HK1001855A - Method of treating opportunistic infections with azaspiranes - Google Patents

Description

Method of treating opportunistic infections with azaspiranes

The present invention relates to a method of treating opportunistic infections in a mammal, including a human, which comprises administering to said mammal in need of such treatment an effective amount of a substituted azaspirane.

Background

Opportunistic infections are an increasingly noteworthy problem in medicine. A large number of various bacteria, viruses, fungi and protozoa can cause opportunistic infections as described in Microbiology 16 edition Appleton Croft.NY.1976. p405. Of particular interest are, for example, Candida species, Pseudomonas species, Listeria species, Pneumocystis carinii, pneumococcus, Neisseria species, Serratia species, Mycobacterium species, Cryptococcus species, Aspergillus species, Cryptosporidium species, herpes simplex, herpes zoster, cytomegalovirus and Toxoplasma species. These organisms (usually part of the common flora) are almost unrelated to the common host, but in some cases they can cause serious diseases. These include, but are not limited to: long term high potency antibiotic therapy, cancer chemotherapy, transplantation and Acquired Immune Deficiency Syndrome (AIDS). In the first two cited examples, biological response modifiers (i.e., compounds with immunostimulatory activity, such as muramyl peptides) are adjunctive therapeutic options for opportunistic infections (Walsh TH et al, Curr Opin Oncol 4: 647-. However, in the latter two cases, immunostimulation is contraindicated. At the time of transplantation, it is expected that the biological response modifier will exacerbate graft rejection against host disease. In AIDS, simple immune stimulation can accelerate disease progression.

Generally, it is not known that immunomodulators have the ability to treat opportunistic infections. Moreover, there is currently no acceptable method for predicting whether some particular class of immunomodulators has utility in treating opportunistic infections.

U.S.4,963,557(Badger I) to Badger, et al discloses compounds of general formula I:

wherein: n is 3 to 7; m is 1 or 2; r¹And R²Identical or different and selected from hydrogen or linear or branched alkyl, provided that R¹And R²The total number of carbon atoms contained is 5 to 10; orR¹And R²Together form a cycloalkyl group having 3 to 7 carbon atoms; r³、R⁴Identical or different and selected from hydrogen or linear alkyl groups having 1 to 3 carbon atoms; or R³And R⁴Combined with the nitrogen atom to form a heterocyclic group having 5 to 8 carbon atoms; or a pharmaceutically acceptable salt or hydrate or solvate of a compound of formula (I).

Badger I discloses a class of novel compounds of general formula I which induce an immunomodulatory effect characterized by stimulation of suppressor cell activity.

Badger does not disclose compounds of formula I as therapeutic opportunistic infectives.

Summary of The Invention

The present invention relates to a method of treating opportunistic infections in a mammal (including a human being) which comprises administering to such mammal in need of such treatment an effective amount of a compound of the formula:

wherein:

n is 3 to 7;

m is 1 or 2;

R¹and R²Identical or different and selected from hydrogen or linear or branched alkyl, with the proviso that R¹And R²The total number of carbon atoms contained is 5 to 10; or R¹And R²Together form a cycloalkyl group having 3 to 7 carbon atoms;

R³and R⁴Identical or different and selected from hydrogen or linear alkyl groups having 1 to 3 carbon atoms; or R³And R4⁴Combined with the nitrogen atom to form a heterocyclic group having 5 to 8 atoms;

or a pharmaceutically acceptable salt or hydrate or solvate of a compound of formula (I).

Detailed Description

The preparation of all compounds of formula (I) and pharmaceutically acceptable salts, hydrates and solvates and formulations thereof is disclosed in U.S.4,963,557, the entire contents of which are incorporated herein by reference.

Preferred compounds for use in the novel process are the dihydrochloride salts of compounds of the general formula (I) wherein R is¹And R²Is propyl, R³And R⁴Is methyl, m is 1 and N is 3, which is N, N-dimethyl-8, 8-dipropyl-2-azaspiro [4, 5]]Decane-2-propylamine dihydrochloride.

Particularly preferred compounds for use in the novel process are the dihydrochloride of a compound of the formula (I) wherein R is¹And R²Is propyl, R³And R⁴Is ethyl, m is 1 and N is 3, which is N, N-diethyl-8, 8-dipropyl-2-azaspiro [4, 5]]Decane-2-propylamine dihydrochloride.

Particularly preferred compounds for use in the novel process are the dihydrochloride of compounds of the general formula (I) in which R is¹And R²Is propyl, R³And R⁴Combined with 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.

The term "compound A" as used herein refers to the dihydrochloride of a compound of the following general formula (I), wherein R is¹And R²Is propyl, R³And R⁴Is methyl, m is 1 and N is 3, which is N, N-dimethyl-8, 8-dipropyl-2-azaspiro [4, 5]]Decane-2-propylamine dihydrochloride.

It has now been found that the compounds of formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof, are useful in the treatment of opportunistic infections in mammals including humans when they are in need thereof. The term "treatment" means prophylaxis or therapy.

Compound a was tested for its ability to treat opportunistic infections in vivo in experiment 1. For experiment 1, compound a was dissolved in saline and CBA/J mice were administered in amounts of 0, 1.5 or 15mg/kg, i.p. daily for 14 days. Saline was used for control mice. On day 8, all mice were injected intravenously with 1X 10⁶Candida albicans (strain B311). Survival was monitored daily until all mice died or they were sacrificed for humane reasons. In mice dosed at 15mg/kg, the mean survival time was significantly increased. In contrast, mice dosed intraperitoneally with 5-fold doses of dexamethasone, an immunosuppressive steroid, at 50mg/kg, showed a significant decrease in mean survival time.

The ability of compound a to treat opportunistic infections was tested in an in vitro experiment (experiment 2). In experiment 2, an oral dose of 20mg/kg of Compound A (5-fold dose/wk) dissolved in 0.5% tragacanth was applied to Lowis mice for 16 days. On day 23, mice were sacrificed and alveolar macrophages were collected by bronchoalveolar lavage. These cells were dispersed in 24-well dishes and evaluated for their ability to kill Candida albicans. The ability of cells taken from mice treated with compound a to kill two candida strains (B311 and B792) was significantly increased.

The ability of compound a to treat opportunistic infections was tested in an in vitro experiment (experiment 3). In experiment 3, alveolar macrophages were collected by washout from untreated mice and incubated in vitro with compound a for 3 days. At this time, the compounds were removed and the cells were evaluated for their ability to kill Candida albicans (strain B792). Statistically, the percent kill related to concentration increased significantly at compound a72 μm. This effect was not due to the direct effect of compound a on candida albicans growth as concentrations up to 12 μm did not work for yeast.

The present invention relates to a method of treating opportunistic infections in mammals, including humans, which comprises administering to such mammals an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof, when such treatment is desired. Conventional dosage forms are prepared by combining a compound of formula (I), or a pharmaceutically acceptable salt or hydrate or solvate thereof, with conventional pharmaceutically acceptable carriers or diluents according to well-known techniques, as described in U.S.4,963,557 to badger (I). The compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to mammals, including humans, in such conventional dosage forms.

The form and nature of the pharmaceutically acceptable carrier or diluent will be determined by the amount of active ingredient combined, the route of administration and other well known parameters, as will occur to those skilled in the art. 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 compound of the general formula (I) ("active ingredient") is not limited, but is generally oral administration or parenteral administration, preferably oral administration.

The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. The dosage range for parenteral administration is preferably from about 0.01mg/kg to about 10mg/kg body weight, most preferably from about 0.1mg/kg to about 1mg/kg per day. Preferably, each parenterally administered dosage unit contains an amount of the active ingredient from about 0.1mg to about 100 mg.

In the case of oral administration, the active compounds of formula (I) can be formulated as liquids (e.g., syrups, suspensions or emulsions), tablets, capsules and lozenges.

Liquid formulations generally consist of suspensions or solutions of the compounds or pharmaceutically acceptable salts in suitable liquid carriers such as: such as ethanol, glycerol, anhydrous solvents (e.g., polyethylene glycol, oils), or water with suspending agents, preservatives, flavoring agents, or coloring agents.

The tablet compositions can be prepared using any suitable pharmaceutical carrier commonly used to prepare solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

The composition can be prepared in the form of a capsule using a conventional sealing process. For example, pills containing the active ingredient can be prepared and filled into hard gelatin capsules using standard carriers; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (e.g., aqueous gums, celluloses, silicates, or oils) and filled into soft capsules.

The daily dosage for oral administration preferably ranges from about 0.01mg/kg body weight to about 10mg/kg body weight. Preferably, each oral dosage unit contains the active ingredient in an amount of from about 0.1mg to about 100 mg.

When it is possible to administer an active ingredient alone, it is preferably provided as a pharmaceutical formulation.

One skilled in the art will appreciate that the optimum amount and spacing of the individual doses of a compound of formula (I), or a pharmaceutically acceptable salt or hydrate or solvate thereof, will depend upon the nature and extent of the condition being treated, the form, route and site of administration and the particular patient being treated, and such optimum can be determined by conventional techniques. It will also be appreciated by those skilled in the art that the optimum 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) to be administered per day and during the course of treatment, can be determined by those skilled in the art using conventional therapeutic determination test procedures.

The method of the present invention for treating opportunistic infections in mammals, including humans, comprises administering to a patient in need of such treatment an effective amount of one of the pharmaceutically active compounds of the present invention.

The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of opportunistic infections in mammals including humans.

The invention also provides a pharmaceutical composition for treating opportunistic infections in mammals, including humans.

The invention also provides a process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I, which process comprises bringing the compound of formula I into association with a pharmaceutically acceptable carrier or diluent.

According to the present invention, no unacceptable toxic effects are expected when the compounds of the present invention are administered.

The following are the results of testing the compounds of the present invention.

FIG. I

N, N-dimethyl-8, 8-dipropyl-2-azaspiro [4, 5] in experiment 1]The use of decane-2-propylamine dihydrochloride (Compound A) for the treatment of opportunistic infections in vivo.FIG. 1 shows a schematic view of a

TABLE I

In experiment 2, N-dimethyl-8, 8-dipropyl-2-azaspiro [4, 5] decane-2-propylamine dihydrochloride (compound A) had the effect of treating ex vivo opportunistic infection.

TABLE 1

Action of mouse bronchoalveolar cells in killing activity of candida

Method of treatment	Strains of the genus candida	Opsonic action	Percent% kill ± s.d.
Control group	B 311	Is free of	31±12
				Control group	B 311	2% mouse serum	56±6
20mg/kg	B 311	Is free of	67±9*
				20mg/kg	B 311	2% mouse serum	84±6*
				Control group	B 792	Is free of	36±4
Control group	B 792	2% mouse serum	79±6
				20mg/kg	B 792	Is free of	71±11*
20mg/kg	B 792	2% mouse serum	94±1*

^*Is significantly larger than that of a control group, and P is less than 0.001

FIG. 2

In experiment 3, N-dimethyl-8, 8-dipropyl-2-azaspiro [4, 5] decane-2-propylamine dihydrochloride (compound A) has the effect of treating the opportunistic infection in a test tube.

FIG. 2

Action of compound (A) on killing candida activity of mouse alveolar macrophage

The data in the above figures and tables (ex vivo, in vitro and in vitro experiments) indicate that the compounds of formula I have unexpected efficacy in treating opportunistic infections.

In addition, the compounds of the present invention can be co-administered with additional 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 limitative of the remainder of the disclosure in any way whatsoever.

Example 1 Capsule composition

An oral dosage form for the administration of the compound of formula (I) was produced by filling the ingredients in the proportions listed in table II below into a standard two-piece hard capsule.

TABLE II ingredient amounts N, N-diethyl-8, 8-dipropyl-2-25 mg azaspiro [4, 5] decane-2-propylamine dihydrochloride lactose 55mg talc 16mg magnesium stearate 4mg

Example 2 parenteral composition for injection

N, N-diethyl-8, 8-dipropyl-2-azaspiro [4, 5] decane-2-propylamine dihydrochloride is stirred in an amount of 1.5% by weight in an aqueous solution of 10% by volume of propylene glycol to produce an injection for administration of the compound of the general formula (I).

EXAMPLE 3 tablet composition

Sucrose, calcium sulfate dihydrate and the compound of general formula (I) listed in table III below were mixed with a 10% gelatin solution in the proportions listed and granulated. The wet granulation is sieved, dried, mixed with starch, talc and stearic acid, sieved and compressed into a tablet.

TABLE III ingredient amounts N, N-diethyl-8, 8-dipropyl-2-20 mg azaspiro [4, 5] decane-2-propylamine dihydrochloride calcium sulfate dihydrate 30mg sucrose 4mg starch 2mg talc 1mg stearic acid 0.5mg

While the foregoing disclosure and examples fully describe the present invention and preferred embodiments thereof, it is to be understood that the invention is not limited to the specifically disclosed embodiments as falling within the scope of the following claims.

Claims (6)

1. A method of treating opportunistic infections in mammals, including humans, in need of such treatment which comprises administering to such humans an effective amount of a compound of the formula or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein:

n is 3 to 7;

m is 1 or 2;

R¹and R²Identical or different and selected from hydrogen or linear or branched alkyl, linear or branchedThe member is R¹And R²The total number of carbon atoms contained is 5 to 10; or R¹And R²Together form a cycloalkyl group having 3 to 7 carbon atoms;

R³and R⁴Identical or different and selected from hydrogen or linear alkyl groups having 1 to 3 carbon atoms; or R³And R⁴Combine with the nitrogen to form a heterocyclic group having 5 to 8 atoms.

2. The process according to claim 1 wherein the compound is N, N-diethyl-8, 8-dipropyl-2-azaspiro [4, 5] decane-2-propylamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The method according to claim 1, wherein the compound is administered orally.

4. The method according to claim 3, wherein the amount of the compound administered per day is from about 0.01mg/kg to about 10 mg/kg.

5. The method according to claim 1, wherein the compound is administered parenterally.

6. The method according to claim 5, wherein the amount of the compound administered per day is from about 0.01mg/kg to about 10 mg/kg.