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WO1995003047A1 - Traitements s'exercant contre le virus de l'immunodeficience chez l'homme - Google Patents

Traitements s'exercant contre le virus de l'immunodeficience chez l'homme Download PDF

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Publication number
WO1995003047A1
WO1995003047A1 PCT/US1994/008253 US9408253W WO9503047A1 WO 1995003047 A1 WO1995003047 A1 WO 1995003047A1 US 9408253 W US9408253 W US 9408253W WO 9503047 A1 WO9503047 A1 WO 9503047A1
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WO
WIPO (PCT)
Prior art keywords
compound
dipropyl
decane
formula
pharmaceutically acceptable
Prior art date
Application number
PCT/US1994/008253
Other languages
English (en)
Inventor
Alison Mary Badger
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1995003047A1 publication Critical patent/WO1995003047A1/fr

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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
    • A61K31/44—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
    • A61K31/41—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

Definitions

  • This invention relates to a method of inhibiting cellular entry 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 HJV in cultures of CD4+ cells from asymptomatic HIV seropositive individuals (Brinchmann et al. CD8+ T cells J. Immunol. 1442961- 2966 (1990)). Further, the immunosuppressive compound cyclosporin A (CsA) has demonstrated a protective effect in several animal models of viral infection.
  • CsA cyclosporin A
  • R ⁇ together form a cyclic alkyl group containing 3-7 carbon atoms;
  • A is absent or present as C1-C7 alkylidene; and
  • R ⁇ is a heterocyclic or heterobicyclic ring, said heterocyclic or heterobicyclic ring thereby containing up to 10 carbon atoms and from 1-3 heteroatoms of the formula > NR ⁇ , where R ⁇ is absent or present as hydrogen, or a straight chain alkyl containing 1-3 carbon atoms; or a pharmaceutically acceptable salt, 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.
  • 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 4-10; or R* and R ⁇ together form a cyclic alkyl group containing 3-7 carbon atoms;
  • A is bond or a Cj-C alkylidene group
  • R3 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
  • 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 protecting groups.
  • Formula (I) compounds are prepared as described in Scheme I where R*,
  • R2, R3 and A are as defined in Formula I and the definition of R ⁇ additionally comprises protecting groups, preferably benzyl protecting groups, which are dissociated to prepare the substituents of R ⁇ as defined in Formula (I) or are dissociated and further reacted to prepare the substituents of R ⁇ as defined in Formula (I)-
  • Scheme I depicts formation of Formula (I) compounds.
  • the starting anhydride compounds are known and are synthesized from available precursors using known procedures.
  • 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)
  • THF tetrahydrofuran
  • a suitable reducing agent preferably, lithium aluminum hydride.
  • Preferred pharmaceutically acceptable salts for basic compounds of Formula (I) include, but are not limited to, hydrochloride, citrate, maleate, lactate, hydrobromide, and sulfate.
  • 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* and R ⁇ are propyl, m is 1, A is a bond, and R ⁇ is 4-piperidine which is 8,8-dipropyl-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 inhibiting cellular entry of HIV in HIV seropositive humans.
  • the compounds of Formula I are tested for their ability to inhibit cellular entry of HIV in the assay described in Sperber, et al., AIDS Research and Human Retroviruses. 9_, No 1, 91-98.
  • This invention relates to a method of inhibiting cellular entry of HTV 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
  • 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 inhibit cellular entry of HIV.
  • 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 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.
  • 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.
  • suitable pharmaceutical 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.
  • suitable pharmaceutical carrier(s) include magnesium
  • 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.
  • 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. While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
  • 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 cellular entry of HIV in HIV seropositive humans comprises administering to a subject in need of such inhibition an effective HIV cellular entry 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 cellular entry of HIV in HIV seropositive humans.
  • the invention also provides for a pharmaceutical composition for use in inhibiting cellular entry of HIV 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)).
  • temperature is in degrees Centigrade ( C).
  • 3-Amino-l-benzylpiperidine, lithium aluminum hydride and tropinone are commercially available.
  • 3R-Pyrrolidine and 3S-pyrrolidine were purchased from CTC Organics (Atlanta, GA).
  • 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-l -carboxy- 1 -acetic acid anhydride for 4,4-dipropylcyclo- hexane- 1 -carboxy- 1 -acetic acid anhydride; mp 331-332°C.
  • the volatiles were stripped off under reduced pressure from the product-maleate solution to yield a dark brown solid.
  • the solid was recrystallized from dichloromethane/ethyl acetate to afford the pure salt as a white crystalline solid.
  • the product salt was solubilized in a minimum of water and the resulting solution basified with 1 M sodium hydroxide and extracted with ethyl ether. The ether extracts were combined, dried over sodium sulfate, filtered, and concentrated to give the desired imide as a viscous oil; 70-75% yield.
  • 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 9 2-f3' ⁇ -8'-Methyl-8'-azabicvclo( ' 3.2.noctaneV8.8-dipropyl-2-azaspiror4.51 decane-dihvdrochloride
  • Example 1 The title compound is prepared according to Example 1 (i-iv) by substituting 4,4-dipropylcyclohexane-l,l-diacetic acid anhydride for 4,4-dipropylcyclohexane- 1 -carboxy- 1 -acetic acid anhydride.
  • 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
  • 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) 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 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)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé d'inhibition de la pénétration cellulaire de virus de l'immunodéficience humaine (VIH) chez des individus séropositifs, consistant en l'administration auxdits individus d'une quantité efficace d'azaspirane substitué.
PCT/US1994/008253 1993-07-23 1994-07-25 Traitements s'exercant contre le virus de l'immunodeficience chez l'homme WO1995003047A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9315341.9 1993-07-23
GB939315341A GB9315341D0 (en) 1993-07-23 1993-07-23 Methods

Publications (1)

Publication Number Publication Date
WO1995003047A1 true WO1995003047A1 (fr) 1995-02-02

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Application Number Title Priority Date Filing Date
PCT/US1994/008253 WO1995003047A1 (fr) 1993-07-23 1994-07-25 Traitements s'exercant contre le virus de l'immunodeficience chez l'homme

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GB (1) GB9315341D0 (fr)
WO (1) WO1995003047A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0717622A1 (fr) * 1993-07-23 1996-06-26 Smithkline Beecham Corporation Procedes de traitement du vih au moyen d'azaspiranes

Citations (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 (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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0717622A1 (fr) * 1993-07-23 1996-06-26 Smithkline Beecham Corporation Procedes de traitement du vih au moyen d'azaspiranes
EP0717622A4 (fr) * 1993-07-23 1998-09-09 Smithkline Beecham Corp Procedes de traitement du vih au moyen d'azaspiranes

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GB9315341D0 (en) 1993-09-08

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