WO2009062371A1 - Dérivés de carbamate et utilisation en tant que médicament - Google Patents

Dérivés de carbamate et utilisation en tant que médicament Download PDF

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WO2009062371A1
WO2009062371A1 PCT/CN2008/001593 CN2008001593W WO2009062371A1 WO 2009062371 A1 WO2009062371 A1 WO 2009062371A1 CN 2008001593 W CN2008001593 W CN 2008001593W WO 2009062371 A1 WO2009062371 A1 WO 2009062371A1
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group
aryl
trifluoromethyl
substituted
methyl
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PCT/CN2008/001593
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English (en)
Chinese (zh)
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Peng Cho Tang
Pingyan Bie
Guangtao Qian
Shibo Yang
Xiangyang Hao
Zhengrong Zhong
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Shanghai Hengrui Pharmaceutical Co., Ltd.
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Publication of WO2009062371A1 publication Critical patent/WO2009062371A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to a novel class of five- and six-membered cyclic carbamate derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same and their use as therapeutic agents, particularly as cholesterol ester transfer protein inhibitors. Background technique
  • Hypercholesterolemia particularly high serum levels of low-density ester protein cholesterol, shows a risk of arteriosclerotic disease.
  • atherosclerosis and its associated coronary heart disease (CHD) stroke and peripheral vascular disease have become a huge obstacle to the global industrialization of the health care system.
  • CHD coronary heart disease
  • CVD coronary heart disease
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Increasing low-density lipoprotein (LDL) cholesterol levels increases the risk of atherosclerosis.
  • epidemiological studies have shown that lowering high-density lipoprotein (HDL) cholesterol levels will also increase the risk of atherosclerosis.
  • HDL high-density lipoprotein
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme
  • reductase inhibitors and clofibrate can only partially increase high-density lipoprotein (HDL) cholesterol levels, and niacin derivatives can significantly increase HDL, but Serious tolerance problems. Therefore, there is a need for drugs that can significantly increase high-density lipoprotein (HDL) cholesterol levels and are well tolerated to prevent atherosclerosis.
  • Metabolic control of lipoprotein levels is a complex and dynamic process involving multiple factors. Many ester proteins in the patient's catabolic regulation mechanisms are related. Among them, cholesterol ester transfer protein (CETP) is an important lipoprotein level metabolic control factor, which is a 70,000 Dalton glycoprotein present in the plasma of humans and other animals. Transports cholesterol esters, triglycerides, and certain phospholipids between protoplast lipoprotein particles.
  • the above lipoprotein microparticles include high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and chylomicrons.
  • CETP catalyzes the transfer of cholesterol esters from high-density lipoprotein (HDL) to apoprotein-containing apoprotein B, especially to very low-density lipoproteins (Hesler, CB, et. al. (1987) Purification and Characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem.
  • CETP lipid transfer activity in pharmacy may increase high-density lipoprotein (HDL) cholesterol levels while lowering low-density lipoprotein (LDL) levels, which is beneficial to the human body.
  • HDL high-density lipoprotein
  • LDL low-density lipoprotein
  • CETP inhibitors have shown that the body can use this mechanism to increase circulating high-density lipoprotein (HDL) cholesterol levels.
  • One study showed that using CETP inhibitors at a dose of 900 mg per day increased HDL cholesterol by 34% after 4 weeks (Circulation, 2002, 105: 2159).
  • the highest dose was administered twice a day at 120 mg twice daily, and high-density lipoprotein (HDL) cholesterol was increased by 106% after 4 weeks (N. Engl. J. Med. , 2004, 350: 1505-15).
  • High-density lipoprotein (HDL) cholesterol levels in plasma by inhibiting CETP activity may give people the anti-atherosclerosis.
  • CETP inhibitors have been shown to have anti-atherosclerotic effects in rabbits, this has not been confirmed in humans (Nature 2000, 406: 203-2071).
  • the present invention describes a process for the preparation of a series of five- and six-membered cyclic carbamate derivatives and their use in medicine, especially as a pharmaceutical application for CETP inhibitors. Summary of the invention
  • R 1 R 2 are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further Substituted by one or more alkyl, aryl, trifluoromethyl or heterocycloalkyl groups;
  • R 3 is selected from a hydrogen atom, a fluorenyl group, an aryl group, an arylalkyl group or a heteroaryl group, wherein the alkyl group, the aryl group, the aryl fluorenyl group or the heteroaryl group is further substituted by one or more halogen or trifluoromethyl groups;
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group, a cycloalkyl group, a trifluoromethyl group, a heterocyclic fluorenyl group, an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, An aryl group, an aryl fluorenyl group, a heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic acid esters;
  • R 7 is selected from a hydrogen atom, a decyl group, an alkenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group; n is 1 work
  • Typical compounds of the invention include, but are not limited to :
  • a pharmaceutical composition comprising a five- and six-membered cyclic carbamate derivative of the formula (I) or a pharmaceutically acceptable salt, carrier or excipient thereof.
  • an inhibitor of cholesteryl ester transfer protein activity comprising a prophylactic or therapeutic agent for hyperlipidemia and a prophylactic or therapeutic agent for atherosclerosis.
  • a cholesterol ester transfer protein activity inhibitor comprising a prophylactic or therapeutic agent for hyperlipidemia and a prophylactic or therapeutic agent for atherosclerosis in a medicament for treating a cardiovascular-related disease the use of.
  • a cholesterol ester transfer protein activity inhibitor comprising a prophylactic or therapeutic agent for hyperlipidemia and a method for preparing a prophylactic or therapeutic agent for atherosclerosis, comprising the steps of:
  • trifluoromethylpyrrole diester is reduced in tetrahydrofuran and lithium aluminum hydrogen at room temperature to obtain trifluoromethylpyrrololate;
  • trifluoromethylpyrrolidone is oxidized in dichloromethane and pyridinium chlorochromate to give trifluoromethylpyrrolidine.
  • Trifluoromethylpyrrolate is reacted with a halogen under heating to obtain a halogen-substituted methylpyrrolidone
  • halogen-substituted methylpyrrolidone is oxidized with cerium nitrate by heating under tetrahydrofuran/water/acetic acid, halogen-substituted pyrrole aldehyde;
  • X is a halogen
  • Trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halotrifluoromethylpyrrolaldehyde;
  • Trifluoromethylpyrrolidonic acid is subjected to reduction reaction with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde.
  • X is a halogen
  • Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further substituted by one or more alkyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic acids Substituted by ester.
  • the (S) configuration of the aryl substituted compound is obtained by coupling a methoxyamino substituted compound of the (S) configuration with an aryl bromide in an ice bath under a nitrogen atmosphere;
  • R'-R 6 is as defined above, and Ar is aryl, arylalkyl or heteroaryl, wherein aryl, aryl fluorenyl, The heteroaryl group is further substituted with one or more alkyl, aryl, decyloxy, carboxylic acid, carboxylic acid esters.
  • the aryl epoxy oxime is subjected to ring-opening reaction with cyanotrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran to obtain a hydroxy-substituted arylpropionitrile;
  • Hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran under a nitrogen atmosphere to obtain a hydroxy-substituted aryl propylamine;
  • Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further substituted by one or more fluorenyl groups, aryl groups, decyloxy groups, Substituted by a carboxylic acid or a carboxylic acid ester. (9) at room temperature, in the inventive step of the invention, 6, 8, with each polysubstituted pyrrole aldehyde, reductive amination to give a polysubstituted pyrrole methylamine;
  • the polysubstituted pyrrole methylamine is cyclized with triphosgene, ruthenium, osmium-diisopropylethylamine to obtain five- and six-membered cyclic carbamates;
  • R'-R 6 is as defined above, and Ar is aryl, aralkyl or heteroaryl, wherein the aryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, aryl, decyloxy , substituted by carboxylic acid and carboxylic acid ester.
  • hydroxy-substituted arylacetic acid is reacted with methanol and azidotrimethylsilyl in benzene at room temperature to obtain a hydroxy-substituted arylethyl ester;
  • the hydroxy-substituted arylethyl ester is brominated in tetrachloromethane with carbon tetrabromide and triphenylphosphine.
  • the polysubstituted pyrrolamine ester is reacted with a bromoarylethyl ester in tetrahydrofuran to give an aryl-substituted pyrrolamine diester;
  • the aryl-substituted pyrrolamine diester is reduced in tetrahydrofuran with a solution of lithium aluminum chloride in tetrahydrofuran to obtain an aryl-substituted pyrrolamine ester;
  • the aryl-substituted pyrrolamine ester is cyclized with triphosgene, ruthenium, osmium-diisopropylethylamine in methylene chloride to obtain five- and six-membered cyclic carbamate compounds;
  • X is a halogen
  • Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic groups Substituted by an acid ester.
  • the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention relates to a process for the preparation of a compound of the invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the process comprising the steps of:
  • a polysubstituted pyrrole methylamine is combined with triphosgene, ruthenium, osmium-diisopropylethylamine to give a 5- or 6-membered cyclic carbamate.
  • R'-R 6 is as defined above, and Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, and an alkane group. Substituted by a substituent of an oxy group, a carboxylic acid or a carboxylic acid ester.
  • the invention relates to a method of preparing a compound of the invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • a halogen-substituted pyrrolidine ester is heated in methanol with hydroxylamine hydrochloride and sodium acetate to obtain a polysubstituted pyrrolamine ester;
  • hydroxy-substituted arylacetic acid is reacted with methanol and azidotrimethylsilane in benzene at room temperature to obtain a hydroxy-substituted arylethyl ester;
  • the polysubstituted pyrrolamine ester is reacted with a bromoarylethyl ester in tetrahydrofuran to give an aryl-substituted pyrrolamine diester;
  • the aryl-substituted pyrrolamine diester is reduced in tetrahydrofuran with a solution of lithium aluminum hydrogen in tetrahydrofuran to obtain an aryl-substituted pyrrolamine ester;
  • the aryl-substituted pyrrolamine ester is cyclized with triphosgene, hydrazine, hydrazine-ethylamine in methylene chloride to obtain five- and six-membered cyclic carbamate compounds;
  • X is a halogen
  • Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl group, the heteroaryl group
  • the step is substituted with one or more substituents selected from the group consisting of fluorenyl, aryl, alkoxy, carboxylic acid or carboxylic acid esters.
  • the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula
  • the preparation method of the intermediate comprises the following steps:
  • trifluoromethylpyrrolidine is reduced in tetrahydrofuran and lithium aluminum hydrogen at room temperature to obtain trifluoromethylpyrrololate;
  • trifluoromethylpyrrolidone is oxidized in dichloromethane and pyridinium chlorochromate to give trifluoromethylpyrrolidine.
  • the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:
  • trifluoromethylpyrrole diester is selectively reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrrolate;
  • Trifluoromethylpyrrolate reacts with halogen under heating to give a halogen-substituted methylpyrrole I
  • halogen-substituted methylpyrrolidone is oxidized with cerium ammonium nitrate under heating in tetrahydrofuran/water/acetic acid, a halogen-substituted pyrrole aldehyde ester;
  • X is a halogen.
  • the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:
  • trifluoromethylpyrrolidine is reduced in trichloromethane with trifluoroacetic acid to obtain trifluoromethylpyrrolidonic acid;
  • Trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halotrifluoromethylpyrrolaldehyde;
  • the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:
  • the preparation method of the intermediate comprises the following steps:
  • Trifluoromethylpyrrolidonic acid is reduced with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde
  • the present invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:
  • X is a halogen
  • Ar is an aryl group, an aralkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by an acid ester.
  • the preparation method of the intermediate comprises the following steps:
  • a halogen-substituted pyrrole aldehyde ester and an aryl-substituted boric acid undergo a SuZuKi coupling reaction to obtain an arylpyrrole aldehyde ester;
  • X is a halogen
  • Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further one or more fluorenyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by ester.
  • the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:
  • I 1 and R 2 are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a trifluoromethyl group or a heterocycloalkane group. Substituted by a substituent.
  • the preparation method of the intermediate comprises the following steps:
  • the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound
  • RR 2 is each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further substituted by one or more selected from the group consisting of an alkyl group, an aryl group, a trifluoromethyl group or a heterocycloalkyl group. Substituted by the base. Further, the present invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:
  • Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent.
  • the preparation method of the intermediate comprises the following steps:
  • (S) benzyloxycarboaminopropionic acid is reductively aminated with methoxy-methylamine in tetrahydrofuran to obtain a methoxyamino-substituted compound of the (S) configuration;
  • the (S) configuration of the aryl substituted compound is obtained by coupling a methoxyamino substituted compound of the (S) configuration with an aryl bromide in an ice bath under a nitrogen atmosphere;
  • Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. Further, the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:
  • Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, and the heteroaryl group are further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, Substituted by a substituent of a carboxylic acid or a carboxylic acid ester.
  • the preparation method of the intermediate comprises the following steps:
  • aryl formaldehyde is cyclized with sodium hydride and trimethyl iodide to give aryl epoxy oxime.
  • the aryl epoxy oxime is subjected to ring-opening reaction with cyanotrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran to obtain a hydroxy-substituted arylpropionitrile;
  • a hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran to obtain a hydroxy-substituted aryl propylamine;
  • Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, and an anthracene group. Substituted by a substituent of an oxy group, a carboxylic acid or a carboxylic acid ester. Further, the present invention relates to a pharmaceutical composition comprising a compound of the formula 1 of the present invention, a salt thereof or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the use of the composition of the present invention for the preparation of a cholesterol ester transfer protein activity inhibitor, the use of the composition of the present invention for the preparation of a medicament for preventing or treating hyperlipidemia, and the preparation of the composition of the present invention for prevention or treatment Use in atherosclerosis drugs.
  • the present invention relates to the use of a compound of the present invention for the preparation of a cholesterol ester transfer protein activity inhibitor, the use of the compound of the present invention for the preparation of a medicament for preventing or treating hyperlipidemia, and the preparation of a compound of the present invention for the prevention or treatment of atherosclerosis Use in hardened drugs.
  • the present invention relates to a method for inhibiting the activity of a cholesterol ester transfer protein comprising administering to a patient a compound of the formula 1, a prodrug compound thereof, or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a method for preventing or treating hyperlipidemia comprising administering to a patient a compound represented by Formula 1, a prodrug compound thereof, or a pharmaceutically acceptable salt thereof, and the present invention relates to a prophylaxis Or a method of treating atherosclerosis, comprising administering to a patient a compound of formula 1, a prodrug compound thereof, or a pharmaceutically acceptable standard thereof
  • Mercapto refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms.
  • a mercapto group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group, a pentyl group or the like is preferable.
  • lower fluorenyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • alkenyl refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • Cyclopentyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring
  • fused ring system means each in the system
  • the rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • Examples of cyclodecyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexanyl, cyclohexadiene, adamantane, cycloheptadene, cycloheptatriene and the like.
  • Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihaloalkyl, hydroxy, nitro, cyano, lower decyloxy, hydrazine.
  • Base, heteroaryl, heterocyclic fluorenyl or -C( 0)OR 7 .
  • Heteroaryl means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen.
  • the ring may be a 5- or 6-membered ring.
  • Examples of the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like.
  • Heterocyclic fluorenyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These rings may also have one or more double bonds. However, these rings do not have a fully conjugated ⁇ - electron system.
  • Unsubstituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl can be substituted or Unsubstituted.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Trifluoromethyl means -CF 3 .
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • trifluoromethylpyrrolediester is selectively reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrroleate; trifluoromethylpyrrolate is reacted with halogen under heating to obtain halogen substitution.
  • Methylpyrrolidone; halogen-substituted methylpyrrolidone is oxidized with cerium ammonium nitrate under heating in tetrahydrofuran/water/acetic acid, halogen-substituted pyrrole aldehyde.
  • trifluoromethylpyrrolidine is reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrrolidonic acid; trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halogenated three. Fluoromethylpyrrolaldehyde.
  • the trifluoromethylpyrrolidonic acid is subjected to a reduction reaction with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde.
  • a halogen-substituted pyrrole aldehyde ester and a substituted boronic acid undergo a SuZuKi coupling reaction to obtain an arylpyrrolidinyl ester.
  • the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound; at room temperature, the nitro compound is hydrogenated and reduced to obtain an amino-substituted compound.
  • aryl formaldehyde is cyclized with sodium hydride and trimethyl iodide to give aryl oxirane; aryl oxirane in tetrahydrofuran with cyanotrimethylsilane, tetrabutyl fluoride
  • the ammonium ring-opening reaction gives a hydroxy-substituted arylpropionitrile; under a nitrogen atmosphere, a hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran to give a hydroxy-substituted aryl propylamine.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula (I) according to the invention or a salt thereof and a pharmaceutically acceptable carrier.
  • the invention further relates to the use of a compound of the formula (I) according to the invention or a salt thereof for the preparation of a cholesterol ester transfer protein inhibitor.
  • BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further described below in conjunction with the examples, but these examples do not limit the scope of the invention.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus.
  • the solvent was deuterated chloroform (CDC1 3 ), deuterated dimethyl sulfoxide (DMSO-D 6 ), internal standard tetramethylsilane (TMS), chemical shift. It is given in units of l (T 6 (ppm).
  • the MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer.
  • Thin layer silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • DMSO-D 6 deuterated dimethyl sulfoxide
  • 3-carbonyl-butyric acid-tert-butyl ester (3.28 g, In glacial acetic acid 9.3 011
  • the temperature is raised to 65 ° C with stirring, and the zinc powder is weighed.
  • a solution of the one-step reaction product 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyric acid ethyl ester lb was added dropwise with a dropping funnel, and zinc powder was added in multiple portions.
  • the temperature of the water bath control system was maintained at about 75 ° C, and the reaction was carried out for 2 hours, and then the temperature was lowered to 40 to 45 ° C, and the reaction was continued overnight.
  • the spot plate was followed to track the completion of the reaction, and 30 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, and then the mixture was extracted with ethyl acetate (50 ml ⁇ 3). The combined organic layers were washed with EtOAc EtOAc EtOAc.
  • the reaction mixture was quenched with a small amount of water, and a small portion of ethyl acetate was added, filtered, and the filter cake was washed with ethyl acetate, and the obtained filter cake was purified by silica gel column chromatography to give the title product 5-methyl-3-trifluoromethyl- 1H-pyrrole-2-hydroxymethyl-4-carboxy acid tert-butyl ester ld (0.765 g), yield 50%.
  • Example 2 of the present invention was repeated, and the compound obtained in Example 2 was used.
  • EtOAc (EtOAc) Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 4 (0.118 g , white solid), yield 33.7%.
  • EtOAc EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the ethyl acetate layer was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjj g), yield 59%.
  • 3,5-di-trifluoromethyl-benzaldehyde 2a (10 g, 0.0413 mmol), nitromethane (9.2 g, 0.151 mol) was dissolved in 200 ml of absolute ethanol under ice-bath and cooled to - 0.2 ° C. Slowly add 17.3 ml of 10% sodium hydroxide solution, keep the temperature below 3 °C, stir the reaction for 4 hours, add 130 ml of 2% acetic acid solution dropwise, keep the temperature below 5 °C, and raise to room temperature. The reaction was stirred overnight and the plate was followed to end the reaction. The reaction solution was concentrated under reduced pressure.
  • EtOAc EtOAc
  • EtOAcjjjjjjjjj The aqueous solution was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated, 462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462462 Hydroxy-ethylamine]-methyl ⁇ -2-methyl-4-trifluoromethyl-1H-pyrrole-3-iodo 8c (1.25 g), yield 80.6%.
  • Example 10 of the present invention The fourth step of the reaction of Example 10 of the present invention was repeated, using the compound obtained in Example 10, 5- ⁇ [2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl -ethylamine]-methyl ⁇ -2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 10c is reacted with triphosgene, hydrazine, hydrazine-diisopropylethylamine, The obtained residue was purified by preparative chromatography chromatography to afford the title product 5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl] Ethyl 2-methyl-4-trifluoromethyl-l-pyrrole-3-carboxylate 11 (erythro) (0.2 g, white solid), yield 4.46.
  • EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjjj Di-trifluoromethyl-phenyl)-2-one-oxazole 3-yl-methyl]-1,2-dimethyl-4-trifluoromethyl-1H-pyrrole 12 (0.028 g, light yellow Solid), yield 44%.
  • Copper chromite (2.0 g) was dissolved in 2 ml of quinoline and heated to an oil bath temperature of 200 ⁇
  • Trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino]-propan-1-hydroxyl 13b is reacted with triphosgene, N,N-diisopropylethylamine, and the residue obtained by preparative chromatography To give the title product 5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl -Methyl)-oxazol-2-one 14 (threo) (0.023 g, pale yellow solid), yield 17.5%.
  • reaction solution was extracted by adding 20 ml of water and 50 ml of ethyl acetate. Combine the organic phase with a saturated aqueous solution of sodium chloride (20 ml ⁇ 1), the organic layer was washed with EtOAc EtOAcjjjjjjjjjjjj Ethyl fluoromethyl-1H-pyrrole-2-carboxylate 15a (0.074 g), Yield: 23%.
  • EtOAc EtOAc
  • Ethyl-1H-pyrrole-2-carboxylic acid ethyl ester 15b (0.062 g, 0.11 mmol), sodium chloride (20 mg) dissolved in 2 ml of methylene chloride, keeping the internal temperature less than 0 ° C, slowly A solution of triphosgene (70 mg, 0.23 mmol) in dichloromethane (2 ml) was added dropwise, and the mixture was stirred for 2 hr, then EtOAc, m.
  • the point plate tracks the reaction.
  • 60 ml of a 5 N diluted hydrochloric acid solution was added, and the obtained mixture was extracted with ethyl acetate (80 ml ⁇ l), and then washed with a saturated aqueous solution of sodium chloride (20 ml ⁇ l), and the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure to give the title product (S)-[2-(3,5-di-trifluoromethyl-benzene Benzyl)-1-methyl-2-keto-ethyl]-carbamic acid benzyl ester 17c (25.1 g), yield 100%, product used for the next reaction.
  • Example 12 of the present invention The first step reaction of Example 12 of the present invention was repeated except that the compound obtained in Example 8 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-keto-oxazole was used. 3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole 8 and 3,5-di-trifluoromethyl-benzyl bromide are used as starting materials to give the title product 3-[1-( 3,5-di-trifluoromethyl-phenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl]-5-(3,5-di-trifluoro Methyl-phenyl)-oxo-2-one 19 (92 mg, white solid), Yield: 61.7%.
  • reaction solution was extracted by adding 20 ml of water and 50 ml of ethyl acetate. The organic phase was combined, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated Ethyl-4-p-tolyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 20a (0.11 g), Yield: 34%.
  • Ethyl 5-formyl-4-iodo-3-trifluoromethyl-1H-pyrrole-2-carboxylate 5c (600 mg, 1.66 mmol), hydroxylamine hydrochloride (238 mg, 3.57 mmol), sodium acetate (293 The mg, 3.57 mmol) was dissolved in 15 ml of methanol, and the reaction was stirred under reflux for 2 hours. In a separate vial, 10 ml of concentrated hydrochloric acid, 30 ml of water, zinc powder (906 mg, 13.94 mmol) were added in sequence, and a small amount of methanol was added to dissolve it.
  • Ethyl 5-aminomethyl-3-trifluoromethyl-1H-pyrrole-2-carboxylate 25a (0.082 g, 0.347 mmol) was dissolved in 20 ml of tetrahydrofuran and (3,5-di-trifluoro Methyl-phenyl)-bromo-acetic acid methyl ester 25d (0.507 g, 1.388 mmol), triethylamine (350 mg, 3.47 mmol). Point plate tracking reaction Bunch. The reaction mixture was concentrated under reduced EtOAc (EtOAc m.
  • Lithium aluminum hydrogen (170 mg, 4.47 mmol) was dissolved in 50 ml of tetrahydrofuran in a dry ice bath.
  • CETP Cholesterol lipid transfer protein
  • HDL high-density lipoprotein
  • apoB apolipoprotein B
  • the principle of CETP inhibitor screening in this experiment is as follows: In the reaction system, the donor molecule containing the fluorescent self-quenching neutral lipid is transferred to the acceptor molecule under the guidance of CETP, thereby losing the inhibition. , causing the system to increase in fluorescence. Inhibition of CETP inhibits lipid transfer, thereby reducing system fluorescence intensity.
  • compositions using CETP inhibitor screening reagents include: donor molecule, receptor molecule, reaction buffer, rabbit serum (CETP enzyme source).
  • test compounds were dissolved in DMSO at a concentration of 1 mM (final reaction concentration 50 uM;).
  • the inhibition rate of each compound was calculated by comparing the fluorescence intensities of the tube to be tested and the positive control tube.
  • Activity of the compounds of the invention was calculated by comparing the fluorescence intensities of the tube to be tested and the positive control tube.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the ratio of the inhibition ratios measured is shown in the following table.

Abstract

L'invention concerne des dérivés de carbamate cycliques à 5 ou 6 éléments représentés par la formule générale (I), leur procédé de préparation, des compositions pharmaceutiques les comprenant, des intermédiaires pour la préparation de la formule générale (I) et un procédé de préparation des intermédiaires, et leur utilisation en tant que médicament, notamment pour les inhibiteurs de la protéine de transfert de l'ester du cholestérol (CEPT).
PCT/CN2008/001593 2007-10-15 2008-09-08 Dérivés de carbamate et utilisation en tant que médicament WO2009062371A1 (fr)

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US9944597B2 (en) 2013-09-16 2018-04-17 The Board Of Regents Of The University Of Texas System Polysubstituted pyrroles having microtubule-disrupting, cytotoxic and antitumor activities and methods of use thereof
US9944602B2 (en) 2014-07-02 2018-04-17 E. I. Du Pont De Nemours And Company Piperidinone herbicides
US10227286B2 (en) 2014-12-08 2019-03-12 Fmc Corporation 3-oxo-3-(arylamino)propanoates, a process for their preparation, and their use in preparing pyrrolidinones
US10294202B2 (en) 2013-12-03 2019-05-21 Fmc Corporation Pyrrolidinones as herbicides
US10405547B2 (en) 2015-04-10 2019-09-10 Fmc Corporation Substituted cyclic amides as herbicides
US10442807B2 (en) 2015-05-12 2019-10-15 Fmc Corporation Aryl substituted bicyclic compounds as herbicides
US10582709B2 (en) 2015-04-27 2020-03-10 Fmc Corporation Butyrolactones as herbicides
US10654804B2 (en) 2015-06-02 2020-05-19 Fmc Corporation Substituted cyclic amides and their use as herbicides
US10875838B2 (en) 2017-03-21 2020-12-29 Fmc Corporation Pyrrolidinones and a process to prepare them
US10906873B2 (en) 2015-05-29 2021-02-02 Fmc Corporation Substituted cyclic amides as herbicides
US11019818B2 (en) 2017-05-30 2021-06-01 Fmc Corporation Herbicidal 3-substituted lactams
US11178873B2 (en) 2015-07-31 2021-11-23 Fmc Corporation Cyclic N-carboxamide compounds useful as herbicides
US11357230B2 (en) 2017-05-30 2022-06-14 Fmc Corporation Herbicidal amides
US11498899B2 (en) 2016-12-21 2022-11-15 Fmc Corporation Nitrone herbicides
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JP5793143B2 (ja) * 2010-07-22 2015-10-14 興和株式会社 光学活性１−ブロモ−１−［３，５−ビス（トリフルオロメチル）フェニル］エタンの製造方法
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US9944597B2 (en) 2013-09-16 2018-04-17 The Board Of Regents Of The University Of Texas System Polysubstituted pyrroles having microtubule-disrupting, cytotoxic and antitumor activities and methods of use thereof
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