CN1066068A - 4-aryl-3-(fragrant heterocyclic radical urea groups) quinoline derivatives - Google Patents

Abstract

其中R¹、R²、R³、R⁴、m、X和Q的定义见下面的叙 述。式I化合物是酰基辅酶A-胆固醇酰基转移酶 (ACAT)的抑制剂，因此可用于降低血脂和作为抗动 脉粥样硬化剂。The present invention relates to a compound of the following formula and a pharmaceutically applicable salt thereof and a new intermediate for synthesizing the compound of the following formula,

Wherein, the definitions of R ¹ , R ² , R ³ , R ⁴ , m, X and Q are described below. Compounds of formula I are inhibitors of acyl-CoA-cholesterol acyltransferase (ACAT) and are therefore useful for lowering blood lipids and as anti-atherosclerotic agents.

Description

The present invention relates to new 4-aryl-3-(aromatic heterocyclic ureido) quinoline derivatives, a pharmaceutical composition containing the compound, and a new 3-nitroquinoline for synthesizing the compound A morphine intermediate and the application of the compound in inhibiting the intestinal absorption of cholesterol, lowering serum cholesterol and eliminating the formation of atherosclerosis. These compounds are inhibitors of acyl-CoA-cholesterol acyltransferase (ACAT).

Cholesterol consumed in the diet (dietary cholesterol) is absorbed as free cholesterol by mucosal cells and the small intestine. Free cholesterol is then esterified by the enzyme ACAT, assembled into particles called chylomicrons, and released into the bloodstream. Chylomicrons are particles in which dietary cholesterol is assembled and transported into the bloodstream. By inhibiting the action of ACAT, the compounds of the present invention prevent intestinal absorption of dietary cholesterol and thus lower serum cholesterol levels. The compounds of the present invention are therefore useful in the prevention of atherosclerosis, heart attack and stroke.

By inhibiting the action of ACAT, the compounds of the present invention are also able to remove cholesterol from blood vessel walls. This action makes the compounds of the invention useful both in preventing or eliminating the formation of atherosclerosis and in preventing heart attacks and strokes.

Other inhibitors of ACAT are described in U.S. Patents 4,716,175 and 4,743,605 (divisional applications of the '175 patent), European Patent Applications with publication numbers 0242610, 0245687, 0252524 and 0354994, and U.S. Patent Application 07/ 648, 677 (filing dated January 31, 1991, and assigned like this application).

Certain urea and thiourea compounds as antiatherogenic agents are described in U.S. Patent 4,623,662 and European Patent Application Publication Nos. 0335374, 0386487, 0370740, 0405233 and 0421456.

The present invention relates to compounds of the following formula and pharmaceutically applicable salts thereof,

in

Each m series is independently selected from zero to 4;

R ¹ is selected from hydrogen, (C ₁ ~ C ₆ ) alkyl, (C ₆ ~ C ₁₂ ) aralkyl, where the aryl part is selected from phenyl, thienyl, furyl and pyridyl;

R ² is selected from hydrogen, (C ₁ ~ C ₆ ) alkyl and (C ₁ ~ C ₆ ) alkoxy;

Each R ³ and R ⁴ is independently selected from hydrogen, halogen, (C ₁ -C ₆ )alkyl optionally substituted by 1 or more halogen atoms, (C ₁ ) alkyl optionally substituted by 1 or more halogen atoms ~C ₆ ) alkoxy, (C ₁ ~C ₆ ) alkylthio, nitro, carboxyl, hydroxyl optionally substituted by (C ₁ ~C ₆ ) alkyl , (C ₁ ~ C ₆ ) acyloxy and NR ¹² R ¹³ , where R ¹² and R ¹³ may be the same or different, and may be selected from the following group: hydrogen, (C ₁ ~ C ₆ ) alkyl, Optionally halogenated (C ₁ ~C ₆ )acyl, optionally halogenated (C ₁ ~C ₆ )alkylsulfonyl, (C ₁ ~C ₆ )alkylaminocarbonyl and (C ₁ ~C ₆ )alkoxy Carbonyl, or R ¹² and R ¹³ together with the nitrogen to which they are attached form a piperidine, pyrrolidine or morpholine ring;

X is sulfur or oxygen,

Q is a group of the following formula,

in

The definition of m is the same as above;

n is zero or 1;

Each 1 series is independently selected from zero to 3;

Each R ⁶ and R ⁷ is independently selected from the following group: halogen, (C ₁ ～C ₆ ) alkyl, (C ₁ ～C ₆ ) haloalkyl, any halogenated (C ₁ ～C ₆ ) Alkoxy, any halogenated (C ₁ ～C ₆ ) alkylthio, (C ₅ ～C ₇ ) cycloalkylthio, phenyl (C ₁ ～C ₆ ) alkylthio, substituted phenylthio, Aromatic heterocyclic thio group, aromatic heterocyclic oxy group, (C ₁ ～C ₆ ) alkylsulfinyl group, (C ₁ ～C ₆ ) alkylsulfinyl group, (C ₅ ～C ₇ ) cycloalkylsulfinyl group , (C ₅ ～C ₇ ) cycloalkylsulfonyl, phenyl (C ₁ ～C ₆ ) alkylsulfinyl, phenyl (C ₁ ～C ₆ ) alkylsulfinyl, substituted phenylsulfinyl , substituted phenylsulfonyl, aromatic heterocyclic sulfinyl, aromatic heterocyclic sulfinyl, and NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ may be the same or different, and they are selected from the following group: hydrogen, ( C ₁ ~ C ₆ ) alkyl, phenyl, substituted phenyl, (C ₁ ~ C ₆ ) acyl, aroyl and substituted aroyl, where the substituted phenyl and substituted aroyl are composed of one or more Substituents independently selected from the following group: (C ₁ ～C ₆ ) alkyl, (C ₁ ～C ₆ ) alkoxy, (C ₁ ～C ₆ ) alkylthio, halogen and trifluoromethane or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached form a piperidine, pyrrolidine or morpholine ring; and B, D, E and G are selected from nitrogen and carbon, provided that one of B, D and E or more are nitrogen, and when G is nitrogen, the group XVI is connected to the nitrogen of formula I at the 4- or 5-position (represented by a and b) of the pyrimidine ring, and any nitrogen atom mentioned here can be oxidized .

As used herein, unless otherwise stated, the term "halogen" includes fluorine, chlorine, bromine and iodine.

Unless otherwise stated, the term "alkyl" as used herein may be linear, branched or cyclic, and may include both linear and cyclic moieties as well as branched and cyclic moieties.

Unless otherwise stated, the term "1 or more substituents" or "1 or more halogen atoms" as used herein means from 1 to the maximum number of substituents possible depending on the position of the bond present.

The present invention also relates to compounds of the formula,

Wherein m, R ³ and R ⁴ are as defined above, provided that R ³ or R ⁴ is not optionally substituted alkylthio. The above compounds are useful intermediates in the synthesis of compounds of formula I.

Preferred compounds of formula I are compounds wherein Q is 6-(C ₁ -C ₃ )alkoxyquinolin-5-yl, 6-(C ₁ -C ₃ )alkylthioquinolin-5- Base, 6-(C ₁ ～C ₃ )alkylquinolin-5-yl, 6-(C ₁ ～C ₃ )alkylthioisoquinolin-5-yl, 6-(C ₁ ～C ₃ )alkane Oxyisoquinolin-5-yl, 4,6-bis[(C ₁ ～C ₃ )alkylthio]-2-methylpyrimidin-5-yl, 4,6-bis[(C ₁ ～C ₃ )Alkylthio]pyrimidin-5-yl, 2,4-bis[(C ₁ ~C ₃ )alkylthio]-6-methylpyridin-3-yl or 2,4-bis[(C ₁ ~C ₃ ) Alkylthio]pyridin-3-yl.

Other preferred compounds of formula I are those wherein R ¹ is hydrogen, R ² is selected from hydrogen and methoxy, and each R ³ and R ⁴ is selected from (C ₁ -C ₆ )alkyl, chloro , fluorine and trifluoromethyl.

Better formula I compound is following compound, wherein Q is 6-methoxyquinolin-5-yl, 6-methylthioquinolin-5-yl, 6-methoxyisoquinolin-5-yl , 6-methylthioisoquinolin-5-yl, 2-methyl-4,6-bis(methylthio)pyrimidin-5-yl, 6-methyl-2,4-bis(methylthio) Pyridin-3-yl, 2,4-bis(ethylthio)pyridin-3-yl, 2,4,6-trimethylpyridin-3-yl, 2,4-dimethoxy-6-methyl Pyridin-3-yl, 6-(4-methoxyphenylthio)quinolin-5-yl and 6-pentylthioquinolin-5-yl.

Preferred specific formula I compounds include:

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido-6-chloro-4-(2-chlorophenyl)quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(2-chlorophenyl)quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-(6-methylthioquinolin-5-yl)-ureido]quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-methylquinoline;

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-methylquinoline;

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-ethylquinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-ethylquinoline;

4-(2-Chlorophenyl)-6-methyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline;

4-(2-Chlorophenyl)-6-ethyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-isopropylquinoline;

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-isopropylquinoline;

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline; and

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6,8-dimethylquinoline .

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(2,4,6-trimethylpyridin-3-yl)ureido]quinoline;

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(2,4-dimethoxy-6-methylpyridin-3-yl)ureido]quinoline;

4-(2-Chlorophenyl)-6-methyl-3-[3-(6-methoxyquinolin-5-yl)ureido]quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-(6-methoxyquinolin-5-yl)ureido]quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-{6-(4-methoxyphenylthio)quinolin-5-yl}ureido]quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-(6-pentylthioquinolin-5-yl)ureido]quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(2-chlorophenyl)-2-methoxy quinoline;

6-Chloro-4-(2-chlorophenyl)-2-methoxy-3-[3-(6-methylthioquinolin-5-yl]ureido]quinoline.

Other compounds of formula I include:

6-Chloro-4-(2-chlorophenyl)-3-[3-(6-methylquinolin-5-yl)ureido]quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-(2,4-diethoxy-6-methylpyridin-3-yl)ureido]quinoline;

3-[3-{2,4-bis(isopropylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(2-chlorophenyl)quinoline;

3-[3-{4,6-bis(ethylthio)pyrimidin-5-yl}ureido]-6-chloro-4-(2-methylphenyl)quinoline;

6-Chloro-4-(2-chlorophenyl)-3-[3-(2-dimethylamino-6-methyl-4-methylthiopyridin-3-yl)ureido]quinoline;

3-[3-{2,4-bis(ethylthio)pyridin-3-yl}ureido]-6-chloro-4-(2-fluorophenyl)quinoline;

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-6-chloro-4-(2-methylphenyl)quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(2-chlorophenyl)-8-methylquin phylloline;

3-[3-{2,4-bis(methylthio)pyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-fluoroquinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(3,4-dimethoxyphenyl)quinone phylloline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-difluoromethylthio-4-phenylquinoline;

3-[3-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-6-difluoromethoxy-4-phenylquinoline;

3-[3-{2,4-bis(ethylthio)pyridin-3-yl}ureido]-8-chloro-4-(2-chlorophenyl)-6-methylquinoline;

3-[3-{2,4-bis(methylthio)pyridin-3-yl}ureido]-6-chloro-4-(2,3,4-trimethoxyphenyl)quinoline;

3-[3-{4,6-bis(ethylthio)-2-methylpyrimidin-5-yl}ureido]-6-chloro-4-(2-methoxyphenyl)quinoline;

3-[3-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6,7-dimethylquinoline ;

3-[3-{4,6-bis(methylthio)pyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-5,6,7-trimethylquinoline; and

3-[3-{2,4-Bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-dimethylaminoquinoline.

The invention also relates to compounds of formula I and II in radiolabeled form, including tritium- and/or ^C14 -labeled compounds. The radioisotope tracer-labeled compound can be used as a tool for research and characteristic identification in animal and human pharmacokinetic analysis and binding assay.

The present invention also relates to a pharmaceutical composition for inhibiting ACAT, inhibiting the intestinal absorption of cholesterol, eliminating or preventing the formation of atherosclerosis or reducing the concentration of serum cholesterol in mammals (including humans), the composition comprising inhibiting ACAT, inhibiting cholesterol Intestinal absorption, elimination or prevention of atherosclerosis formation or reduction of serum cholesterol concentration effective dose of the compound of formula I or its pharmaceutically acceptable salt and pharmaceutical carrier.

The present invention also relates to a method for inhibiting ACAT, inhibiting intestinal absorption of cholesterol, eliminating or preventing the formation of atherosclerosis or lowering serum cholesterol in mammals (including humans), the method comprising administering to mammals an intestinal inhibitor for inhibiting ACAT and inhibiting cholesterol. An effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof for absorbing, eliminating or preventing the formation of atherosclerosis or lowering the concentration of serum cholesterol.

Examples of pharmaceutically acceptable acid addition salts of compounds of formula I include those with hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid , Two - p-toluoyl tartaric acid and metadelic acid salt formation.

Schemes 1-3, set forth below, illustrate the synthesis of compounds of the present invention. R ¹ , R ² , ^{R 3} , R 4 , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ^{12 , R 13 ,} Q, X, B, D in the following schemes and discussions, unless otherwise stated, , E, G, l, m and n are as defined above.

Reaction scheme 1

Reaction Route 2

Reaction Route 3

Scheme 1 illustrates a method for preparing compounds of formula I wherein ^R1 is hydrogen. Referring to reaction scheme 1, the starting compound formula III (which can be prepared according to the method of Synthesis 677 (1980)) reacts with 1,1-bis(methylthio)-2-nitroethylene (IV) to obtain the corresponding formula II compound. The reaction is usually carried out in an inert solvent (such as acetic acid, propionic acid or polyphosphoric acid) at about 100°C-160°C for 2-24 hours. It is best to react in acetic acid at about 120°C for 16 hours.

Then the compound of formula II generated by the above reaction is reduced to generate the corresponding compound of formula V. Applying excess Raney nickel in a suitable inert solvent (such as ethanol, methanol, dioxane, acetone, tetrahydrofuran or dimethylformamide), adding water or not adding water, usually completes the reduction reaction and desulfurization reaction in one step . The reaction is carried out for 1 to 8 hours. The reaction temperature can be between 20°C and 100°C. Preferably, in the presence of excess Raney nickel, react in ethanol at 80°C for 2 to 3 hours to reduce and desulfurize the compound of formula II.

In addition, the compound of formula V can be prepared from the corresponding compound of formula II in a two-step process. The method is as follows: firstly, the compound of formula II is reduced to the corresponding amino derivative, and then desulfurized in two steps to obtain the compound of formula V. The suitable reducing agent in the first step is tin protochloride, titanium (Ⅲ) chloride, iron or zinc, with or without acid catalyst (such as hydrochloric acid or acetic acid), or with hydrogen and suitable catalyst for reduction together, the reduction reaction in 0°C to 100°C for 2 to 16 hours. In the second step, the desulfurization reaction is carried out as described above with an excess of Raney nickel.

Also can press Helv.Chem.Acta.71,531 (1988) described, use copper-aluminum alloy, or press J.Chem.Soc.Chem.Commun., 819 (1990) and J.Chem.Soc. (C ), 1122 (1968), the compound of formula II was subjected to reductive desulfurization reaction with nickel boride.

Alternative synthetic methods for the preparation of compounds of formula V are described in European Patent 0354994A2.

In Z.Chem.8, 294 (1973) and J.Prakt.Chem., 318,39, (1976) described wherein ^R3 and ^R4 are the preparation method of formula II and formula V compound of hydrogen, and A method for preparing compounds of formula II and V wherein R ³ and R ⁴ are hydrogen except one R ³ is 6-chloro.

The resulting compound of formula V is reacted with a compound of formula QN=C=X to give the corresponding urea (X=O) or thiourea (X=S) of formula I-A. Methods for preparing compounds of formula QN=C=X are known in the literature and several methods are reviewed in "Organic Functional Group Preparations, Vol. 1", Chapter 12, Academic Press, New York (1968). The preparation of urea and thiourea from the reaction of amines with isocyanates and isothiocyanates, respectively, is reviewed in "Organic Func-tional Group Preparations, Vol. 2", Chapter 6, Academic Press, New York (1971).

Compounds of formula QN=C=O can be obtained by reacting _QNH2 compounds with 1-6 equivalents of a suitable reagent such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl)carbonate. The reaction is usually carried out in an inert ether, aromatic or chlorinated hydrocarbon solvent such as dioxane, diisopropyl ether, benzene, toluene, dichloromethane or chloroform. The reaction can be carried out in the presence of a base such as a tertiary amine such as pyridine, triethylamine or quinoline. The reaction temperature may range from 0°C to about 120°C, and preferably from 20°C to about 100°C. Preferably, the heterocyclic amine of formula QNH ₂ is reacted with 1-2 equivalents of trichloromethyl chloroformate in refluxing dichloromethane for 18 hours.

The reaction of the formula QN=C=X compound of the formula I-A compound and the compound of formula V is carried out at 20°C to 100°C for about 3 hours in an inert anhydrous solvent such as chloroform, benzene, dimethylformamide, dioxane or tetrahydrofuran. ~30 hours, preferably 16 hours in dimethylformamide at about 80°C.

Alternatively, compounds of formula IA can be prepared by reacting an intermediate of formula _QNH2 with an appropriate quinolin-3-yl isocyanate (prepared as described in European Patent 0354994A2). The reaction is generally carried out under conditions similar to those described above for the reaction of compounds of formula V with QN=C=X compounds.

Compounds of formula I in which ^R1 is other than hydrogen can be prepared according to Scheme 2 and the methods described below.

Referring to Scheme 2, the appropriate starting material V is acylated to produce the corresponding compound of formula VI as described in U.S. Patent 3,798,226, which is incorporated herein by reference.

The R ¹ substituent is added to the compound of formula VI by reacting the compound of formula VI with a compound of formula R ¹ Z wherein Z is a leaving group. Suitable leaving groups include halogen, (C ₁ ~C ₆ ) alkanesulfonyloxy (such as methanesulfonyloxy, ethylsulfonyloxy, etc.) and (C ₆ ~C ₁₀ ) arylsulfonyloxy ( Such as benzenesulfonyloxy, p-toluenesulfonyloxy, etc.). Suitable solvents for this reaction include inert solvents such as tetrahydrofuran (THF), dimethoxyethane (DME) and N,N-dimethylformamide. The reaction can be accelerated in the presence of a base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium amide or potassium tert-butoxide. The reaction is usually carried out at a temperature of 20°C to about 120°C, and preferably at a temperature of 0°C to about 100°C. A preferred solvent is dimethylformamide and a preferred base is sodium hydride.

Hydrolysis of the resulting amide of formula VII affords the corresponding amine of formula VIII. Hydrolysis is usually performed in a protic solvent such as a lower alcohol (such as methanol, ethanol, or propanol) or acetic acid. The hydrolysis is preferably carried out in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid in an amount of 2 to 20 moles (preferably 3 to 15 moles) per mole of the compound of formula VII. The reaction temperature is in the range of 60°C to about 120°C, preferably 70°C to 100°C.

Alternatively, compounds of formula VIII wherein R ¹ is not hydrogen can be prepared by first following the method described in U.S. Patent 3,798,226, using a suitable acylating agent [such as R ¹⁵ COCl or [R ¹⁵ CO] ₂ O, Wherein R ¹⁵ is the same as R ¹ , but R ¹⁵ contains 1 methylene less than R ¹ ] acylate the corresponding compound of formula V, and then use a suitable reducing agent such as lithium aluminum hydride, bis(2-methoxy Sodium aluminum ethoxy) or dimethylborane reduces the resulting amide to the desired compound of formula VIII. The reduction reaction is usually carried out in an inert solvent such as tetrahydrofuran, dioxane or dimethoxyethane at a temperature of 25°C to about 110°C.

Compounds of formula VIII can be converted to the corresponding desired compounds of formula I-B by the methods described above and shown in Scheme 1 for the preparation of compounds of formula I-A from compounds of formula V.

Aminopyrimidine and aminopyridine intermediates (such as formula Q- _NH compound) used in the present invention are known in the literature, or can be various pyrimidine and pyridine intermediates known in the literature or can buy Prepared by methods known in the art. Commercially available pyrimidine and pyridine intermediates include 4,6-dichloro-5-nitropyrimidine, 2,4-dihydroxy-6-methylpyrimidine, 4,6-dihydroxy-2-methyl Pyrimidine, 5-nitrobarbituric acid, 2-hydroxy-4-methyl-3-nitropyridine and 3,4-dihydroxypyridine. Many pyrimidines and pyridines can be found in the monographs "The Pyrimidines" by DJ Brown (1962) and "Pyridine and its Derivatives" by R.A. Abramovitch (1961), Interscience Publishers, Inc., New York, NY, and their supplements References for intermediate preparation methods. The above-mentioned pyridines and pyrimidines can be converted into the corresponding aminopyridines and aminopyrimidines intermediates (see "The Pyrimidine" published by DJ Brown (1962) and "Pyridine and its Derivatives" published by RA Abramovitch (1961), Interscience Publishers, Inc. ., New York, NY, and their supplements), which can be applied to the synthesis of the compounds of the present invention according to methods well known to those skilled in the art.

The preparation of certain aminopyridine and aminopyrimidine intermediates is described in more detail below.

4,6-disubstituted-5-aminopyrimidines can be prepared by reacting suitably substituted 4,6-dihydroxypyrimidine with a nitrating agent such as an acetic acid solution of fuming nitric acid at 15°C to about 40°C for 1 to about 5 hours derivative. Use a chlorinating agent such as phosphorus oxychloride without a base or in the presence of a base (preferably diethylaniline), react at 100°C to about 115°C for 0.5 to about 2 hours, and the resulting 5-nitropyrimidine compounds can be Transform into 4,6-dichloro-5-nitropyrimidine intermediates. A method for carrying out this transformation is described in J. Chem. Soc., 3832 (1954).

4,6-bis(alkylthio)-5-nitropyrimidine derivatives can be prepared as follows: make a suitable dichloro intermediate and 2 equivalents of sodium alkylthiolate in a solvent such as dimethylformamide Or in methanol (methanol is better), react at 0°C to about 30°C (preferably at room temperature) for about 4 to about 16 hours.

4, the one-substitution reaction of 6-dichloro-5-nitropyrimidine intermediate is carried out as follows: make 4,6-dichloro-5-nitropyrimidine intermediate and 1 equivalent nucleophilic reagent in inert solvent ( Such as dimethylformamide or tetrahydrofuran), react at 0°C to about 100°C (depending on the reactivity of the nucleophile) for 4 to about 16 hours. The resulting -chloro derivatives are then reacted with an equivalent amount of a different nucleophile to obtain disubstituted derivatives with different substituents on the 4 and 6 carbon atoms of the pyrimidine ring. The corresponding 5-aminopyrimidine derivatives can be obtained by reducing 4,6-disubstituted-5-nitropyrimidine with a reducing agent such as stannous chloride and concentrated hydrochloric acid, or with hydrogen and a suitable catalyst.

2,4-disubstituted-3-aminopyridine derivatives (such as 2, For the preparation method of 4-dihydroxy-6-methyl-3-nitropyridine, see J. Hetercyclic Chem., 1970, 7, 389). Then use the reaction conditions similar to the above-mentioned pyrimidine series compounds to convert the generated 2,4-dihydroxy-3-nitropyridine into 2,4-dichloro-3-nitropyridine, 2,4-disubstituted-3 - nitropyridines and 2,4-disubstituted-3-aminopyridines.

Appropriately substituted-hydroxypyrimidines and pyridines can be converted to nitro-hydroxy and nitro-chloro derivatives in a similar manner. The nitro-chloro intermediate is then reacted with a suitable sulfur, oxygen or nitrogen nucleophile to give an oxygen, sulfur or nitrogen substituted nitro derivative which can be reduced to the desired aminopyrimidine or pyridine .

The synthesis of certain 5-aminoquinolines and 5-aminoisoquinolines used as reactants in Schemes 1 and 2 is illustrated in Scheme 3. Referring to Scheme 3, 5-aminoquinolines and isoquinolines of formulas (XV) and (XVII) can be prepared as follows. Using a nitrating agent such as nitric acid or potassium nitrate (an acid catalyst such as sulfuric acid can be used or not), react at 0°C to 100°C for 2 to 16 hours, and the nitrated product X of quinoline or isoquinoline of formula IX can be obtained respectively. Then the obtained formula X nitro compound is reacted with a reducing agent such as stannous chloride, iron, zinc, or with hydrogen and a suitable catalyst, with or without an acid catalyst (such as hydrochloric acid), at 0° to 100°C for 2 After ~16 hours, the corresponding 5-aminoquinoline or 5-aminoisoquinoline of formula XI is obtained.

Wherein B or D is nitrogen, R ¹⁴ is (C ₁ ~ C ₆ ) alkyl, (C ₅ ~ C ₇ ) cycloalkyl, phenyl (C ₁ ~ C ₄ ) alkyl, phenyl, substituted phenyl , aromatic heterocyclic group or substituted aromatic heterocyclic group, the compound of formula XIII can be prepared as follows. Make formula X compound (wherein l is at least 1, and 1 R ⁷ is-Cl, it is connected on the 6-position of quinoline ring or isoquinoline ring) and formula R ¹⁴ SH compound (wherein R ¹⁴ is as defined above) and alkali (such as sodium hydride), or react the above-mentioned compound of formula X with the compound of formula R ¹⁴ SNa (where R ¹⁴ is as defined above), the reaction is carried out in an inert solvent (such as tetrahydrofuran), and the reaction temperature is -10 ° C ~ At room temperature, the reaction time is about 4 to 16 hours. A preferred reaction temperature is -10°C. The above reaction gives the compound of formula XII, and then the compound of formula XII can be converted into the corresponding 5-aminoquinoline or isoquinoline of formula XIII according to the above method for reducing the compound of formula X.

In any of the above reactions, pressure is not critical unless otherwise stated. Preferred reaction temperatures for the above reactions are indicated, if known. In general, the preferred reaction temperature for each reaction is the lowest temperature at which the product can be formed. By monitoring with thin layer chromatography, it is possible to determine the preferred reaction temperature for a particular reaction.

2-Substituted-5-aminoquinolines can be used to prepare compounds of formula I wherein ^R² is other than hydrogen. 2-Substituted-5-aminoquinolines can be prepared according to the method of Ikeda (EP 0421456). These are then used in place of compounds of formula V and VIII in Schemes 1 and 2, respectively, to yield 2-substituted compounds of formula I wherein ^R1 is hydrogen or is not hydrogen, respectively.

The novel compounds of formula I and their pharmaceutically acceptable salts are useful as inhibitors of acyl-CoA-cholesterol acyltransferase (ACAT). Accordingly, the compounds of the present invention inhibit the intestinal absorption of cholesterol in mammals and are useful in the treatment of high serum cholesterol in mammals, including humans. "Treatment" as used herein means both preventing and alleviating high serum cholesterol. The compounds of the present invention can be administered to the subject in need of treatment by various conventional routes of administration, including oral administration, parenteral administration and topical administration. Generally speaking, the dosage of the compound of the present invention for oral or parenteral administration is 0.5-30 mg/kg body weight, preferably 0.8-5 mg/kg body weight of the patient to be treated per day. Thus, for an adult human having a body weight of about 70 kg, a usual dosage is from 35 to about 2000 mg per day. However, some variation in dosage will necessarily occur depending upon the condition of the condition being treated and the activity of the compound employed. In any case, for each patient, the appropriate dosage will be determined according to the individual to whom the drug is to be administered.

A compound of formula I or a pharmaceutically acceptable salt thereof may be administered alone or in combination with a pharmaceutical carrier in single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The resulting pharmaceutical composition can be easily administered in various dosage forms (eg, tablets, powders, lozenges, syrups, injection solutions, etc.). The above-mentioned pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients and the like, if necessary. Thus, for oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may also contain various disintegrants such as starch, alginic acid and certain complexed silicon acid salts) and binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used in the manufacture of tablets. Solid compositions of the same type can also be used as fillers for soft and hard gelatin capsules. Preferred fillers for capsules include lactose and high molecular weight polyethylene glycols. If an aqueous suspension or elixir is desired for oral administration, the basic active ingredient may be mixed with various sweetening or flavoring agents, coloring substances or dyes (and, if desired, emulsifying or suspending agents). ) and diluents (such as water, ethanol, polyethylene glycol, glycerin and their mixtures) together.

For parenteral administration, solutions of a compound of formula I or a pharmaceutically acceptable salt thereof in sesame or peanut oil, in aqueous propylene glycol or in sterile aqueous solution may be used. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Said solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, sterile aqueous media for use are readily available by ordinary techniques to those skilled in the art.

The effect of the compounds of the present invention as ACAT inhibitors can be determined by a number of general biological or pharmacological assays. For example, the ACAT inhibitory activity of compounds of formula I was determined in the following manner. According to the method described by Bilheimer, JT, Meth. Enzymol., 111, p. 286-293 (1985) with minor modifications, ACAT was performed on microsomes isolated from Sprague-Dawley strain rats fed a mixed balanced diet. test. Microsomes obtained from rat liver were subjected to differential centrifugation and washed with assay buffer prior to application. The test mixture contained 25μl BSA (40mg/ml), 30μl rat liver microsomal solution (100μg microsomal protein), 20μl test buffer (0.1MK ₂ po ₄ , 1.0mM reduced glutathione, pH7.4), 20μg Cholesterol in 100 µl of 0.6% Trition WR-1339 in assay buffer and 5 µl of test compound in 100% DMSO (total volume 180 µl). The assay mixture was incubated at 37°C for 30 min. The reaction was initiated by adding 20 µl of 14°C-Oleoyl-CoA (1000 µM, 2,000 dpm/nmol) and proceeded at 37°C for 15 minutes. The reaction was quenched by adding 1 ml ETOH. Lipids were extracted into 4 ml hexane. A 3 ml aliquot was dried under nitrogen and resuspended in 100 [mu]l chloroform. 50 µl of the chloroform solution was spotted on a heat-activated TLC plate and developed with hexane:ether:acetic acid (85:15:1, V:V:V). The radioactivity of the cholestenyl esters was quantified on a Berthold LB 2842 Linear TLC analyzer. Based on the DMSO control test, the activity of inhibiting ACAT was calculated.

The inhibitory effect of the compounds of formula I on the intestinal absorption of cholesterol can be determined according to the method described by Melchoir and Harwell (J. Lipid. Res., 26, 306-315 (1985)).

The present invention cites the following examples. It should be understood, however, that the present invention is not limited by the specific descriptions of these examples. Melting points are uncorrected. Deuterochloroform (CDCl ₃ ) or D ₆ -dimethyl sulfoxide (DMSO-D ₆ ) solution was used to measure the proton nuclear magnetic resonance spectrum ( ¹ H NMR) and ¹³ C nuclear magnetic resonance spectrum ( ¹³ C NMR), and the peak The positions of are expressed in parts per million (PPm) with tetramethylsilane as internal standard. Peak shapes are indicated by the following abbreviations: S, singlet; d, doublet; t, triplet; g, quartet; m, multiplet; b, broad; c, complex; h, septet.

Example 1

5-amino-6-methoxyquinoline

The commercially available 6-methoxyquinoline (13.80g) was nitrated according to the method of Campbell et al. (J.Am.Chem.Soc., 1946,68,1559) to obtain 5-nitro-6-methyl Oxyquinoline (17.51g). The crude product was directly reduced by the method of Jacobs et al. (J. Am. Chem. Soc., 1920, 42, 2278) to give 5-amino-6-methoxyquinoline (6.25 g). m.p.152.5～154.5℃.

Example 2

5-amino-6-methylthioquinoline

Commercially available 6-chloroquinoline (33.3 g) was nitrated as described in Example 1 to give 5-nitro-6-chloroquinoline (20.36 g). This product (15 g) was reacted with sodium methylthiolate according to Massie's method (Iowa State Coll. J. Sci. 1946, 21, 41; CA 41: 3044 g) to give 5-nitro-6-methylthio Quinoline (13.61g). This product (3.70g) was reduced with iron powder (5.62g) and hydrochloric acid (15ml) in 50% ethanol in water (50ml) to give 5-amino-6-methylthioquinoline (3.0g). m.p.88.5～90.5℃.

Example 3

3-Amino-2,4-bis(methylthio)-6-methylpyridine

Under stirring and nitrogen flow, slowly add 20.8g (0.1mol) 3-nitro-2,4-dichloro-6-methylpyridine to 15.5g (0.22mol) sodium methylthiolate in 200ml methanol solution 150ml methanol solution. A precipitate formed and the mixture was stirred overnight at room temperature. The mixture was then filtered and the solids were washed with methanol and water. 3-Nitro-2,4-bis(methylthio)-6-methylpyridine (18.9 g, 82% yield) was obtained as a yellow solid, m.p. 172-176°C.

¹ H NMR (CDCl ₃ ): δ 2.45 (s, 3H); 2.51 (s, 3H); 2.55 (s, 3H); 6.77 (s, 1H).

18.9 g (0.082 mol) of 3-nitro-2,4-bis(methylthio)-6-methylpyridine and 18.9 g of Raney nickel were dissolved in 600 ml of 1,4-dioxane and 300 ml of The mixture in ethanol was shaken with hydrogen (15 psi) for 3.5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under vacuum. The solid residue was chromatographed on silica gel (650g) eluting with 9:1 hexane/ethyl acetate to give 14.0g (85% yield) of the title compound as an off-white solid.

NMR (CDCl ₃ ): δ 2.42 (s, 3H); 2.44 (s, 3H); 2.59 (s, 3H); 4.02 (b, 2H); 6.72 (s, 1H).

The title compounds of Examples 4-6 were prepared according to the method of Example 3.

Example 4

3-Amino-2,4-bis(methylthio)pyridine

(79% yield).

¹ H NMR (CDCl ₃ ): δ 2.45 (s, 3H); 2.60 (s, 3H); 4.14 (b, 2H); 6.88 (d, 1H); 7.90 (d, 1H).

Example 5

3-Amino-2,4-bis(ethylthio)pyridine

(86% yield).

¹ H NMR (CDCl ₃ ): δ1.29 (t, 3H); 1.34 (t, 3H); 2.91 (q, 3H); 3.21 (q, 3H); 4.30 (b, 2H); ); 7.86(d, 1H).

Example 6

3-Amino-2,4-bis(ethyl)-6-methylpyridine

(86% yield).

¹ H NMR (CDCl ₃ ): δ1.30 (t, 3H); 1.32 (t, 3H); 2.40 (s, 3H); 2.90 (q, 2H); 3.18 (q, 2H); ); 6.79(s, 1H).

Example 7

6-Chloro-4-(2-chlorophenyl)-2-methylthio-3-nitroquinoline

2-Amino-2', 5-dichlorobenzophenone hydrochloride (1.6g, 5.3mmol) and 1,1-bis(methylthio)-2-nitroethylene (875mg, 5.3mmol) 12ml of acetic acid solution was heated at 120°C overnight. The reaction mixture was cooled to room temperature, 30 ml of water was added, and the resulting mixture was extracted twice with 60 ml of ethyl acetate. The ethyl acetate extract was washed twice with 50 mL of water, twice with 50 mL of saturated sodium bicarbonate solution, and with 50 mL of brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (440g, 230-400mesh) eluting with 85:15 hexane/ethyl acetate to give the title compound as a yellow solid (1.65g, 72% yield).

¹ H 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 compounds of Examples 8-9B were prepared in a similar manner to Example 7.

Example 8

4-(2-Chlorophenyl)-6-methyl-2-methylthio-3-nitroquinoline

The yield was 74%.

¹ H 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

4-(2-Chlorophenyl)-6-ethyl-2-methylthio-3-nitroquinoline

The yield was 65%.

¹ H NMR (300 MHz, 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

4-(2-Chlorophenyl)-6,8-dimethyl-2-methylthio-3-nitroquinoline

The yield was 8%.

¹ H 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 yield of 4-(2-chlorophenyl)-6-isopropyl-2-methylthio-3-nitroquinoline was 74%.

¹ H 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-chlorophenyl)quinoline

A mixture of Raney nickel (21g) in 30ml of acetone was heated to reflux for 2 hours with mechanical stirring. The mixture was cooled to room temperature, allowed to settle, and the acetone was removed by suction filtration. A solution of 6-chloro-4-(2-chlorophenyl)-2-methylthio-3-nitroquinoline (1.3 g, 3.6 mmol) in 25 ml of hot ethanol was added, and the resulting mixture was heated to reflux under mechanical stirring for 2 hours . The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residual yellow oil was chromatographed on silica gel (300g) eluting with 8:2 dichloromethane/ethyl acetate to give the title compound as a white solid (900mg, 85% yield).

¹ H NMR (300 MHz, 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).

The title compounds of Examples 11 and 12 were prepared in a similar manner to Example 10.

Example 11

3-Amino-4-(2-chlorophenyl)-6-methylquinoline

The yield was 68%.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.37 (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-chlorophenyl)-6-ethylquinoline

The yield was 54%.

¹ H NMR (300 MHz, 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-chlorophenyl)-6,8-dimethylquinoline

The yield was 30%.

¹ H 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-chlorophenyl)-6-isopropylquinoline

The yield was 79%.

¹ H 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-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-6-chloro-4-(2-chlorophenyl)quinoline

Mix 3-amino-6-chloro-4-(2-chlorophenyl)quinoline (174mg, 0.6mmol) and 4,6-bis(methylthio)-2-methylpyrimidin-5-yl under a stream of nitrogen A solution of the isocyanate (136mg, 0.6mmol) in 3ml of dimethylformamide was heated at 80°C overnight. The reaction mixture was then cooled to room temperature, diluted with 30 mL of ethyl acetate, and filtered to remove some insoluble solids. The filtrate was washed twice with 30 mL of water and 30 mL of brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a solid. This solid was triturated with 20 mL of 6:4 ethyl acetate/hexane and filtered to give the title compound as a white solid (110 mg). The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (100g) eluting with 6:4 ethyl acetate/hexane to give the title compound as a white solid (40mg), total 150mg (48%).

¹ H 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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido-6-chloro-4-(2-chlorophenyl)quinoline

Mix 3-amino-6-chloro-4-(2-chlorophenyl)quinoline (174mg, 0.6mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl under a stream of nitrogen A solution of the isocyanate (136mg, 0.6mmol) in 3ml of dimethylformamide was heated at 80°C overnight. The reaction mixture was then cooled to room temperature, diluted with 30 mL of ethyl acetate, washed twice with 30 mL of water and 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solid residue was triturated with 10 mL of 4:1 hexane/ethyl acetate and filtered to afford the title compound as a white solid (140 mg, 45% yield).

¹ H NMR (300 MHz, 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 compounds of Examples 15-33 were prepared in a similar manner to Examples 13 and 14.

Example 15

6-Chloro-4-(2-chlorophenyl)-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline

The yield was 30%.

¹ H NMR (300MHz, DMSO-D ₆ ): δ2.55 (s, 3H), 7.05 (d, 1H), 7.47～7.91 [total 8H, including 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-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-methylquinoline

The yield was 23%.

¹ H 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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-methylquinoline

The yield was 29%.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.31 (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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-ethylquinoline

The yield was 43%.

¹ H NMR (300 MHz, 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-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-ethylquinoline

The yield was 36%.

¹ H NMR (300 MHz, 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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6-isopropylquinoline

The yield was 45%.

¹ H 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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-4-(2-chlorophenyl)-6,8-dimethylquinoline

The yield was 8%.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.30 (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-{4,6-bis(methylthio)-2-methylpyrimidin-5-yl}ureido]-4-(2-chlorophenyl)-6-isopropylquinoline

The yield was 45%.

¹ H 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

4-(2-Chlorophenyl)-6-ethyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline

The yield was 37%.

¹ H 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

4-(2-Chlorophenyl)-6-methyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline

The yield was 35%.

¹ H 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

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline

The yield was 25%.

¹ H 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

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(2,4,6-trimethylpyridin-3-yl)ureido]quinoline

The yield was 8%.

¹ H NMR (300 MHz, 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

4-(2-Chlorophenyl)-6-isopropyl-3-[3-(2,4-dimethoxy-6-methylpyridin-3-yl)ureido]quinoline

The yield was 50%.

¹ H 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

4-(2-Chlorophenyl)-6-methyl-3-[3-(6-methoxyquinolin-5-yl)ureido]quinoline;

The yield was 11%.

¹ H NMR (300 MHz, 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-chlorophenyl)-3-[3-(6-methoxyquinolin-5-yl)ureido]quinoline

The yield was 26%.

¹ H 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-chlorophenyl)-3-[3-{6-(4-methoxyphenylthio)quinolin-5-yl}ureido]quinoline

The yield was 47%.

¹ H 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-chlorophenyl)-3-[3-(6-pentylthioquinolin-5-yl)ureido]quinoline

The yield was 52%.

¹ H 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-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureido]-6-chloro-4-(2-chlorophenyl)-2-methoxy quinoline

The yield was 18%.

¹ H 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-chlorophenyl)-2-methoxy-3-[3-(6-methylthioquinolin-5-yl)ureido]quinoline

The yield was 32%.

¹ H 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.