AU3595193A - A method for delaying HIV induced AIDS by administration of substituted azasperane compounds - Google Patents
A method for delaying HIV induced AIDS by administration of substituted azasperane compoundsInfo
- Publication number
- AU3595193A AU3595193A AU35951/93A AU3595193A AU3595193A AU 3595193 A AU3595193 A AU 3595193A AU 35951/93 A AU35951/93 A AU 35951/93A AU 3595193 A AU3595193 A AU 3595193A AU 3595193 A AU3595193 A AU 3595193A
- Authority
- AU
- Australia
- 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.)
- Granted
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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
Description
METHODS
This invention relates to a method of preventing or delaying the occurrence of acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV) seropositive humans which comprises administering to such human an effective therefore amount of a substituted azaspirane.
Background of the Invention
The use of immunosuppressive/immunomodulatory agents has been shown to suppress viral replication.
Specifically, immunomodulating CD8 lymphocytes have been shown to suppress replication of HIV in peripheral blood mononuclear cells (Waler et al. Science, 2-21:1563-6 (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 (Brinch ann et al. CD8+ T cells J. Immunol. 144 2961-2966 (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-B 5 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-seroposi ive non-AIDS patients with CsA increases T4 cells and inhibits lymphadenopathy has also been reported. (Andrieu et al. Clin. Immunol, and immnmopathol . 46:181-198 (1988)) .
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 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.
Badger I discloses compounds of Formula I as a novel class of 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 preventing or delaying the occurrence of AIDS in HIV seropositive humans.
Summary of the Invention This invention relates to a method of preventing or delaying the occurrence of AIDS in HIV seropositive humans which comprises administering to such mammal an effective therefor 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or
R1 and R2 together 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 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 R2 are propyl, R3 and R4 are methyl, is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2- azaspiro[4,5]decane-2-propanamine dihydrochloride.
A preferred compound used in the novel method is a compound of Formula (I) where R1 and R2 are propyl, R^ 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 and salts thereof.
This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for preventing or delaying the occurrence of AIDS in HIV seropositive humans.
This invention relates to a method of delaying or preventing the occurrence of AIDS which comprises administering to an HIV seropositive human an effective therefor 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) or a
pharmaceutically acceptable salt or hydrate or solvate thereof is administered to an HIV seropositive human in an amount sufficient to prevent or delay the occurrence of AIDS.
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 or 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.
In addition, the compounds of the present invention can be co-administered with further active ingredients, such as other 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-dimethyl-8,8-dipropyl-2- 25 mg azaspiro[4,5]decane-2-propanamine dihydrochloride
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
EXAMPLE 2 - TN ECTABLE PARENTERAL COMPOSITION
An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-dimeth l-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride in 10% by volume propylene glycol in water.
Example 3 - Tablet Compos on
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.
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 (18)
1. A method for preventing or delaying the occurrence of acquired immunodeficiency syndrome (AIDS) in human immumodeficiency virus (HIV) seropositive humans which comprises administering to such human an effective therefor 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R1 and R2 together 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 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.
2. The method of 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 method of claim 1 wherein the compound is administered orally.
4. The method of claim 3 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
5. The method of claim 1 wherein the compound is administered parenterally.
6. The method of claim 5 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
7. Use 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R1 and R2 together 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 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 preventing or delaying the occurrence of aquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV) seropositive humans.
8. The use according to claim 7 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.
9. The use according to claim 7 wherein the compound is administered orally.
10. The use according to claim 9 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
11. The use according to claim 7 wherein the compound is administered parenterally.
12. The use according to claim 11 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
13. A pharmaceutical composition for use in preventing or delaying the occurrence of aquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV) seropositive humans, comprising a compound of the formula:
(I) 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 or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R! and R2 together 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 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.
14. A composition according to claim 13 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.
15. A composition according to claim 13 wherein the compound is administered orally.
16. A composition according to claim 15 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
17. A composition according to claim 13 wherein the compound is administered parenterally.
18. A composition according to claim 17 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929201803A GB9201803D0 (en) | 1992-01-28 | 1992-01-28 | Methods |
| GB9201803 | 1992-01-28 | ||
| PCT/US1993/000730 WO1993014760A2 (en) | 1992-01-28 | 1993-01-27 | Methods |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3595193A true AU3595193A (en) | 1993-09-01 |
| AU666175B2 AU666175B2 (en) | 1996-02-01 |
Family
ID=10709398
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU35951/93A Ceased AU666175B2 (en) | 1992-01-28 | 1993-01-27 | A method for delaying HIV induced AIDS by administration of substituted azasperane compounds |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0624089A4 (en) |
| JP (1) | JPH07503252A (en) |
| KR (1) | KR950700068A (en) |
| AU (1) | AU666175B2 (en) |
| CA (1) | CA2128535A1 (en) |
| GB (1) | GB9201803D0 (en) |
| WO (1) | WO1993014760A2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9315306D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315340D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315351D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| US7273859B2 (en) * | 2004-05-12 | 2007-09-25 | Bristol-Myers Squibb Company | HIV integrase inhibitors: cyclic pyrimidinone compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US181704A (en) * | 1876-08-29 | Improvement in flour-dressing machines | ||
| US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
| JPH06501468A (en) * | 1990-09-24 | 1994-02-17 | スミスクライン・ビーチャム・コーポレイション | Method |
| ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
-
1992
- 1992-01-28 GB GB929201803A patent/GB9201803D0/en active Pending
-
1993
- 1993-01-27 JP JP5513407A patent/JPH07503252A/en active Pending
- 1993-01-27 EP EP93904671A patent/EP0624089A4/en not_active Withdrawn
- 1993-01-27 CA CA002128535A patent/CA2128535A1/en not_active Abandoned
- 1993-01-27 WO PCT/US1993/000730 patent/WO1993014760A2/en not_active Application Discontinuation
- 1993-01-27 AU AU35951/93A patent/AU666175B2/en not_active Ceased
- 1993-01-27 KR KR1019940702596A patent/KR950700068A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993014760A3 (en) | 1993-09-02 |
| AU666175B2 (en) | 1996-02-01 |
| EP0624089A4 (en) | 1994-12-14 |
| JPH07503252A (en) | 1995-04-06 |
| GB9201803D0 (en) | 1992-03-11 |
| EP0624089A1 (en) | 1994-11-17 |
| KR950700068A (en) | 1995-01-16 |
| CA2128535A1 (en) | 1993-08-05 |
| WO1993014760A2 (en) | 1993-08-05 |
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