AU652583B2 - Methods - Google Patents

Methods

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Publication number
AU652583B2
AU652583B2 AU86310/91A AU8631091A AU652583B2 AU 652583 B2 AU652583 B2 AU 652583B2 AU 86310/91 A AU86310/91 A AU 86310/91A AU 8631091 A AU8631091 A AU 8631091A AU 652583 B2 AU652583 B2 AU 652583B2
Authority
AU
Australia
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
AU86310/91A
Other versions
AU8631091A (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.)
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 AU8631091A publication Critical patent/AU8631091A/en
Application granted granted Critical
Publication of AU652583B2 publication Critical patent/AU652583B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Description

METHODS
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.
Baf- qrrm-T-d of the Inven _ on
Badger et al., U.S. Patent No. 4,963,557 issued October 16, 1990, (Badger) discloses compounds of the formula
wherein: n is 3-7; m is 1 or 2; R^ and R^ 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 R1 and R2 when taken together is 5-10; or R! and R2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; R^ and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R and R4 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.
Badger does not disclose or claim that compounds of Formula I have utility in treating disease states which are exacerbated or caused by excessive glucose levels.
Summary of e Tnvf.nt.ion
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
wherein: n is 3-7; m is 1 or 2;
R1 and R2 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 R1 and R2 when taken together is 5-10; or R1 and R2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; R3 and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R^ and R4 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.
Detailed Description of the Tnvention
The preparation of all compounds of Formula (I) and pharmaceutically acceptable salts, hydrates and solvates and formulations thereof is disclosed in U.S. Patent No. 4,963,557 the entire disclosure of which is hereby incorporated by reference.
As used herein, the term "compound A" refers to the dihydrochloride salt of a compound of Formula (I) where R1 and R2 are propyl, R^ and R4 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.
It has now been discovered that 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. Preferably, the disease state is autoimmune diabetes mellitus.
Compound A was tested for its in vivo potency in inhibiting autoimmune diabetes mellitus in rats. To perform the experiment a total of 75 Biobreeding/Worcester (BB/Wor) highly inbred (>30 generations sib-mated, and virus antibody free) diabetes-prone (diabetes appears spontaneously beginning ~60 days of age and by -120 days of age diabetes incidence reaches -85-95% in both sexes) rats, 27 male and 48 female (University of Massachusetts, Worcester, NIH Contract Colony) were used. 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:
Group 1 Male control, no treatment Group 2 Female control, no treatment Group 3 Male vehicle control, dosed orally once a day with vehicle alone. Group 4 Female vehicle control, dosed orally once a day with vehicle alone. Group 5 Male test group, dosed orally once a day with 15 mg/kg of compound A. Group 6 Female test group, dosed oraly once a day with 15 mg/kg of compound A.
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. Thus, 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.
It will be recognized by one of skill in the art that 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. The term 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.
Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg. Preferably each oral dosage unit will contain the active ingredient in an amount of from about 0.5 mg to about 70 mg.
While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
It will be recognized by one of skill in the art that 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.
Following are the results of testing the compounds of this invention.
Table T
The effect of 2-( (1-piperidinyl)propyl)-8, 8-dipropyl- 2-azaspiro[4,5]decane dihydrochloride (Compound A) on inhibiting autoimmune diabetes mellitus in BB/Wor rats. Table T
The data in the above table demonstrates the therapeutic effect of compounds of Formula I on the inhibition of autoimmune diabetes mellitus.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. EXAMPLE 1 - CAPSULE COMPOSTTTON
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-azasρiro[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.
While the above descriptions and examples fully describe the invention and the preferred embodiments thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming within the scope of the following claims.

Claims (10)

What is claimed is:
1. A method of prophylactically or therapeutically 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 compound of the formula
wherein: n is 3-7; m is 1 or 2;
R! and R2 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 R1 and R2 when taken together is 5-10; or R1 and R2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms;
R3 and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R^ and R4 are joined together with the nitrogen to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
2. The method of claim 1 wherein the disease state is autoimmune diabetes mellitus.
3. The method of claim 2 wherein the compound is N,N-dimethyl-8,8-diρropyl-2-azaspiro[4,5]decane-2- propanamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
4. The method of claim 3 wherein the compound is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride.
5. The method of claim 2 wherein the compound is 2- ( (1-ρiperidinyl)propyl)-8,8-dipropyl-2- azaspiro[4,5]decane; or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 wherein the compound is 2- ( (1-piperidinyl)propyl)-8, 8-dipropyl-2-azaspiro[4,5]decane dihydrochloride.
7. The method according to claim 1 wherein the compound is administered orally.
8. The method according to of claim 1 wherein the compound is administered parenterally.
9. The method according to claim 1 wherein from about 0.1 to 2000 mg of compound is administered per day.
10. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for use in the prophylactical or therapeutical treatment of a disease state which is exacerbated or caused by excessive glucose levels.
AU86310/91A 1990-09-24 1991-09-18 Methods Ceased AU652583B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US58732290A 1990-09-24 1990-09-24
US587322 1990-09-24
PCT/US1991/006778 WO1992004899A1 (en) 1990-09-24 1991-09-18 Methods

Publications (2)

Publication Number Publication Date
AU8631091A AU8631091A (en) 1992-04-15
AU652583B2 true AU652583B2 (en) 1994-09-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
AU86310/91A Ceased AU652583B2 (en) 1990-09-24 1991-09-18 Methods

Country Status (5)

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

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
WO1997044030A1 (en) * 1996-05-17 1997-11-27 Anormed Inc. Use of substituted azaspirane in the treatment of asthma

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989002889A1 (en) * 1987-09-28 1989-04-06 Smithkline Beckman Corporation Immunomodulatory azaspiranes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989002889A1 (en) * 1987-09-28 1989-04-06 Smithkline Beckman Corporation Immunomodulatory azaspiranes
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes

Also Published As

Publication number Publication date
EP0550595A4 (en) 1993-09-08
CA2092177A1 (en) 1992-03-25
WO1992004899A1 (en) 1992-04-02
AU8631091A (en) 1992-04-15
JPH06501468A (en) 1994-02-17
EP0550595A1 (en) 1993-07-14

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