucose in 96 orifice plates.Method is as follows:
Under 37 ℃, containing 5%CO 2Humidification incubator (Ultra-Tech WJ301D; Baxter Scientific Products, West Chester, PA, USA) in, cell is cultured in and is supplemented with 10% hyclone (FBS), 2mM L-glutaminate (L-Glu), 1 * non essential amino acid (NEAAs), 1% Sodium Pyruvate, contains or do not contain in the Eagle culture medium (DMEM) of 1 * Dulbecco improvement of 4.5g/L glucose, all reagent all from Invitrogen (Carlsbad, CA, USA).Inoculation contains 1 * 10 in each hole of the flat microplate in 96 holes 3To 3 * 10 3The cell suspension culture of individual cell (100ml).The cell growth was used alamarBlue according to the explanation of manufacturer after 1 to 3 day TMDyeing (1: 10 volume reagent; Biosource Intemational, Camarillo, CA USA) measures the cell growth.
The selective power of table 4. embodiment 1 chemical compound anticancer cell in adding or do not add the glucose liquid grown culture of (representing) with (+) Glu and (-) Glu.
(-)Glu (+)Glu (-)Glu (+)Glu (-)Glu (+)Glu
Cell line Panc-1 Panc-1 HCT-116 HCT-116 Pc3M/N Pc3M/N
IC80μM 0.1 ＞1 0.1 1 0.1 1
As implied above, the chemical compound of test implementation example 25 to 60, except that chemical compound 53 does not have the activity, described chemical compound is grown at the living cells of the lowering of concentration low 50% that table 3 shows at least, and culture medium and Panc-1, HCT-116, Pc3M/N, HEPG2, ASPC1 or the H460 cell that does not contain glucose used in described test.
Embodiment 62: the reduction of the anchorage dependence growth (soft agar) of cancerous cell.
Test implementation example 1 chemical compound in liquid culture and soft agar also.More specifically, under 37 ℃, containing 5%CO 2Humidification incubator (Ultra-Tech WJ301D; BaxterScientific Products, West Chester, PA, USA) in, cell is cultured in the Eagle culture medium (DMEM) of the 1 * Dubecco improvement that is supplemented with 10% hyclone (FBS), 2mM L-glutaminate, 1 * non essential amino acid and 1% Sodium Pyruvate, perhaps is cultured among the RPMI 1640 that is supplemented with 10%FBS and 2mM L-glutaminate, all reagent are all from Invitrogen, Carlsbad, CA, USA.Inoculation contains 1 * 10 in the fluid medium in each hole of flat microplate, 96 holes or semi-solid agar culture medium 3To 3 * 10 3The cell suspension culture of individual cell, and under 37 ℃, cultivated respectively 3 days and 7 days.Use PerSeptive BiosystemsCytoFluor  Series 4000 porous microplate reader, pass through alamarBlue TMDyeing (1: 10 volume reagent; Biosource International, Camarillo, CA USA) measures the cell growth, uses the emission with 590 ± 35nm place of exciting at 530 ± 25nm place.The result is presented in the following table 5.
The ability of table 5: embodiment 1 chemical compound anticancer cell in liquid culture and soft agar cultivation.
Cell type Cell line IC50(μM)
Liquid culture Soft agar
Breast carcinoma MCF7 T47D 0.03-0.1 ～0.03 ＜0.03 ＜0.03
Colon cancer SKBR3 MDA-231 MDA_MB-435 HS578 HCT116 HCT116-P53(-) HT29 SW480 DLD1 ～1 0.1-0.3 0.3-1 0.1-0.3 ＞1 ＞1 ＞1 0.3-1 0.3-1 ～1 ＜0.03 0.03-0.1 0.03-0.1 0.1-0.3 0.1-0.3 0.03-0.1 0.3-1 ～1
Carcinoma of prostate PC3M/N PC3 DU145 ＞1 0.1-0.3 ＞1 ～0.3 0.1-0.3 0.3-1
Cancer of pancreas Panc-1 ASPC-1 0.3-1 0.3-1
Ovary C. cancer A2780 OVCAR-1 PA-1 OVCAR-8 SK-OV-3 OVCAR-4 OVCAR-5 Caov-3 0.03-0.1 0.03-0.1 0.03-0.1 0.1-0.3 0.1-0.3 0.1-0.3 0.03-0.1 0.03-0.1 0.03-0.1 0.03-0.1 0.03-0.1
The NSCL cancer A549 NCI-H460 0.1-0.3 0.1-0.33 0.033-0.1 0.03-0.1
Hepatocarcinoma Hep3B 0.3-1
Melanoma UACC62 UACC257 A2058 0.1-0.3 ～0.1 0.1-0.3 0.03-0.1 0.1-0.3
Normally HUVEC W138 0.03-0.1 0.1-0.3
IMR90 CCD112/N 0.1-0.3 ～1
As shown in table 5, embodiment 1 chemical compound (under listed concentration level) demonstrates the cell growth of the listed cell line of reduction at least 50% in liquid culture or soft agar cultivation.
Embodiment 63: tumor size reduces in the colon cancer heteroplastic transplantation model.
Use the active anticancer of intraperitoneal and two kinds of single therapies of oral administration test implementation example 1 chemical compound in nude mouse xenotransplantation model in late period.Inoculate female athymism naked (nu/nu) mice with the HCT116 colon cancer cell, and allow tumor growth to volume be about 150mm 3Give mice with embodiment 1 chemical compound or contrast by oral or intraperitoneal then.As shown in Figure 1, the result shows that compared with the control gross tumor volume significantly reduces, and does not have overt toxicity, i.e. body weight change minimum (embodiment 1 chemical compound is called as IMST8-p in Fig. 1).
Embodiment 64: the reduction of tumor growth in nonsmall-cell lung cancer (NSCL) heteroplastic transplantation model.
The active anticancer of test implementation example 57 chemical compounds in the early stage model of nude mouse xenotransplantation.With naked (nu/nu) mice of the female athymism of H460 NSCL cell inoculation and be divided into two groups.Give carrier (contrast) to first group, to second group every day intraperitoneal give embodiment 57 chemical compounds (6 times/week).As shown in Figure 2, compared with the control, observe that H460 tumor size significantly reduces (p＜0.05) and do not have overt toxicity in the mice of accepting embodiment 57 chemical compounds (being designated as IMST8D1b in Fig. 2).
Embodiment 65: have synergistic combination
Also in the nude mouse heteroplastic transplantation model, tested the anti-tumor activity of the The compounds of this invention that makes up with at least a other chemotherapeutics.
A. inoculate female athymism naked (nu/nu) mice with the PC3 prostate gland cancer cell.When gross tumor volume reaches about 100mm 3The time, animal is divided into 4 groups, and makes that the average external volume of tumor is similar in 4 groups.Give carrier (in contrast) to first group, give embodiment 1 chemical compound (every day is oral) to second group, the 3rd group is given amycin (intraperitoneal) and make up (intraperitoneal amycin/oral embodiment 1 chemical compound) to the 4th group.The result shows (embodiment 1 chemical compound is called as IMST8 among Fig. 3) in Fig. 3.As seen in Figure 3, the therapeutic alliance of embodiment 1 chemical compound and amycin is very effective for reducing PC3 xenotransplantation in mid-term growth of tumor.
B. inoculate female athymism naked (nu/nu) mice with the PC3 prostate gland cancer cell.When gross tumor volume reaches about 100mm 3The time, animal is divided into 4 groups, and makes that the average external volume of tumor is similar in 4 groups.Give carrier (in contrast) to first group, give embodiment 1 chemical compound (every day is oral) to second group, the 3rd group is given Paclitaxel (paclitaxel) (intraperitoneal) and make up (intraperitoneal paclitaxel/oral embodiment 1 chemical compound) to the 4th group.The result shows (embodiment 1 chemical compound is called as IMST8 among Fig. 4) in Fig. 4.As seen in Figure 4, Paclitaxel (paclitaxel) single therapy has significantly reduced tumor size; And the therapeutic alliance of embodiment 1 chemical compound and Paclitaxel shows the further reduction to tumor growth.
Following table 6 has been summed up the result of heteroplastic transplantation experiment, shows that The compounds of this invention (being embodiment 1 chemical compound or embodiment 57 chemical compounds) reduces or suppress the usefulness of tumor growth.
Table 6
Tumor type Cell Dosage regimen The result
Colon HCT116 Embodiment 1 (intraperitoneal) Tumor reduces (25%)
Prostate PC3 Embodiment 1 (+amycin) Tumor reduces (72%)
Prostate PC3 Embodiment 1 (+Paclitaxel) Tumor reduces (83%)
NSCL H460 Embodiment 57 (intraperitoneal) Tumor reduces (41%)
The full content of incorporating all lists of references that this paper quotes into.Be to be understood that above detailed description only is intended to illustrate some preferred embodiment of the present invention.Be not intended to limit by any way the scope of the present invention described in claim.
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Claims (61)

1. the compositions that contains the quinoline of salt form; wherein said salt is selected from acetate; trifluoroacetate; carbonate; bicarbonate; benzoate; Salicylate; glucuronate salt; lactate; tartrate; mucate; gluconate; succinate; glutamate, Glu; aspartate; maleate; citrate; glutarate; phosphate; sulfate; mesylate; fluoroform sulphonate; toluene fulfonate; benzene sulfonate; 1, the 2-ethanedisulphonate; the 2-isethionate; the 2-naphthalene sulfonate; esilate; camsilate; sulfamate; cyclohexyl-n-sulfonate; the 2-mercapto-pyridine-n-oxide; ciclopirox; acetyl group-11-ketone-beta boswellic acid; celastrol; the dihydro celastrol; glycyrrhizic acid; maloic acid and 18-β-Gan Caotingsuan.
2. compositions as claimed in claim 1, wherein said salt is selected from acetate, trifluoroacetate, carbonate, bicarbonate, benzoate, Salicylate, glucuronate salt, lactate, tartrate, mucate, gluconate, succinate, glutamate, Glu, aspartate, maleate, citrate, glutarate, phosphate, sulfate, mesylate, fluoroform sulphonate, toluene fulfonate, benzene sulfonate, 1, the 2-ethanedisulphonate, the 2-isethionate, the 2-naphthalene sulfonate, esilate, camsilate, sulfamate and cyclohexyl-n-sulfonate.
3. compositions as claimed in claim 1, wherein said salt are phosphate or sulfate.
4. compositions as claimed in claim 1, wherein said salt are selected from 2-mercapto-pyridine-n-oxide, ciclopirox, acetyl group-11-ketone-beta boswellic acid, celastrol, dihydro celastrol, glycyrrhizic acid, maloic acid and 18-β-Gan Caotingsuan.
5. the compositions that contains the quinoline of salt form wherein uses the strong acid fluoropolymer resin to prepare described salt.
6. compositions as claimed in claim 5, wherein said resin are sulfonated polystyrene or Dowex-50.
7. following formula: compound or the acceptable salt of its medicine:
Figure A2006800025900003C1
Wherein:
R is selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl and C 7-C 18The phenylalkyl that replaces;
Perhaps, R and R 6Form the heterocycle of heterocycle or replacement;
Perhaps, R and R 4Form the heterocycle of heterocycle or replacement;
R 1Be selected from hydrogen, alkyl, alkoxyl, halogen, cyano group, nitro, CO 2R 7, C (O) NR 7R 8, C=NR 9-NR 7R 8,-CH=NR 7With-NR 7R 8, R wherein 7And R 8Be independently selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl or C 7-C 18The phenylalkyl that replaces;
Perhaps ,-NR 7R 8Be combined to form heterocycle, the ring-type C of heterocycle, replacement 2-C 7The ring-type C of assorted alkylidene or replacement 2-C 7Assorted alkylidene, the heterocycle of wherein said replacement and the ring-type C of replacement 2-C 7Assorted alkylidene also comprises oxo and formula=NR 9Replacement, R wherein 9Be selected from hydrogen, C 1-C 12Alkyl and C 1-C 12The alkyl that replaces;
R 2, R 3, R 4And R 6Be independently selected from hydrogen, C 1-C 12Alkyl, C 1-C 12Alkyl that replaces and halogen or following one of various: a)-(CH 2) nCO 2R 10B)-(CH 2) nCON (R 10) 2C)-(CH 2) nCN; And d) (CH 2) nSO 2R 10
R wherein 10Be selected from hydrogen, C 1-C 12Alkyl and C 1-C 12The alkyl that replaces, and n is 0 to 4; And
R 5Be selected from C 1-C 12Alkyl, C 1-C 12The alkyl, phenyl, the phenyl of replacement, naphthyl, the naphthyl of replacement, heterocycle, the heterocycle of replacement, the ring-type C that replace 2-C 7The ring-type C of assorted alkylidene and replacement 2-C 7Assorted alkylidene.
8. chemical compound as claimed in claim 7, wherein R is C 1-C 6Alkyl or C 7-C 18Phenylalkyl.
9. chemical compound as claimed in claim 7, wherein R 2, R 3, R 4And R 6Be hydrogen, C independently 1-C 6Alkyl or halogen.
10. chemical compound as claimed in claim 7, wherein R 7And R 8Be C independently 1-C 6Alkyl, C 1-C 6The alkyl or the C that replace 7-C 18Phenylalkyl.
11. chemical compound as claimed in claim 7, wherein NR 7R 8Form the heterocycle of 4 to 8 atoms, it contains 0 to 3 other hetero atom that is selected from N, O or S, and described heterocycle is by oxo or formula=NR 9At random replace.
12. chemical compound as claimed in claim 7, wherein NR 7R 8Be selected from morpholine-4-base, piperazine-1-base, 3-oxo piperazine-1-base, high piperazine-1-base, imidazoles-1-base, 2-oxo-imidazole alkane-1-base, 2-oxoimidazolinium-1-base and 2-iminoimidazoline-1-base.
13. chemical compound as claimed in claim 7, wherein R 5Be C 1-C 12Alkyl, C 1-C 12The heteroaryl of naphthyl, heteroaryl or the replacement of the phenyl of the alkyl that replaces, phenyl, replacement, naphthyl, replacement.
14. chemical compound as claimed in claim 7, wherein R 9And R 10Be hydrogen or C independently 1-C 6Alkyl.
15. contain the pharmaceutical composition of described compositions of claim 1 and drug acceptable carrier.
16. reduce the method for mammalian cancer cells growth, it comprises the described compositions of claim 1 to described cancerous cell application of treatment effective dose.
17. the method for treatment mammalian cancer, it comprises the described compositions of claim 15 of the mammalian subject of suffering from described cancer being treated effective dose.
18. method as claimed in claim 17, wherein said cancer is selected from cancer, sarcoma, adenoma, hepatocarcinoma, hepatoblastoma, rhabdomyoblastoma, esophageal carcinoma, thyroid carcinoma, the neuroganglion blastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, ewing's tumor, leiomyosarcoma, rhabdotheliosarcoma, colon cancer, cancer of pancreas, breast carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hematoma, cancer of biliary duct, melanoma, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, neck cancer, testicular tumor, pulmonary carcinoma, minicell and nonsmall-cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, multiple myeloma, rectal cancer, thyroid cancer, head and neck cancer, the brain cancer, the cancer of peripheral nervous system, central nervous system's cancer, nerve metrocyte carcinoma, endometrial cancer, the bone marrow lymphoma, leukemia, lymphoma, the lymphocytic hyperplasia disease, acute myelocytic leukemia, chronic leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma.
19. method as claimed in claim 17, wherein said cancer is selected from carcinoma of prostate, breast carcinoma, skin carcinoma, colon cancer, pulmonary carcinoma and cancer of pancreas.
20. contain the pharmaceutical composition of described chemical compound of claim 7 and drug acceptable carrier.
21. reduce the method for mammalian cancer cells growth, it comprises the described chemical compound of claim 7 to described cancerous cell application of treatment effective dose.
22. the method for treatment mammalian cancer, it comprises the described compositions of claim 20 of the mammalian subject of suffering from described cancer being treated effective dose.
23. method as claimed in claim 22, wherein said cancer is selected from cancer, sarcoma, adenoma, hepatocarcinoma, hepatoblastoma, rhabdomyoblastoma, esophageal carcinoma, thyroid carcinoma, the neuroganglion blastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, ewing's tumor, leiomyosarcoma, rhabdotheliosarcoma, colon cancer, cancer of pancreas, breast carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hematoma, cancer of biliary duct, melanoma, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, neck cancer, testicular tumor, pulmonary carcinoma, minicell and nonsmall-cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, multiple myeloma, rectal cancer, thyroid cancer, head and neck cancer, the brain cancer, the cancer of peripheral nervous system, central nervous system's cancer, nerve metrocyte carcinoma, endometrial cancer, the bone marrow lymphoma, leukemia, lymphoma, the lymphocytic hyperplasia disease, acute myelocytic leukemia, chronic leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma.
24. method as claimed in claim 22, wherein said cancer is selected from carcinoma of prostate, breast carcinoma, skin carcinoma, colon cancer, pulmonary carcinoma and cancer of pancreas.
25. following formula: compound or the acceptable salt of its medicine:
Figure A2006800025900006C1
Wherein:
A is selected from the heteroaryl of phenyl, heteroaryl or the replacement of phenyl, replacement, and wherein said replacement can also comprise-OR 3,-CHO ,-CN ,-CONR 3R 4Or CO 2R 3
R is selected from C 1-C 12Alkyl, C 1-C 12The alkyl, phenyl, the phenyl of replacement, the C that replace 7-C 18Phenylalkyl and C 7-C 18The phenylalkyl that replaces;
R 1And R 2Be independently selected from hydrogen, C 1-C 12Alkyl, C 1-C 12The alkyl, heterocycle, the heterocycle of replacement, the ring-type C that replace 2-C 7The ring-type C of assorted alkylidene, replacement 2-C 7The bicyclic heterocycle of assorted alkylidene, bicyclic heterocycle, replacement, halogen ,-CHO and cyano group, perhaps one of following formula :-OR 3,-NR 3R 4,-C (O) NR 3R 4With-CO 2R 3And
R 3And R 4Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl and C 7-C 18The phenylalkyl that replaces;
Condition is that at least a following eliminating takes place:
A) R is not C 1-C 4Alkyl or ethoxy;
B) R 17 of described quinoline basic ring be not methyl, dimethylamino, methoxyl group or heptan amino; Perhaps
C) A is not the pyrroles who replaces, wherein i) replacement on 2 and 5 of described pyrroles is methyl; Or ii) the replacement on 1 of described pyrroles is phenyl, alkyl, cyclohexyl or methoxy ethyl.
26. at least a following eliminating wherein takes place in chemical compound as claimed in claim 25:
A) R is not C 1-C 6Alkyl or hydroxy alkyl; Perhaps
B) R 1Not C 1-C 4Alkyl, alkoxyl, dialkyl amido or alkyl amino; Perhaps
C) A is not the pyrroles who replaces, wherein i) replacement on 2 and 5 of described pyrroles is C 1-C 4Alkyl; Or ii) the replacement on 1 of described pyrroles is phenyl, benzyl, alkyl, cyclohexyl or alkoxyethyl.
27. chemical compound as claimed in claim 25, wherein A is substituted, and it has the heteroaryl of phenyl, heteroaryl or the replacement of phenyl, replacement.
28. chemical compound as claimed in claim 27, wherein said phenyl or heteroaryl are by C 1-C 12The C of alkyl, replacement 1-C 12Alkyl, OR 3, halogen ,-CHO ,-CN ,-CONR 3R 4Or-CO 2R 3Replace.
29. chemical compound as claimed in claim 25, wherein A is phenyl, thiophenyl, furyl, indyl, the imidazole radicals Huo isoxazolyl that replaces arbitrarily.
30. chemical compound as claimed in claim 29, wherein A is substituted and described replacement is selected from C 1-C 12Alkyl, C 1-C 12The phenyl of the alkyl that replaces, phenyl, phenoxy group, benzyloxy, replacement ,-CHO and alkoxyl.
31. chemical compound as claimed in claim 30, wherein said replacement be selected from methyl, butyl, phenyl, phenoxy group, benzyl, benzyloxy ,-CHO and methoxyl group.
32. chemical compound as claimed in claim 29, wherein R is an alkyl.
33. chemical compound as claimed in claim 32, wherein R is a methyl.
34. reduce the method for mammalian cancer cells growth, it comprises the following formula: compound of described cancerous cell application of treatment effective dose or the acceptable salt of its medicine:
Wherein:
A is selected from the heteroaryl of phenyl, heteroaryl and the replacement of phenyl, replacement, and wherein said replacement can also comprise-OR 3,-CHO ,-CN ,-CONR 3R 4Or CO 2R 3
R is selected from hydrogen, C 1-C 12Alkyl, C 1-C 12The alkyl, phenyl, the phenyl of replacement, the C that replace 7-C 18Phenylalkyl and C 7-C 18The phenylalkyl that replaces;
R 1And R 2Be independently selected from hydrogen, C 1-C 12Alkyl, C 1-C 12The alkyl, heterocycle, the heterocycle of replacement, the ring-type C that replace 2-C 7The ring-type C of assorted alkylidene, replacement 2-C 7The bicyclic heterocycle of assorted alkylidene, bicyclic heterocycle, replacement, halogen ,-CHO and cyano group, perhaps one of following formula :-OR 3,-NR 3R 4,-C (O) NR 3R 4With-CO 2R 3And
R 3And R 4Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Alkynyl, C 1-C 12The alkyl, the C that replace 2-C 12The thiazolinyl, the C that replace 2-C 12The alkynyl, the C that replace 7-C 18Phenylalkyl and C 7-C 18The phenylalkyl that replaces.
35. method as claimed in claim 34, wherein A is the pyrroles of pyrroles or replacement.
36. method as claimed in claim 35, wherein said pyrroles its 2 and 5 by C 1-C 12Alkyl replaces; And at its 1 by C 1-C 12Alkyl, phenyl, heteroaryl or-CHO replaces.
37. method as claimed in claim 36, wherein said pyrroles its 2 and 5 by methyl substituted; Perhaps its 1 by butyl, phenyl, pyridine radicals or-CHO replaces.
38. method as claimed in claim 34, wherein R 1Be dialkyl amido, halogen or alkoxyl.
39. method as claimed in claim 38, wherein R 16 or 7 of described quinolyl.
40. method as claimed in claim 39, wherein R 1Be dimethylamino, bromine, chlorine or methoxyl group.
41. method as claimed in claim 34, wherein R 2Be hydrogen.
42. method as claimed in claim 41, wherein R is an alkyl.
43. method as claimed in claim 42, wherein R is methyl or ethyl.
44. method as claimed in claim 34, wherein A is phenyl, thiophenyl, furyl, indyl, the imidazole radicals Huo isoxazolyl that replaces arbitrarily.
45. method as claimed in claim 44, wherein A is substituted and described replacement is selected from C 1-C 12Alkyl, C 1-C 12The phenyl of the alkyl that replaces, phenyl, phenoxy group, replacement, benzyloxy ,-CHO, alkoxyl and dialkyl amido.
46. method as claimed in claim 45, wherein said replacement be selected from methyl, butyl, phenyl, phenoxy group, benzyl, benzyloxy ,-CHO, dimethylamino and methoxyl group.
47. method as claimed in claim 34, wherein R 1Be amino, mono-substituted amino or dibasic amino.
48. method as claimed in claim 47, wherein R 1Be alkyl amino or dialkyl amido.
49. method as claimed in claim 48, wherein R 1It is dimethylamino.
50. contain the pharmaceutical composition of described compositions of claim 25 and drug acceptable carrier.
54. method as claimed in claim 37, wherein said cancer is selected from cancer, sarcoma, adenoma, hepatocarcinoma, hepatoblastoma, rhabdomyoblastoma, esophageal carcinoma, thyroid carcinoma, the neuroganglion blastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, ewing's tumor, leiomyosarcoma, rhabdotheliosarcoma, colon cancer, cancer of pancreas, breast carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hematoma, cancer of biliary duct, melanoma, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, neck cancer, testicular tumor, pulmonary carcinoma, minicell and nonsmall-cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, multiple myeloma, rectal cancer, thyroid cancer, head and neck cancer, the brain cancer, the cancer of peripheral nervous system, central nervous system's cancer, nerve metrocyte carcinoma, endometrial cancer, the bone marrow lymphoma, leukemia, lymphoma, the lymphocytic hyperplasia disease, acute myelocytic leukemia, chronic leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma.
55. method as claimed in claim 34, wherein said cancer is selected from carcinoma of prostate, breast carcinoma, skin carcinoma, colon cancer, pulmonary carcinoma and cancer of pancreas.
56. the combination of the described chemical compound of claim 7 and another chemotherapeutics.
57. combination as claimed in claim 56, wherein said another chemotherapeutics is paclitaxel or amycin.
58. combination as claimed in claim 56, wherein said another chemotherapeutics is an inhibitors of kinases.
59. the combination of the described chemical compound of claim 25 and another chemotherapeutics.
60. combination as claimed in claim 59, wherein said another chemotherapeutics is paclitaxel or amycin.
61. combination as claimed in claim 59, wherein said another chemotherapeutics is an inhibitors of kinases.
62. the combination of the described chemical compound of claim 34 and another chemotherapeutics.
63. combination as claimed in claim 62, wherein said another chemotherapeutics is paclitaxel or amycin.
64. combination as claimed in claim 62, wherein said another chemotherapeutics is an inhibitors of kinases.
CNA2006800025905A 2005-01-18 2006-01-18 Novel quinolinium salts and derivatives Pending CN101106992A (en)

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