WO1996003126A1 - Method of treating opportunistic infections with azaspiranes - Google Patents
Method of treating opportunistic infections with azaspiranes Download PDFInfo
- Publication number
- WO1996003126A1 WO1996003126A1 PCT/US1995/008915 US9508915W WO9603126A1 WO 1996003126 A1 WO1996003126 A1 WO 1996003126A1 US 9508915 W US9508915 W US 9508915W WO 9603126 A1 WO9603126 A1 WO 9603126A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- opportunistic infections
- formula
- pharmaceutically acceptable
- carbon atoms
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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 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.
- Candida sp. Pseudomonas sp., Listeria sp., Pneumocvstis carinii, Pneumococci, Neisseria sp., Salmonella sp., Mycobacteria sp., Cryptococcus sp., Aspergillis sp., Cryptosporidium 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,
- a Biologic Response Modifier i.e., compounds with
- immunostimulatory activity e.g. muramylpeptides
- 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.
- 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
- n 3-7;
- n 1 or 2;
- R 1 and R 2 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 1 and R 2 when taken together is 5-10; or R 1 and R 2 together form a cyclic alkyl group having 3-7 carbon atoms;
- R 3 and R 4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R 3 and R 4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms;
- a preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R 2 are propyl, R 3 and R 4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride.
- a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R 2 are propyl, R 3 and R 4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2- azaspiro[4.5]decane-2-propanamine dihydrochloride.
- a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R 2 are propyl, R 3 and R 4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl dihydrochloride.
- compound A refers to the dihydrochloride salt of a compound of Formula (I) where R 1 and R 2 are propyl, R 3 and R 4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride.
- pharmaceutically acceptable salts or hydrates or solvates thereof are useful for treating opportunistic infections in a mammal, including a human, in need thereof.
- treating is meant prophylactic or therapeutic therapy.
- Compound A was tested for its in vivo ability to treat opportunistic infections in Experiment 1.
- Compound A was dissolved in saline and administered to CBA/J mice, at 0, 1.5, or 15 mg/kg, by daily intraperitoneal injection for 14 days.
- Control mice received saline.
- all mice received an intravenous injection of 1x10 6 Candida Albicans (Strain B311). Survival was monitored daily until all mice died or were sacrificed for humane reasons. There was a significant increase in the mean survival time in the mice that received 15 mg/kg.
- mice that received intraperitoneal 5 doses of dexamethasone (an immunosuppressive steriod) at 50 mg/kg showed a significant decrease in mean survival time.
- Compound A was tested in an ex vivo experiment (Experiment 2) for its ability to treat opportunistic infections.
- Experiment 2 Lewis rats received oral doses of 20 mg/kg of Compound A dissolved in 0.5% Tragacanth (5 doses/wk) for 16 days. On day 23 the rats were sacrificed and alveolar macrophages were collected by brochoalveolar lavage. The cells were dispensed into 24 well dishes and their ability to kill Candida albicans evaluated. There was a significant increase in the ability of cells from rats treated with Compound A to kill two strains (B311 and B792) of Candida.
- Compound A was tested in an in vitro experiment (Experiment 3) for its ability to treat opportunistic infections.
- Experiment 3 alveolar macrophges were collected by lavage from untreated rats and were incubated with Compound A in vitro for 3 days. At that time, the compound was washed off and the cells ability to kill Candida albicans (Strain B792) was evaluated. There was a statistically significant concentration dependent increase in kill percentage at ⁇ 2 uM Compound A. This effect is not due to a direct effect of Compound A on the growth of Candida albicans as concentrations up to 12 uM had no effect on the yeast.
- 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
- 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
- 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 carriers) 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 carriers 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.
- suitable pharmaceutical carrier(s) 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;
- a dispersion or suspension can be prepared using any suitable pharmaceutical carriers), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- suitable pharmaceutical carriers 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.
- 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.
- 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.
- the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to treat opportunistic infections
- 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 II, below.
- An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride in 10% by volume propylene glycol in water.
- Example 3 Tablet Composition
- sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table III below are mixed and granulated in the proportions shown with a 10% gelatin solution.
- the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX9700626A MX9700626A (en) | 1994-07-23 | 1995-07-14 | Method of treating opportunistic infections with azaspiranes. |
AU31909/95A AU684384B2 (en) | 1994-07-23 | 1995-07-14 | Method of treating opportunistic infections with azaspiranes |
US08/507,487 US5786376A (en) | 1994-07-23 | 1995-07-14 | Methods of treating opportunistic infections with azaspiranes |
KR1019970700433A KR970704446A (en) | 1994-07-23 | 1995-07-14 | Treatment of opportunistic infections with azaspirane (Treatment of opportunistic infections with azaspiranes) |
JP8505798A JPH10503202A (en) | 1994-07-23 | 1995-07-14 | Treatment of opportunistic infections with azaspirans |
CZ1997209A CZ286482B6 (en) | 1994-07-23 | 1995-07-14 | Medicament for treating casual infections in mammals including human beings |
NZ290974A NZ290974A (en) | 1994-07-23 | 1995-07-14 | Treatment of opportunistic infections with axaspirane compounds |
EP95928072A EP0804201A4 (en) | 1994-07-23 | 1995-07-14 | Method of treating opportunistic infections with azaspiranes |
BR9508332A BR9508332A (en) | 1994-07-23 | 1995-07-14 | Method of treating opportunistic infections with azaspirans |
NO19970284A NO310096B1 (en) | 1994-07-23 | 1997-01-22 | Use of azaspirans |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9414902.8 | 1994-07-23 | ||
GB9414902A GB9414902D0 (en) | 1994-07-23 | 1994-07-23 | Methods |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996003126A1 true WO1996003126A1 (en) | 1996-02-08 |
Family
ID=10758802
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/008915 WO1996003126A1 (en) | 1994-07-23 | 1995-07-14 | Method of treating opportunistic infections with azaspiranes |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0804201A4 (en) |
JP (1) | JPH10503202A (en) |
KR (1) | KR970704446A (en) |
CN (1) | CN1157564A (en) |
AU (1) | AU684384B2 (en) |
BR (1) | BR9508332A (en) |
CA (1) | CA2195778A1 (en) |
CZ (1) | CZ286482B6 (en) |
GB (1) | GB9414902D0 (en) |
HU (1) | HUT77379A (en) |
MX (1) | MX9700626A (en) |
NO (1) | NO310096B1 (en) |
NZ (1) | NZ290974A (en) |
WO (1) | WO1996003126A1 (en) |
ZA (1) | ZA956098B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5744495A (en) * | 1995-07-13 | 1998-04-28 | Smithkline Beecham Corporation | N, N-diethyl-8, 8-dipropyl-2-azaspiro 4.5! decane-2-propanamine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
PT100566B (en) * | 1991-06-07 | 1999-06-30 | Smithkline Beecham Corp | IMMUNOMODULATOR AZASPIRANES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, PREPARATION AND USE |
-
1994
- 1994-07-23 GB GB9414902A patent/GB9414902D0/en active Pending
-
1995
- 1995-07-14 CA CA002195778A patent/CA2195778A1/en not_active Abandoned
- 1995-07-14 NZ NZ290974A patent/NZ290974A/en unknown
- 1995-07-14 WO PCT/US1995/008915 patent/WO1996003126A1/en not_active Application Discontinuation
- 1995-07-14 HU HU9700201A patent/HUT77379A/en unknown
- 1995-07-14 KR KR1019970700433A patent/KR970704446A/en not_active Application Discontinuation
- 1995-07-14 BR BR9508332A patent/BR9508332A/en not_active Application Discontinuation
- 1995-07-14 EP EP95928072A patent/EP0804201A4/en not_active Withdrawn
- 1995-07-14 CN CN95195052A patent/CN1157564A/en active Pending
- 1995-07-14 CZ CZ1997209A patent/CZ286482B6/en not_active IP Right Cessation
- 1995-07-14 JP JP8505798A patent/JPH10503202A/en active Pending
- 1995-07-14 MX MX9700626A patent/MX9700626A/en not_active IP Right Cessation
- 1995-07-14 AU AU31909/95A patent/AU684384B2/en not_active Ceased
- 1995-07-21 ZA ZA956098A patent/ZA956098B/en unknown
-
1997
- 1997-01-22 NO NO19970284A patent/NO310096B1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5744495A (en) * | 1995-07-13 | 1998-04-28 | Smithkline Beecham Corporation | N, N-diethyl-8, 8-dipropyl-2-azaspiro 4.5! decane-2-propanamine |
Also Published As
Publication number | Publication date |
---|---|
ZA956098B (en) | 1996-05-23 |
AU684384B2 (en) | 1997-12-11 |
GB9414902D0 (en) | 1994-09-14 |
JPH10503202A (en) | 1998-03-24 |
NO970284D0 (en) | 1997-01-22 |
EP0804201A4 (en) | 2000-04-26 |
HUT77379A (en) | 1998-04-28 |
KR970704446A (en) | 1997-09-06 |
EP0804201A1 (en) | 1997-11-05 |
MX9700626A (en) | 1997-05-31 |
CN1157564A (en) | 1997-08-20 |
NO310096B1 (en) | 2001-05-21 |
AU3190995A (en) | 1996-02-22 |
CZ286482B6 (en) | 2000-04-12 |
CA2195778A1 (en) | 1996-02-08 |
CZ20997A3 (en) | 1997-10-15 |
NZ290974A (en) | 1999-08-30 |
BR9508332A (en) | 1997-11-04 |
NO970284L (en) | 1997-03-19 |
HU9700201D0 (en) | 1997-04-28 |
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