Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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

Definitions

• This invention relates to a method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering to such mammal an effective therefor amount of a substituted azaspirane.
• m is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 4-10; or R 1 and R 2 together form a cyclic alkyl group containing 3-7 carbon atoms; A is absent or present as C 1 -C 7 alkyl; and R 3 is a heterocyclic or heterobicyclic ring, said heterocyclic or heterobicyclic ring thereby containing up to 10 carbon atoms and from 1-3
• R 4 is absent or present as hydrogen, or a straight chain alkyl
• This invention relates to a method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering to such mammal an effective therefor amount of a compound of the formula
• n 1 or 2;
• R 1 and R 2 are the same or different and are
• R 1 and R 2 are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 4-10; or R 1 and R 2 together form a cyclic alkyl group containing 3-7 carbon atoms;
• A is absent or present as C 1 -C 7 alkyl
• R 3 is a heterocyclic or heterobicyclic ring, said heterocyclic or heterobicyclic ring thereby containing up to 10 carbon atoms and from 1-3 heteroatoms of the formula , where R 4 is absent or present as hydrogen, or a straight chain alkyl containing 1-3 carbon atoms; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• hypolipidemia as used in the
• antihyperlipidemic as used herein is meant the lowering of excessive lipid concentrations to desired levels.
• Preferred lipids of which high levels thereof are treated by the presently invented methods, are;
• cholesterol cholesterol, triglycerides and low-density lipoproteins.
• the compounds of this invention are prepared by procedures described here below and illustrated by the examples. Reagents, protecting groups and functionality of the molecule must be consistent with the proposed chemical transformations. Steps in the synthesis must be compatible with the functional groups and the
• the starting anhydride compounds are known and are synthesized from available precursors using known procedures. According to Scheme I, a solution of an anhydride compound (a) and a substituted primary amine compound are added to an appropriate organic solvent, preferably xylene or toluene, to form a reaction mixture. This reaction mixture is stirred at reflux with constant water removal, and evaporated to form formula (b) compounds.
• an appropriate organic solvent preferably xylene or toluene
• Formula (c) compounds are prepared by adding to a formula (b) compound dissolved in a suitable organic solvent, such as tetrahydrofuran (THF), a suitable reducing agent, preferably, lithium aluminum hydride.
• a suitable organic solvent such as tetrahydrofuran (THF)
• THF tetrahydrofuran
• a suitable reducing agent preferably, lithium aluminum hydride.
• Preferred pharmaceutically acceptable salts for basic compounds of Formula (I) include, but are not limited to, hydrochloride, citrate, maleate, lactate,
• the compounds of Formula (I) may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent.
• a preferred compound of Formula (I), as used herein, is the compound where R 1 and R 2 are propyl, m is 1, A is absent, and R 3 is 4-piperidine which is 8,8-dipropyl-2-azaspiro[4,5]decane-2-(4-piperidine).
• This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for treatment of hyperlipidemia in a mammal, including humans, in need of such treatment.
• hyperlipidemia comprises administering to a mammal, including humans, in need thereof an effective therefor amount of a compound of Formula I.
• An effective antihyperlipidemic amount of a compound of Formula I comprises administering to a mammal, including humans, in need thereof an effective therefor amount of a compound of Formula I.
• ingredient is useful in treating, prophylactically or therapeutically, any disease state in a mammal
• disease states include hyperlipidemic syndromes, atherosclerosis and transplant arteriolosclerosis. Particularly preferred is the disease state of atherosclerosis.
• This invention relates to a method of treatment of hyperlipidemia, in a mammal, including a human, in need thereof which comprises administering an effective therefor amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof.
• a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof comprises administering an effective therefor amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof.
• pharmaceutically acceptable salt or hydrate or solvate thereof can be administered to such mammal, including a human, in a conventional dosage form prepared by
• pharmaceutically acceptable salt or hydrate or solvate thereof is administered to a mammal, including a human, in need of antihyperlipidemic activity in an amount sufficient to lower lipid concentration to desired levels.
• the route of administration of the Formula (I) compound is not critical but is usually oral or
• parenteral preferably oral.
• parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration.
• the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• the daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 1 mg/kg.
• the daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight.
• each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
• each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
• the compounds of Formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
• a liquid formulation will generally consist of a suspension or solution of the compound or
• composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier (s) routinely used for preparing solid formulations .
• Such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
• a composition in the form of a capsule can be prepared using routine encapsulation procedures.
• pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable
• compositions for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• an active ingredient While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
• pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being
• the optimal course of treatment i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof given per day and duration of therapy can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• the compounds of the present invention can be co-administered with further active ingredients, such as other compounds known for the treatment of elevated lipid levels such as acyl-CoA: Cholesterol acyItransferase (ACAT) inhibitors, HMGCoA reductase inhibitors and bile acid sequestrants.
• ACAT Cholesterol acyItransferase
• 4-Amino-1-benzylpiperidine, lithium aluminum hydride and tropinone were purchased from the Aldrich Chemical Co. (Milwaukee, WI).
• 3R-Pyrrolidine and 3S-pyrrolidine were purchased from CTC Organics (Atlanta, GA).
• the reaction mixture was heated at reflux with a Dean-Stark trap until 1 equivalent of water was collected in the trap.
• the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a white solid.
• the crude imide was dissolved in excess ethyl acetate followed by two washes with saturated aqueous sodium bicarbonate solution to remove any residual acid-amide from the product.
• the organic phase was dried over sodium sulfate, filtered, and concentrated to give the desired imide as a white solid; mp 148-149°C; 90-95% yield.
• reaction mixture was hydrogenated at 60 psi hydrogen pressure in a Parr hydrogenation apparatus at room temperature until hydrogen uptake had ceased (48-96h).
• the catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure. The residue was dissolved in water and then basified with 10% NaOH. The resulting aqueous emulsion was extracted with ethyl ether. The organic phase was dried over sodium sulfate, filtered and concentrated to give the debenzylated diamine product as a colorless oil; 90-95% yield.
• the white solid was recrystallized from ethanol or methanol; mp 298-300°C; yield 85-90%.
• Example 1 The title compound is prepared according to Example 1 (iv) by substituting 2-(4-(N-Methyl)piperidinyl-8,8- dipropyl-2-azaspiro[4.5]-decane for 2-(4-Piperidinyl)- 8,8-dipropyl-2-azaspiro[4.5]-decane; mp 332-334°C.
• Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 4, 4-diethylcyclohexane-l- carboxy-1-acetic acid anhydride for 4, 4-dipropylcyclo- hexane-1-carboxy-l-acetic acid anhydride; mp 331-332°C.
• Example 7 The title compound is prepared according to Example 7 (i-iii) by substituting 3- ⁇ -Amino-8-methyl-8-azabicyclo(3.2.1)octane (3 ⁇ -aminotropane) for 3-aminogainaclidine.
• the dihydrochloride was isolated as described in Example 7 (iii); yield 60% as a white amorphous solid; m.p. 234-235°C. in 60% yield. Elemental analyses suggest that the title compound was isolated as the monohydrate.
• Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 3- ⁇ -aminotropane for 3- ⁇ -aminotropane.
• the dihydrochloride was isolated as a white amorphous solid; m.p. 245-247°C. Elemental analyses suggest that the title compound was isolated as the monohydrate.
• the title compound is prepared according to Example 1 (i-iv) by substituting 4,4-dipropylcyclohexane-1,1-diacetic acid anhydride for 4,4-dipropylcyclohexane-1-carboxy-1-acetic acid anhydride.
• An oral dosage form for administering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the
• sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below are mixed and granulated in the proportions shown with 10% gelatin solution.
• the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

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• 1991
  • 1991-10-25 GB GB919122721A patent/GB9122721D0/en active Pending
• 1992
  • 1992-10-15 WO PCT/US1992/008786 patent/WO1993007871A1/en not_active Application Discontinuation
  • 1992-10-15 EP EP19920922182 patent/EP0609335A4/de not_active Withdrawn
  • 1992-10-15 JP JP5507789A patent/JPH07500595A/ja active Pending
  • 1992-10-15 AU AU28750/92A patent/AU2875092A/en not_active Abandoned

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