EP0583346A1 - Bicyclic amides as inhibitors of acyl-coenzyme a: cholesterol acyl transferase - Google Patents
Bicyclic amides as inhibitors of acyl-coenzyme a: cholesterol acyl transferaseInfo
- Publication number
- EP0583346A1 EP0583346A1 EP92910760A EP92910760A EP0583346A1 EP 0583346 A1 EP0583346 A1 EP 0583346A1 EP 92910760 A EP92910760 A EP 92910760A EP 92910760 A EP92910760 A EP 92910760A EP 0583346 A1 EP0583346 A1 EP 0583346A1
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- EP
- European Patent Office
- Prior art keywords
- substituted
- compound
- group
- formula
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/06—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/14—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to bicyclic amides and to pharmaceutical compositions containing such compounds, for use in the treatment and prevention of atherosclerosis.
- Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, cigarette smoking and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk.
- ACAT cholesterol acyl transferase
- R 1 and R 2 are independently H, lower alkyl, lower alkoxy or halo; j is an integer of from 1 to 3; and R 3 is an alkyl chain of 1 to 23 carbon atoms, saturated or unsaturated, or an alkyl chain as defined wherein each unsaturated ethylenic group is replaced by a
- R 1 and R 2 are independently H, halo, lower alkyl or lower alkoxy; and -C(O)-R is a 7-23 C unsaturated fatty acid radical in which each ethylenic group is replaced by a cyclopropanyl group.
- X is H, OH, lower alkyl, halogen, lower alkoxy, amino or dialkylamino; Y is -CH 2 -, -CH 2 CH 2 -, -O- or -S-; n is 1 , 2 or 3; m is 0 or 1 ; R 1 is phenyl, pyridyl, or X-substituted phenyl or pyridyl; R 2 is lower alkyl or X-substituted aryl; and R is lower alkyl or hydroxy- or phenyl- substituted lower alkyl.
- R is alkyl; R 1 is alkoxy or acyloxy; R 2 is lower alkyl; and R 3 is lower alkyl, aryl or heteroaryl.
- Novel compounds of the present invention which show significant in vivo anti-atherosclerotic activity are represented by the formula
- Ar 1 and Ar 2 are independently selected from the group consisting of phenyl, R 2 -substituted phenyl, heteroaryl or R 2 -substituted heteroaryl, wherein R 2 is 1 to 3 substituents independently selected from the group consisting of halogeno, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and lower dialkylamino;
- X, Y and Z are independently selected from the group consisting of -CH 2 -, -CH(alkyl)-, -C(alkyl) 2 -, -NH-, -N(alkyl)-, -O- and -SO r , wherein r is 0, 1 or 2, and m, n and p are 0 or 1 , such that 0 ⁇ (m+n+p) ⁇ 4, provided that only one of X,Y or Z is -NH-, -N(alkyl)-, -O- or -SO r ;
- R 1 is an alkyl chain of 1 to 25 carbon atoms, branched or straight, saturated or containing one or more double bonds; an alkyl chain of 1 to 25 carbon atoms as defined substituted by one or more substituents selected from the group consisting of phenyl, R 2 -substituted phenyl, heteroaryl and R 2 -substituted heteroaryl; an alkyl chain of 1 to 25 carbon atoms as defined interrupted by one or more Q groups, wherein Q is independently selected from the group consisting of -O-, -SO r , phenylene, R 2 -substituted phenylene, heteroarylene and R 2 -substituted heteroarylene; an interrupted alkyl chain of 1 to 25 carbon atoms as defined substituted by one or more substituents selected from the group consisting of phenyl, R 2 -substituted phenyl, heteroaryl and R 2 -substituted heteroaryl; an alky
- Ar 1 and Ar 2 are independently selected from the group consisting of phenyl, lower alkoxy-substituted phenyl, amino-substituted phenyl, hydroxy-substituted phenyl or pyridyl.
- Another group of preferred compounds is that wherein one of X, Y or Z is an oxygen atom and -(X) m -(Y) n -(Z) p -, together with the carbons to which they are attached, form a six membered ring
- Ar 1 and Ar 2 are both phenyl.
- Yet another group of preferred compounds is that wherein -(X) m -(Y) n -(Z) p -, together with the carbon to which they are attached, form a 5-C ring, and Ar 1 and Ar 2 are independently chosen from the group consisting of phenyl, nitro-substituted phenyl, amino-substituted phenyl, lower alkoxy-substituted phenyl and hydroxy-substituted phenyl.
- the invention in another aspect, relates to pharmaceutical compositions comprising an ACAT inhibitor of the present invention in a pharmaceutically acceptable carrier.
- THF tetrahydrofuran
- DCC dicyclohexylcarbodiimide
- EDCI 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- lower alkyl means straight or branched alkyl chains of 1 to 6 carbon atoms and “lower alkoxy” similarly refers to alkoxy groups having 1 to 6 carbon atoms.
- Halogeno refers to fluorine, chlorine, bromine or iodine radicals.
- Phenylene means a bivalent phenyl group, including ortho, meta and para-substitution and "heteroarylene” similarly means a bivalent heteroaryl group.
- Heteroaryl means an aromatic group having 5 or 6 ring members wherein 1-3 ring members are independently selected from the group consisting of nitrogen, oxygen and sulfur.
- heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl and thienyl.
- the alkyl chain as defined in R 1 can be a radical of a synthetic or natural fatty acid, either saturated or containing one or more carbon to carbon double bonds, or can be an interrupted alkyl chain wherein one or more of the carbon atoms in the chain can be replaced by an -O-, -SO r , phenylene or heteroarylene group; and when the alkyl chain is greater than 4 carbons in length it can be additionally
- the alkyl chain or interrupted alkyl chain may be independently substituted on different carbon atoms, di-substituted on one carbon atom, or both.
- alkyl chains are as follows, wherein the group -C(O)R 1 is named: palmitoyl, stearoyl and 2,2-dimethyldodecanoyl.
- Examples of unsaturated -C(O)R 1 groups are oleoyl, linoieoyl, linolenoyl, elaidoyl, eicosatetraenoyl, eicosapentaenoyl and arachidonoyl.
- Examples of -C(O)R 1 groups wherein the carbon atoms are substituted are diphenylacetyl, 3,3-diphenylpropionyl and 2,3-diphenylpropionyl.
- Examples of -C(O)R 1 groups wherein carbon atoms in the chain are replaced are: 3-methoxy-4-(tetradecyloxy)-benzoyl, 11 -[N-(2,2-diphenylacetyl)amino]undecanoyl and phenoxyundecanoyl.
- An example of a di-substituted amino -C(O)R 1 group is N,N-diphenylaminocarbonyl.
- Compounds of the invention have at least two
- asymmetrical carbon atoms and therefore include rotational isomers.
- the invention includes all possible stereoisomers in both pure form and in admixture, including racemic mixtures.
- Isomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials or by separating isomers of a compound of formula I.
- isomers may include geometric isomers, e.g. when R 1 contains a double bond. All such isomers are contemplated for this invention.
- Compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids.
- suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art.
- the salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
- the free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
- the free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
- Certain compounds of the invention are acidic (e.g., those compounds which possess a phenol or carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
- a carboxylic acid of formula II can be converted to the acid chloride by treatment with thionyl or oxalyl chloride in a solvent such as CH 2 CI 2 , then reacted with an amine of formula III in the presence of a tertiary amine base such as Et 3 N, DMAP or NMM:
- the acid of formula II and the amine of formula III can be reacted in the presence of a coupling agent such as DCC or EDCl and a base such as Et 3 N, DMAP or NMM in a solvent such as CH 2 CI 2 or THF at a temperature of 0°C to 23°C.
- a coupling agent such as DCC or EDCl and a base such as Et 3 N, DMAP or NMM
- a solvent such as CH 2 CI 2 or THF at a temperature of 0°C to 23°C.
- the carboxy group of acid II can be activated via the
- Compounds of formula lb wherein one of Ar 1 or Ar 2 is R 2 -substituted phenyl and R 2 is hydroxy, can be prepared by treating a compound of formula la, wherein one of Ar 1 or Ar 2 is R 2 -substituted phenyl and R 2 is methoxy, with BBr3.
- a compound of formula la can be added to a mixture of NaH and EtSH in DMF and heated at reflux to prepare a compound of formula lb.
- Compounds of formula Id wherein one of Ar 1 or Ar 2 is R 2 -substituted phenyl and R 2 is a primary amino group, can be prepared by hydrogenation over a suitable catalyst, e.g.5% Pd/C, of a compound of formula Ic, wherein one of Ar 1 or Ar 2 is R 2 -substituted phenyl and R 2 is a nitro group.
- a suitable catalyst e.g.5% Pd/C
- Compounds of formula If, wherein R 1 is N,N-diphenylamino can be prepared by treatment of an amine of formula III with triphosgene and Et 3 N followed by reaction with diphenylamine at reflux:
- Compounds of the formula Ig, wherein R 2a and R 2b are independently hydrogen or chloro can be prepared by treating a compound of the formula Ih with an appropriate quantity of a suitable chlorinating agent, e.g. sulfuryl chloride, in dry organic solvent, e.g. a mixture of CH 2 CI 2 and ether.
- a suitable chlorinating agent e.g. sulfuryl chloride
- dry organic solvent e.g. a mixture of CH 2 CI 2 and ether.
- a method for preparing a compound of the formula Ig, wherein R 2a and R 2b are independently hydrogen or methyl comprises treating a compound of the formula Ih with formaldehyde, 10% aqueous KOH in DMF and heating the mixture followed by hydrogenation of the product so obtained at elevated pressure, e.g. 60 psi hydrogen, with a suitable catalyst, e.g. 20% Pd(OH) 2 on carbon, and using an
- a ketone of formula IV is converted to an oxime of formula XXV by treatment with hydroxylamine hydrochloride and NaOAc in MeOH.
- the oxime XXV is treated with chlorodiphenylphosphine and Et 3 N to form a phosphinylimine XXVI.
- Reduction of the phosphinylimine to a cis-phosphonamide XXVII with DIBAL-H followed by hydrolysis with HCI in MeOH forms the desired cis-amine:
- a method for preparing a trans-amine of formula III-trans involves reducing a ketone of formula IV to a cis-alcohol of formula VI-cis using a suitable reducing agent, such as DIBAL-H.
- a suitable reducing agent such as DIBAL-H.
- the alcohol VI-cis is converted to the desired trans-amine via the trans-azide VII-trans as described above for VI-trans:
- Ketones of formula IV can be prepared by several methods.
- a nitrile of formula VIII is treated with a suitable base, such as NaH, then reacted with a halide of formula IX to form a nitrile of formula X.
- the nitrite VIII is treated with the halide IX and 50% sodium hydroxide (aqueous) in the presence of a suitable phase transfer catalyst such as tetra-n-butylammonium chloride to form the nitrile X.
- the nitrile X is subjected to hydrolysis under either acidic or basic conditions to form a carboxylic acid of formula XI.
- the acid of formula XI can be converted to the acid chloride by treatment with thionyl or oxalyl chloride in a solvent such as CH 2 CI 2 , then treated with a Lewis acid, such as anhydrous AICI 3 , to form the ketone IVa:
- a nitrile of formula X can be combined with NaCl and AlCl 3 , then heated to 180°C, followed by hydrolysis to directly form the ketone IVa.
- a nitrile of formula VIII is condensed with an aldehyde of formula XXI under basic conditions to form an unsaturated nitrile of formula XXII.
- the unsaturated nitrile of formula XXH is reduced using NaBH 4 in EtOH to a nitrile of formula X which is converted to a ketone of formula IVa as described above:
- the unsaturated nitrile XXII can be reduced by hydrogenation at 50 psi of hydrogen in the presence of a suitable catalyst such as 10% Pd/C.
- a ketone of formula XII is condensed with an aldehyde of formula XIII under basic conditions to form a ketone of the formula XIV.
- the ketone of formula XIV is reacted with potassium cyanide and HOAc to form a ketonitrile of formula XV.
- ketones of formula XII and aldehydes of formula XIII are commercially available or can be prepared by well known methods.
- a ketone of formula IV can be prepared by treatment of a ketone of formula XVI with chlorine to form an ⁇ -chloro-ketone of formula XVII.
- organometallic reagent of formula XVIII, wherein M is Li, Ce or MgBr produces an alcohol of formula XIX.
- Reaction of the alcohol XIX with ethylgrignard reagent in a suitable solvent such as THF at reflux temperature forms the desired ketone IV:
- ketones of formula XVI and organometallic reagents of formula XVIII are commercially available or can readily be prepared via procedures well known to those skilled in the art.
- Another method of preparing a ketone of formula IV involves reacting an enol acetate of formula XX with an aryl halide of formula XXI and tri-n-butyltin methoxide in the presence of a suitable catalyst such as [(ortho-tolyl) 3 P] 2 PdCl 2 :
- ketones of formula IVc wherein Ar 1 is R 2 -substituted phenyl; and -(X) m -(Y) n -(Z) p -, together with the carbons to which they are attached, comprise a 5-C ring, an aldehyde of formula XIII and a lactone of formula XXIII are treated with sodium ethoxide in EtOH at reflux to form an indanedione of formula XXIV.
- the indanedione of formula XXIV is treated with NH 4 OAC in EtOH at reflux, then reduced with zinc dust to form the desired ketone IVc:
- Enol acetates of formula XX can be prepared by reacting a ketone of formula XVI with isopropenyl acetate in the presence of a catalytic amount of a suitable acid, such as pTSA.
- Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction.
- the following table shows some typical protecting groups:
- compounds of this invention are inhibitors of ACAT in vitro and in whole animal models the compounds have been found to significantly reduce the formation of liver cholesterol esters.
- compounds of this invention are hypocholesterolemic and hypolipidemic agents by virtue of their ability to inhibit the esterification and intestinal absorption of cholesterol; they are therefore useful in the treatment and prevention of atherosclerosis in mammals, in particular in humans.
- the present invention therefore also relates to a method of treating atherosclerosis, in particular by reducing serum cholesterol, which method comprises administering to a mammal in need of such treatment a
- hypocholesterolemic effective amount of a compound of this invention is preferably administered in a pharmaceutically acceptable carrier suitable for oral administration.
- the in vitro and in vivo activity of the present compounds can be determined by the following procedures.
- This assay measures the activity of ACAT by measuring the ACAT-mediated transfer of tritiated oleic acid from acyl-CoA to cholesterol to give labelled cholesterol oleate.
- Rat liver microsomes are used as the source of ACAT.
- Assays are performed in round bottom microtiterplates using a total incubation volume of 50 ⁇ L. Each incubation well receives 10 ⁇ L assay buffer (0.5M KHPO 4 , 10 ⁇ M dithiothreitol, pH 7.4), 7.5 ⁇ L of 40 mg/mL BSA (Bovine Serum Albumin) and 12.5 ⁇ g of microsomal protein.
- assay buffer 0.5M KHPO 4 , 10 ⁇ M dithiothreitol, pH 7.4
- BSA Bovine Serum Albumin
- test compound in sufficient amount to bring the final concentration to from 0.1 to 25 ⁇ M
- reference compound in sufficient amount to bring the final concentration to from 0.1 to 25 ⁇ M
- vehicle control is added and the final volume brought to 47 ⁇ L.
- the microtiterplate is then floated on the surface of a 37°C water bath for fifteen minutes. Incubations are started by the addition of 3 ⁇ L 3H-acyl CoA (1 ⁇ Ci/well, final concentration of 10 ⁇ M acyl CoA). The plate is then returned to the water bath for 15 minutes. The incubations are then terminated by application of 15 ⁇ Lfrom each incubation to individual lanes on a thin layer plate (Silica Gel GF 20 ⁇ 20 cm).
- the inhibition is plotted against drug doses on a log scale and the
- mice Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds.
- Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds.
- the animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral gavage of 0.2 mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by 1M injection of ketamine and sacrificed by decapitation. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis. Data is reported as percent reduction of lipid versus control.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of this invention and a
- the compounds of formula I can be administered in any conventional oral dosage form such as capsules, tablets, powders, cachets, suspensions or solutions.
- the formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques.
- Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrates, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
- the daily hypocholesterolemic or hypolipidemic dose of a compound of formula I is about 7 to about 30 mg/kg of body weight per day.
- the dosage level is therefore from about 500 to about 2000 mg of drug per day, given in a single dose or 2-4 divided doses.
- the exact dose is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight condition and response of the patient.
- Step A Dissolve benzaldehyde (489 mL, 4.816 mol) and p-methoxyphenylacetonitrile (598 mL, 4.414 mol) in 95% EtOH (1.5 L). Stir the solution at room temperature while adding 40% aqueous KOH (489 g, 8.732 mol, in 863 mL water) in 2.2 L of 95% EtOH. Stir the mixture for an additional 1.5 h at room temperature, then collect the crystals by suction filtration, wash with water and cold 95% EtOH, and air dry. The weight of the white, crystalline product (mp 92-94°C, lit.
- Step B Suspend the product of step A (16.01 g, 68.13 mmol) in absolute EtOH (200 mL) at 60-70°C under N 2 . Add solid NaBH4 (2.589 g, 68.13 mmol) in portions over 10 min, and stir the mixture at the same temperature for 2 h. Cool the reaction mixture to ambient temperature and quench with water. Pour the mixture into a volume of water and acidify with cone. HCI. Extract the product into two portions of ether. Combine the organic layers, wash with water and brine, then dry over anhydrous Na 2 SO 4 . Filter the product solution and evaporate to give the crude product (15.88 g, 98.4%), mp 66-67°C.(lit. 104°C), which can be used without further purification. Alternatively, isolate the product by diluting the crude reaction mixture with several volumes of water, and collect the resulting precipitate by suction filtration (99%).
- Step C Combine the product of step B (932.8 g, 3.94 mol) and ethylene glycol (9 L), add a solution of KOH (673 g, 12.02 mol) in water (2.1 L), and heat the mixture at reflux overnight (internal
- Step A Add 10% aqueous NaOH (38 mL) to a solution of p-anisaldehyde (25 mL, 0.206 mol) and acetophenone (23.97 mL, 0.206 mol) in EtOH (500 mL). Stir the mixture at room temperature over night. Dilute the mixture with water and extract with ether. Combine the ethereal extracts, wash with water and brine, dry over Na 2 SO 4 and concentrate to a solid. Recrystallize the solid from ether/hexanes to provide 27.51 g (56%) of 4'-methoxychalcone, mp 72-74°C.
- Step B Add KCN (11.27 g, 0.173 mol) in water (25 mL) to a 100 °C solution of 4'-methoxychalcone (27.51 g 0.115 mol) and HOAc (7.5 mL, 0.128 mol) in 2-methoxyethanol (200 mL). The reaction is complete in ⁇ 10 min. Cool the resulting solution to room temperature and pour into a mixture of ice and water (1 L). Extract the mixture with EtOAc. Combine the organic extracts, wash with water and brine, dry over Na 2 SO 4 , filter and concentrate in vacuo.
- Step C Add a solution of NaOH (34.56 g, 863.9 mmol) in water (375 mL) to a solution of 2-(4'-methoxyphenyl)-4-phenyl-4-oxo-butyronitrile (22.92 g, 86.39 mmol) in EtOH (160 mL). Heat the resulting mixture to reflux under nitrogen and monitor the progress of the hydrolysis by TLC (30% EtOAc/hexane, Ce stain). When all of the starting nitrile is consumed, after ⁇ 5h, cool the reaction to room temperature. Dilute the solution with water(1 L), and stir while acidifying with 10% aqueous HCI (pH ⁇ 1-2).
- Step D Dissolve 2-(4'-methoxyphenyl)-4-phenyl-4- oxobutyric acid (18.07 g, 63.55 mmol) in a mixture of MeOH ( ⁇ 25 mL) and HOAc (125 mL). Purge the resulting solution with nitrogen. Add 10% Pd/C (2 g) and hydrogenate on a Parr apparatus over night at ⁇ 55 psi. Vacuum filter the mixture through celite. Thoroughly wash the filter cake with 25% MeOH/ CH 2 CI 2 (300 mL).
- step D treat 2-
- Step A Prepare a solution of sodium ethoxide using sodium (10.12 g, 0.44 mol) and 200 mL of absolute EtOH under N 2 .
- Step B Dissolve the product from step A (3.01 g, 11.94 mmol) in EtOH (200 mL) under N 2 and treat with ammonium acetate (17.98 g, 233 mmol). Heat mixture at reflux for 4 h and then cool to room temperature. Add zinc dust (7.5 g, 115 mmol) and heat the mixture at reflux for 2.5 h more. Filter the yellow reaction mixture while hot, and dilute the filtrate with water until cloudy. Allow the filtrate to stand in the freezer overnight. Collect the resulting crystals by filtration, wash successively with cold 6 N HCl and water, and dry to obtain the title compound (1.45 g, 51.0%), mp 144-146 °C.
- Step A Bubble chlorine gas through a 0°C solution of 1-tetralone (93 mL, 0.70 mol) in CH 2 CI 2 (500 mL). Closely monitor the reaction by TLC (50% CH 2 CI 2 /hexane). When all of the 1-tetralone is consumed, wash the reaction mixture successively with saturated NaHCO 3 , water and brine, dry over Na 2 SO 4 and concentrate to an oil. Dissolve the oil in ether (150 mL) and place in the freezer. Collect the resulting crystals via vacuum filtration and wash with cold hexane. Dry the crystals in vacuo to afford 73.26 g of a solid.
- Step C Add ethylmagnesium bromide (1.76 mL, 5.27 mmol, M in) dropwise to a 0°C solution of 2-chloro-1-phenyl-1,2,3,4- tetrahydronaphth-1-ol (1.36 g, 5.27 mmol) in dry benzene (20 mL). Stir the solution at 0°C for 30 min and heat to reflux for 5 hours. Cool the mixture to room temperature and quench with saturated NH 4 CI
- Step A Heat a mixture of benzosuberone (12.34 g, 77.02 mmol), isopropenyl acetate (17.8 mL, 161.7 mmol) and pTSA (0.146 g, 0.77 mmol) at reflux overnight ( ⁇ 20 h). Distill the mixture, discarding the fraction distilling from 60-90°C. Cool the pot residue to room
- Step B Combine the product of step A (30.18 g, 149.2 mmol), tri-n-butyltin methoxide (43 mL, 149.2 mmol), palladium acetate (0.336 g, 1.492 mmol), tri-o-tolylphospine (0.908 g, 2.984 mmol), p-bromoanisole (19 mL, 149.2 mmol) and anhydrous toluene (300 mL), and heat the mixture to 100 °C overnight. Cool to room temperature and add 5 volumes of EtOAc and 250 mL of 2.5 M KF (aq.). Stir the mixture overnight and vacuum filter.
- Step B Combine 4-phenyl-2-(4'-pyridyl)butyronitrile (0.61 g, 2.68 mmol), NaCI (3.13 g, 53.6 mmol) and AlCl 3 (14.29 g, 107.2 mmol) and heat to 180 °C. After 30 minutes, cool the reaction mixture to 0 °C and pour it into water. Add 15% NaOH (aqueous) until the solution is clear and basic. Extract with ether, combine the ethereal extracts, wash with water and brine, dry over Na 2 SO 4 , and concentrate to a residue. Chromatograph the residue on silica gel using 100% EtOAc to obtain 0.45 g (75%) of the title compound, mp 87-90°C
- Step A Add DIBAL-H (83.8 mL, 83.8 mmol, 1 M in THF) dropwise to a -78 °C solution of 2-(4'-methoxy-phenyl)-1,2,3,4-tetrahydronaphthalen-1-one (7.15 g, 27.94 mmol) in anhydrous THF (150 mL). Allow the reaction to come to room temperature overnight. Cool the mixture to 0 °C and quench with sodium sulfate decahydrate. Stir the mixture overnight, then vacuum filter and thoroughly wash the fiitercake with THF. Concentrate the filtrate in vacuo, then
- Step B Add Ph 3 P (4.54 g, 17.3 mmol) to a -20 °C (dry ice/carbon tetrachloride) solution of 2-(4'-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (3.52 g, 13.84 mmol) in THF (100 mL). Add DEAD (3.05 mL, 19.4 mmol) dropwise to the mixture, followed by addition of diphenylphosphoryl azide (3.72 mL, 17.3 mmol) in the same manner. Allow the mixture to warm to room temperature overnight.
- Step A Heat a mixture of 2-(4'-methoxyphenyl)-1,2,3,4- tetrahydronaphthalen-1-one (6.22 g, 24.7 mmol), hydroxylamine hydrochloride (5.14 g, 74 mmol), NaOAc (6.1 g, 74 mmol), water (12 mL) and MeOH (45 mL) at reflux overnight. Concentrate the reaction mixture to approximately 50% of its original volume, dilute with water and cool to room temperature. Partition between EtOAc and water and extract the aqueous phase with EtOAc. Combine the organic extracts, wash with water and brine, dry over Na 2 SO 4 , and concentrate to a residue.
- Step B Add a solution of chlorodiphenylphosphine (3.98 mL, 22.2 mmol) in CH 2 CI 2 (20 mL), via cannula, to a -40 °C solution of the oxime from step A (5.93 g, 22.2 mmol) and Et3N (3.1 mL, 22.2 mmol) in a 1:1 mixture of CH 2 CI 2 /petroleum ether (50 mL each). Allow the reaction mixture to slowly warm to room temperature ( ⁇ 2h). Analyze the reaction mixture by TLC (50% EtOAc/hexane) to check for the presence of starting material. If starting material remains, re-cool the reaction mixture to -40 °C and treat with Et 3 N (0.62 mL, 4.4 mmol) and
- chlorodiphenylphosphine (0.80 mL, 4.4 mmol). Again allow the mixture to warm to room temperature. Filter the solution and concentrate the filtrate in vacuo to a foam. Dissolve the foam in benzene, dry over Na 2 SO 4 , filter and concentrate in vacuo to isolate the phosphinylimine (11.48 g, -115% crude yield).
- Step C Add 6N aqueous HCI (100 mL) to a room temperature solution of the phosphonamide from step B (8.68 g, 19.1 mmol) in MeOH (300 mL). Stir the mixture overnight, then concentrate the mixture in vacuo and partition the residue between 3N HCI and EtOAc. Extract with EtOAc, reserving the organic extracts. Adjust the pH of the aqueous layer to pH ⁇ 9 with aqueous Na 2 CO 3 (saturated). Extract with CH 2 CI 2 , combine the CH 2 CI 2 extracts, wash with water, dry over Na 2 SO 4 and concentrate to give the title compound (2.73 g, 56%).
- Preparation 9 cis-2-(4'-methoxyphenvl)benzosuberamine Step A Slowly add NaBH4 (1.84 g, 48.7 mmol) in small portions to a 0 °C solution of 2-(4'-methoxyphenyl)benzo-suberone (4.32 g, 16.2 mmol) in MeOH (75 mL). Allow the mixture to stir until gas evolution ceases ( ⁇ 10 min). Quench by the addition of aqueous 3N HCI (10 mL). Remove most of the solvent in vacuo. Partition the residue between 3N HCI and EtOAc. Extract with EtOAc, then combine the extracts, wash with water and brine, dry over anhydrous Na 2 SO 4 and concentrate to 3.7 g.of an oil.
- Step B Add borane THF complex (27.6 mL, 27.6 mmol, 1M in THF) to a 0 °C solution of the olefin from step A (3.14 g, 12.5 mmol) in THF (50 mL). Allow the solution to warm to room temperature overnight. Cool the solution to 0 °C and add 3N aqueous NaOH (28 mL), then slowly add 30% H 2 O 2 (28 mL). Stir the resulting mixture overnight, then extract with EtOAc. Combine the extracts, wash successively with aqueous NaHCO 3 (saturated), water and brine, dry over Na 2 SO 4 , filter and concentrate to a solid. Recrystallize the solid from EtOAc/hexane to afford the desired alcohol, mp 87.5-88.5°C.
- Step B Treat the oxime methyl ether from step A (72.1 g, 285 mmol) with 1 M borane in THF (700 mL, 700 mmol) under N 2 . Stir the mixture at room temperature overnight, then at reflux for 5 h. Cool the reaction mixture, and quench the excess borane with water. When bubbling ceases, bring the mixture to ca. pH 1 with concentrated HCI, stir vigorously at 50°C for 2 h, then stir at room temperature for 5 h more. Pour the mixture into water and extract twice with diethyl ether. Basify the aqueous phase to pH 9-10 with KOH and extract three times with ether. Combine the latter organic extracts , wash with brine and dry with Na 2 SO 4 .
- the opposite enantiomer can be similarly prepared by using di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid in the reverse order.
- Extract with ether combine the ethereal extracts, wash with water and brine, dry over Na 2 SO 4 and concentrate to a residue. Chromatograph the residue on silica gel with 30-50% EtOAc/ hexanes to obtain a solid. Further purify the solid by HPLC (silica gel, 30% EtOAc/ hexane) to give 0.5 g of the title compound (mp 103.5-107.5°C).
- Example 3AA (0.596 g, 1.422 mmol) in 10 mL of dry DMF at 0°C. Stir the mixture at 0°C for 30 min. then at room temperature for 4 hours. Pour the mixture into water and extract with EtOAc. Wash the EtOAc extract with water, then dry the extract over Na 2 S ⁇ 4. Filter then evaporate the solvent to give a residue. Chromatograph the residue over silica gel (10:1 CH 2 CI 2 /EtOAc) to give 0.479 g of the title
- Example 3 Dissolve the product of Example 3 (1.0 g) in 30 mL of dry CH 2 CI 2 . Slowly add (dropwise) 0.09 mL of sulfuryl chloride followed by 3 mL of anhydrous ether. Stir the mixture at room temperature for 2 hours, then slowly pour the mixture into ice water. Extract with CH 2 CI 2 , wash the extract with water, then dry the extract over MgSO 4 . Filter, evaporate the solvent, then recrystallize the residue from
- Example 3AA Combine the compound of Example 3AA (5.0 g) in 30 mL of 37% aqueous formaldehyde with 25 mL of 10 % KOH (aqueous) in 100 mL of DMF and heat the mixture at 65-70°C for 2 hours. Add 10 mL of formaldehyde and 10 mL of 10 % KOH and continue heating for 2 hours. Pour the mixture into water and extract with EtOAc. Treat the aqueous layer with brine and again extract with EtOAc. Combine the extracts and dry over Na 2 SO 4 , then filter and evaporate to a residue. Chromatograph the residue over silica gel (using 1 :1 hexane/EtOAc) to give 0.45 g of monohydroxymethylated product and 0.48 g of bis- hydroxymethylated product.
- the compounds of Examples 1-9 were tested for in vitro ACAT inhibitory activity and for the ability to lower the level of cholesteryl esters in vivo.
- the results of these tests are as follows:
- the following formulations exemplify some of the dosage forms of this invention.
- active compound designates a compound of formula I, preferably N-[2-(4'-hydroxyphenyl)indanyl]- ⁇ - phenylbenzeneacetamide.
- this compound may be replaced by an equally effective amount of other compounds of formula I.
Abstract
Nouveaux amides bicycliques de la formule (I) dans laquelle Ar2 et Ar2 présentent phényle, phényle substitué par R2, hétéroaryle ou hétéroaryle substitué par R2, R2 étant 1 à 3 constituants indépendamment sélectionnés dans le groupe formé d'halogéno, hydroxy, alkyle inférieur, alcoxy inférieur, nitro, amino, alkylamino inférieur et dialkylamino inférieur; X, Y, et Z sont -CH2-, -CH(alkyle)-, -C(alkyle)2-, -NH-, -N(alkyle)-, -O- ou -SOr-, r étant 0, 1, ou 2 et m, n et p étant 0 ou 1; R1 est une chaîne alkyle de 1 à 25 atomes de carbone, une chaîne alkyle substituée par un ou plusieurs groupes hétéroaryle ou phényle éventuellement sustitués, une chaîne alkyle -0-, S0r-, phénylène, phénylène substitué par R2, des groupes hétéroarylène ou hétéroarylène substitués par R2, une chaîne alkyle interrompue substituée par un ou plusieurs groupes phényle ou hétéroaryle éventuellement substitués, une chaîne alkyle de 4 à 25 atomes de carbone, interrompue par un ou plusieurs groupes -NH-, -C(O)- ou -N(alkyle inférieur)-, une chaîne alkyle interrompue de 4 à 25 atomes de carbone substituée par un ou plusieurs groupes phényle, phényle substitué par R2, hétéroaryle ou hétéroaryle substitué par R2, un groupe diphénylamino, un groupe amino diphényle substitué par R2, un groupe dihétéroarylamino ou un groupe amino di-hétéroaryle substitué par R2, ou un sel pharmaceutiquement acceptable desdits amides, utile dans le traitement de l'arthérosclérose.New bicyclic amides of formula (I) in which Ar2 and Ar2 have phenyl, phenyl substituted by R2, heteroaryl or heteroaryl substituted by R2, R2 being 1 to 3 constituents independently selected from the group formed of halo, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and lower dialkylamino; X, Y, and Z are -CH2-, -CH (alkyl) -, -C (alkyl) 2-, -NH-, -N (alkyl) -, -O- or -SOr-, r being 0, 1 , or 2 and m, n and p being 0 or 1; R1 is an alkyl chain of 1 to 25 carbon atoms, an alkyl chain substituted by one or more heteroaryl or phenyl groups optionally substituted, an alkyl chain -0-, SO0-, phenylene, phenylene substituted by R2, heteroarylene or heteroarylene groups substituted by R2, an interrupted alkyl chain substituted by one or more phenyl or heteroaryl groups optionally substituted, an alkyl chain of 4 to 25 carbon atoms, interrupted by one or more groups -NH-, -C (O) - or -N (lower alkyl) -, an interrupted alkyl chain of 4 to 25 carbon atoms substituted by one or more phenyl groups, phenyl substituted by R2, heteroaryl or heteroaryl substituted by R2, a diphenylamino group, an amino diphenyl group substituted by R2, diheteroarylamino group or an amino di-heteroaryl group substituted by R2, or a pharmaceutically acceptable salt of said amides, useful in the treatment of atherosclerosis.
Description
Claims
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US68462391A | 1991-04-12 | 1991-04-12 | |
US684623 | 1991-04-12 |
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EP0583346A1 true EP0583346A1 (en) | 1994-02-23 |
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EP92910760A Withdrawn EP0583346A1 (en) | 1991-04-12 | 1992-04-09 | Bicyclic amides as inhibitors of acyl-coenzyme a: cholesterol acyl transferase |
EP92106148A Pending EP0508425A1 (en) | 1991-04-12 | 1992-04-09 | Bicyclic amides as inhibitors of acyl-coenzyme a: cholesterol acyl transferase |
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EP (2) | EP0583346A1 (en) |
JP (1) | JPH0825973B2 (en) |
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WO (1) | WO1992018462A1 (en) |
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US5631365A (en) | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US6107494A (en) * | 1994-09-13 | 2000-08-22 | G.D. Searle And Company | Substituted 5-aryl-benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
US5994391A (en) * | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
US6262277B1 (en) | 1994-09-13 | 2001-07-17 | G.D. Searle And Company | Intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
EP0781278B1 (en) * | 1994-09-13 | 2001-03-14 | Monsanto Company | Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
US6268392B1 (en) | 1994-09-13 | 2001-07-31 | G. D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors |
US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
JP3720395B2 (en) | 1994-09-20 | 2005-11-24 | 京都薬品工業株式会社 | Novel heterocyclic derivative, production method thereof and pharmaceutical use thereof |
SI0826679T1 (en) * | 1996-08-29 | 2002-04-30 | Eli Lilly And Company | Naphthyl compounds and compositions |
FR2763335B1 (en) * | 1997-05-16 | 2000-11-24 | Adir | NOVEL SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US6221897B1 (en) | 1998-06-10 | 2001-04-24 | Aventis Pharma Deutschland Gmbh | Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use |
JP2002533414A (en) | 1998-12-23 | 2002-10-08 | ジー.ディー.サール エルエルシー | Combination of ileal bile acid transport inhibitors and bile acid sequestrants for cardiovascular applications |
US6462091B1 (en) | 1998-12-23 | 2002-10-08 | G.D. Searle & Co. | Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications |
PL348508A1 (en) | 1998-12-23 | 2002-05-20 | Searle Llc | Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications |
JP2002533408A (en) | 1998-12-23 | 2002-10-08 | ジー.ディー.サール エルエルシー | Combination of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular applications |
CN1342090A (en) | 1998-12-23 | 2002-03-27 | G·D·瑟尔有限公司 | Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular disease |
EP1340510A1 (en) | 1998-12-23 | 2003-09-03 | G.D. Searle LLC. | Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications |
KR20010099937A (en) | 1998-12-23 | 2001-11-09 | 윌리암스 로저 에이 | Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications |
EP1286984A2 (en) | 2000-03-10 | 2003-03-05 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
EP1448546A4 (en) | 2001-11-02 | 2005-02-02 | Searle Llc | Novel mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (asbt) and taurocholate uptake |
JP2005521653A (en) | 2002-01-17 | 2005-07-21 | ファルマシア コーポレイション | Novel alkyl / arylhydroxy or ketothiepine compounds as inhibitors of advanced sodium co-dependent bile acid transport (ASBT) and taurocholate uptake |
AU2002952453A0 (en) * | 2002-11-01 | 2002-11-21 | Novogen Research Pty Ltd | Aminated isoflavonoid derivatives and uses thereof |
EP1904069B1 (en) | 2005-07-15 | 2018-06-13 | Albany Molecular Research, Inc. | Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US8053603B2 (en) * | 2006-01-06 | 2011-11-08 | Sunovion Pharmaceuticals Inc. | Tetralone-based monoamine reuptake inhibitors |
CL2008000684A1 (en) | 2007-03-09 | 2008-08-01 | Indigene Pharmaceuticals Inc | PHARMACEUTICAL COMPOSITION THAT INCLUDES METFORMIN R - (+) LIPOATE AND A HMG-COA REDUCTASE INHIBITOR; UNIT DOSE FORMULATION; AND USE IN THE TREATMENT OF A DIABETIC COMPLICATION. |
LT2498611T (en) * | 2009-11-13 | 2018-04-25 | Celgene International Ii Sarl | Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
PT3406142T (en) | 2009-11-13 | 2021-03-26 | Receptos Llc | Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
EP2706999B1 (en) | 2011-05-13 | 2019-08-28 | Celgene International II Sàrl | Selective heterocyclic sphingosine 1 phosphate receptor modulators |
WO2013063512A1 (en) | 2011-10-28 | 2013-05-02 | Lumena Pharmaceuticals, Inc | Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases |
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US3704323A (en) | 1969-12-23 | 1972-11-28 | Squibb & Sons Inc | Indane derivatives |
US4456619A (en) * | 1978-09-18 | 1984-06-26 | Sandoz, Inc. | Amides of 2-alkynoic acids and use for inhibiting accumulation of cholesterol ester in arterial walls |
US4248893A (en) * | 1978-12-30 | 1981-02-03 | Sandoz, Inc. | Arterial wall cholesterol ester reducing cyclopropanyl-bearing amides |
DE3583780D1 (en) * | 1984-08-31 | 1991-09-19 | Otsuka Pharma Co Ltd | 2,3-DIHYDRO-1H-INDENE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
PT84806B (en) | 1986-05-03 | 1989-12-29 | Beecham Group Plc | PROCESS FOR THE PREPARATION OF BENZOPYRANES |
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1992
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- 1992-04-09 AU AU18868/92A patent/AU1886892A/en not_active Abandoned
- 1992-04-09 JP JP4510016A patent/JPH0825973B2/en not_active Expired - Lifetime
- 1992-04-09 EP EP92106148A patent/EP0508425A1/en active Pending
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