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WO1993007871A1 - Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes - Google Patents

Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes Download PDF

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Publication number
WO1993007871A1
WO1993007871A1 PCT/US1992/008786 US9208786W WO9307871A1 WO 1993007871 A1 WO1993007871 A1 WO 1993007871A1 US 9208786 W US9208786 W US 9208786W WO 9307871 A1 WO9307871 A1 WO 9307871A1
Authority
WO
WIPO (PCT)
Prior art keywords
mammal
compound
need
carbon atoms
composition according
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.)
Ceased
Application number
PCT/US1992/008786
Other languages
English (en)
Inventor
Peter John Bugelski
William David Kerns
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to US08/211,881 priority Critical patent/US5455247A/en
Priority to EP19920922182 priority patent/EP0609335A4/fr
Priority to JP5507789A priority patent/JPH07500595A/ja
Publication of WO1993007871A1 publication Critical patent/WO1993007871A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention se rapporte à un procédé de traitement de l'hyperlipidémie chez un mammifère, y compris un humain, qui requiert un tel traitement, le procédé consistant à administrer à ce mammifère une quantité suffisante d'un azaspirane substitué.
PCT/US1992/008786 1991-10-25 1992-10-15 Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes Ceased WO1993007871A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/211,881 US5455247A (en) 1991-10-25 1992-10-15 Methods for the treatment of hyperlipidemia using azaspiranes
EP19920922182 EP0609335A4 (fr) 1991-10-25 1992-10-15 Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes.
JP5507789A JPH07500595A (ja) 1991-10-25 1992-10-15 アザスピラン類を用いる高脂血症の治療方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9122721.5 1991-10-25
GB919122721A GB9122721D0 (en) 1991-10-25 1991-10-25 Methods

Publications (1)

Publication Number Publication Date
WO1993007871A1 true WO1993007871A1 (fr) 1993-04-29

Family

ID=10703551

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/008786 Ceased WO1993007871A1 (fr) 1991-10-25 1992-10-15 Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes

Country Status (5)

Country Link
EP (1) EP0609335A4 (fr)
JP (1) JPH07500595A (fr)
AU (1) AU2875092A (fr)
GB (1) GB9122721D0 (fr)
WO (1) WO1993007871A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0587800A4 (en) * 1991-06-07 1994-06-29 Smithkline Beecham Corp Immunomodulatory azaspiranes
EP0752856A4 (fr) * 1993-04-28 1997-09-10 Smithkline Beecham Corp Procedes pour traiter l'hyperlipidemie
US5708019A (en) * 1993-04-28 1998-01-13 Smithkline Beecham Corporation Methods of treating hyperlipidemia using azaspirane derivatives
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4291030A (en) * 1980-07-25 1981-09-22 Unimed, Inc. Method of lowering blood cholesterol
DE3522578A1 (de) * 1984-06-26 1986-01-02 Ciba-Geigy Ag, Basel Spiroverbindung und verfahren zu ihrer herstellung
PT100566B (pt) * 1991-06-07 1999-06-30 Smithkline Beecham Corp Azaspiranos imunomoduladores, composicoes farmaceuticas que os contem, sua preparacao e seu uso

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0609335A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0587800A4 (en) * 1991-06-07 1994-06-29 Smithkline Beecham Corp Immunomodulatory azaspiranes
EP0752856A4 (fr) * 1993-04-28 1997-09-10 Smithkline Beecham Corp Procedes pour traiter l'hyperlipidemie
US5708019A (en) * 1993-04-28 1998-01-13 Smithkline Beecham Corporation Methods of treating hyperlipidemia using azaspirane derivatives
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Also Published As

Publication number Publication date
EP0609335A4 (fr) 1994-10-12
JPH07500595A (ja) 1995-01-19
EP0609335A1 (fr) 1994-08-10
GB9122721D0 (en) 1991-12-11
AU2875092A (en) 1993-05-21

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