WO1991013616A1 - NOUVEAUX INHIBITEURS DE HMG-CoA REDUCTASE - Google Patents

NOUVEAUX INHIBITEURS DE HMG-CoA REDUCTASE Download PDF

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Publication number
WO1991013616A1
WO1991013616A1 PCT/US1990/001276 US9001276W WO9113616A1 WO 1991013616 A1 WO1991013616 A1 WO 1991013616A1 US 9001276 W US9001276 W US 9001276W WO 9113616 A1 WO9113616 A1 WO 9113616A1
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WIPO (PCT)
Prior art keywords
hydroxy
pyran
trans
ethenyl
tetrahydro
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PCT/US1990/001276
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English (en)
Inventor
John Robinson Regan
Kent William Neuenschwander
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Rorer International (Overseas) Inc.
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Publication date
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Priority to PCT/US1990/001276 priority Critical patent/WO1991013616A1/fr
Publication of WO1991013616A1 publication Critical patent/WO1991013616A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, 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
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • the present invention relates to compounds,
  • the invention relates to trans-6-[(2-aryl-substituted cycloalkenyl and substituted cycloalkyl)-alkenyl and alkyl]-3,4,5,6-tetrahydro- 2H-pyran-2-ones, the corresponding ring opened hydroxy acids derived therefrom and pharmaceutically acceptable salts thereof which are potent inhibitors of the enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase (hereinafter HMG-CoA reductase), pharmaceutical compositions thereof, and a method of inhibiting biosynthesis of cholesterol for the treatment of atherosclerosis, hyperlipidemia and hypercholesterolemia.
  • HMG-CoA reductase 3-hydroxy-3- methylglutaryl-coenzyme A reductase
  • Inhibitors of HMG-CoA are effective in lowering blood plasma cholesterol level as well as inhibiting the biosynthesis of cholesterol in humans. As such, inhibitors of HMG- CoA are useful in the prevention and treatment of coronary heart diseases.
  • the prior art recognizes the importance of such compounds, e.g., Bethridge et al., Brit. Med. J., 4,500 (1975) and Brown et al., Scientific American, 58 Nov. (1984). Illustrative references directed to such compounds follow.
  • U.S. Patent No. 4,681,893 to B. D. Roth pertains to trans-6-[2-(3-or 4-carboxamido-substituted pyrrol-1-yl)alkyl]- 4-hydroxy-pyran-2-ones useful as hypochloesterolemic agents.
  • U.S. Patent No. 4,282,155 to Smith et al. is directed to 6(R)-[2-(8'-Etherified-hydroxy-2',6'-dimethylpolyhydronaphthyl-1')ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-ones for inhibition of biosynthesis of cholesterol.
  • U.S. Patent No. 4,567,289 to Willard et al. relates to methyl, ethyl, n-propyl, 2-(acetylamino) ethyl, or 1-(2,3-dihydroxy)propyl ester of E-(3R,5S)-7-(4'-fluoro-3,3',5-trimethyl- [1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acid that are HMG-CoA reductase inhibitors.
  • U.S. Patent No. 4,611,067 to Volante et al. discloses a process for the preparation of HMG-CoA reductase inhibitors which contain a 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.
  • Y is:
  • X, X 1 and X 2 are independently:
  • R 1 and R 2 are independently: alkyl
  • R 3 and R 4 are independently:
  • R is:
  • n is:
  • “Lower alkyl” means a saturated or unsaturated aliphatic hydrocarbon which may be either straight- or branched-chained containing from 1 to 4 carbon atoms.
  • Alkyl means a saturated or unsaturated aliphatic hydrocarbon which may be either straight-or branched-chained containing from one to ten carbon atoms.
  • Alkoxy means an alkyl oxy group in which "alkyl” is as previously defined. Lower alkoxy groups are preferred which include methoxy, ethoxy, n-propoxy, i-propoxy, sec-propoxy, and n-butoxy.
  • Aryl means an aromatic hydrocarbon radical having 6 to 10 carbon atoms.
  • the preferred aryl groups are phenyl, substituted phenyl and naphthyl.
  • substituted means "alkyl", “halogen” or "hydroxyalkyl” substitution.
  • the pharmaceutically acceptable salts of the present invention include those formed from sodium, potassium,
  • the invention encompasses optical and stereoisomers of the compounds and mixtures thereof defined by the structural formula.
  • steps a through f can be replaced with steps l aand m as shown hereunder,
  • the starting materials were obtained from the Aldrich Chemical Co. but they may also be synthesized in accordance with methods known in the art.
  • Step 1 1-(4-Fluorophenyl)-1-hydroxy-3,3,5,5- tetramethylcyclo-hexane
  • reaction mixture was then poured onto ice and 500 ml of IN HCl . After stirring for 0.5 hour, the layers were separated. The aqueous layer was extracted once with ether and the
  • Step 3 1-Bromo-2-(4-fluorophenyl)-4,4,6,6- tetramethylcyclohex-2-ene
  • benzoylperoxide (2.42 g, 10 mmoles) were added to a 0.5 M CCl 4 solution of 23.2 g (100 mmoles) of the product from Step 2. The resulting mixture was heated at reflux for 0.5 hour.
  • Step 4 2-Diethylamino-2-[ 2- (A-fluorophenyl)-4,4,6,6-tetramethylcyclohex-2-enel acetonitrile
  • Step 5 2-(4-Fluorophenyl)-4,4,6,6-tetramethylcyclohex-2- ene-1-carboxaldehyde
  • the aldehyde obtained in Step 5 (130 g, 50 mmoles) was dissolved in a solution of 50 ml of THF and 50 ml of ethanol. To this solution was added 0.62 ml (5 mmoles) of 1,5- diazabicyclo-[4,3,0]-non-5-ene and the reaction mixture stirred at room temperature for 50 hours. The reaction mixture then was diluted with ether and extracted with dilute HCl, saturated NaHCO 3 , and brine. The solvents were evaporated in vacuo and the residue purified by flash chromatography on silica gel .
  • Step 7 (E)-3-[2-(4-fluorophenyl)-4,4,6,6- tetramethylcyclohex-enyl]-2-propenaldehyde
  • reaction mixture was poured into H 2 O and extracted with ether.
  • organic layer was extracted with brine and the solvents evaporated in vacuo.
  • Step 8 Methyl (E) -7- [ 2- (4-fluorophenyl)-4,4,6,6- tetramethyl-cyclohexenyl]-5-hydroxy-3-oxo-6-heptenoate
  • Step 9 Methyl (E)-7-[2-(4-fluorophenyl)-4,4,6,6- tetramethyl-cyclohexenyl]-3,5-dihydroxy-6-heptenoate
  • the 5-hydroxy-3-keto ester (10.02 g, 24 mmoles) prepared in Step 8 was dissolved in 60ml of dry THF and treated with triethylborane (1 M in THF, 36 ml, 36 mmoles). After aging for 5 minutes at room temperature, the reaction mixture was cooled to -98°C (MeOH-liquid N 2 bath). Sodium borohydride (1.04 g, 27.6 mmoles) was added, followed by dropwise addition of methanol (24 ml) over a 30 minute period. The reaction mixture was stirred for 30 minutes at -98°C and over the next 30 minutes was allowed to warm to -60°C. At -60°C the reaction mixture was quenched by the dropwise addition of 30% H 2 O 2 (50 ml) in H 2 O (125 ml).
  • reaction mixture then was warmed to room temperature and stirred for 30 minutes. It was poured into 1 liter ethyl acetate and extracted with 620 ml of 1N HCl. The organic layer was washed with saturated NaHCO 3 and brine.
  • Step 10 (E)-7-[2-(4-fluorophenyl)-4,4,6,6- tetramethylcyclohex-enyl]-3,5-dihydroxy-6-heptenoic acid
  • a 1N NaOH solution (30 ml, 30 mmoles) was added to a solution of the 3 ,5-dihydroxyester prepared in Step 9 (9.70 g, 24 mmoles) and 60 ml of ethanol. After stirring for 10 minutes, the ethanol was evaporated in vacuo. The residue was redissolved in H 2 O and extracted twice with ether. The aqueous layer was acidified with 33 ml of 1N HCl and extracted twice with H 2 CCl 2 . The H 2 CCl 2 was removed in vacuo.
  • Step 11 Trans-(E)-6-[2-[2-(4-fluorophenyl)-4,4,6,6- tetramethyl-cyclohexenyl]ethenyl]-3,4,5,6-tetrahydro-4- hydroxy-2H-pyran-2-one
  • Step 1 2-Chloro-4,4,6,6-tetramethylcyclohex-1-ene-1-carboxaldehyde
  • Phosporus oxychloride (46.6 ml, 500 mmoles) was added dropwise over a 45 minute period, to an ice cold solution of 47.69 g (652 mmoles) of dimethylformamide and 145 ml of trichloroethylene. The reaction mixture was warmed to room temperature and stirred an additional 1.5 hours. To the resulting reaction mixture was added dropwise a solution of 77.13 g (500 mmoles) of 3,3,5,5-tetramethylcyclohexanone in 145 ml of trichloroethylene.
  • the reaction mixture was heated to 70°C for 5 hours, then cooled and stirred overnight at room temperature.
  • reaction mixture was cooled in an ice bath and treated dropwise with a solution of 185 g (2.25 moles) of sodium acetate in 400 ml of H 2 O.
  • the resulting layers were separated and the organic layer was washed once with 500 ml of H 2 O and twice with 250 ml of brine. After drying over
  • Step 2 2-(4-Fluoro-3-methylphenyl)-4,4,6,6- tetramethylcyclo-hex-1-ene-1-carboxaldehyde
  • a Grignard reagent freshly prepared from 55.96 g (296 mmoles) of 3-bromo-6-fluorotoluene, 11.39 ml (131.6 mmoles) of dibromoethane, and 13.0 g (534.5 mmoles) of magnesium powder in 400 ml of dry THF was added slowly in an ice cold solution, under nitrogen, of 6.57 g (32.9 mmoles) of copper (II) acetate monohydrate, 26.4 g (131.6 mmoles) of 2-chloro-4,4, 6, 6-tetramethylcyclohex-1-ene-1-carboxaldehyde and 395 ml of dry THF.
  • Example 1 essentially following the process of either Example 1 or
  • Example 2 the following five membered ring compounds can be made, respectively: trans-(E)-6-[2- ⁇ 2-(4-fluorophenyl)-4,4,5,5- tetramethylcyclopent-1-ene)ethenyl]-3,4,5,6-tetrahydro-4- hydroxy-2H-pyran-2-one; trans-(E)-6-[2- ⁇ 2-(4-fluorophenyl)-4-ethyl-5,5- dimethylcyclopent-1-ene)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy- 2H-pyran-2-one;
  • Example 2 Using the starting materials 3,3,6,6- tetramethylcyclohepta-none, 3-phenyl-6,6- dimethylcycloheptanone, 3 , 6-dimethylcyclohep-tanone, 3,3- diethyl-6,6-dimethylcycloheptanone, and essentially following the process of either Example 1 or Example 2 the following seven membered ring compounds can be made, respectively: trans-(E)-6-[2- ⁇ 2-(4-fluorophenyl)-4,4,7,7- tetramethylcyclohept-1-ene ⁇ ethenyl]-3,4,5,6-tetrahydro-4- hydroxy-2H-pyran-2-one; trans-(E)-6-[2- ⁇ 2-(4-fluorophenyl)-4-phenyl-7,7-dimethylcyclohept-1-ene)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2- one;
  • Step 2 Methyl 2- (4-fluorophenyl)-4-hydroxy-4,6,6-trimethyl- cyclohex-2-en-1-carboxylate
  • Step 4 2-(4-Fluorophenyl)-4-methoxy-4,6,6- trimethylcyclohex-2-en-1-carboxaldehyde
  • Step 6 ( ⁇ )-3-[2-(4-fluorophenyl)-4-methoxy-4,6,6-trimethyl- cyclohex-1-en-1-yl]propenal
  • Step 7 Methyl (E)-7-[2-(4-fluorophenyl)-4-methoxy-4,6,6- trimethylcyclohex-1-en-1-yl]-5-hydroxy-3-oxohept-6-enoate
  • Step 8 Methyl (E)-7-[ 2-(4-fluorophenyl)-4-methoxy-4,6,6- trimethylcyclohex-1-en-1-yl]-3,5-dihydroxyhept-6-enoate
  • Step 9 Trans-(E)-6-[2-[2-(4-fluorophenyl)-4-methoxy-4,6,6- trimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetra- hydro-2H-pyran-2-one
  • Step 1 1-Hydroxymethyl-2-(4-fluoro-3-methylphenyl)-4-t- butyl-dimethylsiloxy-6,6-dimethylcyclohex-2-ene
  • Step 2 (E)-3-[2-(4-fluoro-3-methylphenyl)-4-t- butyldimethyl-siloxy-6,6-dimethylcyclohex-1-en-1-yl]propenal
  • Step 3 Methyl (E)-7-[2-(4-fluoro-3-methylphenyl)-4-t- butyldi-methylsiloxy-6,6-dimethylcyclohex-1-en-1-yl]-5- hydroxy-3-oxohept-6-enoate
  • Step 4 Methyl (E)-7-[2-(4-fluoro-3-methylphenyl)-4-t- butyldi-methylsiloxy-6,6-dimethylcyclohex-1-en-1-yl]-3,5- dihydroxyhept-6-enoate
  • Step 5 Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-t- butyl-dimethylsiloxy-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]- 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one
  • Step 6 Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4- hydroxy-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy- 3,4,5,6-tetra-hydro-2H-pyran-2-one
  • the compounds of the present invention are useful as hypocholesterolemic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol through inhibition of the enzyme HMG-CoA reductase. Having such ability, the compounds are incorporated into pharmaceutically acceptable carriers and administered to a patient in need of such cholesterol biosynthesis inhibition orally or
  • Such pharmaceutical formulations to contain at least one compound according to the invention.
  • Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • the compositions may be formulated in the form of tablets,
  • capsules lozenges, trochees, hard candies, powders, aqueous suspensions, or solutions, injectable solutions, elixirs, syrups and the like and may contain one or more agents
  • sweetening agents selected from the group including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a pharmaceutically acceptable preparation.
  • the particular carrier and the ratio of active compound to carrier are determined by the solubility and chemical
  • excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used in producing tablets.
  • excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc
  • lactose and high molecular weight polyethylene glycols are among the preferred
  • the carrier can be emulsifying or suspending agents.
  • the dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief.
  • Doses may vary, depending on the age, severity, body weight and other conditions of the patients but are ordinarily in the area of 5 mg/kg to 500 mg/kg of body weight in oral administration; such may, of course be given in two to four divided doses. With other forms of administration equivalent or adjusted doses will be administered depending on the route of administration.
  • the first method used (designated HMGR Screen) was as follows. Male rats were acclimated to an alternate 12 hour light-dark cycle for a period of 2-3 weeks. The animals, weighing 180-230 g, were fed ad libitum a rat chow containing 2% cholestyramine for 5 days prior to sacrifice at the middark period. Liver microsomes were prepared and HMGR enzyme was solubilized from the microsomes by freeze-thaw
  • the enzyme preparation was stored at -80°C in 300 ⁇ l portion samples.
  • the enzyme Prior to use, the enzyme was activated at 37°C for 30 minutes in a reaction mixture.
  • the reaction mixture contained in a volume of 240 ⁇ l : 0.14 M potassium phosphate buffer (pH 7.0); 0.18 M KCl; 3.5 mM EDTA; 10 mM dithiothreitol; 0.1 mg/ml BAA;
  • Mevinolin (a lactone form) was then converted to its sodium salt, mevinolinic acid, by
  • the second method (designated Ex-Vivo Non-Fasted and Ex- Vivo Fasted) used was as follows. Rats of 170-210 g were maintained on a low cholesterol diet for one week prior to use. Drugs (identified in Table I) were given orally in 0.5%
  • Mcllwain tissue chopper and were suspended in the same buffer. Aliquots of the suspension containing 100 mg tissue were pipetted to culture tubes which contained [ 14 C] sodium acetate (2 ⁇ Ci, 1 mM). The tubes were gassed with 95%

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne de nouveaux inhibiteurs de 3-hydroxy-3-méthylglutaryl-coenzyme A réductase utiles en tant qu'agents antihypercholestérolémiques représentés par la formule (I), et les acides hydroxy à anneaux ouverts correspondants dérivés de ces derniers ainsi que leurs sels pharmaceutiquement acceptables. L'invention concerne également des compositions pharmaceutiques renfermant lesdits composés ainsi qu'un procédé permettant d'inhiber la biosynthèse du cholestérol avec ces derniers.
PCT/US1990/001276 1990-03-08 1990-03-08 NOUVEAUX INHIBITEURS DE HMG-CoA REDUCTASE WO1991013616A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014314A1 (fr) * 1999-08-20 2001-03-01 Nippon Kayaku Kabushiki Kaisha Derives de benzene a substituants aromatiques et procedes de preparation de ceux-ci
US6271418B1 (en) 2000-02-22 2001-08-07 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
WO2019076269A1 (fr) 2017-10-16 2019-04-25 清华大学 Inhibiteur de la voie de l'acide mévalonique et composition pharmaceutique correspondante
CN111662262A (zh) * 2020-06-29 2020-09-15 怀宁大有医药科技有限公司 6-(4-((2-环己硫基乙基)氨基)苯基)四氢-2h-吡喃-2-酮的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282155A (en) * 1980-02-04 1981-08-04 Merck & Co., Inc. Antihypercholesterolemic compounds
US4503072A (en) * 1982-12-22 1985-03-05 Merck & Co., Inc. Antihypercholesterolemic compounds
US4622338A (en) * 1985-03-11 1986-11-11 G. D. Searle & Co. Substituted glutaric acid lactones in the treatment of hyperlipidemia
US4772626A (en) * 1986-01-31 1988-09-20 Merck & Co., Inc. Antihypercholesterolemic compounds
US4863957A (en) * 1987-12-21 1989-09-05 Rorer Pharmaceutical Corporation Novel HMG-CoA reductase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282155A (en) * 1980-02-04 1981-08-04 Merck & Co., Inc. Antihypercholesterolemic compounds
US4503072A (en) * 1982-12-22 1985-03-05 Merck & Co., Inc. Antihypercholesterolemic compounds
US4622338A (en) * 1985-03-11 1986-11-11 G. D. Searle & Co. Substituted glutaric acid lactones in the treatment of hyperlipidemia
US4772626A (en) * 1986-01-31 1988-09-20 Merck & Co., Inc. Antihypercholesterolemic compounds
US4863957A (en) * 1987-12-21 1989-09-05 Rorer Pharmaceutical Corporation Novel HMG-CoA reductase inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014314A1 (fr) * 1999-08-20 2001-03-01 Nippon Kayaku Kabushiki Kaisha Derives de benzene a substituants aromatiques et procedes de preparation de ceux-ci
US6271418B1 (en) 2000-02-22 2001-08-07 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
US6340772B2 (en) 2000-02-22 2002-01-22 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
WO2019076269A1 (fr) 2017-10-16 2019-04-25 清华大学 Inhibiteur de la voie de l'acide mévalonique et composition pharmaceutique correspondante
CN111662262A (zh) * 2020-06-29 2020-09-15 怀宁大有医药科技有限公司 6-(4-((2-环己硫基乙基)氨基)苯基)四氢-2h-吡喃-2-酮的合成方法
CN111662262B (zh) * 2020-06-29 2023-04-28 陕西大美化工科技有限公司 6-(4-((2-环己硫基乙基)氨基)苯基)四氢-2h-吡喃-2-酮的合成方法

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