EP0771199A1 - Methods - Google Patents

Methods

Info

Publication number
EP0771199A1
EP0771199A1 EP95928070A EP95928070A EP0771199A1 EP 0771199 A1 EP0771199 A1 EP 0771199A1 EP 95928070 A EP95928070 A EP 95928070A EP 95928070 A EP95928070 A EP 95928070A EP 0771199 A1 EP0771199 A1 EP 0771199A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
decane
dipropyl
pharmaceutically acceptable
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.)
Withdrawn
Application number
EP95928070A
Other languages
German (de)
French (fr)
Inventor
Alison Mary Badger
Peter John Bugelski
Danuta J. Herzyk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 Corp filed Critical SmithKline Beecham Corp
Publication of EP0771199A1 publication Critical patent/EP0771199A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/439Heterocyclic 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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/4025Heterocyclic 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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41641,3-Diazoles
    • A61K31/41781,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/438The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/468-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders

Definitions

  • This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.
  • Opportunistic infections are an increasing problem in medicine. Opportunistic infections can be caused by a wide variety of bacteria, viruses, fungi and protozoa, as described in Microbiology 16th edition. Appleton Crofts. NY, 1976, p 405. Of particular interest are e.g. Candida sp.. Pseudomonas sp.. Listeria sp.. Pneumocvstis carinii. Pneumococci. Neisseria sp.. Salmonella sp.. Mvcobacteria sp.. Crvptococcus sp.. Aspergillis sp.. Crvptosporidium sp.. Herpes simplex.
  • Herpes zoster Cytomegalovirus and Toxoplasma sp. These organisms, which are often part of the normal flora, are rarely a cause for concern in normal hosts but, under certain circumstances, can cause serious disease. These circumstances include but are not limited to: prolonged high dose antibiotic therapy, cancer chemotherapy, transplantation and acquired immunodeficiency syndrome (AIDS) .
  • a Biologic Response Modifier i.e., compounds with immunostimulatory activity, e.g. muramylpeptides
  • immunostimulation may be contraindicated.
  • a Biologic Response Modifier would be expected to exacerbate graft rejection of graft versus host disease.
  • simple immunostimulation may accelerate disease progression.
  • Immunomodulatory agents are, in general, not known for their ability to treat opportunistic infections. Further, there is presently no acceptable means for predicting whether a particular class of immunomodulatory agents will have utility in treating opportunistic infections.
  • R ⁇ together form a cyclic alkyl group containing 3-7 carbon atoms;
  • A is absent or present as C1-C7 alkylidene;
  • R*- 5 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.
  • This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of the formula
  • 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 C1-C7 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 1 , 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 R3 as defined in Formula (I).
  • 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 R3 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 (T-HF), a suitable reducing agent, preferably, lithium aluminum hydride.
  • a suitable organic solvent such as tetrahydrofuran (T-HF)
  • T-HF 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 treating opportunistic infections in a mammal, including a human, in need thereof.
  • treating is meant prophylactic or therapeutic therapy.
  • the compounds of Formula I are tested for their in vivo ability to treat opportunistic infections in Experiment 1.
  • a compound of Formula I is dissolved in saline and administered to CBA/J mice, at, for example, 0, 1.5, or 15 mg kg, by daily intraperitoneal injection for 14 days.
  • Control mice receive saline.
  • all mice receive an intravenous injection of about lxl 0 ⁇ Candida Albicans (Strain B311 or another strain). Survival is monitored daily until all mice die or are sacrificed for humane reasons. A positive result is indicated by a significant increase in the mean survival time in the mice that receive a compound of Formula I.
  • the compounds of Formula I are tested in an £)c vivo experiment
  • Experiment 2 for their ability to treat opportunistic infections.
  • Lewis rats receive oral doses of a compound of Formula I dissolved in, for example, 0.5% Tragacanth for a period of several days, preferably about 16 days. Subsequently, the rats were sacrificed and alveolar macrophages are collected by brochoalveolar lavage. The cells are dispensed into well dishes and their ability to kill Candida albicans are evaluated.
  • the compounds of Formula I are tested in an in vitro experiment (Experiment 3) for their ability to treat opportunistic infections.
  • Experiment 3 alveolar macrophges are collected by lavage from untreated rats and were incubated with a compound of Formula I in vitro for several days. The compound is subsequently washed off and the cells ability to kill Candida albicans is evaluated.
  • This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal 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 mammal including a 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 No. 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 a mammal, including a human in an amount sufficient to treat opportunistic infections.
  • 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 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 carriers) 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. 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 treating opportunistic infections in a mammal, including a human comprises administering to a subject in need of such treatment an effective 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 treatment of opportunistic infections in a mammal, including a human.
  • the invention also provides for a pharmaceutical composition for use in the treatment of opportunistic infections in a mammal, including a human.
  • 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 of diluent. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
  • the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to treat opportunistic infections.
  • 3-Amino-l-benzylpiperidine, lithium aluminum hydride and tropinone are commercially available.
  • 3R-Pyrrolidine and 3S-pyrrolidine were purchased from CTC Organics (Atlanta, GA).
  • 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.
  • 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-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
  • 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.

Landscapes

  • 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)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Invented is a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.

Description

METHODS This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.
Background of the Invention
Opportunistic infections are an increasing problem in medicine. Opportunistic infections can be caused by a wide variety of bacteria, viruses, fungi and protozoa, as described in Microbiology 16th edition. Appleton Crofts. NY, 1976, p 405. Of particular interest are e.g. Candida sp.. Pseudomonas sp.. Listeria sp.. Pneumocvstis carinii. Pneumococci. Neisseria sp.. Salmonella sp.. Mvcobacteria sp.. Crvptococcus sp.. Aspergillis sp.. Crvptosporidium sp.. Herpes simplex. Herpes zoster. Cytomegalovirus and Toxoplasma sp. These organisms, which are often part of the normal flora, are rarely a cause for concern in normal hosts but, under certain circumstances, can cause serious disease. These circumstances include but are not limited to: prolonged high dose antibiotic therapy, cancer chemotherapy, transplantation and acquired immunodeficiency syndrome (AIDS) . In the first two examples cited, a Biologic Response Modifier, (i.e., compounds with immunostimulatory activity, e.g. muramylpeptides ) would be the adjunct treatment of choice for an opportunistic infection ( Walsh TH et al. Curr Opin Oncol 4:647- 655, 1992). In the latter two examples, however, immunostimulation may be contraindicated. In the case of transplantation, a Biologic Response Modifier would be expected to exacerbate graft rejection of graft versus host disease. In AIDS, simple immunostimulation may accelerate disease progression.
Immunomodulatory agents are, in general, not known for their ability to treat opportunistic infections. Further, there is presently no acceptable means for predicting whether a particular class of immunomodulatory agents will have utility in treating opportunistic infections.
Badger, et al. International Application No. PCT/US92/04834, International Publication No. WO/92/22294, published December 23, 1992 (Badger I) discloses compounds of formula in which: m is 1 or 2; R* 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 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 C1-C7 alkylidene; and R*-5 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.
Badger (I) does not disclose compounds of Formula (I) as agents for treating opportunistic infections .
Summary of the Invention This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of the formula
in which: 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 C1-C7 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
Cj^alkyl group; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Detailed Description of the Invention
The preparation of the compounds of Formula (I) and pharmaceutically acceptable salts, hydrates and solvates and formulations thereof is disclosed in International Application No. PCT/US92/04834, International Publication Number
WO 92/22294, published December 23, 1992, the disclosure of which is hereby incoporated by reference.
Examples of 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 R1, 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 R3 as defined in Formula (I).
SCHEME I
LiALH4
Scheme I depicts formation of Formula (I) compounds. 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 (T-HF), a suitable reducing agent, preferably, lithium aluminum hydride.
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 treating opportunistic infections in a mammal, including a human, in need thereof. By the term "treating" is meant prophylactic or therapeutic therapy.
The compounds of Formula I are tested for their in vivo ability to treat opportunistic infections in Experiment 1. To perform Experiment 1 a compound of Formula I is dissolved in saline and administered to CBA/J mice, at, for example, 0, 1.5, or 15 mg kg, by daily intraperitoneal injection for 14 days. Control mice receive saline. On or about day 8, all mice receive an intravenous injection of about lxl 0^ Candida Albicans (Strain B311 or another strain). Survival is monitored daily until all mice die or are sacrificed for humane reasons. A positive result is indicated by a significant increase in the mean survival time in the mice that receive a compound of Formula I. The compounds of Formula I are tested in an £)c vivo experiment
(Experiment 2) for their ability to treat opportunistic infections. In Experiment 2 Lewis rats receive oral doses of a compound of Formula I dissolved in, for example, 0.5% Tragacanth for a period of several days, preferably about 16 days. Subsequently, the rats were sacrificed and alveolar macrophages are collected by brochoalveolar lavage. The cells are dispensed into well dishes and their ability to kill Candida albicans are evaluated.
The compounds of Formula I are tested in an in vitro experiment (Experiment 3) for their ability to treat opportunistic infections. In Experiment 3 alveolar macrophges are collected by lavage from untreated rats and were incubated with a compound of Formula I in vitro for several days. The compound is subsequently washed off and the cells ability to kill Candida albicans is evaluated. This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal 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 mammal including a 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 No. WO 92/22294, published December 23, 1992.
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 a mammal, including a human in an amount sufficient to treat opportunistic infections. The route of administration of the Formula (I) ("active ingredient") 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 carriers) 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. 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.
The method of this invention of treating opportunistic infections in a mammal, including a human, comprises administering to a subject in need of such treatment an effective 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 treatment of opportunistic infections in a mammal, including a human.
The invention also provides for a pharmaceutical composition for use in the treatment of opportunistic infections in a mammal, including a human.
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 of diluent. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to treat opportunistic infections. 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.
I. SYNTHETIC EXAMPLES
In the following Examples, temperature is in degrees Centigrade (°C). 4,4-Dipropylcyclohexane-l-carboxy-l -acetic acid anhydride, 4,4- diethylcyclohexane- 1-carboxy-l -acetic acid anhydride, 4,4-dipropylcyclohexane- 1,1 -diacetic acid anhydride, and 4,4-diethylcyclohexane- 1 , 1 -diacetic acid anhydride were synthesized as described in U.S. Patent 4,963,557.
4-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 2-14-Piperidinyπ-8.8-dipropyl-2-azaspiro-"4.51-decane dihydrochloride
(i) 2-r4-(N-Benzyl)piperidinyll-8.8-dipropyl-2-azaspiror4.51-decane-1.3- decane To a solution of 4,4-dipropylcyclohexane-l-carboxy-l -acetic acid anhydride (1 molar equivalent) in xylene was added 4-amino-l-benzylpiperidine (1 molar equivalent). 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.
(ii) 2-r4-(N-BenzyDpiperidinyll-8.8-dipropyl-2-azaspiror4.51-decane To a mixture of lithium aluminum hydride (3.2 molar equivalents) in tetrahydrofuran was added dropwise a solution of 2-[4-(N-benzyl)piperidinyl]-8,8- dipropyl-2-azaspiro[4.5]-decane -1,3-dione (1 molar equivalent) in tetrahydrofuran. The reaction mixture was stirred for 2-6 h following completion of addition. The excess hydride was quenched with sodium sulfate-decahydrate and the resulting mixture was filtered and the filtrate was concentrated to give the desired diamine as a viscous, colorless oil. The oil was used directly without further purification; yield 90-95%.
(iii) 2-(4-Piperidinvn-8.8-dipropvl-2-azaspiror4.51-decane To a suspension of 10% palladium-on-carbon (0.1 molar equivalents) in a 7.5% formic acid in methanol solution was added 2-[4-(N-benzyl)piperidinyl]-8,8- dipropyl-2-azaspiro[4.5]-decane (1 molar equivalent). The reaction mixture was hydrogenated at 60 psi hydrogen pressure in a Parr hydrogenation apparatus at room temperature until hydrogen uptake had ceased (48-96h). The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure. The residue was dissolved in water and then basified with 10% NaOH. The resulting aqueous emulsion was extracted with ethyl ether. The organic phase was dried over sodium sulfate, filtered and concentrated to give the debenzylated diamine product as a colorless oil; 90-95% yield. (iv) 2-( -Piperidinyπ-8.8-dipropyl-2-azaspirof4.51-decane dihydrochloride 2-(4-Piperidinyl)-8,8-dipropyl-2-azaspiro[4.5]-decane was dissolved in a minimum of anhydrous ethanol and added to a cooled solution of hydrogen chloride in ethanol. On addition of a large volume of ether, a white precipitate formed which was isolated by Alteration. The white solid was recrystallized from ethanol or methanol; mp 298-300°C; yield 85-90%.
EXAMPLE ? 2-f4-(N-MethyDpiperidinylV8.8-dipropyl-2-azaspiro-r4.51-decane dihydrochloride
(i) 2-f4-fN-Methvnpiperidinvl-8.8-dipropyl-2-azaspiror4.51-decane To a solution of 2-(4-piperidinyl)-8,8-dipropyl-2- azaspiro[4.5]-decane (1 molar equivalent prepared according to Example 1 (iii)) in acetonitrile was added 37% aqueous formaldehyde (5 molar equivalents) and sodium cyanoborohydride (1.6 molar equivalents). The reaction mixture was stirred overnight at room temperature. Added 2 N KOH and extracted the reaction mixture twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellow viscous oil. The residue was purified by chromatography on silica gel using MeOH/ethyl acetate/cone, ammonium hydroxide (74/24/1.5) as eluant. The product was isolated as a colorless oil; yield 60%.
(ii) 2-f4-N-Methvnpiperidinvl-8.8-dipropyl-2-azaspirof4.51-decane dihydrochloride 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 3 2-f4-Piperidinvn-8.8-diethvl-2-azaspiror4.51-decane dihydrochloride
The title compound is prepared according to Example 1 (i-iv) by substituting 4,4-diethylcyclohexane- 1-carboxy-l -acetic acid anhydride for 4,4-dipropylcyclo- hexane-l-carboxy-1 -acetic acid anhydride; mp 331-332°C. EXAMPLE 4 2-f2-(4-ImidazolyDethyiy8.8-dipropyl-2-azaspiror4.51decane dihydrochloride
(i) 2-(2-r4-ImidazolyDethylV8.8-dipropyl-2-azaspiror4.51decane The title compound is prepared according to Example 1 (i-iii) by substituting histamine for 4-amino-l-benzylpiperidine.
(ii) 2-(2-(4-Imidazolyl)ethylV8.8-dipropyl-2-azaspiror4.51decane dihydrochloride 2-(2-(4-ImidazolyI)ethyl)-8,8-dipropyl-2-azaspiro-[4.5]decane was dissolved in a minimum amount of ethanol and a solution of HCl(g)/EtOH was added. The dihydrochloride did not precipitate. The solution was concentrated to dryness and placed in a vacuum oven overnight at 60 / 5 mm to give the desired dihydrochloride salt as a white solid: yield 72%; m.p. 258-262°C.
EXAMPLE 5 2-(3R-pvrrolidinvlV8.8-dipropvl-2-azaspiror4.51-decane dimaleate
(i) 2-f3R-pyrrolidinyl)-8.8-dipropyl-2-azaspiro[4.51-decane-1.3-dione To a solution of 4,4-dipropylcyclohexane- 1 -carboxy- 1 -acetic acid anhydride
(1 molar equivalent) in xylene was added 3R-aminopyrrolidine (1 molar equivalent). 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 viscous, dark brown oil. The crude product was dissolved in methanol and a methanol solution containing maleic acid (1 molar equivalent) was added. 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. (ii) 2-(3R-pyrrolidinyl -8.8-dipropyl-2-azaspiror4.51-decane
To a mixture of lithium aluminum hydride (3.2 molar equivalents) in ethyl ether was added dropwise a solution of 2-(3R-pyrrolidinyl)-8,8-dipropyl-2- azaspiro[4.5]-decane- 1,3-dione (1 molar equivalent) in ethyl ether. The reaction mixture was stirred for 2-6 h after addition was completed. The excess hydride was quenched with sodium sulfate-decahydrate and the resulting mixture was filtered.
The filtrate was concentrated under reduced pressure to give the diamine as a viscous, colorless oil; 80-85% yield.
(iii) 2-r3R-pvrrolidinvn-8.8-dipropvl-2-azaspiror4.51-decane dimaleate
2-(3R-pyrrolidinyl)-8,8-dipropyl-2-azaspiro[4.5]-decane was dissolved in methanol and a methanol solution containing maleic acid (2 molar equivalents) was added. The solvent volume was reduced under vacuum. A 10% hexane in ethyl acetate solution was carefully added to the product-methanol solution to form a white precipitate which was isolated by filtration. The white solid product required no further purification; mp 168.5-170°C; 70-80% yield.
EXAMPLE S 2-(3S-pvrrolidinvlV8.8-dipropvl-2-azasρiror4.51-decane dimaleate
The title compound is prepared according to Example 5 (i-iii) by substituting 3S-aminopyrrolidine for 3R-aminopyrroldine; mp 169.5-170.5°C.
EXAMPLE 7 2-f3'-Ouinuclidinvn-8.8-dipropvl-2-azaspirof4.51-decanedihvdrochloride
(i) 2-(3'-Ouinuclidinvn-8.8-dipropvl-2-azaspiror4.51decane-l-3-dione To a solution of 4,4-dipropylcyclohexane-l-carboxy-l -acetic acid anhydride (1 molar equivalent) in toluene was added 3-aminoquinuclidine (1 molar equivalent). The reaction mixture was heated to reflux with stirring using a Dean- Stark trap until the volume of water collected was unchanged (approximately five hours), and then allowed to cool. The toluene was evaporated under reduced pressure and the residue partitioned between ethyl acetate and IN sodium hydroxide solution. The organic phase was separated, washed with water, dried (MgSO4) and evaporated to give 2-(3-quinuclidinyl)-8,8-dipropyl-2-azaspiro[4.5]decane- 1,3-dione ( 94%) as a yellow oil which solidified on standing. This was used without further purification.
(ii) 2-f3'-Ouinuclidinyl -8.8-dipropyl-2-azaspiror4.51decane To a stirred suspension of lithium aluminum hydride (3.5 molar equivalents) in the THF (80 ml) at 0°C under argon was added a solution of 2-(3'-quinuclidinyl)- 8,8-dipropyl-2-azaspiro [4.5]decane- 1,3-dione (1 molar equivalent) in THF dropwise over 45 minutes. The reaction mixture was allowed to warm to room temperature then stirred overnight. Sodium sulfate decahydrate was added slowly in portions to quench the unreacted LAH and the resulting suspension of solids was filtered and the filtrate evaporated under reduced pressure to yield a residual colorless oil.
(iii) 2-f3'-OuinuclidinylV8.8-dipropyl-2-azaspiror4.51decane dihydrochloride
2-(3'-Quinuclidinyl)-8,8-dipropyl-2-azaspiro[4.5]decane was dissolved in a small volume of ethanol and a solution of saturated hydrogen chloride in ethanol was added. Upon addition of a large volume of ether a white precipitate formed which was filtered and dried giving the title compound (yield 70%) as a white amorphous solid; mp 277-278°C. Elemental analysis suggest that the title compound was isolated as the monohydrate.
EXAMPLE S 2-r3'-α-f8,-Methyl-8-azabicvclof3.2.n-8.8-dipropyl-2-azaspiror4.51decane dihydrochloride
(i) 3-«-Amino-8-methvl-8-azabicvclof3.2.1 toctane ( 3-a-aminotropane) A solution of tropinone (5.0 g) in ethanol containing palladium on activated carbon (10%, 2.0 g) was saturated with ammonia at 0° C then hydrogenated on a Parr apparatus at 50 psi for 24 hours. The mixture was filtered through celite and evaporated under reduced pressure. The colorless residual oil was used without further purification.
The above amine (0.5 g) in methanol (5 ml) was treated with 1 ml of phenyl isothiocyanate. After stirring for 30 minutes and triturating with ether, a crystalline solid precipitated which was filtered off and recrystallized from ethyl acetate. The thioureide melted at 156-157°C (A. Stoll, E. Tucker and A. Ebnother, Helv. Chim. Acta 38, 559 (1955) and S. Archer, T.R. Lewis and M.J. Unser, J. Am. Chem. Soc. 79, 4194 (1957) report melting points of the endo thioureide as 153-154°C and 160- 161°C, respectively.)
(ii) 3-β-Amino-8-methvl-8-azahicvclof 3.2.1 ^octane (3β-aminotropane^
Prepared by sodium/amyl alcohol reduction of tropinone oxime (M.S. Hadley and F.D. King U.S. 4, 273, 778 for exact procedures).
The corresponding β-aminotropane thioureide melted at 178-179°C (R. Willstatler and W. Moller Ber., 31, 1202 (1898) and S. Arther, T.R. Lewis and M.J. Unser, J. Am. Chem. Soc. 79, 4194 (1957) report melting points of 171-172°C and 173- 175°C, respectively)
(iii) 2-f3'-α-(8'-Methyl-8'-azabicvclof3.2.1VoctaneV8.8-dipropyl-2- azaspirof4.5] decane dihydro-chloride The title compound is prepared according to Example 7 (i-iii) by substituting
3-β-Amino-8-methyl-8-azabicyclo(3.2.1)octane (3β-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 die monohydrate.
EXAMPLE 9 2-(3'β-8'-Methvl-8'-azabicvclo(3.2.noctaneV8.8-dipropvl-2-azaspiror4.51 decane-dihvdrochloride
The title compound is prepared according to Example 1 (i-iv) by substituting 3-β-aminotropane for 3-α-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 10 2-(4-PiperidinyO-9.9-dipropyl-3-azaspiror4.51-decane dihydrochloride
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-1 -acetic acid anhydride. II. Composition Examples
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
8,8-dipropyl-2-azaspiro[4,5]decane -2-(4-piperidine) 25 mg dihydrochloride
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
EXAMPLE 2 - INJECTABLE PARENTERAL COMPOSITION
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.
Table II
Ingredients Amounts
8,8-dipropyl-2-azaspiro[4,5]decane-2-(4-piperidine) 20 mg dihydrochloride calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg
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

What is claimed is:
1. A method for treating opportunistic infections in a mammal, including a human, in need thereof, which comprises administering to such mammal an effective amount of a compound of the formula
in which: m is l 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 Rl and R? together form a cyclic alkyl group containing 3-7 carbon atoms; A is a bond or a C \ -Cη 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 Cj.
3alkyl group; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
2. The method of claim 1 wherein the compound is 8,8-dipropyl-2- azaspiro[4.5]decane-2-(4-piperidine); 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.
EP95928070A 1994-07-23 1995-07-14 Methods Withdrawn EP0771199A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9414901A GB9414901D0 (en) 1994-07-23 1994-07-23 Methods
GB9414901 1994-07-23
PCT/US1995/008866 WO1996003123A1 (en) 1994-07-23 1995-07-14 Methods

Publications (1)

Publication Number Publication Date
EP0771199A1 true EP0771199A1 (en) 1997-05-07

Family

ID=10758801

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95928070A Withdrawn EP0771199A1 (en) 1994-07-23 1995-07-14 Methods

Country Status (4)

Country Link
EP (1) EP0771199A1 (en)
JP (1) JPH10503492A (en)
GB (1) GB9414901D0 (en)
WO (1) WO1996003123A1 (en)

Family Cites Families (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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9603123A1 *

Also Published As

Publication number Publication date
JPH10503492A (en) 1998-03-31
GB9414901D0 (en) 1994-09-14
WO1996003123A1 (en) 1996-02-08

Similar Documents

Publication Publication Date Title
KR100545435B1 (en) Indoline derivatives and their use as 5-ht2 receptor ligands
US4219550A (en) Cis- and trans- octahydropyridopyrrolobenzheterocycles
KR20150004441A (en) Bicyclic heteroaryl inhibitors of pde4
EP0859610A1 (en) Ibogamine congeners
DE3640641A1 (en) NEW HETEROAROMATIC AMINE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
JPH0267282A (en) Tetracyclic ketaone
RU2132683C1 (en) Use of indole derivatives as 5-hti-agonists
EP0213499A2 (en) Amino acid derivatives, process for their preparation and use
US5834478A (en) Morphinan hydroxamic acid compounds
JPH10502657A (en) Heterocyclic fused morphinoid derivatives
JPH02167280A (en) Lactam derivative
JPH05132430A (en) Use of glycine/nmda receptor ligand relating to therapy of drug dependence and withdrawal symptoms
WO1993015735A1 (en) (non descriptive)-a method for delaying hiv individual aids by administration of substituted azaspirane compounds
NZ234726A (en) 2,3-dihydro-1-(pyridinylamino)-indoles and pharmaceutical compositions
WO1996003123A1 (en) Methods
WO1993007871A1 (en) Methods for the treatment of hyperlipidemia using azaspiranes
AU2003281042A1 (en) Therapeutic or preventive agent for nausea/vomiting
EP0587800B1 (en) Immunomodulatory azaspiranes
WO1995003048A1 (en) Anti-hiv azaspiranes
WO1995003047A1 (en) Human immunodeficiency virus treatments
WO1995003046A1 (en) A method of inhibiting the production of hiv
US5455247A (en) Methods for the treatment of hyperlipidemia using azaspiranes
EP0523013B1 (en) Use of benzimidazoline-2-oxo-1-carboxylic acid derivatives in the treatment of organic mental diseases
WO1994004151A1 (en) Compositions of substituted azaspiranes and methods of treating psoriasis therewith
CA2213241C (en) Indole derivative for the treatment of migraine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970217

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB IT LI NL

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19970731