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EP0550595A1 - Methodes - Google Patents

Methodes

Info

Publication number
EP0550595A1
EP0550595A1 EP91917436A EP91917436A EP0550595A1 EP 0550595 A1 EP0550595 A1 EP 0550595A1 EP 91917436 A EP91917436 A EP 91917436A EP 91917436 A EP91917436 A EP 91917436A EP 0550595 A1 EP0550595 A1 EP 0550595A1
Authority
EP
European Patent Office
Prior art keywords
compound
pharmaceutically acceptable
azaspiro
decane
acceptable salt
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
EP91917436A
Other languages
German (de)
English (en)
Other versions
EP0550595A4 (en
Inventor
Alison Mary Badger
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.)
Anormed Inc
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 EP0550595A1 publication Critical patent/EP0550595A1/fr
Publication of EP0550595A4 publication Critical patent/EP0550595A4/en
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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • This invention relates to a method of treating a disease state which is exacerbated or caused by excessive glucose levels, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective therefore amount of a substituted azaspirane.
  • This invention relates to a method of treating, prophylactically or therapeutically, a disease state which is exacerbated or caused by excessive glucose levels, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective therefore amount of a compound of the formula
  • R 1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 5-10; or R 1 and R 2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; R3 and R 4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R ⁇ and R 4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
  • compound A refers to the dihydrochloride salt of a compound of Formula (I) where R 1 and R 2 are propyl, R ⁇ and R 4 are joined together with the nitrogen atom to form a saturated heterocyclic group having 5 carbon atoms, m is 1 and n is 3 which is 2-((l- piperidinyl)propyl)-8,8-dipropyl-2-azaspiro[4,5]decane dihydrochloride.
  • compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof are useful in treating, prophylactically or therapeutically, a disease state which is exacerbated or caused by excessive glucose levels, in a mammal, including a human. in need thereof.
  • the disease state is autoimmune diabetes mellitus.
  • Compound A was tested for its in vivo potency in inhibiting autoimmune diabetes mellitus in rats.
  • BB/Wor Biobreeding/Worcester
  • highly inbred >30 generations sib-mated, and virus antibody free
  • diabetes-prone diabetes-prone
  • 27 male and 48 female Universality of Massachusetts, Worcester, NIH Contract Colony
  • the rats were maintained on tap water and standard laboratory chow which were available .ad. libitum.
  • the 75 rats were set up in 6 groups as follows:
  • Compound A and the vehicle (0.5% gum tragacanth) were administered orally by gavage begining at age 25 days and continuing until the age of 120 days or until the onset of diabetes.
  • the rats were monitored daily for urine glucose.
  • Diabetes as used herein, is defined as glucosuria (>.4+ by Testape) (Eli Lilly Canada Inc., Toronto) and a blood glucose .>200mg/dl (tail vein) . Blood glucose levels were determined on a Glucose Analyzer II Beckman Instruments, Fullerton California.
  • the rats treated with compound A realized a significant decrease in the incidence of diabetes.
  • the administration of a compound-of Formula I results in a therapeutic inhibition of autoimmune diabetes mellitus.
  • This invention relates to a method of treating a disease state which is exacerbated or caused by excessive glucose levels, in a mammal, including a human, in need thereof which comprises administering an effective therefore 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, including a human, 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, such as those described in Badger, U.S. Patent No. 4,963,557.
  • the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to a mammal, including a human, in need of the prevention or inhibition of excessive glucose levels in an amount sufficient to prevent or inhibit said excessive glucose levels.
  • the route of administration of the Formula (I) compound may be oral or parenteral.
  • parenteral as used herein includes intravenous, transdermal, intramuscular, subcutaneous, intranasal, intrarectal, 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 100 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 20 mg/kg.
  • the daily oral dosage regimen will preferably be from about 0.5 mg to about 2000 mg.
  • 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 0.5 mg to about 70 mg.
  • 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 for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • 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 proportions shown in Table II, below.
  • An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of 2-((l- piperidinyl)propyl)-8,8-dipropyl-2-azaspiro[4,5]decane dihydrochloride in 10% by volume propylene glycol in water.
  • Example 3 Composition for Administration by Inhalation
  • An aerosol form for administering Formula (I) compounds is produced by dissolving 10 mg of 2-((l- piperidinyl)propyl)-8, 8-dipropyl-2-azas ⁇ iro[4,5]decane dihydrochloride in ethanol (6-8 ml) and 0.1 -0.2% of a lubricating agent, such as polysorbate 85 or oleic acid, in an aerosol container and dispersing such mixture in a propellant, such as freon, preferably in a combination of (1,2 dichlorotetrafluoroethane) and difluorochloro methane.
  • a propellant such as freon

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Méthode de traitement d'un état pathologique qui est exacerbé ou causé par des niveaux excessifs de glucose chez un mammifère, y compris chez l'homme. Le traitement consiste à administrer au mammifère souffrant de cet état pathologique une dose efficace d'un azaspirane substitué.
EP19910917436 1990-09-24 1991-09-18 Methods Ceased EP0550595A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58732290A 1990-09-24 1990-09-24
US587322 1990-09-24

Publications (2)

Publication Number Publication Date
EP0550595A1 true EP0550595A1 (fr) 1993-07-14
EP0550595A4 EP0550595A4 (en) 1993-09-08

Family

ID=24349331

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910917436 Ceased EP0550595A4 (en) 1990-09-24 1991-09-18 Methods

Country Status (5)

Country Link
EP (1) EP0550595A4 (fr)
JP (1) JPH06501468A (fr)
AU (1) AU652583B2 (fr)
CA (1) CA2092177A1 (fr)
WO (1) WO1992004899A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9201803D0 (en) * 1992-01-28 1992-03-11 Smithkline Beecham Corp Methods
GB9217116D0 (en) * 1992-08-13 1992-09-23 Smithkline Beecham Corp Methods
EP0910373A1 (fr) * 1996-05-17 1999-04-28 AnorMED Inc. Utilisation d'azaspirane substitue dans le traitement de l'asthme

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

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY vol. 11, no. 7, 1989, pages 839 - 846 BADGER, A.M. ET AL 'INHIBITION OF ANIMAL MODELS OF AUTOIMMUNE DISEASE AND THE INDUCTION OF NON-SPECIFIC SUPPRESSOR CELLS BY SK&F 105685 AND RELATED AZASPIRANES' *
JOURNAL OF AUTOIMMUNITY vol. 6, no. 1, February 1993, pages 39 - 49 RABINOVITCH, A. ET AL 'PREVENTION OF DIABETES AND INDUCTION OF NON-SPECIFIC SUPPRESSOR CELL ACTIVITY IN THE BB RAT BY AN IMMUNOMODULATORY AZASPIRANE, SK&F 106610' *
JOURNAL OF MEDICINAL CHEMISTRY vol. 33, no. 11, November 1990, pages 2963 - 2970 BADGER, A.M. ET AL 'ANTIARTHRITIC AND SUPPRESSOR CELL INDUCING ACTIVITY OF AZASPIRANES: STRUCTURE-FUNCTION RELATIONSHIPS OF A NOVEL CLASS OF IMMUNOMODULATORY AGENTS' *
See also references of WO9204899A1 *

Also Published As

Publication number Publication date
EP0550595A4 (en) 1993-09-08
CA2092177A1 (fr) 1992-03-25
AU8631091A (en) 1992-04-15
JPH06501468A (ja) 1994-02-17
WO1992004899A1 (fr) 1992-04-02
AU652583B2 (en) 1994-09-01

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