EP0654997A1 - Compositions d'azaspiranes substituees et procedes de traitement du psoriasis a l'aide de ces dernieres - Google Patents

Compositions d'azaspiranes substituees et procedes de traitement du psoriasis a l'aide de ces dernieres

Info

Publication number
EP0654997A1
EP0654997A1 EP93920102A EP93920102A EP0654997A1 EP 0654997 A1 EP0654997 A1 EP 0654997A1 EP 93920102 A EP93920102 A EP 93920102A EP 93920102 A EP93920102 A EP 93920102A EP 0654997 A1 EP0654997 A1 EP 0654997A1
Authority
EP
European Patent Office
Prior art keywords
compound
carbon atoms
pharmaceutically acceptable
solvate
hydrate
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.)
Withdrawn
Application number
EP93920102A
Other languages
German (de)
English (en)
Other versions
EP0654997A4 (fr
Inventor
Alison Mary Badger
Don Edgar Griswold
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
Publication of EP0654997A1 publication Critical patent/EP0654997A1/fr
Publication of EP0654997A4 publication Critical patent/EP0654997A4/fr
Withdrawn legal-status Critical Current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
    • A61K31/40—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
    • A61K31/41—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
    • A61K31/435—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
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • This invention relates to a method of treatment of psoriasis in a mammal in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.
  • R! and R2 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 Rl and R ⁇ when taken together is 4-10; or R* and R ⁇ together form a cyclic alkyl group containing 3-7 carbon atoms; A is absent or present as C -C- alkyl; and
  • R3 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 ⁇ NR ⁇ , where R ⁇ 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.
  • treatment and derivatives thereof as used in the specification and in the claims is meant that a mammal in need of antipsoriatic activity is cured of or provided with acceptable symptomatic relief from the disease.
  • mammal as used herein is meant warm-blooded vertebrate animals, including all that possess hair and suckle their young.
  • said mammal is a human.
  • R! and R ⁇ 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 and R ⁇ when taken together is 4-10; or R ⁇ and R ⁇ together form a cyclic alkyl group containing 3-7 carbon atoms; A is absent or present as C1-C7 alkyl; and
  • R3 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 ⁇ NR ⁇ , where R ⁇ 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.
  • Preferred compounds of the invention for use in the presently invented method include:
  • Formula (I) compounds are prepared as described in Scheme I where Rl, R2, R and A are as defined in Formula I and the definition of R3 additionally comprises protecting groups, preferably benzyl protecting groups, which are dissociated to prepare the substituents of R ⁇ as defined in Formula (I) or are dissociated and further reacted to prepare the substituents of R ⁇ as defined in Formula (I).
  • Scheme I depicts formation of Formula (I) compounds.
  • the starting anhydride compounds are known and are synthesized from available precursors using known procedures.
  • 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.
  • 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)
  • a suitable reducing agent preferably, lithium aluminum hydride.
  • Pharmaceutically acceptable salts and their preparation are well known to those of skill in the art.
  • Preferred pharmaceutically acceptable salts for basic compounds of Formula (I) include, but are not limited to, hydrochloride, citrate, maleate, lactate, hydrobromide, and sulfate.
  • 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* and R ⁇ are propyl, m is 1, A is absent, and R ⁇ 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 psoriasis in a mammal in need of such treatment.
  • This invention relates to a method of treatment of psoriasis in a mammal in need thereof which comprises administering an effective 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 can be administered to such mammal in a conventional dosage form prepared by combining a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to a mammal in need of antipsoriatic activity in an amount sufficient to cure or provide acceptable symptomatic relief from the disease.
  • the route of administration of the Formula (I) compound is not critical but is usually oral, parenteral or topical, preferably topical.
  • the present invention is 4/04151
  • 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.
  • the daily topical dosage regiment will preferably be from about 0.01 mg/kg to about 10 mg kg.
  • 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.
  • each topical 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 pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) 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 pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • the compounds of the present invention are also administered in the form of a pharmaceutical composition- comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration.
  • These topical pharmaceutical compositions may be in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • These topical pharmaceutical compositions containing the compounds of the present invention ordinarily include above 0.1% to 15%, preferably about 0.1 to 5%, and more preferably about 0.1% to 2%, of the active compound, in a mixture with a pharmaceutically acceptable carrier.
  • 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.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a 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 treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that 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 or therapies known for the treatment of psoriasis such as; keratinolytics, topical corticosteroids, coal tar and ultraviolet light or cyclosporine A.
  • temperature is in degrees Centigrade (°C).
  • 4,4-Dipropylcyclohexane-l-carboxy-l -acetic acid anhydride 4,4- diethylcyclohexane-1-carboxy-l-acetic acid anhydride, 4,4-dipropylcyclohexane-l,l-diacetic acid anhydride, and
  • 4-Amino-l-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 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.
  • Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 4,4-diethylcyclohexane-l-carboxy-l -acetic acid anhydride for 4,4-dipropylcyclo- hexane-l-carboxy-1 -acetic acid anhydride; mp 331-332°C.
  • the solid was recrystallized from dichloromethane/ethyl acetate to afford the pure salt as a white crystalline solid.
  • the product salt was solubilized in a minimum of water and the resulting solution basified with 1 M sodium hydroxide and extracted with ethyl ether. The ether extracts were combined, dried over sodium sulfate, filtered, and concentrated to give the desired imide as a viscous oil; 70-75% yield.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (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)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de traitement du psoriasis chez un mammifère atteint de cette maladie, selon lequel on administre audit mammifère une quantité efficace d'une azaspirane substituée.
EP93920102A 1992-08-13 1993-08-12 Compositions d'azaspiranes substituees et procedes de traitement du psoriasis a l'aide de ces dernieres. Withdrawn EP0654997A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB929217121A GB9217121D0 (en) 1992-08-13 1992-08-13 Methods
GB9217121 1992-08-13
PCT/US1993/007699 WO1994004151A1 (fr) 1992-08-13 1993-08-12 Compositions d'azaspiranes substituees et procedes de traitement du psoriasis a l'aide de ces dernieres

Publications (2)

Publication Number Publication Date
EP0654997A1 true EP0654997A1 (fr) 1995-05-31
EP0654997A4 EP0654997A4 (fr) 1997-09-17

Family

ID=10720233

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93920102A Withdrawn EP0654997A4 (fr) 1992-08-13 1993-08-12 Compositions d'azaspiranes substituees et procedes de traitement du psoriasis a l'aide de ces dernieres.

Country Status (4)

Country Link
EP (1) EP0654997A4 (fr)
JP (1) JPH08500593A (fr)
GB (1) GB9217121D0 (fr)
WO (1) WO1994004151A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002229A1 (fr) * 1990-08-10 1992-02-20 Smithkline Beecham Corporation Compositions immunosuppressives
WO1992022294A1 (fr) * 1991-06-07 1992-12-23 Smithkline Beecham Corporation Azaspiranes immunomodulateurs
WO1994004150A1 (fr) * 1992-08-13 1994-03-03 Smithkline Beecham Corporation Procedes de traitement du psoriasis a l'aide d'azaspirannes substitues

Family Cites Families (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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002229A1 (fr) * 1990-08-10 1992-02-20 Smithkline Beecham Corporation Compositions immunosuppressives
WO1992022294A1 (fr) * 1991-06-07 1992-12-23 Smithkline Beecham Corporation Azaspiranes immunomodulateurs
WO1994004150A1 (fr) * 1992-08-13 1994-03-03 Smithkline Beecham Corporation Procedes de traitement du psoriasis a l'aide d'azaspirannes substitues

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ARCHIVES OF DERMATOLOGY, vol. 116, no. 1, 1980, pages 51-55, XP000677543 D.N. SAUDER ET AL.: "SUPPRESSOR CELL FUNCTION IN PSORIASIS" *
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, vol. 11, no. 7, 1989, pages 839-846, XP000677549 A.M. BADGER ET AL.: "INHIBITION OF ANIMAL MODELS OF AUTOIMMUNE DISEASE AND THE INDUCTION OF NON-SPECIFIC SUPPRESSOR CELLS BY SK&F 105685 AND RELATED AZASPIRANES" *
J.E.F. REYNOLDS: "MARTINDALE, THE EXTRA PHARMACOPOEIA" 1989 , THE PHARMACEUTICAL PRESS , LONDON XP002034973 * page 594 - page 595 * *
See also references of WO9404151A1 *
Z. HAUTKR., vol. 66, no. S2, 1991, pages 55-60, XP000677526 R. ENGST ET AL.: "EVALUATION OF IMMUNOSUPPRESSIVE ACTING ANTIPSORIATIC AGENTS" *

Also Published As

Publication number Publication date
WO1994004151A1 (fr) 1994-03-03
JPH08500593A (ja) 1996-01-23
GB9217121D0 (en) 1992-09-23
EP0654997A4 (fr) 1997-09-17

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