EP0711160A1 - Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes - Google Patents

Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes

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Publication number
EP0711160A1
EP0711160A1 EP94922685A EP94922685A EP0711160A1 EP 0711160 A1 EP0711160 A1 EP 0711160A1 EP 94922685 A EP94922685 A EP 94922685A EP 94922685 A EP94922685 A EP 94922685A EP 0711160 A1 EP0711160 A1 EP 0711160A1
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EP
European Patent Office
Prior art keywords
compound
replication
formula
inhibiting
pharmaceutically acceptable
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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Withdrawn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
EP94922685A
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German (de)
French (fr)
Other versions
EP0711160A4 (en
Inventor
Alison Mary Badger
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0711160A1 publication Critical patent/EP0711160A1/en
Publication of EP0711160A4 publication Critical patent/EP0711160A4/en
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • This invention relates to a method of inhibiting the replication of human immunodeficiency viruses (HIV) in HIV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.
  • HIV human immunodeficiency viruses
  • CD8+ T cells have been shown to inhibit the replication of HIV in cultures of CD4+ cells from asymptomatic HIV seropositive individuals (Brinchmann et al. CD8+ T cells L Immunol. 1442961-2966 (1990)).
  • the immunosuppressive compound cyclosporin A (CsA) has demonstrated a protective effect in several animal models of viral infection. Particularly, chronic treatment with CsA before and after infection with LP-BM5 murine leukemia virus has proven effective against the development of immunodeficiency disease (Cerny, A. et al. Eur. J. Immunol. 21:1747-50 (1991)).
  • Badger I discloses compounds of Formula I as a class of novel compounds which induce an immunomodulatory effect which is characterized by the stimulation of suppressor cell activity.
  • Rl 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 and R- when taken together is 5-10; or R* and R- together form a cyclic alkyl group having 3-7 carbon atoms;
  • R3 and R ⁇ are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R ⁇ 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.
  • a preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R- ⁇ are propyl, R3 and R 4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride.
  • a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R-2 are propyl, R3 and R 4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2- azaspiro[4.5]decane-2-propanamine dihydrochloride.
  • a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R2 are propyl, R3 and R 4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl dihydrochloride.
  • This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for inhibiting HIV replication in HIV seropositive humans.
  • the compounds of Formula I are tested for their ability to inhibit HIV replication in the assay described in Sperber, et al., AIDS Research and Human Retroviruses. 9 No.l.91-98.
  • This invention relates to a method of inhibiting HIV replication which comprises administering to an HIV seropositive human 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 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 (I), U.S. Patent No. 4,963,557.
  • a compound of Formula (I) ("Active Ingredient") or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to an HIV seropositive human in an amount sufficient to inhibit HIV replication.
  • 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.
  • each parenteral 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. Examples of 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 pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils
  • the daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg kg of total body weight.
  • each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 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. 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.
  • the method of this invention of inhibiting HIV replication in HIV seropositive humans comprises administering to a subject in need of such inhibition an effective HIV replication inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in inhibiting HIV replication in HIV seropositive humans.
  • the invention also provides for a pharmaceutical composition for use inhibiting HIV replication in HIV seropositive humans which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into association with the pharmaceutically acceptable carrier or diluent.
  • the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to prevent or delay the occurrence of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, formerly called azidothymidine (AZT)).
  • further active ingredients such as compounds known to prevent or delay the occurrence of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, formerly called azidothymidine (AZT)).
  • EXAMPLE 1 - CAPSULE COMPOSITION 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 I, below.
  • An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride in 10% by volume propylene glycol in water.
  • Example 3 Tablet Composition
  • sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below are mixed and granulated in the proportions shown with a 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)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Invented is a method of inhibiting the replication of human immunodeficiency viruses (HIV) in HIV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.

Description

METHOD OF INHIBITING THE REPLICATION OF HUMAN IMMUNODEFICIENCY VIRUSES WITH SUBSTITUTED AZASPIRANES
This invention relates to a method of inhibiting the replication of human immunodeficiency viruses (HIV) in HIV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.
Background of the Invention
Numerous agents are presently available which inhibit the replication of human immunodeficiency viruses in T cells and monocytes (Yarchoan et al., Lancet (1986); 1:575-580 and Broder et al., Lancet (1985); 2:627-630). These compounds are limited in their usefulness due to significant toxicities and viral resistance associated with their long-term use Volberding, et al., N. Engl J. Med 1990; 322:941-949. Additionally, certain selected immunosuppressive/immunomodulatory agents have demonstrated an ability to suppress viral replication. Specifically, immunomodulating CD8 lymphocytes have been shown to suppress replication of HIV in peripheral blood mononuclear cells (Walker et al. Science. 234:1563-6 (1986)) and activated CD8+ T cells have been shown to inhibit the replication of HIV in cultures of CD4+ cells from asymptomatic HIV seropositive individuals (Brinchmann et al. CD8+ T cells L Immunol. 1442961-2966 (1990)). Further, the immunosuppressive compound cyclosporin A (CsA) has demonstrated a protective effect in several animal models of viral infection. Particularly, chronic treatment with CsA before and after infection with LP-BM5 murine leukemia virus has proven effective against the development of immunodeficiency disease (Cerny, A. et al. Eur. J. Immunol. 21:1747-50 (1991)). Evidence that treatment of AIDS and HIV-seropositive non- AIDS patients with CsA increases T4 cells and inhibits lymphadenopathy has also been reported. (Andrieu et al. Clin. Immunol, and Immumopathol. 4^:181-198 (1988)). However, none of the above references suggest that immunosuppresseve/immunomodulatory agents in general will have utility in inhibiting HIV replication in HIV seropositive humans. Further, none of the above references teaches or suggest a means for predicting whether a particular immunosuppressive/immunomodulatory agent will have utility in inhibiting HIV replication in HIV seropositive humans.
Badger, et al., U.S. Patent No. 4,963,557 (Badger I) 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R and R^ when taken together is 5-10; or R-*- and R2 together form a cyclic alkyl group having 3-7 carbon atoms; R*-*-* and R^ are the same or different and are selected from hydrogen or straight chain alkyl having 1-
3 carbon atoms; or R^ and R^ 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 I discloses compounds of Formula I as a class of novel compounds which induce an immunomodulatory effect which is characterized by the stimulation of suppressor cell activity.
Badger I does not disclose the compounds of Formula I as agents for inhibiting HIV replication in HIV seropositive humans.
Summary of the Invention This invention relates to a method of inhibiting HIV replication in HIV seropositive humans which comprises administering to such human an effective amount of a compound of the formula
wherein: n is 3-7; m is 1 or 2;
Rl 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 and R- when taken together is 5-10; or R* and R- together form a cyclic alkyl group having 3-7 carbon atoms;
R3 and R^ are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R^ 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 Invention 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.
A preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R-^ are propyl, R3 and R4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride.
A particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R-2 are propyl, R3 and R4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2- azaspiro[4.5]decane-2-propanamine dihydrochloride.
A particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R2 are propyl, R3 and R4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl dihydrochloride.
This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for inhibiting HIV replication in HIV seropositive humans.
The compounds of Formula I are tested for their ability to inhibit HIV replication in the assay described in Sperber, et al., AIDS Research and Human Retroviruses. 9 No.l.91-98.
This invention relates to a method of inhibiting HIV replication which comprises administering to an HIV seropositive human 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 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 (I), 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. A compound of Formula (I) ("Active Ingredient") or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to an HIV seropositive human in an amount sufficient to inhibit HIV replication.
The route of administration of the Formula (I) compound is not critical but is usually oral or parenteral, preferably oral.
The term 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. Preferably, each parenteral 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 composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of 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. For example, 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 daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg kg of total body weight. Preferably each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 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 and duration of therapy, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
The method of this invention of inhibiting HIV replication in HIV seropositive humans comprises administering to a subject in need of such inhibition an effective HIV replication inhibiting amount of a pharmaceutically active compound of the present invention.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in inhibiting HIV replication in HIV seropositive humans.
The invention also provides for a pharmaceutical composition for use inhibiting HIV replication in HIV seropositive humans which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into association with the pharmaceutically acceptable carrier or diluent.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to prevent or delay the occurrence of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, formerly called azidothymidine (AZT)).
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 COMPOSITION 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 I, below.
Table I
INGREDIENTS AMOUNTS
N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- 25 mg propanamine dihydrochloride
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
EXAMPLE 2 - INJECTABLE PARENTERAL COMPOSITION
An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride in 10% by volume propylene glycol in water.
Example 3 - Tablet Composition The sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
Table II
Ingredients Amounts N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane- 20 mg 2-propanamine dihydrochloride calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc l mg stearic acid 0.5 mg
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

What is claimed is:
Use of a compound 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R* and R- when taken together is 5-10; or R**- and R2 together 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 R3 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; in the manufacture of a medicament for inhibiting the replication of human immunodeficiency viruses (HTV) in HIV seropositive humans.
2. The use according to claim 1 wherein the compound is N,N- diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
3. The use according to claim 1 wherein the compound is administered orally.
4. The use according to claim 3 wherein from about 0.01 mg kg to about 10 mg kg of compound is administered per day.
5. The use according to claim 1 wherein the compound is administered parenterally.
6. The use according to claim 5 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
EP94922685A 1993-07-23 1994-07-22 Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes Withdrawn EP0711160A4 (en)

Applications Claiming Priority (3)

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GB9315340 1993-07-23
GB939315340A GB9315340D0 (en) 1993-07-23 1993-07-23 Methods
PCT/US1994/008276 WO1995003042A1 (en) 1993-07-23 1994-07-22 Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes

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EP0711160A1 true EP0711160A1 (en) 1996-05-15
EP0711160A4 EP0711160A4 (en) 1998-09-09

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GB9315351D0 (en) * 1993-07-23 1993-09-08 Smithkline Beecham Corp Methods
GB9315306D0 (en) * 1993-07-23 1993-09-08 Smithkline Beecham Corp Methods
BR9601909A (en) * 1995-07-13 1999-10-13 Smithkline Beecham Corp N, n-diethyl-8,8-dipropyl-2-azaspiro (4,5) decane-2-propan amine dimaleate
US6025364A (en) * 1996-05-17 2000-02-15 Anormed, Inc. Method of treating asthma

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014462A1 (en) * 1991-02-19 1992-09-03 Smithkline Beecham Corporation Cytokine inhibitors
WO1993014760A2 (en) * 1992-01-28 1993-08-05 Smithkline Beecham Corporation Methods
WO1993015735A1 (en) * 1992-01-28 1993-08-19 Smithkline Beecham Corporation (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds
WO1995003048A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Anti-hiv azaspiranes
WO1995003049A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Methods of treating hiv with azaspiranes
WO1995003041A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes

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 (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014462A1 (en) * 1991-02-19 1992-09-03 Smithkline Beecham Corporation Cytokine inhibitors
WO1993014760A2 (en) * 1992-01-28 1993-08-05 Smithkline Beecham Corporation Methods
WO1993015735A1 (en) * 1992-01-28 1993-08-19 Smithkline Beecham Corporation (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds
WO1995003048A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Anti-hiv azaspiranes
WO1995003049A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Methods of treating hiv with azaspiranes
WO1995003041A1 (en) * 1993-07-23 1995-02-02 Smithkline Beecham Corporation Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BADGER A M ET AL: "ANTIARTHRITIC AND SUPPRESSOR CELL INDUCING ACTIVITY OF AZASPIRANES:STRUCTURE-FUNCTION RELATIONSHIPS OF A NOVEL CLASS OF IMMUNOMODULATORY AGENTS" JOURNAL OF MEDICINAL CHEMISTRY, vol. 33, no. 11, November 1990, pages 2963-2970, XP000605424 *
P.S. SARIN ET AL.: "INHIBITION OF HTLV-III REPLICATION IN CELL CULTURES" NATO ASI SER., SER. A, vol. 120, 1986, pages 329-42, XP002069579 *
S. GOODMAN: "THERAPEUTIC EFFECTS OF ORGANIC GERMANIUM" MEDICAL HYPOTHESES, vol. 26, 1988, pages 207-215, XP002069578 *
See also references of WO9503042A1 *

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CA2167842A1 (en) 1995-02-02
EP0711160A4 (en) 1998-09-09
WO1995003042A1 (en) 1995-02-02
ZA945418B (en) 1995-05-10
NZ269991A (en) 1999-07-29
AU7370994A (en) 1995-02-20
CN1130871A (en) 1996-09-11
JPH09500648A (en) 1997-01-21
GB9315340D0 (en) 1993-09-08

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