WO1995003042A1 - Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues - Google Patents
Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues Download PDFInfo
- Publication number
- WO1995003042A1 WO1995003042A1 PCT/US1994/008276 US9408276W WO9503042A1 WO 1995003042 A1 WO1995003042 A1 WO 1995003042A1 US 9408276 W US9408276 W US 9408276W WO 9503042 A1 WO9503042 A1 WO 9503042A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- replication
- formula
- inhibiting
- pharmaceutically acceptable
- Prior art date
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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
- A61K31/435—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)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94922685A EP0711160A4 (fr) | 1993-07-23 | 1994-07-22 | Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues |
NZ269991A NZ269991A (en) | 1993-07-23 | 1994-07-22 | Inhibiting hiv replication; comprises use of azaspirane compounds to prepare medicaments |
JP7505332A JPH09500648A (ja) | 1993-07-23 | 1994-07-22 | 置換アザスピランによるヒト免疫不全ウイルス複製の阻害法 |
AU73709/94A AU7370994A (en) | 1993-07-23 | 1994-07-22 | Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9315340.1 | 1993-07-23 | ||
GB939315340A GB9315340D0 (en) | 1993-07-23 | 1993-07-23 | Methods |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995003042A1 true WO1995003042A1 (fr) | 1995-02-02 |
Family
ID=10739357
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/008276 WO1995003042A1 (fr) | 1993-07-23 | 1994-07-22 | Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0711160A4 (fr) |
JP (1) | JPH09500648A (fr) |
CN (1) | CN1130871A (fr) |
AU (1) | AU7370994A (fr) |
CA (1) | CA2167842A1 (fr) |
GB (1) | GB9315340D0 (fr) |
NZ (1) | NZ269991A (fr) |
WO (1) | WO1995003042A1 (fr) |
ZA (1) | ZA945418B (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0713391A1 (fr) * | 1993-07-23 | 1996-05-29 | Smithkline Beecham Corporation | Procede d'inhibition de la production de virus de l'immunodeficience chez l'homme au moyen d'azaspiranes substitues |
EP0717622A1 (fr) * | 1993-07-23 | 1996-06-26 | Smithkline Beecham Corporation | Procedes de traitement du vih au moyen d'azaspiranes |
US5744495A (en) * | 1995-07-13 | 1998-04-28 | Smithkline Beecham Corporation | N, N-diethyl-8, 8-dipropyl-2-azaspiro 4.5! decane-2-propanamine |
US6025364A (en) * | 1996-05-17 | 2000-02-15 | Anormed, Inc. | Method of treating asthma |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
GB9201804D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
GB9201803D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
GB9315298D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
GB9315351D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
GB9315306D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
-
1993
- 1993-07-23 GB GB939315340A patent/GB9315340D0/en active Pending
-
1994
- 1994-07-22 CN CN94193381A patent/CN1130871A/zh active Pending
- 1994-07-22 CA CA002167842A patent/CA2167842A1/fr not_active Abandoned
- 1994-07-22 NZ NZ269991A patent/NZ269991A/xx unknown
- 1994-07-22 WO PCT/US1994/008276 patent/WO1995003042A1/fr not_active Application Discontinuation
- 1994-07-22 EP EP94922685A patent/EP0711160A4/fr not_active Withdrawn
- 1994-07-22 AU AU73709/94A patent/AU7370994A/en not_active Abandoned
- 1994-07-22 ZA ZA945418A patent/ZA945418B/xx unknown
- 1994-07-22 JP JP7505332A patent/JPH09500648A/ja not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
Non-Patent Citations (3)
Title |
---|
CHEMICAL ABSTRACTS, Volume 117, No. 23. issued 07 December 1992, BADGER et al.: "Azaspirane Derivatives as Cytokine Inhibitors", see page 83, column 2, abstract no. 226312z; & WO,A,9214462. * |
CHEMICAL ABSTRACTS, Volume 119, No. 17, issued 25 October 1993, BADGER: "Preventing or Delaying Occurrence of Acquired Immunodeficiency Syndrome with Azaspiranes", see page 90, column 1, abstract no. 174173z; & WO,A,9314760. * |
See also references of EP0711160A4 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0713391A1 (fr) * | 1993-07-23 | 1996-05-29 | Smithkline Beecham Corporation | Procede d'inhibition de la production de virus de l'immunodeficience chez l'homme au moyen d'azaspiranes substitues |
EP0717622A1 (fr) * | 1993-07-23 | 1996-06-26 | Smithkline Beecham Corporation | Procedes de traitement du vih au moyen d'azaspiranes |
EP0713391A4 (fr) * | 1993-07-23 | 1998-09-09 | Smithkline Beecham Corp | Procede d'inhibition de la production de virus de l'immunodeficience chez l'homme au moyen d'azaspiranes substitues |
EP0717622A4 (fr) * | 1993-07-23 | 1998-09-09 | Smithkline Beecham Corp | Procedes de traitement du vih au moyen d'azaspiranes |
US5744495A (en) * | 1995-07-13 | 1998-04-28 | Smithkline Beecham Corporation | N, N-diethyl-8, 8-dipropyl-2-azaspiro 4.5! decane-2-propanamine |
US6025364A (en) * | 1996-05-17 | 2000-02-15 | Anormed, Inc. | Method of treating asthma |
Also Published As
Publication number | Publication date |
---|---|
EP0711160A4 (fr) | 1998-09-09 |
AU7370994A (en) | 1995-02-20 |
JPH09500648A (ja) | 1997-01-21 |
EP0711160A1 (fr) | 1996-05-15 |
CN1130871A (zh) | 1996-09-11 |
ZA945418B (en) | 1995-05-10 |
CA2167842A1 (fr) | 1995-02-02 |
GB9315340D0 (en) | 1993-09-08 |
NZ269991A (en) | 1999-07-29 |
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