WO1995003048A1 - Azaspiranes anti-hiv - Google Patents

Azaspiranes anti-hiv Download PDF

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Publication number
WO1995003048A1
WO1995003048A1 PCT/US1994/008254 US9408254W WO9503048A1 WO 1995003048 A1 WO1995003048 A1 WO 1995003048A1 US 9408254 W US9408254 W US 9408254W WO 9503048 A1 WO9503048 A1 WO 9503048A1
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WO
WIPO (PCT)
Prior art keywords
compound
decane
dipropyl
formula
use according
Prior art date
Application number
PCT/US1994/008254
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 WO1995003048A1 publication Critical patent/WO1995003048A1/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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine

Definitions

  • This invention relates to a method of inhibiting the replication of human immunodeficiency viruses (HIV) in HTV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.
  • HAV human immunodeficiency viruses
  • CD8+ T cells have been shown to inhibit the replication of HIV in cultures of CD4+ cells from asymptomatic HTV 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
  • 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 absent or present as Cj-C 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 4 , 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 1 and R-- together form a cyclic alkyl group containing 3-7 carbon atoms;
  • A is bond or a Cj-C alkylidene group; and 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 C ⁇ _3alkyl group; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • 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*, R , 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
  • 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 and their preparation are well known to those of skill in the art.
  • 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 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. No 1, 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) International Publication Number WO 92/22294, published December 23, 1992.
  • 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 HIV replication.
  • 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 ca ⁇ ier(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 ca ⁇ ier(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 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.
  • 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 the inhibition of of HIV replication in HIV seropositive humans.
  • the invention also provides for a pharmaceutical composition for use in 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 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.
  • 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 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.
  • Example 2 The title compound is prepared according to Example 1 (i-iv) by substituting 4,4-dipropylcyclohexane- 1 , 1 -diacetic acid anhydride for 4,4-dipropylcyclohexane- 1-carboxy-l -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.
  • 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.
  • 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)
  • Emergency Medicine (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 réplication des virus d'immunodéficience chez l'homme (VIH) chez des individus séropositifs consistant en l'adminsitration auxdits individus d'une quantité efficace d'azaspirane substitué.
PCT/US1994/008254 1993-07-23 1994-07-25 Azaspiranes anti-hiv WO1995003048A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9315298.1 1993-07-23
GB939315298A GB9315298D0 (en) 1993-07-23 1993-07-23 Methods

Publications (1)

Publication Number Publication Date
WO1995003048A1 true WO1995003048A1 (fr) 1995-02-02

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GB (1) GB9315298D0 (fr)
WO (1) WO1995003048A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0711160A1 (fr) * 1993-07-23 1996-05-15 Smithkline Beecham Corporation Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues
US6107307A (en) * 1998-06-19 2000-08-22 Eli Lilly And Company Inhibition of serotonin reuptake

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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0711160A1 (fr) * 1993-07-23 1996-05-15 Smithkline Beecham Corporation Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues
EP0711160A4 (fr) * 1993-07-23 1998-09-09 Smithkline Beecham Corp Procede d'inhibition de la replication des virus de l'immunodeficience humaine a l'aide d'azaspirannes substitues
US6107307A (en) * 1998-06-19 2000-08-22 Eli Lilly And Company Inhibition of serotonin reuptake

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Publication number Publication date
GB9315298D0 (en) 1993-09-08

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