WO1994009774A1 - Composes biologiquement actifs et leur procede de fabrication - Google Patents

Composes biologiquement actifs et leur procede de fabrication Download PDF

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Publication number
WO1994009774A1
WO1994009774A1 PCT/US1993/010164 US9310164W WO9409774A1 WO 1994009774 A1 WO1994009774 A1 WO 1994009774A1 US 9310164 W US9310164 W US 9310164W WO 9409774 A1 WO9409774 A1 WO 9409774A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
formula
group
effective amount
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PCT/US1993/010164
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English (en)
Inventor
Yuan-Ching P. Chiang
Tesfaye Biftu
Original Assignee
Merck & Co., Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US07/966,764 external-priority patent/US5256689A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU55387/94A priority Critical patent/AU5538794A/en
Publication of WO1994009774A1 publication Critical patent/WO1994009774A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Definitions

  • Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
  • MEVACOR ® lovastatin
  • ZOCOR ® sivastatin
  • Squalene synthase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
  • This invention relates to compounds of structural formula (I) which are useful as cholesterol lowering agents:
  • R 2 is or
  • Z 2 is
  • R 3 is -H or C 1-4 alkyl
  • n zero or 1
  • R 4 is joined together with the carbon to which R 3 is attached to form a monocyclic or bicyclic ring system, and R 3 represents the bond between R 4 and the carbon to which R 3 is attached,
  • alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, such as, e.g., methyl (Me), ethyl (Et), iso-propyl (i-Pr), and tert-butyl (t- Bu).
  • Acyl, i.e. -COCH 3 is abbreviated herein as "Ac”
  • phenyl is "Ph”
  • ethyl acetate is "EtOAc.”
  • the compounds of formula I can be prepared from (IS, 3S, 4S, 5R, 6R, 7R)-1-[(4S)-acetoxy-3-methyl-ene-5-methyl-6-phenyl]- hexyl-4,6,7-trihydroxy-6-O-(4,6-dimethyl-2-octenoyl)-2,8-dioxabicylco[3.2.1]octane-3,4,5-tricarboxylic acid (referred to herein as Compound IA), or (IS, 3S, 4S, 5R, 6R, 7R)-1-[(4)-acetoxy-5-methyl-6- phenyl]hexyl-4,6,7-tri-hydroxy-6-O-(6-methyl-9-phenyl-4-nonenoyl)- 2,8-dioxabicyclo[3.2.1]-octane-3,4,5-tricarboxylic acid (referred to herein as Compound IC) according to the sequences described in
  • Schemes A, B and C The preparation of the starting materials, IA and IC, are described in U.S. Patents 5,096,923 and 5,102,907, respectively.
  • Schemes A-C depict the use of Compound IA and derivatives thereof, the same methods can be used employing Compound IC and its derivatives.
  • Scheme C, as well as Schemes A and B, can be used to make the compounds of the invention, but can also be used by one skilled in the art to synthesize a broader range of C-3, C-4 diester products.
  • C-3 monoesters (1) may be prepared by several procedures. Stirring IA in an alcohol of formula Z 1 -OH, wherein Z 1 is defined above, in the presence of an acid such as sulfuric acid or hydrochloric acid that can be added or generated in situ by the addition of acetylchloride to the alcohol solvent used gives selective esterification at C-3 to produce (1).
  • an acid such as sulfuric acid or hydrochloric acid that can be added or generated in situ by the addition of acetylchloride to the alcohol solvent used gives selective esterification at C-3 to produce (1).
  • IA-3,4-diesters can be prepared from C-3 monoesters (1) by stirring a C-3 monoester (1) with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and an appropriate alkyl halide of formula Z 2 -X, wherein X is a halide such as -Cl, -Br, or -I and Z 2 is defined above, in a solvent such as benzene, tetrahydrofuran (THF) or acetonitrile.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • Z 2 alkyl halide of formula Z 2 -X, wherein X is a halide such as -Cl, -Br, or -I and Z 2 is defined above, in a solvent such as benzene, tetrahydrofuran (THF) or acetonitrile.
  • This reaction condition also produces the C
  • the C-3 benzyl ester (2) formed can be used as a C-3 protecting group. This allows modification of the C-4 and C-5 carboxyl groups to produce (3) by forming esters in these positions with an isourea reagent such as O-t-butyl-N,N'-diisopropyl-isourea.
  • IA-4,5-di-t-butyl diester (4) can be prepared from IA-3-benzyl-4,5-di-t-butyl ester (3) by removing the benzyl group by hydrogenolysis with Pd/C and hydrogen gas or transfer hydrogenolysis with Pd/C and methyl cyclohexadiene.
  • IA-4,5-di-t-butyl diester (4) can be modified at the C-3 position by several procedures.
  • IA-4,5-di-t-butyl diester (4) may be treated with N-methyl morpholine followed by isobutylchloroformate to form a mixed anhydride which reacts well with various alcohols to form the corresponding IA-3-Z 1 -4,5-di-t-butyl triesters (5).
  • IA-4,5-di-t-butyl diester (4) may also be treated with coupling reagents such as carbonyl diimidazole, thionyl chloride, benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) or any of the other standard coupling reagents known to those skilled in the art, such as dicyclohexylcarbodiimide (DCC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolone (EEDQ), followed by an alcohol to form esters (5).
  • coupling reagents such as carbonyl diimidazole, thionyl chloride, benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) or any of the other standard coupling reagents known to those skilled in the art, such as di
  • IA-4,5-di-t-butyl diester (4) can be converted to the triester (5) by stirring with an Z 1 O-N,N'-dialkyl-isourea in a solution such as toluene, benzene, acetonitrile, tetrahydrofuran (THF) and/or dimethoxyethane (DME).
  • a solution such as toluene, benzene, acetonitrile, tetrahydrofuran (THF) and/or dimethoxyethane (DME).
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • the C-4,C-5-di-t-butyl ester groups may be removed later by stirring the triester (5) formed with trifluoroacetic acid (TFA) in methylene chloride to form (1).
  • TFA trifluoroacetic acid
  • the C-3 monoesters (1) thus produced may be transformed into the
  • the triester (5) can be selectively saponified at the C-4 position by action of certain Lewis acids such as thionyl chloride, tin(IV) chloride or hydrogen fluoride.
  • a catalytic amount of tin(IV) chloride is used for the saponification, e.g. between 0.05 to 0.5 equivalents per one equivalent of triester (5), with stirring at room temperature for about one to twenty hours; 0.05 equivalents of tin(IV) chloride with stirring for 18 to 20 hours is preferred.
  • An excess of thionyl choloride is used to saponify the triester (5), e.g., from about 40 to 60 eqivalents of thionyl chloride per one equivalent of (5), and the reaction is stirred for about 3 to 4 days at room temperature.
  • a large excess of hydrogen fluoride e.g. about 350 to 400 equivalents, is used per one equivalent of (5), and the reaction is stirred for about 8 hours to obtain the diester (6).
  • the C-3,C-5 diester (6) may also be esterified at the 4-carboxylic acid by using the procedures described in Scheme B for producing the triester (5) from the C-4,C-5-di-t-butyl diester (4).
  • esterification procedures include treatment of (6) with one equivalent each of N-methyl morpholine and isobutylchloroformate to form a mixed anhydride followed by treatment with from one to five equivalents of an alcohol of formula Z 2 -OH per equivalent of (6);
  • the triester (7) may be purified by flash chromatography on silica gel using solvents such as ethyl acetate and methylene chloride.
  • the purified triester (7) may be deprotected by stirring with
  • TLA trifluoroacetic acid
  • TLA trifluoroacetic acid
  • the triester (5) can be made via the route shown in Scheme B, or alternatively it can be prepared by reacting compound (1) with t-butyl-O-N,N'-diisopropylisourea.
  • Compound (1) is prepared via the method shown in Scheme A.
  • the present invention is also directed to a method of treating hypercholesterolemia which comprises the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound represented by structural formula (I) and pharmaceutically acceptable salts thereof.
  • the compounds of this invention are useful as antihypercholesterolemic agents for the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia and the like diseases. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Active metabolites of the instant compounds are contemplated within the scope of the invention. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but daily dosage for adults is within a range of from about 20 mg to 2000 mg
  • the present invention is also directed to a method of inhibiting squalene synthase which comprises the administration to a subject in need of such treatment of a nontoxic therapeutically effective amount of compound represented by structural formula (I) and pharmaceutically acceptable salts thereof.
  • a method of inhibiting squalene synthase which comprises the administration to a subject in need of such treatment of a nontoxic therapeutically effective amount of compound represented by structural formula (I) and pharmaceutically acceptable salts thereof.
  • squalene synthase are useful in treating disease conditions such as, but not limited to, hypercholesterolemia which result from the action of the enzyme squalene synthase. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Active metabolites of the instant compounds are contemplated within the scope of the invention. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but daily dosage for adults is within a range of from about 20 mg to 2000 mg
  • the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N-N'-dibenzylethylen-diamine,
  • chloroprocaine diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • the compounds of this invention may also be administered in combination with other cholesterol lowering agents such as those which inhibit an enzymatic pathway in the biosynthesis of cholesterol.
  • examples of such agents would include, but are not limited to, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, and squalene epoxidase inhibitors.
  • HMG-CoA reductase inhibitors include, but are not limited to, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, and squalene epoxidase inhibitors.
  • Illustrative of such inhibitors are lovastatin, simvastatin, pravastatin and fluvastatin.
  • HMG-CoA synthase inhibitors are: the beta-lactone derivatives disclosed in U.S. Patent Nos. 4,806,564, 4,816,477, 4,847,271, and 4,751,237; the beta-lactam derivatives disclosed in
  • cholesterol lowering agents that may be administered include niacin, probucol, and the fibric acids, clofibrate and gemfibrozil.
  • Representative of such combinations are those containing about 10-400 mg of a compound of formula (I) in combination with about 20-100 mg of an HMG-CoA reductase inhibitor, 20-200 mg of a HMG-CoA synthase inhibitor, or 2-200 mg of a squalene epoxidase inhibitor, or up to 1000 mg of probucol, up to 2 g of clofibrate, 2 to 8 g of niacin, and 800 to 1500 mg gemfibrozil or 20 to 300 mg of an LDL-receptor gene inducer.
  • the compounds of this invention may also be any organic compound having the same side chain length.
  • the compounds of this invention may also be any organic compound having the same side chain length.
  • nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract.
  • pharmaceutically acceptable nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract. Examples of such polymers include
  • the relative amounts of the compounds of this invention and these polymers is between 1:100 and 1:15,000.
  • the compound to be tested is dissolved in 5%
  • EMULPHOR ® in 0.9% NaCl at a concentration of 24 mg/kg.
  • the solution of the test compound is given by gavage to each mouse in a dose volume that does not exceed 0.15 ml per mouse. Six mice per group are dosed this way. After dosing of the animals, a 30 minute incubation period is allowed to elapse, and then each animal receives subcutaneously a dose of the radiolabelled tracer tritiated mevalono-lactone, 0.5 microcuries, in 25 ⁇ l of saline.
  • the tracer used is incorporated into cholesterol and the incorporation is used as a measure of in vivo cholesterol synthesis. After dosing with the tracer, another 30 minutes is allowed to elapse and then the animals are sacrificed.
  • each liver is removed and saponified in a solution of 40% KOH/ethyl alcohol overnight at 60°C. Next, the liver/40%
  • KOH/ethyl alcohol mixture is extracted with petroleum ether (2 ⁇ 10ml) to remove the non-saponifiables, then one half of the organic layer is counted in a liquid scintillation counter.
  • the numbers (DPMs) observed are expressed as a percentage of the control value to obtain percent inhibition of cholesterol synthesis.
  • the control used is the vehicle (EMULPHOR ® and saline).
  • Step 1 Preparation of IA-3-ethyl ester (Compound 1 in Scheme A wherein Z 1 is ethyl)
  • Step 1 IC-3-n-propyl ester
  • Step 2 Preparation of IA-3-benzyl-4.5-di-t-butyl triester
  • Step 4 Preparation of IA-3-allyl-4,5-di-t-butyl triester
  • an oral composition of a compound of this invention 20 mg of the compound lb from Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • a 0.1 mmol sample of the free acid of a compound of formula (I) is dissolved in 10 mL of ethyl acetate.
  • the resulting solution is saturated with gaseous ammonia upon which the ammonium salt precipitates from solution.
  • a solution of 0.1 mmol of the free acid of a compound of formula (I) in 20 mL 6:4 methanol/water is treated with an aqueous solution of 0.1 mmol of calcium hydroxide.
  • the solvents are
  • Step 1 Preparation of IA-3-n-propyl-4.5-di-butyl triester

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de la formule structurelle (I) et à un procédé de fabrication de ces composés de la formule (I) consistant à saponifier de façon sélective l'ester C-4 à l'aide d'acides de Lewis tels que le chlorure de thionyle, le chlorure de stannate IV ou le fluorure d'hydrogène. Les composés de la formule (I) sont utiles comme agents réducteurs du taux de cholestérol.
PCT/US1993/010164 1992-10-26 1993-10-22 Composes biologiquement actifs et leur procede de fabrication WO1994009774A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55387/94A AU5538794A (en) 1992-10-26 1993-10-22 Biologically active compounds and process therefor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US966,971 1978-12-06
US96697192A 1992-10-26 1992-10-26
US966,764 1992-10-26
US07/966,764 US5256689A (en) 1991-05-10 1992-10-26 Cholesterol lowering compounds

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WO1994009774A1 true WO1994009774A1 (fr) 1994-05-11

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016184A1 (fr) * 1995-11-02 1997-05-09 Warner-Lambert Company Procede et composition pharmaceutique visant a reguler la concentration lipidique
WO2000038723A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert de l'ester de cholesteryle et d'agents sequestrants de l'acide biliaire, utilisees dans le cadre de toubles cardio-vasculaires
WO2000038721A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert du cholesteryle-ester et de derives de l'acide nicotinique utilisees dans le cadre de troubles cardio-vasculaires
WO2000038725A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons utilisees dans le cadre de troubles cardio-vasculaires
WO2000038727A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de transport de l'acide biliaire ileal et de derives de l'acide fibrique utilisees dans le cadre de maladies cardio-vasculaires
WO2000038724A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert de l'ester de cholesteryle et de derives de l'acide fibrique utilisees dans le cadre de troubles cardio-vasculaires

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055487A (en) * 1990-03-21 1991-10-08 Merck & Co., Inc. Novel anti-fungal compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055487A (en) * 1990-03-21 1991-10-08 Merck & Co., Inc. Novel anti-fungal compounds

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016184A1 (fr) * 1995-11-02 1997-05-09 Warner-Lambert Company Procede et composition pharmaceutique visant a reguler la concentration lipidique
US6143755A (en) * 1995-11-02 2000-11-07 Warner-Lambert Company Pharmaceutical methods of treatment with ACAT inhibitors and HMG-CoA reductase inhibitors
US6093719A (en) * 1995-11-02 2000-07-25 Warner-Lambert Company Method and pharmaceutical composition for regulating lipid concentration
WO2000038725A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons utilisees dans le cadre de troubles cardio-vasculaires
WO2000038727A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de transport de l'acide biliaire ileal et de derives de l'acide fibrique utilisees dans le cadre de maladies cardio-vasculaires
WO2000038724A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert de l'ester de cholesteryle et de derives de l'acide fibrique utilisees dans le cadre de troubles cardio-vasculaires
WO2000038721A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert du cholesteryle-ester et de derives de l'acide nicotinique utilisees dans le cadre de troubles cardio-vasculaires
WO2000038723A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert de l'ester de cholesteryle et d'agents sequestrants de l'acide biliaire, utilisees dans le cadre de toubles cardio-vasculaires
EP1336413A1 (fr) * 1998-12-23 2003-08-20 G.D. Searle LLC. Combinaisons d'inhibiteurs de transport de l'acide biliaire iléal et de dérivés de l'acide fibrique pour indications cardiovasculaires
EP1340510A1 (fr) * 1998-12-23 2003-09-03 G.D. Searle LLC. Combinaisons d'inhibiteurs de la protéine de transfert de l'ester de cholestéryle utilisées dans le cadre de troubles cardio-vasculaires
EP1340509A1 (fr) * 1998-12-23 2003-09-03 G.D. Searle LLC. Combinaisons d'inhibiteurs de la protéine de transfert de l'ester de cholestéryle et de dérivés de l'acide fibrique utilisées dans le cadre de troubles cardio-vasculaires
EP1340508A1 (fr) * 1998-12-23 2003-09-03 G.D. Searle LLC. Combinaisons d'inhibiteurs de la protéine de transfert du cholestéryle-ester et de dérivés de l'acide nicotinique utilisées dand le cadre de troubles cardio-vasculaires
EP1354604A1 (fr) * 1998-12-23 2003-10-22 G.D. Searle LLC. Combinaisons pour indications cardiovasculaires
US6890958B2 (en) 1998-12-23 2005-05-10 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
EA009466B1 (ru) * 1998-12-23 2007-12-28 Джи.Ди. Сирл Ллс Ингибитор белка, переносящего эфир холестерила

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