WO1993015735A1 - (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds - Google Patents
(non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds Download PDFInfo
- Publication number
- WO1993015735A1 WO1993015735A1 PCT/US1993/000712 US9300712W WO9315735A1 WO 1993015735 A1 WO1993015735 A1 WO 1993015735A1 US 9300712 W US9300712 W US 9300712W WO 9315735 A1 WO9315735 A1 WO 9315735A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- azaspiro
- decane
- pharmaceutically acceptable
- dipropyl
- Prior art date
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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
-
- 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
- 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
Definitions
- This invention relates to a method of preventing
- HIV human immunodeficiency virus
- seropositive humans which comprises administering to
- immunomodulating CD8 lymphocytes have
- CsA compound cyclosporin A
- R 1 and R 2 different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 4-10; or R.1 and R 2 together form a cyclic alkyl group containing 3-7 carbon atoms/ A is absent or present as C 1 -C 7 alkyl; and R 3 is a heterocyclic or heterobicyclic ring, said heterocyclic or heterobicyclic ring thereby containing up to 10 carbon atoms and from 1-3
- R 4 is absent or present as hydrogen, or a straight chain alkyl
- n 1 or 2;
- R 1 and R 2 are the same or different and are
- R 1 and R 2 are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 4-10; or R 1 and R 2 together form a cyclic alkyl group containing 3-7 carbon atoms;
- A is bond or a C 1 -C 7 alkylene group/
- R 3 is a heterocyclic or heterobicyclic ring, said heterocyclic or heterobicyclic ring being a 5 to 13 membered ring system containing carbon and 1-3 nitrogen atoms and the nitrogen atoms may be substituted with hydrogen or a C 1-3 alkyl group;
- heterocyclic and heterobicyclic rings of the present invention include/ piperidine pyrroldine, imidazole and quinuclidine.
- the compounds of this invention are prepared by procedures described here below and illustrated by the examples. Reagents, protecting groups and functionality of the molecule must be consistent with the proposed chemical transformations. Steps in the synthesis must be compatible with the functional groups and the
- the starting anhydride compounds are known and are synthesized from available precursors using known procedures. According to Scheme I, a solution of an anhydride compound (a) and a substituted primary amine compound are added to an appropriate organic solvent, preferably xylene or toluene, to form a reaction mixture. This reaction mixture is stirred at reflux with constant water removal, and evaporated to form formula (b) compounds.
- Formula (c) compounds are prepared by adding to a formula (b) compound dissolved in a suitable organic solvent, such as tetrahydrofuran (THF), a suitable reducing agent, preferably, lithium aluminum hydride.
- a suitable organic solvent such as tetrahydrofuran (THF), a suitable reducing agent, preferably, lithium aluminum hydride.
- the compounds of Formula (I) may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent.
- a preferred compound of Formula (I) is the compound where R 1 and R 2 are propyl, m is 1, A is a bond, and R 3 is 4-pi ⁇ eridine which is 8,8-dipro ⁇ yl-2-azaspiro[4,5]decane-2-(4-piperidine).
- 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 preventing or delaying the occurrence of AIDS which comprises
- a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered 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 is administered 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.
- 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) ("active ingredient”) compound is not critical but is usually oral or parenteral, preferably oral.
- parenteral as used herein includes
- each parenteral dosage unit will contain the active
- 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
- 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.
- 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
- each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
- 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
- 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 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)).
- retrovir the brand name for zidovudine, formerly called azidothymidine (AZT)
- the reaction mixture was heated at reflux with a Dean-Stark trap until 1 equivalent of water was collected in the trap.
- the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a white solid.
- the crude imide was dissolved in excess ethyl acetate followed by two washes with saturated aqueous sodium bicarbonate solution to remove any residual acid-amide from the product.
- the organic phase was dried over sodium sulfate, filtered, and concentrated to give the desired imide as a white solid/ mp 148-149°C; 90-95% yield.
- the white solid was recrystallized from ethanol or methanol; mp 298-300°C; yield 85-90%.
- Example 1 The title compound is prepared according to Example 1 (iv) by substituting 2-(4-(N-Methyl)piperidinyl-8,8-dipropyl-2-azaspiro[4.5]-decane for 2-(4-Piperidinyl)-8,8-dipropyl-2-azaspiro[4.5]-decane; mp 332-334°C.
- Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 4,4-diethylcyclohexane-1-carboxy-1-acetic acid anhydride for 4,4-dipropylcyclohexane-1-carboxy-1-acetic acid anhydride; mp 331-332°C.
- Example 7 The title compound is prepared according to Example 7 (i-iii) by substituting 3- ⁇ -Amino-8-methyl-8-azabicyclo (3.2.1) octane (3 ⁇ -aminotropane) for 3-aminogainaclidine.
- the dihydrochloride was isolated as described in Example 7 (iii); yield 60% as a white amorphous solid; m.p. 234-235°C.in 60% yield. Elemental analyses suggest that the title compound was isolated as the monohydrate.
- Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 3- ⁇ -aminotropane for 3- ⁇ -aminotropane.
- the dihydrochloride was isolated as a white amorphous solid; m.p. 245-247°C. Elemental analyses suggest that the title compound was isolated as the monohydrate.
- An oral dosage form for administering Formula (1) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the
- An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of 8,8-dipropyl-2-azaspiro[4,5]decane-2-(4-piperidine)
- sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below are mixed and granulated in the proportions shown with 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)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- AIDS & HIV (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5514099A JPH07504405A (en) | 1992-01-28 | 1993-01-27 | Method for delaying AIDS in HIV individuals by administration of substituted azaspiran compounds |
EP93904656A EP0727993A1 (en) | 1992-01-28 | 1993-01-27 | (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9201804.3 | 1992-01-28 | ||
GB929201804A GB9201804D0 (en) | 1992-01-28 | 1992-01-28 | Methods |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993015735A1 true WO1993015735A1 (en) | 1993-08-19 |
Family
ID=10709399
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/000712 WO1993015735A1 (en) | 1992-01-28 | 1993-01-27 | (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0727993A1 (en) |
JP (1) | JPH07504405A (en) |
AU (1) | AU3594293A (en) |
GB (1) | GB9201804D0 (en) |
WO (1) | WO1993015735A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0587800A1 (en) * | 1991-06-07 | 1994-03-23 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
EP0711160A1 (en) * | 1993-07-23 | 1996-05-15 | Smithkline Beecham Corporation | Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes |
EP0713391A1 (en) * | 1993-07-23 | 1996-05-29 | Smithkline Beecham Corporation | Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes |
EP0717622A1 (en) * | 1993-07-23 | 1996-06-26 | Smithkline Beecham Corporation | Methods of treating hiv with azaspiranes |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
PT100566B (en) * | 1991-06-07 | 1999-06-30 | Smithkline Beecham Corp | IMMUNOMODULATOR AZASPIRANES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, PREPARATION AND USE |
-
1992
- 1992-01-28 GB GB929201804A patent/GB9201804D0/en active Pending
-
1993
- 1993-01-27 EP EP93904656A patent/EP0727993A1/en not_active Withdrawn
- 1993-01-27 JP JP5514099A patent/JPH07504405A/en active Pending
- 1993-01-27 WO PCT/US1993/000712 patent/WO1993015735A1/en not_active Application Discontinuation
- 1993-01-27 AU AU35942/93A patent/AU3594293A/en not_active Abandoned
Non-Patent Citations (4)
Title |
---|
CHEMICAL ABSTRACTS, Volume 111, No. 17, 15361r, issued 23 October 1989, (Columbus, Ohio, U.S.A.), BADGER et al., "Preparation of N-Aminoakyl-2-Azasprio[4,5] Decanes and Analog as Immunosuppressants", (Dept. Immunol., Smith Kline Beckman Corp., King of Prussia, PA 19406-0939 USA); & EP,A,310 321, 05 April 1989. * |
CHEMICAL ABSTRACTS, Volume 113, No. 21, issued 19 November 1990, (Columbus, Ohio, U.S.A.), BADGER et al., "Antiarthritic and Suppressor Cell Inducing Activity of Azaspiranes: Structure-Function Relationships of Novel Class of Immunodulatory Agents", (Dept. Immunol., Smith Kline and French Lab., King of * |
CHEMICAL ABSTRACTS, Volume 86, No. 9, issued 28 February 1977, (Columbus, Ohio, U.S.A.), EL-TELBANY et al., "Synthesis of Certain Spiro Compounds for Pharmacological Study, Part II", (Fac. Pharm., Cairo, Egypt); & J. PHARM BELG. 1976, 31(4), pp. 403-10, the Abstract No. 55229n. * |
See also references of EP0727993A4 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0587800A1 (en) * | 1991-06-07 | 1994-03-23 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
EP0587800A4 (en) * | 1991-06-07 | 1994-06-29 | Smithkline Beecham Corp | Immunomodulatory azaspiranes |
EP0711160A1 (en) * | 1993-07-23 | 1996-05-15 | Smithkline Beecham Corporation | Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes |
EP0713391A1 (en) * | 1993-07-23 | 1996-05-29 | Smithkline Beecham Corporation | Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes |
EP0717622A1 (en) * | 1993-07-23 | 1996-06-26 | Smithkline Beecham Corporation | Methods of treating hiv with azaspiranes |
EP0713391A4 (en) * | 1993-07-23 | 1998-09-09 | Smithkline Beecham Corp | Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes |
EP0711160A4 (en) * | 1993-07-23 | 1998-09-09 | Smithkline Beecham Corp | Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes |
EP0717622A4 (en) * | 1993-07-23 | 1998-09-09 | Smithkline Beecham Corp | Methods of treating hiv with azaspiranes |
Also Published As
Publication number | Publication date |
---|---|
JPH07504405A (en) | 1995-05-18 |
AU3594293A (en) | 1993-09-03 |
EP0727993A1 (en) | 1996-08-28 |
EP0727993A4 (en) | 1996-10-02 |
GB9201804D0 (en) | 1992-03-11 |
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