EP0771199A1 - Procedes - Google Patents

Procedes

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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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non 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
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs 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)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un procédé permet de traiter des infections opportunistes chez un mammifère, y compris chez l'être humain, par l'administration d'une quantité efficace d'une azaspirane substituée.
EP95928070A 1994-07-23 1995-07-14 Procedes Withdrawn EP0771199A1 (fr)

Applications Claiming Priority (3)

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

Publications (1)

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

Family

ID=10758801

Family Applications (1)

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

Country Status (4)

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

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
WO1996003123A1 (fr) 1996-02-08
JPH10503492A (ja) 1998-03-31
GB9414901D0 (en) 1994-09-14

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