CN1066068A - 4-aryl-3-(fragrant heterocyclic radical urea groups) quinoline derivatives - Google Patents
4-aryl-3-(fragrant heterocyclic radical urea groups) quinoline derivatives Download PDFInfo
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- CN1066068A CN1066068A CN92103010A CN92103010A CN1066068A CN 1066068 A CN1066068 A CN 1066068A CN 92103010 A CN92103010 A CN 92103010A CN 92103010 A CN92103010 A CN 92103010A CN 1066068 A CN1066068 A CN 1066068A
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- quinoline
- chloro
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Salt that the present invention relates to following formula: compound and pharmaceutically be suitable for and the new intermediate that is used for synthetic following formula: compound,
R wherein
1, R
2, R
3, R
4, m, X and Q the definition narration of face as follows.Therefore formula I compound is the inhibitor of ACAT (ACAT), can be used for blood fat reducing and as antiatherosclerotic.
Description
The present invention relates to new 4-aryl-3-(fragrant heterocyclic radical urea groups) quinoline derivatives, the medicinal compositions that contains this compounds, the new 3-nitroquinoline class intermediate that is used for synthetic this compounds and this compounds suppressing the cholesterol intestinal absorption, reducing serum cholesterol and eliminating the application that atherosclerosis forms.This compounds is the inhibitor of ACAT (ACAT).
The cholesterol that is consumed in the diet (dietary cholesterol exposure) by mucomembranous cell and small intestine with the free cholesterol absorption.The free cholesterol is assembled in the particle that is called chylomicron, and is discharged in the blood flow by enzyme ACAT esterification then.Chylomicron is a particle, and therein, dietary cholesterol exposure is assembled and be transported in the blood flow.By suppressing the effect of ACAT, The compounds of this invention can stop the intestinal absorption dietary cholesterol exposure, therefore can reduce serum cholesterol content.Prevention of arterial is atherosis so The compounds of this invention can be used for, heart attack and apoplexy.
By suppressing the effect of ACAT, The compounds of this invention can also be removed cholesterol from vessel wall.This effect makes The compounds of this invention both can be used for stoping or eliminating atherosclerotic formation, can prevent heart attack and apoplexy again.
Other inhibitor of ACAT are referring to United States Patent (USP) 4,716,175 and 4,743, the dividing an application of 605(' 175 patents), publication No. is 0242610,0245687,0252524 and 0354994 european patent application, and U.S. Patent application 07/648, the 677(date of application 1991,1,31, and transfer the possession of the same with the application).
As some ureas of antiatherosclerotic and thiourea referring to United States Patent (USP) 4,623,662 and publication No. be 0335374,0386487,0370740,0405233 and 0421456 european patent application.
The salt that the present invention relates to following formula: compound and pharmaceutically be suitable for,
Wherein
Each m system is independently selected from zero～4;
R
1System is selected from hydrogen, (C
1～C
6) alkyl, (C
6～C
12) aralkyl, aryl moiety system is selected from phenyl, thienyl, furyl and pyridyl here;
R
2System is selected from hydrogen, (C
1～C
6) alkyl and (C
1～C
6) alkoxyl group;
Each R
3And R
4(the C that system is independently selected from hydrogen, halogen, is replaced arbitrarily by one or more halogen atoms
1～C
6) the alkyl, (C that replaces arbitrarily by one or more halogen atoms
1～C
6) the alkoxyl group, (C that replaces arbitrarily by one or more halogen atoms
1～C
6) alkylthio, nitro, by (C
1～C
6) carboxyl, the hydroxyl, (C of any esterification of alkyl
1～C
6) acyloxy and NR
12R
13, R here
12And R
13Can be identical or different, and can be selected from next group group: hydrogen, (C
1～C
6) alkyl, halogenated (C arbitrarily
1～C
6) acyl group, halogenated (C arbitrarily
1～C
6) alkyl sulphonyl, (C
1～C
6) alkyl amino-carbonyl and (C
1～C
6) alkoxy carbonyl, perhaps R
12And R
13Form piperidines, tetramethyleneimine or morpholine ring with the nitrogen that it connected;
X is sulphur or oxygen,
Q is the following formula group,
Wherein
The definition of m is the same;
N is zero or 1;
Each 1 is to be independently selected from zero～3;
Each R
6And R
7System is independently selected from next group group: halogen, (C
1～C
6) alkyl, (C
1～C
6) haloalkyl, halogenated (C arbitrarily
1～C
6) alkoxyl group, halogenated (C arbitrarily
1～C
6) alkylthio, (C
5～C
7) cycloalkylthio, phenyl (C
1～C
6) alkylthio, the thiophenyl of replacement, aromatic heterocycle sulfenyl, aromatic heterocycle oxygen base, (C
1～C
6) alkyl sulphinyl, (C
1～C
6) alkyl sulphonyl, (C
5～C
7) cycloalkyl sulfinyl, (C
5～C
7) naphthene sulfamide base, phenyl (C
1～C
6) alkyl sulphinyl, phenyl (C
1～C
6) alkyl sulphonyl, the phenyl sulfinyl of replacement, phenyl sulfonyl, aromatic heterocycle sulfinyl, aromatic heterocycle alkylsulfonyl and the NR of replacement
10R
11, R here
10And R
11Can be identical or different, they are to be selected from next group group: hydrogen, (C
1～C
6) alkyl, phenyl, the phenyl of replacement, (C
1～C
6) aroyl of acyl group, aroyl and replacement, the aroyl of phenyl of Qu Daiing and replacement is to be replaced by one or more substituting groups that are independently selected from next group here: (C
1～C
6) alkyl, (C
1～C
6) alkoxyl group, (C
1～C
6) alkylthio, halogen and trifluoromethyl, perhaps R
10And R
11Form piperidines, tetramethyleneimine or morpholine ring with the nitrogen that it connected; And B, D, E and G system are selected from nitrogen and carbon, and condition is that one or more are nitrogen among B, D and the E, and when G is nitrogen, and group X VI was connected on the nitrogen of formula I with 4 of pyrimidine ring or 5 (representing with a and b), and arbitrary nitrogen-atoms described here can be oxidized.
Except as otherwise noted, otherwise terminology used here " halogen " comprises fluorine, chlorine, bromine and iodine.
Except as otherwise noted, otherwise terminology used here " alkyl " can be straight chain, side chain or cyclic, and can comprise straight chain and cyclic part and side chain and cyclic part.
Except as otherwise noted, otherwise terminology used here " one or more substituting groups " or " one or more halogen atoms " be meant from 1 to substituting group according to the possible maximum number of the key position that exists.
The invention still further relates to following formula: compound,
Wherein m, R
3And R
4Definition the same, condition is R
3Or R
4It or not the alkylthio that replaces arbitrarily.Above-claimed cpd is a useful as intermediates in syntheticcompoundofformula.
Formula I compound is following compound preferably, and wherein Q is 6-(C
1～C
3) alkoxyl group quinoline-5-base, 6-(C
1～C
3) alkylthio quinoline-5-base, 6-(C
1～C
3) alkyl quinoline-5-base, 6-(C
1～C
3) alkylthio isoquinoline 99.9-5-base, 6-(C
1～C
3) alkoxyl group isoquinoline 99.9-5-base, 4, the two ((C of 6-
1～C
3) alkylthio)-2-methylpyrimidine-5-base, 4, the two ((C of 6-
1～C
3) alkylthio) pyrimidine-5-base, 2, the two ((C of 4-
1～C
3) alkylthio)-6-picoline-3-base or 2, the two ((C of 4-
1～C
3) alkylthio) pyridin-3-yl.
Other preferably formula I compound be following compound, wherein R
1Be hydrogen, R
2System is selected from hydrogen and methoxyl group and each R
3And R
4System is selected from (C
1～C
6) alkyl, chlorine, fluorine and trifluoromethyl.
Better formula I compound is following compound, wherein Q is 6-methoxy quinoline-5-base, 6-methylthio group quinoline-5-base, 6-methoxyl group isoquinoline 99.9-5-base, 6-methylthio group isoquinoline 99.9-5-base, 2-methyl-4, two (methylthio group) pyrimidines of 6--5-base, 6-methyl-2, two (methylthio group) pyridin-3-yls of 4-, 2, two (ethylmercapto group) pyridin-3-yls of 4-, 2,4,6-trimethylpyridine-3-base, 2,4-dimethoxy-6-picoline-3-base, 6-(4-anisole sulfenyl) quinoline-5-base and 6-penta sulfenyl quinoline-5-base.
Concrete preferably formula I compound comprises:
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups-6-chloro-4-(2-chloro-phenyl-) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methylthio group quinoline-5-yl)-urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline;
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-ethyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline;
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline; With
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6, the 8-dimethyl quinoline.
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4,6-trimethylpyridine-3-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4-dimethoxy-6-picoline-3-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-3-(3-6-(4-anisole sulfenyl) and quinoline-5-yl } urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-penta sulfenyl quinoline-5-yl) urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-)-2 methoxy quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 2-methoxyl group-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline.
Other formula I compound comprises:
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-toluquinoline-5-yl) urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(2,4-diethoxy-6-picoline-3-yl) urea groups) quinoline;
3-(3-{ 2, two (iprotiazem the base)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-) quinoline;
3-(3-{ 4, two (ethylmercapto group) pyrimidines of 6--5-yl } urea groups)-6-chloro-4-(2-aminomethyl phenyl) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(2-dimethylamino-6-methyl-4-methylthio group pyridin-3-yl) urea groups) quinoline;
3-(3-{ 2, two (ethylmercapto group) pyridin-3-yls of 4-} urea groups)-6-chloro-4-(2-fluorophenyl) quinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-6-chloro-4-(2-aminomethyl phenyl) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-)-the 8-toluquinoline;
3-(3-{ 2, two (methylthio group) pyridin-3-yls of 4-} urea groups)-4-(2-chloro-phenyl-)-6-fluorine quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(3, the 4-Dimethoxyphenyl) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-difluoro methylthio group-4-phenylquinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-6-difluoro-methoxy-4-phenylquinoline;
3-(3-{ 2, two (ethylmercapto group) pyridin-3-yls of 4-} urea groups)-8-chloro-4-(2-chloro-phenyl-)-the 6-toluquinoline;
3-(3-{ 2, two (methylthio group) pyridin-3-yls of 4-} urea groups)-6-chloro-4-(2,3, the 4-trimethoxyphenyl) quinoline;
3-(3-{ 4, two (the ethylmercapto group)-2-methylpyrimidines of 6--5-yl } urea groups)-6-chloro-4-(2-p-methoxy-phenyl) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6, the 7-dimethyl quinoline;
3-(3-{ 4, two (methylthio group) pyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-5,6, the 7-trimethylquinoline; With
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-dimethylamino quinoline.
The present invention also relates to the compound of the radio-label mark pattern of formula I and formula II, comprise tritium and/or C
14The compound of mark.The compound of described radio-label mark can be used as animal and human's pharmacokinetic analysis and the instrument of differentiating in conjunction with research in the test and characteristic.
The invention still further relates to and suppress ACAT, the intestinal absorption that suppresses cholesterol, elimination or stop atherosclerosis formation or the medicinal compositions of reduction serum cholesterol concentration in Mammals (comprising the people), said composition comprises and suppresses ACAT, the intestinal absorption that suppresses cholesterol, elimination or stop atherosclerosis formation or the formula I compound of reduction serum cholesterol concentration effective dose or its salt and pharmaceutical carrier that pharmaceutically is suitable for.
The method that the present invention also relates to suppress ACAT, the intestinal absorption that suppresses cholesterol, elimination or the formation of prevention atherosclerosis in Mammals (comprising the people) or reduce serum cholesterol, this method comprise to Mammals takes formula I compound or its salt that pharmaceutically is suitable for that suppresses ACAT, the intestinal absorption that suppresses cholesterol, elimination or the formation of prevention atherosclerosis or reduce the serum cholesterol concentration effective dose.
The example of the acid salt that pharmaceutically is suitable for of formula I compound has the salt that forms with hydrochloric acid, tosic acid, fumaric acid, citric acid, succsinic acid, Whitfield's ointment, oxalic acid, Hydrogen bromide, phosphoric acid, methylsulfonic acid, tartrate, two-toluoyl base tartrate and inclined to one side peach acid.
The reaction scheme 1-3 that lists has below illustrated the synthetic of The compounds of this invention.Except as otherwise noted, otherwise following reaction scheme and in question R
1, R
2, R
3, R
4, R
6, R
7, R
10, R
11, R
12, R
13, Q, X, B, D, E, G, l, m and n definition the same.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 1 has illustrated and has prepared wherein R
1Method for the formula I compound of hydrogen.Referring to reaction scheme 1, make the method preparation of initial compounds formula III (can by Synthesis 677(1980)) with 1, two (methylthio group)-2-nitroethylenes (IV) reactions of 1-obtain corresponding formula II compound.This reaction is usually in inert solvent (as acetate, propionic acid or polyphosphoric acid), in about 100 ℃～160 ℃ reactions 2～24 hours.Be preferably in the acetate about 120 ℃ the reaction 16 hours.
The formula II compound that top reaction is generated reduces then, generates corresponding formula V compound.Use excessive Raney nickel, in suitable inert solvent (as ethanol, methyl alcohol, diox, acetone, tetrahydrofuran (THF) or dimethyl formamide), add entry or do not add entry, reduction reaction and one step of desulphurization reaction are finished.This reaction was carried out 1～8 hour.Temperature of reaction can be at 20 ℃～100 ℃.Be preferably in excessive Raney nickel and exist down, in ethanol, made reduction of formula II compound and desulfurization in 2～3 hours 80 ℃ of reactions.
In addition, can be from corresponding formula II compound with two-stage process preparation formula V compound, its method is as follows: at first formula II compound is reduced into corresponding aminoderivative, carries out the desulfurization of the step then, obtain formula V compound.The 1st step appropriate reductant has tin protochloride, titanium chloride (III), iron or zinc, uses or without acid catalyst (example hydrochloric acid or acetate), perhaps reduces together with hydrogen and appropriate catalyst, and reduction reaction was carried out 2～16 hours in 0 ℃～100 ℃.In the 2nd step, carry out desulphurization reaction by the above with excessive Raney nickel.
Also can be by Helv.Chem.Acta.71,531(1988) described, with copper-aluminium alloy, perhaps press J.Chem.Soc.Chem.Commun., 819(1990) and J.Chem.Soc.(C), 1122(1968) described, make formula II compound carry out reduction and desulfurization reaction with nickel borides.
In European patent 0354994A2, narrated the other synthetic method of preparation formula V compound.
At Z.Chem.8,294(1973) and J.Prakt.Chem., 318,39, narrated wherein R in (1976)
3And R
4Be the formula II of hydrogen and the preparation method of formula V compound, and wherein except that 1 R is arranged
3Be outer all the other R of 6-chlorine
3And R
4Be the formula II of hydrogen and the preparation method of formula V compound.
The formula V compound and the formula QN=C=X compound one that generate are reacted, obtain corresponding urea of formula I-A (X=O) or thiocarbamide (X=S).The method of preparation formula QN=C=X compound is known in the literature, and at " Organic Functional Group Preparations, Vol.1 ", 12 chapters, Academic Press, SOME METHODS has been commented in (1968) in New York.At " Organic Func-tional Group Preparations, Vol.2 ", 6 chapters, Academic Press, commented in New York (1971) by amine respectively with the method for isocyanates and isosulfocyanate prepared in reaction urea and thiocarbamide.
Make QNH
2Reagent that compound and 1～6 a great deal of are suitable such as phosgene, trichloromethyl chloro-formic ester or two (trichloromethyl) carbonate reaction can obtain formula QN=C=O compound.This reaction is carried out in inert ether, aromatic hydrocarbon or chlorinated hydrocarbon solvent such as diox, Di Iso Propyl Ether, benzene, toluene, methylene dichloride or chloroform usually.Reaction can be carried out in the presence of alkali such as tertiary amine (as pyridine, triethylamine or quinoline).Temperature of reaction can be 0 ℃～about 120 ℃ scope, and 20 ℃～about 100 ℃ better.Preferably with formula QNH
2Heterocyclic amine and the reaction 18 hours in the methylene dichloride that refluxes of the trichloromethyl chloro-formic ester of 1～2 a great deal of.
Being reflected in inert anhydrous solvent such as chloroform, benzene, dimethyl formamide, diox or the tetrahydrofuran (THF) in 20 ℃～100 ℃ of the formula QN=C=X compound of production I-A compound and formula V compound carried out about 3～30 hours, was preferably in the dimethyl formamide in about 80 ℃ of reactions 16 hours.
In addition, formula I-A compound can be pressed the method preparation: make formula QNH
2Intermediate and suitable quinoline-3-based isocyanate (making) reaction by the described method of European patent 0354994A2.This reaction is carried out under the conditions of similarity of the above formula V compound and the reaction of QN=C=X compound usually.
R wherein
1The formula I compound that is not hydrogen can be by the method preparation of reaction scheme 2 and the following stated.
Referring to reaction scheme 2, according to United States Patent (USP) 3,798,226(incorporates this patent in this application into own forces as a reference) described, with suitable starting raw material V acidylate, generate corresponding formula VI compound.
Through type VI compound and formula R
1Z compound (wherein Z is a leavings group) reaction is with R
1Substituting group is added on the formula VI compound.Suitable leavings group comprises halogen, (C
1～C
6) alkane sulfonyloxy (as mesyloxy, ethanesulfonyloxy group etc.) and (C
6～C
10) arylsulfonyloxy (as phenylsulfonyloxy, tolysulfonyl oxygen base etc.).The suitable solvent of this reaction comprises inert solvent such as tetrahydrofuran (THF) (THF), glycol dimethyl ether (DME) and N, dinethylformamide.This reaction is quickened.This reaction is carried out at 20 ℃～about 120 ℃ usually, and carries out better at 0 ℃～about 100 ℃.Solvent is a dimethyl formamide preferably, and alkali is sodium hydride preferably.
Formula VII amide hydrolysis with generating obtains corresponding formula VIII amine.Hydrolysis is carried out in the active solvent of proton such as lower alcohol (as methyl alcohol, ethanol or propyl alcohol) or acetate usually.Hydrolysis is preferably in mineral acid (example hydrochloric acid, Hydrogen bromide or sulfuric acid) and exists down, carries out with the amount of 2～20 moles (3～15 moles better) by every mole of formula VII compound.Temperature of reaction is 60 ℃～about 120 ℃ scope, at 70 ℃～100 ℃ better.
In addition, R wherein
1Be not that the formula VIII compound of hydrogen can be pressed the method preparation: press United States Patent (USP) 3,798 earlier, 226 described methods, with suitable acylating agent (as R
15COCl or (R
15CO)
2O, wherein R
15With R
1Identical, but R
15Compare R
1Contain 1 methylene radical less) with corresponding formula V compound acylation, using appropriate reductant such as lithium aluminum hydride, two (2-methoxy ethoxy) the aluminium sodium of hydrogenation or two boranes then is required formula VIII compound with the reduction of amide that generates.This reduction reaction in inert solvent such as tetrahydrofuran (THF), diox or glycol dimethyl ether, is carried out in 25 ℃～about 110 ℃ usually.
By above-described method with by shown in the reaction scheme 1 of formula V compound formula I-A compound, formula VIII compound can be transformed into corresponding needed formula I-B compound.
Aminopyrimidine of using among the present invention and aminopyridine intermediate are (suc as formula Q-NH
2Compound) is known in the literature, perhaps can makes by methods known in the art by the known various pyrimidines that maybe can buy and pyridines intermediate in the document.The pyrimidine that can buy on the market and pyridines intermediate comprise 4,6-two chloro-5-nitro-pyrimidines, 2,4-dihydroxyl-6-methylpyrimidine, 4,6-dihydroxyl-2-methylpyrimidine, 5-nitrobarbituric acid, 2-hydroxy-4-methyl-3-nitropyridine and 3,4-dihydroxy-pyridine.In monograph " The Pyrimidines " by D. J.Brown(1962) publish and " Pyridine and its Derivatives " by R.A.Abramovitch(1961) publish, Interscience Publishers, Inc., New York, and the reference that can find many pyrimidines and pyridines intermediate preparation method in their addendum N.Y..Above-mentioned pyridine and pyrimidines can be transformed into corresponding aminopyridine and Aminopyrimidines intermediate (seeing that " The Pyrimidine " is by D.J.Brown(1962) publication and " Pyridine and its Derivatives " by R.A.Abramovitch(1961) publish, Interscience Publishers, Inc., New York, N.Y., and their addendum), the method that can know by the professional in present technique field is applied to the synthetic of The compounds of this invention with them.
Narrate some aminopyridine and Aminopyrimidines intermediates preparation below in more detail.
Make 4 of suitable replacement, the acetic acid solution of 6-dihydroxy-pyrimidine and nitrating agent such as nitrosonitric acid can make 4,6-two replacement-5-aminopyrimidine analog derivatives in 15 ℃～about 40 ℃ of reactions 1～about 5 hours.With chlorizating agent such as phosphoryl chloride,,, the 5-nitro-pyrimidine compounds that generates can be transformed into 4,6-two chloro-5-nitro-pyrimidine class intermediates 100 ℃～about 115 ℃ of reactions 0.5～about 2 hours without alkali or in the presence of alkali (preferably Diethyl Aniline).Carry out the method for this transformation and see J.Chem.Soc., 3832(1954).
4, two (the alkylthio)-5-nitro-pyrimidine analog derivatives of 6-can be pressed the method preparation: make two suitable chloromethylated intermediates and 2 a great deal of alkyl sulfide hydroxy acid sodium in solvent such as dimethyl formamide or methyl alcohol (methyl alcohol is better), in about 4～about 16 hours of 0 ℃～about 30 ℃ (being preferably in room temperature) reaction.
4, one substitution reaction of 6-two chloro-5-nitro-pyrimidine class intermediates is undertaken by laxative remedy: make 4,6-two chloro-5-nitro-pyrimidine intermediates and 1 a great deal of nucleophilic reagent are in inert solvent (as dimethyl formamide or tetrahydrofuran (THF)), 0 ℃～about 100 ℃ (reactivity according to nucleophilic reagent is decided) reaction 4～about 16 hours.Make then generation-reaction of the chlorine derivative nucleophilic reagent different with 1 a great deal of, obtain on 4 and 6 carbon atoms of pyrimidine ring, having the disubstituted derivatives of different substituents.With reductive agent such as tin protochloride and concentrated hydrochloric acid, perhaps with hydrogen and appropriate catalyst reduction 4,6-two replacement-5-nitro-pyrimidines obtain corresponding 5-aminopyrimidine analog derivative.
Make suitable 2,4-dihydroxy-pyridine and nitrating agent such as concentrated nitric acid were in 80 ℃～about 100 ℃ of reactions 15～60 minutes, can make 2,4-two replacement-3-aminopyridine analog derivatives (for example 2, the preparation method of 4-dihydroxyl-6-methyl-3-nitro pyridine sees J.Hetercyclic Chem., 1970,7,389).With the reaction conditions that is similar to above-mentioned pyrimidine compounds, with 2 of generation, 4-dihydroxyl-3-nitropyridine is transformed into 2,4-two chloro-3-nitropyridines, 2,4-two replacement-3-nitropyridines and 2,4-two replacement-3-aminopyridine then.
By similar method, can with suitable replacement-hydroxy pyrimidine and pyridine be transformed into nitro-hydroxy derivatives and nitro-chlorine derivative.Make nitro-chloromethylated intermediate and suitable sulphur, oxygen or nitrogen nucleophile reaction then, obtain the nitro-derivative that oxygen, sulphur or nitrogen replace, this nitro-derivative can be reduced into required aminopyrimidine or pyridine.
In reaction scheme 1 and 2, be used as the explanation in reaction scheme 3 of synthesizing of some the 5-quinolylamine of reactant and 5-aminoisoquinoline.Referring to reaction scheme 3, the 5-quinolylamine of formula (X V) and (X VII) and isoquinoline 99.9 can be pressed the method preparation.With nitrating agent such as nitric acid or saltpetre (can use acid catalyst such as sulfuric acid, also can),, can obtain the nitration product X of formula IX quinoline or isoquinoline 99.9 respectively in 0 ℃～100 ℃ reactions 2～16 hours.Then the formula X nitro-compound that obtains is used reductive agent such as tin protochloride, iron, zinc, perhaps use hydrogen and appropriate catalyst, acid catalyst (example hydrochloric acid) is arranged or do not have acid catalyst,, obtain corresponding formula XI 5-quinolylamine or 5-aminoisoquinoline in 0 °～100 ℃ reactions 2～16 hours.
Wherein B or D are nitrogen, R
14Be (C
1～C
6) alkyl, (C
5～C
7) cycloalkyl, phenyl (C
1～C
4) the formula X III compound of fragrant heterocyclic radical of phenyl, fragrant heterocyclic radical or replacement of alkyl, phenyl, replacement can press the method preparation.(wherein l is at least 1, and 1 R to make formula X compound
7Be-Cl, it is connected on quinoline ring or isoquinoline 99.9 ring 6) with formula R
14SH compound (R wherein
14Definition the same) and alkali (as sodium hydride) reaction, perhaps make above-mentioned formula X compound and formula R
14SNa compound (R wherein
14Definition the same) reaction, reaction is to carry out in inert solvent (as tetrahydrofuran (THF)), temperature of reaction is-10 a ℃～room temperature, the reaction times is about 4～16 hours.Temperature of reaction is-10 ℃ preferably.Above-mentioned reaction obtains formula XII compound, and the method by above-mentioned reduction-type X compound changes formula XII compound into corresponding formula X III 5-quinolylamine or isoquinoline 99.9 then.
In above-mentioned arbitrary reaction, except as otherwise noted, otherwise pressure is not critical.If know, above-mentioned reaction temperature of reaction is preferably indicated.In general, each reacts preferably that temperature of reaction is the minimum temperature that can generate product.With the thin-layer chromatography monitoring, can determine specifically to react temperature of reaction preferably.
2-replacement-5-quinolylamine can be used to prepare wherein R
2Be not the formula I compound of hydrogen, 2-replacement-5-quinolylamine can be by Ikeda(European patent 0421456) the method preparation.Then they are used for surrogate response route 1 and 2 Chinese style V and formula VIII compound respectively, generate wherein R respectively
1Be hydrogen or be not the formula I 2-substitution compound of hydrogen.
New formula I compound and the salt that pharmaceutically is suitable for thereof can be used as the inhibitor of ACAT (ACAT).Therefore, The compounds of this invention can suppress the intestinal absorption of cholesterol in the Mammals, and can be used for the treatment of the Mammals high anteserum cholesterol of (comprising the people)." processing " described here means and not only can prevent but also can alleviate high anteserum cholesterol.Can take compound of the present invention for the sick body of needs treatment by the route of administration (comprising oral administration, non-) of various routines through gastrointestinal administration and topical.In general, the oral or non-dosage that gives The compounds of this invention through gi tract is preferably 0.8～5mg/kg body weight for needing sick body 0.5～30mg/kg every day body weight of treatment.Therefore, for the adult of body weight for about 70kg, dosage commonly used is every day 35～about 2000mg.But, treat the situation of sick body and the compound activity of application as required, aspect dosage, carry out some changes and also will inevitably take place.To each sick body, determine proper dosage in any case according to the individuality of taking medicine.
The salt that formula I compound or its pharmaceutically are suitable for can be taken separately by single dose or multidose, perhaps takes with pharmaceutical carrier.Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The medicinal compositions that generates can easily be taken with multiple formulation (as tablet, pulvis, lozenge, syrup, injection solution etc.).If desired, above-mentioned medicinal compositions can contain other composition such as seasonings, tackiness agent, vehicle etc.Therefore, for oral administration, the tablet that contains various vehicle (as Trisodium Citrate, lime carbonate and calcium phosphate) can also contain various disintegrating agents (as starch, alginic acid and some compound silicate) and tackiness agent (as polyvinylpyrrolidone, sucrose, gelatin and Sudan Gum-arabic).In addition, lubricant (as Magnesium Stearate, sodium lauryl sulfate and talcum) is generally used for preparing tablet.The solids composition of same-type can also be used for soft gelatin capsule and hard gelatin capsule as weighting agent.Capsule weighting agent preferably comprises lactose and high-molecular weight polyoxyethylene glycol.If wish aqueous suspension or elixir are used for oral administration, basic effective constituent and various sweeting agent or seasonings, coloring material or dyestuff (if desired, also emulsifying agent or suspensoid should be arranged) and thinner (as water, ethanol, polyoxyethylene glycol, glycerine and their mixed solution) can be prepared together so.
Through gastrointestinal administration, can use formula I compound or its salt that pharmaceutically is suitable for for non-at sesame oil or peanut oil, aqueous solution of propylene glycol or the solution in aseptic aqueous solution.If desired, should be suitably with above-mentioned aqueous pharmaceutical buffering, and at first liquid diluent etc. is oozed with the salt solution of capacity or glucose.Described solution is particularly useful for through intravenous injection, intramuscularly, subcutaneous injection and peritoneal injection administration.In this respect, the aseptic aqueous medium of application can easily be obtained by general technology by the professional who is familiar with the present technique field.
Can measure the effect of The compounds of this invention by many general biology or pharmacology test as the ACAT inhibitor.For example, measure the activity that formula I compound suppresses ACAT in the following method.According to Bilheimer, J.T, Meth.Enzymol., 111, P.286～293(1985) described and through less improved method, carry out the ACAT test with isolated microsome in the Sprague-Dawley strain big white mouse that feeds the combined balance system feed.The microsome that obtains from rat liver passes through differential centrifugation, and washes with the test damping fluid before using.Test mixture contains 25 μ l BSA(40mg/ml), 30 μ l rat liver microsome solution (100 μ g microsomal protein), 20 μ l test damping fluid (0.1M K
2Po
4, the 1.0mM reduced glutathione, pH7.4), the test buffered soln of 100 μ l, the 0.6% Trition WR-1339 of 20 μ g cholesterol and the solution (cumulative volume is 180 μ l) that 5 μ l test compounds are dissolved in 100% DMSO.With test mixture in 37 ℃ of incubation 30min.Add 14 ℃-Oleoyl-CoA(1000 of 20 μ l μ M, 2,000 dpm/nmol) starting reaction and carried out 15 minutes in 37 ℃.Adding 1ml ETOH stops reaction.With lipid extraction in the 4ml hexane.The 3ml sample aliquot is dry under nitrogen, is suspended to once more in the 100 μ l chloroforms.50 μ l chloroformic solution points on the TLC of heat-activated thin plate, and are used hexane: ether: acetate (85: 15: 1, V: V: V) launch.The radioactivity that on Berthold LB 2842 Linear TLC analysers, quantitatively adds the cholestene ester.With the DMSO controlled trial is benchmark, calculates the activity that suppresses ACAT.
Formula I compound suppresses the effect of intestinal absorption cholesterol can be by Melchoir and Harwell(J.Lipid.Res., 26,306～315(1985)) described method measures.
The present invention enumerates following example.But should be realized that the restriction that the present invention is not specified by these examples.Fusing point is not calibrated.With deuteriochloroform (CDCl
3) or D
6-dimethyl sulfoxide (DMSO) (DMSO-D
6) solution carry out proton NMR spectrum (
1H NMR) and
13The C nuclear magnetic resonance spectrum (
13C NMR) mensuration, and the position at peak is made interior mark with PPM (PPm) expression with tetramethylsilane.The shape at peak is represented with following abbreviation: S, and unimodal; D, doublet; T, triplet; G, quartet; M, multiplet; B, broad peak; C, complicated peak; H, septet.
Example 1
5-amino-6-methoxy quinoline
The method (J.Am.Chem.Soc., 1946,68,1559) that the 6-methoxy quinoline of having bought on the market (13.80g) is pressed Campbell etc. is carried out nitrated, obtains 5-nitro-6-methoxy quinoline (17.51g).This crude product is pressed the method (J.Am.Chem.Soc., 1920,42,2278) of Jacobs etc. and is directly reduced, and obtains 5-amino-6-methoxy quinoline (6.25g).m.p.152.5～154.5℃。
Example 2
5-amino-6-methylthio group quinoline
The 6-chloroquinoline (33.3g) of having bought on the market is undertaken nitrated by example 1 described method, obtain 5-nitro-6-chloroquinoline (20.36g).Method (Iowa State Coll.J.Sci.1946,21,41 that this product (15g) and methyl thiolic acid sodium are pressed Massie; CA 41: 3044g) react, obtain 5-nitro-6-methylthio group quinoline (13.61g).This product (3.70g) obtains 5-amino-6-methylthio group quinoline (3.0g) with 50% aqueous ethanolic solution (50ml) reduction of iron powder (5.62g) and hydrochloric acid (15ml).m.p.88.5～90.5℃。
Example 3
3-amino-2, two (the methylthio group)-6-picolines of 4-
Stir and nitrogen gas stream under, to 15.5g(0.22mol) add 20.8g(0.1mol at leisure in the 200ml methanol solution of carbothiolic acid sodium) 3-nitro-2, the 150ml methanol solution of 4-two chloro-6-picolines.Generate precipitation, with mixture in stirred overnight at room temperature.Then mixture after filtration, solid is used methyl alcohol and water washing successively.Obtain 3-nitro-2, two (the methylthio group)-6-picolines (18.9g, productive rate are 82%) of 4-are yellow solid, m.p.172～176 ℃.
1H NMR（CDCl
3）：δ2.45（s，3H）;2.51（s，3H）;2.55（s，3H）;6.77（s，1H）。
In the Pa Er hydrogenation apparatus with 18.9g(0.082mol) 3-nitro-2, two (methylthio group)-6-picolines of 4-and 18.9g Raney nickel be at 600ml1, a mixture in 4-diox and the 300ml ethanol and hydrogen (15Psi) oscillates 3.5 hours.Leach catalyzer, under vacuum, filtrate is concentrated into dried.Solid residue is through silica gel (650g) chromatography, and with 9: 1 hexane/ethyl acetate wash-outs, obtaining the 14.0g(productive rate was 85%) title compound, be the off-white color solid.
NMR（CDCl
3）：δ2.42（s，3H）;2.44（s，3H）;2.59（s，3H）;4.02（b，2H）;6.72（s，1H）。
The title compound for preparing example 4～6 by the method for example 3.
Example 4
3-amino-2, two (methylthio group) pyridines of 4-
(productive rate is 79%).
1H NMR（CDCl
3）：δ2.45（s，3H）;2.60（s，3H）;4.14（b，2H）;6.88（d，1H）;7.90（d，1H）。
Example 5
3-amino-2, two (ethylmercapto group) pyridines of 4-
(productive rate is 86%).
1H NMR（CDCl
3）：δ1.29（t，3H）;1.34（t，3H）;2.91（q，3H）;3.21（q，3H）;4.30（b，2H）;6.93（d，1H）;7.86（d，1H）。
Example 6
3-amino-2, two (the ethyl)-6-picolines of 4-
(productive rate is 86%).
1H NMR（CDCl
3）：δ1.30（t，3H）;1.32（t，3H）;2.40（s，3H）;2.90（q，2H）;3.18（q，2H）;4.18（b，2H）;6.79（s，1H）。
Example 7
6-chloro-4-(2-chloro-phenyl-)-2-methylthio group-3-nitroquinoline
With 2-amino-2 ', (1.6g, 5.3mmol) and 1, (875mg, 12ml acetic acid solution 5.3mmol) is in 120 ℃ of heated overnight for two (the methylthio group)-2-nitroethylenes of 1-for 5-dichloro benzophenone hydrochloride.Reaction mixture is cooled to room temperature, adds 30ml water, ethyl acetate extraction 2 times of gained mixture, each 60ml.Acetic acid ethyl acetate extract washes with water 2 times, each 50ml, and with saturated sodium bicarbonate solution washing 2 times, each 50ml uses the water washing of 50ml salt again, then through anhydrous sodium sulfate drying, filtration and concentrated under vacuum.Resistates with 85: 15 hexane/ethyl acetate wash-outs, obtains title compound through silica gel (440g, 230～400 orders) chromatography, is yellow solid (1.65g, productive rate are 72%).
1H NMR（300MHz，CDCl
3）：δ2.75（s，3H），7.25（c，2H），7.42（m，1H），7.49（m，1H），7.57（m，1H），7.71（m，1H），8.01（d，1H）。
The title compound for preparing example 8～9B by example 7 similar methods.
Example 8
The 4-(2-chloro-phenyl-)-6-methyl-2-methylthio group-3-nitroquinoline
Productive rate is 74%.
1H NMR（300MHz，CDCl
3）：δ2.40（s，3H），2.75（s，3H），7.00（s，1H），7.25（m，1H），7.40（m，1H），7.47（m，1H），7.57（m，1H），7.60（m，1H），7.97（d，1H）。
Example 9
The 4-(2-chloro-phenyl-)-6-ethyl-2-methylthio group-3-nitroquinoline
Productive rate is 65%.
1H NMR（300MHz，CDCl
3）：δ1.19（t，3H），2.69（q，2H），2.75（s，3H），7.01（d，1H），7.26（m，1H），7.40（m，1H），7.47（m，1H），7.56（m，1H），7.64（m，1H），7.99（d，1H）。
Example 9A
The 4-(2-chloro-phenyl-)-6,8-dimethyl-2-methylthio group-3-nitroquinoline
Productive rate is 8%.
1H NMR（300MHz，CDCl
3）：δ2.35（s，3H），2.39（s，3H），2.77（s，3H），6.84（s，1H），7.22（m，1H），7.30～7.57（c，4H）。
Example 9B
The 4-(2-chloro-phenyl-)-6-sec.-propyl-2-methylthio group-3-nitroquinoline productive rate is 74%.
1H NMR（300MHz，CDCl
3）：δ1.21（d，6H），2.75（s，3H），2.94（m，1H），7.03（s，1H），7.28（m，1H），7.45（m，2H），7.56（m，1H），7.69（m，1H），8.00（d，1H）。
Example 10
3-amino-6-chloro-4-(2-chloro-phenyl-) quinoline
With the mixture of Raney nickel (21g) in 30ml acetone reflux 2 hours under mechanical stirring.Mixture is cooled to room temperature, make its sedimentation, and suction filtration is removed acetone.Add 6-chloro-4-(2-chloro-phenyl-)-2-methylthio group-3-nitroquinoline (1.3g, 25ml hot ethanol solution 3.6mmol), gained mixture reflux 2 hours under mechanical stirring.Reaction mixture is cooled to room temperature, filters, and under vacuum filtrate is concentrated.Remaining yellow oil with 8: 2 dichloromethane/ethyl acetate wash-outs, obtains title compound through silica gel (300g) chromatography, is white solid (900mg, productive rate are 85%).
1H NMR（300MHz，CDCl
3）：δ3.88（b，2H），7.08（d，1H），7.29（C，1H），7.33（m，1H），7.48（c，2H），7.63（c，1H），7.96（d，1H），8.63（S，1H）。
Prepare the title compound of example 11 and 12 by example 10 similar methods.
Example 11
3-amino-4-(2-chloro-phenyl-)-the 6-toluquinoline
Productive rate is 68%.
1H NMR（300MHz，CDCl
3）：δ2.37（s，3H），3.70（b，2H），6.87（s，1H），7.29（c，2H），7.46（c，2H），7.63（c，1H），7.92（d，1H），8.56（s，1H）。
Example 12
3-amino-4-(2-chloro-phenyl-)-6-ethyl quinoline
Productive rate is 54%.
1H NMR（300MHz，CDCl
3）：δ1.18（t，3H），2.65（q，2H），3.70（b，2H），6.88（s，1H），7.32（c，2H），7.46（c，2H），7.63（c，1H），7.94（d，1H），8.55（s，1H）。
Example 12A
3-amino-4-(2-chloro-phenyl-)-6, the 8-dimethyl quinoline
Productive rate is 30%.
1H NMR（300MHz，CDCl
3）：δ2.32（s，3H），2.76（s，3H），3.68（b，2H），6.72（s，1H），7.16（s，1H），7.29（q，1H），7.45（q，2H），7.62（q，1H），8.58（s，1H）。
Example 12B
3-amino-4-(2-chloro-phenyl-)-6-isopropyl quinoline
Productive rate is 79%.
1H NMR（300MHz，CDCl
3）：δ1.2（d，6H），2.9（h，1H），3.68（b，2H），6.9（d，1H），7.3～7.42（c，2H），7.46（c，2H），7.63（m，1H），7.95（d，1H），8.55（d，1H）。
Example 13
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-) quinoline
Under nitrogen gas stream with 3-amino-6-chloro-4-(2-chloro-phenyl-) (174mg, 0.6mmol) and 4,6-is two, and (methylthio group)-2-methylpyrimidine-(136mg, 3ml dimethyl formamide solution 0.6mmol) is in 80 ℃ of heated overnight for the 5-based isocyanate for quinoline.Then reaction mixture is cooled to room temperature,, removes by filter some insoluble solids with the dilution of 30ml ethyl acetate.Filtrate water washing 2 times, each 30ml uses the water washing of 30ml salt again, then through anhydrous sodium sulfate drying, filtration and be condensed into a solid under vacuum.This solid is ground with 6: 4 ethyl acetate/hexane of 20ml, filter, obtain title compound, be white solid (110mg).Filtrate concentrates under vacuum, and resistates with 6: 4 ethyl acetate/hexane wash-outs, obtains title compound through silica gel (100g) chromatography, is white solid (40mg) that total amount is 150mg(48%).
1H NMR（300MHz，DMSO-D
6）：δ2.45（s，6H），2.58（s，3H），7.01（m，1H），7.49（b，1H），7.63～7.75（c，3H），7.81（b，1H），8.03（b，1H），8.09（d，1H），8.43（b，1H），9.58（s，1H）。
Example 14
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups-6-chloro-4-(2-chloro-phenyl-) quinoline
Under nitrogen gas stream with 3-amino-6-chloro-4-(2-chloro-phenyl-) (174mg, 0.6mmol) and 2,4-is two, and (methylthio group)-6-picoline-(136mg, 3ml dimethyl formamide solution 0.6mmol) is in 80 ℃ of heated overnight for the 3-based isocyanate for quinoline.Reaction mixture is cooled to room temperature then, with the dilution of 30ml ethyl acetate, washes with water 2 times, and each 30ml uses the water washing of 30ml salt again, through anhydrous sodium sulfate drying, filtration and concentrated under vacuum.Solid residue is ground with 4: 1 hexane/ethyl acetate of 10ml, filter, obtain title compound, be white solid (140mg, productive rate are 45%).
1H NMR（300MHz，DMSO-D
6）：δ2.41（s，3H），2.46（s，3H），2.52（s，3H），6.90（c，1H），7.00（s，1H），7.50（b，1H），7.68（m，3H），7.83（b，1H），7.94（b，1H），8.09（d，1H），8.33（c，1H），9.63（s，1H）。
The title compound for preparing example 15～33 by example 13 and 14 similar methods.
Example 15
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline
Productive rate is 30%.
1H NMR(300MHz, DMSO-D
6): δ 2.55(s, 3H), and 7.05(d, 1H), 7.47～7.91 (amount to 8H, comprise 7.55(m, 2H), 7.70(m, 2H), 7.78(d, 1H)), 8.00(d, 1H), 8.10(m, 2H), 8.77(s, 1H), 8.84(m, 1H), 9.59(s, 1H).
Example 16
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline
Productive rate is 23%.
1H NMR（300MHz，CDCl
3）：δ2.37（s，3H），2.41（s，6H），2.62（s，3H），5.71（b，1H），6.12（b，1H），6.87（s，1H），7.15（d，1H），7.28～7.51（c，4H），8.04（d，1H），9.75（s，1H）。
Example 17
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline
Productive rate is 29%.
1H NMR（300MHz，CDCl
3）：δ2.31（s，3H），2.36（s，3H），2.39（s，3H），2.50（s，3H），5.60（b，1H），6.09（b，1H），6.47（s，1H），6.84（s，1H），7.12（d，1H），7.25～7.45（c，4H），8.03（d，1H），9.82（s，1H）。
Example 18
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline
Productive rate is 43%.
1H NMR（300MHz，CDCl
3）：δ1.16（t，3H），2.31（s，3H），2.39（s，3H），2.50（s，3H），2.64（q，2H），5.65（b，1H），6.12（b，1H），6.48（s，1H），6.86（s，1H），7.12（d，1H），7.25～7.40（c，3H），7.47（d，1H），8.00（d，1H），9.83（s，1H）。
Example 19
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline
Productive rate is 36%.
1H NMR（300MHz，CDCl
3）：δ1.18（t，3H），2.40（s，6H），2.59（s，3H），2.67（g，2H），6.92（s，1H），7.20（b，1H），7.34～7.54（c，6H），8.20（d，1H），9.84（s，1H）。
Example 20
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline
Productive rate is 45%.
1H NMR（300MHz，DMSO-D
6）：δ1.16（d，6H），2.41（s，3H），2.46（s，3H），2.50（s，3H），2.91（m，1H），6.87（b，2H），7.36～7.86（c，6H），7.99（d，1H），8.26（b，1H），99.49（b，1H）。
Example 21
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6, the 8-dimethyl quinoline
Productive rate is 8%.
1H NMR（300MHz，CDCl
3）：δ2.30（s，6H），2.39（s，3H），2.49（s，3H），2.79（s，3H），5.64（b，1H），6.05（b，1H），6.47（s，1H），6.69（s，1H），7.10（d，1H），7.25（m，2H），7.36（m，2H），9.84（s，1H）。
Example 22
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline
Productive rate is 45%.
1H NMR（300MHz，DMSO-D
6）：δ1.18（d，6H），2.45（s，6H），2.58（s，3H），2.92（m，1H），6.90（s，1H），7.44（b，1H），7.63（c，3H），7.80（b，1H），7.90（b，1H），8.00（d，1H），8.37（s，1H），9.44（s，1H）。
Example 23
The 4-(2-chloro-phenyl-)-and 6-ethyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline
Productive rate is 37%.
1H NMR（300MHz，DMSO-D
6）：δ1.17（t，3H），2.55（s，3H），2.66（g，2H），6.90（s，1H），7.42～7.86（c，8H），7.98（d，2H），8.06（d，1H），8.70（s，1H），8.84（m，1H），9.43（s，1H）。
Example 24
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline
Productive rate is 35%.
1H NMR（300MHz，DMSO-D
6）：δ2.37（s，3H），2.55（s，3H），6.89（s，1H），7.40～7.85（c，8H），7.96（t，2H），8.06（d，1H），8.70（s，1H），8.84（m，1H），9.42（s，1H）。
Example 25
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline
Productive rate is 25%.
1H NMR（300MHz，CDCl
3）：δ1.13（d，6H），2.48（s，3H），2.85（m，1H），5.98（b，1H），6.38（b，1H），6.77（s，1H），6.85（c，1H），7.04（c，2H），7.14（m，1H），7.38（c，1H），7.50（m，2H），8.03（m，2H），8.18（d，1H），8.86（b，1H），9.84（s，1H）。
Example 26
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4,6-trimethylpyridine-3-yl) urea groups) quinoline
Productive rate is 8%.
1H NMR（300MHz，CDCl
3）：δ1.18（d，6H），2.13（b，3H），2.32（b，3H），2.49（s，3H），2.9（h，1H），6.41（b，1H），6.78（s，1H），6.88（d，1H），7.1（d，1H），7.32（m，1H），7.39（m，2H），7.51（q，1H），8.04（d，1H），9.72（s，1H）。
Example 27
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4-dimethoxy-6-picoline-3-yl) urea groups) quinoline
Productive rate is 50%.
1H NMR（300MHz，CDCl
3）：δ1.2（d，6H），2.43（s，3H），2.9（h，1H），3.74（s，3H），3.79（s，3H），5.64（s，1H），6.28（s，1H），6.39（s，1H），6.87（d，1H），7.17（g，1H），7.3～7.48（c，3H），7.52（q，1H），8.06（d，1H），9.79（s，1H）。
Example 28
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline;
Productive rate is 11%.
1H NMR（300MHz，CDCl
3）：δ2.32（s，3H），3.91（s，3H），6.0（s，1H），6.17（s，1H），6.75（s，1H），6.84（d，1H），7.04（m，2H），7.15（t，1H），7.38（c，3H），8.0（d，1H），8.07（d，1H），8.21（d，1H），8.80（m，1H），9.88（s，1H）。
Example 29
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline
Productive rate is 26%.
1H NMR（300MHz，CDCl
3）：δ3.91（s，3H），6.04（s，1H），6.22（s，1H），6.8（d，1H），6.94～7.08（m，3H），7.15（t，1H），7.37（m，1H），7.41（d，1H），7.48（q，1H），8.03（d，1h），8.08（d，1H），8.21（d，2H），8.81（m，1H），9.99（s，1H）。
Example 30
6-chloro-4-(2-chloro-phenyl-)-3-(3-6-(4-anisole sulfenyl) and quinoline-5-yl } urea groups) quinoline
Productive rate is 47%.
1H NMR（300MHz，CDCl
3）：δ3.84（s，3H），6.03（b，1H），6.53（b，1H），6.84（b，1H），6.9～7.16（c，7H），7.4（c，3H），7.5（q，1H），7.84（d，1H），8.04（d，1H），8.2（d，1H），8.86（m，1H），10.02（s，1H）。
Example 31
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-penta sulfenyl quinoline-5-yl) urea groups) quinoline
Productive rate is 52%.
1H NMR（300MHz，CDCl
3）：δ0.87（t，3H），1.22～1.48（c，4H），1.67（m，2H），2.95（t，2H），5.99（b，1H），6.42（b，1H），6.8（d，1H），6.97（d，1H），7.03（d，1H），7.15（t，1H），7.39（q，1H），7.49（q，1H），7.55（d，1H），8.02（q，2H），8.18（d，1H），8.87（q，1H），9.98（s，1H）。
Example 32
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-)-2 methoxy quinoline
Productive rate is 18%.
1H NMR（300MHz，CDCl
3）：δ2.34（s，3H），2.47（s，3H），2.5（s，3H），4.12（s，3H），6.05（b，1H），6.6（s，1H），7.14（d，1H），7.38～7.54（c，6H），7.81（d，1H）。
Example 33
6-chloro-4-(2-chloro-phenyl-)-and 2-methoxyl group-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline
Productive rate is 32%.
1H NMR（300MHz，CDCl
3）：δ2.45（s，3H），4.11（s，3H），6.08（b，1H），6.42（b，1H），7.14（d，1H），7.29～7.67（c，7H），7.8（d，1H），7.94（b，1H），8.05（d，1H），8.84（m，1H）。
Claims (12)
1, the method for preparing following formula: compound,
Wherein
Each m system is independently selected from zero～4;
R
1System is selected from hydrogen, (C
1～C
6) alkyl, (C
6～C
12) aralkyl, aryl moiety system is selected from phenyl, thienyl, furyl and pyridyl here;
R
2System is selected from hydrogen, (C
1～C
6) alkyl and (C
1～C
6) alkoxyl group;
Each R
3And R
4(the C that system is independently selected from hydrogen, halogen, is replaced arbitrarily by one or more halogen atoms
1～C
6) the alkyl, (C that replaces arbitrarily by one or more halogen atoms
1～C
6) the alkoxyl group, (C that replaces arbitrarily by one or more halogen atoms
1～C
6) alkylthio, nitro, by (C
1～C
6) carboxyl, the hydroxyl, (C of any esterification of alkyl
1～C
6) acyloxy and NR
12R
13, R here
12And R
13Can be identical or different, and can be selected from next group group: hydrogen, (C
1～C
6) alkyl, halogenated (C arbitrarily
1～C
6) acyl group, halogenated (C arbitrarily
1～C
6) alkyl sulphonyl, (C
1～C
6) alkyl amino-carbonyl and (C
1～C
6) alkoxy carbonyl, perhaps R
12And R
13Form piperidines, tetramethyleneimine or morpholine ring with the nitrogen that it connected;
X is sulphur or oxygen,
Q is the following formula group,
Wherein
The definition of m is the same;
N is zero or 1;
Each 1 is to be independently selected from zero～3;
Each R
6And R
7System is independently selected from next group group: halogen, (C
1～C
6) alkyl, (C
1～C
6) haloalkyl, halogenated (C arbitrarily
1～C
6) alkoxyl group, halogenated (C arbitrarily
1～C
6) alkylthio, (C
5～C
7) cycloalkylthio, phenyl (C
1～C
6) alkylthio, the thiophenyl of replacement, aromatic heterocycle sulfenyl, aromatic heterocycle oxygen base, (C
1～C
6) alkyl sulphinyl, (C
1～C
6) alkyl sulphonyl, (C
5～C
7) naphthene sulfamide base, (C
5～C
7) naphthene sulfamide base, phenyl (C
1～C
6) alkyl sulphinyl, phenyl (C
1～C
6) alkyl sulphonyl, the phenyl sulfinyl of replacement, phenyl sulfonyl, aromatic heterocycle sulfinyl, aromatic heterocycle alkylsulfonyl and the NR of replacement
10R
11, R here
10And R
11Can be identical or different, they are to be selected from next group group: hydrogen, (C
1～C
6) alkyl, phenyl, the phenyl of replacement, (C
1～C
6) aroyl of acyl group, aroyl and replacement, the aroyl of phenyl of Qu Daiing and replacement is to be replaced by one or more substituting groups that are independently selected from next group here: (C
1～C
6) alkyl, (C
1～C
6) alkoxyl group, (C
1～C
6) alkylthio, halogen and trifluoromethyl, perhaps R
10And R
11Form piperidines, tetramethyleneimine or morpholine ring with the nitrogen that it connected; And
B, D, E and G system are selected from nitrogen and carbon, and condition is that one or more are nitrogen among B, D, the E, and when G is nitrogen, and group X VI was connected on the nitrogen of formula I with 4 of pyrimidine ring or 5 (representing with a and b), and arbitrary nitrogen-atoms described here can be oxidized,
This method comprises makes following formula: compound and formula Q-N=C=X (wherein the definition of Q and X is the same) reaction,
R wherein
1, R
2, R
3, R
4The same with the definition of m.
2, the method for preparing following formula: compound,
R wherein
3, R
4It is the same with the definition of m,
This method comprises makes formula III compound and the reaction of formula IV compound,
R wherein
3, R
4It is the same with the definition of m,
3, in accordance with the method for claim 1, wherein Q is 6-(C
1～C
3) alkoxyl group quinoline-5-base, 6-(C
1～C
3) alkylthio quinoline-5-base, 6-(C
1～C
3) alkyl quinoline-5-base, 6-(C
1～C
3) alkylthio isoquinoline 99.9-5-base, 6-(C
1～C
3) alkoxyl group isoquinoline 99.9-5-base, 4, the two ((C of 6-
1～C
3) alkylthio)-2-methylpyrimidine-5-base, 4, the two ((C of 6-
1～C
3) alkylthio) pyrimidine-5-base, 2, the two ((C of 4-
1～C
3) alkylthio)-6-picoline-3-base or 2, the two ((C of 4-
1～C
3) alkylthio) pyridin-3-yl.
4, in accordance with the method for claim 3, R wherein
1Be hydrogen, R
2Definition the same, each R
3And R
4System is selected from hydrogen, (C
1～C
4) alkyl, chlorine, fluorine and trifluoromethyl.
5, in accordance with the method for claim 4, R wherein
2Be hydrogen.
6, in accordance with the method for claim 4, R wherein
2Be (C
1～C
6) alkoxyl group.
7, in accordance with the method for claim 1, above-mentioned formula I series of compounds is selected from next group:
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups-6-chloro-4-(2-chloro-phenyl-) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methylthio group quinoline-5-yl)-urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-the 6-toluquinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-ethyl quinoline;
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-ethyl-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline;
3-(3-{ 4, two (the methylthio group)-2-methylpyrimidines of 6--5-yl } urea groups)-4-(2-chloro-phenyl-)-6-isopropyl quinoline;
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(6-methylthio group quinoline-5-yl) urea groups) quinoline; With
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-4-(2-chloro-phenyl-)-6, the 8-dimethyl quinoline.
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4,6-trimethylpyridine-3-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-sec.-propyl-3-(3-(2,4-dimethoxy-6-picoline-3-yl) urea groups) quinoline;
The 4-(2-chloro-phenyl-)-and 6-methyl-3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-methoxy quinoline-5-yl) urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-3-(3-6-(4-anisole sulfenyl) and quinoline-5-yl } urea groups) quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 3-(3-(6-penta sulfenyl quinoline-5-yl) urea groups) quinoline;
3-(3-{ 2, two (the methylthio group)-6-picolines of 4--3-yl } urea groups)-6-chloro-4-(2-chloro-phenyl-)-2 methoxy quinoline;
6-chloro-4-(2-chloro-phenyl-)-and 2-methoxyl group-3-(3-(6-methylthio group quinoline-5-yl) urea groups) quinoline.
8, in accordance with the method for claim 1, wherein Q is 6-methoxy quinoline-5-base, 6-methylthio group quinoline-5-base, 6-methoxyl group isoquinoline 99.9-5-base, 6-methylthio group isoquinoline 99.9-5-base, 2-methyl-4, the two methylthio groups of 6-() pyrimidine-5-base, 6-methyl-2, two (methylthio group) pyridin-3-yls of 4-, 2, two (ethylmercapto group) pyridin-3-yls of 4-, 2,4,6-trimethylpyridine-3-base, 2,4-dimethoxy-6-picoline-3-base, 6-(4-anisole sulfenyl) quinoline-5-base and 6-penta sulfenyl quinoline-5-base.
9, in accordance with the method for claim 1, wherein said formula I compound comprises a kind of radio-label marker at least.
10, in accordance with the method for claim 9, wherein said radio-label marker be tritium or
14C.
11, in accordance with the method for claim 2, wherein said formula I compound comprises a kind of radio-label marker at least.
12, in accordance with the method for claim 11, wherein said radio-label marker be tritium or
14C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69232391A | 1991-04-26 | 1991-04-26 | |
| US692,323 | 1991-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1066068A true CN1066068A (en) | 1992-11-11 |
Family
ID=24780107
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92103010A Pending CN1066068A (en) | 1991-04-26 | 1992-04-25 | 4-aryl-3-(fragrant heterocyclic radical urea groups) quinoline derivatives |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0590094A1 (en) |
| JP (1) | JPH0776215B2 (en) |
| CN (1) | CN1066068A (en) |
| AU (1) | AU1879792A (en) |
| BR (1) | BR9205939A (en) |
| CA (1) | CA2108014A1 (en) |
| CZ (1) | CZ395592A3 (en) |
| DE (1) | DE9290049U1 (en) |
| FI (1) | FI934710A (en) |
| HU (1) | HUT65748A (en) |
| IE (1) | IE921330A1 (en) |
| IL (1) | IL101627A0 (en) |
| MX (1) | MX9201916A (en) |
| NO (1) | NO933837L (en) |
| NZ (1) | NZ242493A (en) |
| PT (1) | PT100426A (en) |
| TW (1) | TW197436B (en) |
| WO (1) | WO1992019614A1 (en) |
| YU (1) | YU44592A (en) |
| ZA (1) | ZA922976B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601677A (en) * | 2013-11-19 | 2014-02-26 | 清华大学 | Preparation method of 2-alkylsulfenylquinoline derivative |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE175196T1 (en) * | 1992-01-23 | 1999-01-15 | Pfizer | 4-PHENYL-3-(HETEROARYLUREIDO)-1,2-DIHYDRO-2-OXOCINOLINE DERIVATIVES, AS ANTIHYPERCHOLESTEROLEMIC AND ANTIATHEROSCLEROTIC AGENTS |
| US5565472A (en) * | 1992-12-21 | 1996-10-15 | Pfizer Inc. | 4-aryl-3-(heteroarylureido)-1,2-dihydro-2-oxo-quinoline derivatives as antihypercholesterolemic and antiatherosclerotic agents |
| NZ264063A (en) * | 1993-08-13 | 1995-11-27 | Nihon Nohyaku Co Ltd | N-(2-phenylpyrid-3-yl)- and n-(4-phenylpyrimidin-5-yl)-n'-phenylurea derivatives and pharmaceutical compositions |
| US5843957A (en) * | 1995-05-19 | 1998-12-01 | Sumitomo Pharmaceuticals Company, Ltd. | Naphthyridine derivatives |
| CA2222687A1 (en) * | 1995-05-31 | 1996-12-05 | Masami Muraoka | Novel naphthyridine derivatives |
| CA2272068A1 (en) * | 1996-11-26 | 1998-06-04 | Masami Muraoka | Novel naphthyridine derivatives |
| WO1999043659A1 (en) | 1998-02-25 | 1999-09-02 | Sumitomo Pharmaceuticals Co., Ltd. | Pyridone derivatives and process for producing the same |
| US6452008B2 (en) | 1998-02-25 | 2002-09-17 | Sumitomo Pharmaceuticals Company, Limited | Pyridone derivatives and process for preparing the same |
| WO2005058834A2 (en) * | 2003-12-12 | 2005-06-30 | Wyeth | Quinolines useful in treating cardiovascular disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE892088L (en) * | 1988-07-12 | 1990-01-12 | William Henry Deryk Morris | Quinoline derivatives, their production and use |
| WO1991004027A1 (en) * | 1989-09-15 | 1991-04-04 | Pfizer Inc. | New n-aryl and n-heteroarylamide and urea derivatives as inhibitors of acyl coenzyme a: cholesterol acyl transferase (acat) |
| TW205037B (en) * | 1989-10-06 | 1993-05-01 | Takeda Pharm Industry Co Ltd |
-
1992
- 1992-03-16 HU HU9303025A patent/HUT65748A/en active IP Right Revival
- 1992-03-16 CA CA002108014A patent/CA2108014A1/en not_active Abandoned
- 1992-03-16 BR BR9205939A patent/BR9205939A/en not_active Application Discontinuation
- 1992-03-16 AU AU18797/92A patent/AU1879792A/en not_active Abandoned
- 1992-03-16 JP JP4510186A patent/JPH0776215B2/en not_active Expired - Lifetime
- 1992-03-16 DE DE9290049U patent/DE9290049U1/en not_active Expired - Lifetime
- 1992-03-16 WO PCT/US1992/001801 patent/WO1992019614A1/en not_active Application Discontinuation
- 1992-03-16 EP EP92923349A patent/EP0590094A1/en not_active Withdrawn
- 1992-03-16 CZ CS923955A patent/CZ395592A3/en unknown
- 1992-03-17 TW TW081102005A patent/TW197436B/zh active
- 1992-03-24 ZA ZA922976A patent/ZA922976B/en unknown
- 1992-04-16 IL IL101627A patent/IL101627A0/en unknown
- 1992-04-24 YU YU44592A patent/YU44592A/en unknown
- 1992-04-24 NZ NZ242493A patent/NZ242493A/en unknown
- 1992-04-24 IE IE133092A patent/IE921330A1/en not_active Application Discontinuation
- 1992-04-24 MX MX9201916A patent/MX9201916A/en not_active IP Right Cessation
- 1992-04-24 PT PT100426A patent/PT100426A/en not_active Application Discontinuation
- 1992-04-25 CN CN92103010A patent/CN1066068A/en active Pending
-
1993
- 1993-10-25 NO NO933837A patent/NO933837L/en unknown
- 1993-10-25 FI FI934710A patent/FI934710A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601677A (en) * | 2013-11-19 | 2014-02-26 | 清华大学 | Preparation method of 2-alkylsulfenylquinoline derivative |
| CN103601677B (en) * | 2013-11-19 | 2015-11-18 | 清华大学 | Prepare the method for 2-alkylthio quinoline |
Also Published As
| Publication number | Publication date |
|---|---|
| NO933837L (en) | 1993-10-25 |
| FI934710A0 (en) | 1993-10-25 |
| BR9205939A (en) | 1994-09-27 |
| JPH06501025A (en) | 1994-01-27 |
| HU9303025D0 (en) | 1994-01-28 |
| AU1879792A (en) | 1992-12-21 |
| HUT65748A (en) | 1994-07-28 |
| TW197436B (en) | 1993-01-01 |
| ZA922976B (en) | 1993-10-25 |
| WO1992019614A1 (en) | 1992-11-12 |
| DE9290049U1 (en) | 1994-01-05 |
| MX9201916A (en) | 1992-11-01 |
| NZ242493A (en) | 1994-08-26 |
| JPH0776215B2 (en) | 1995-08-16 |
| CZ395592A3 (en) | 1994-02-16 |
| EP0590094A1 (en) | 1994-04-06 |
| PT100426A (en) | 1993-08-31 |
| CA2108014A1 (en) | 1992-10-27 |
| IE921330A1 (en) | 1992-11-04 |
| IL101627A0 (en) | 1992-12-30 |
| YU44592A (en) | 1994-12-28 |
| FI934710A (en) | 1993-10-25 |
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