CZ20997A3 - Azaspiran and pharmaceutical composition containing thereof - Google Patents

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

This invention relates to the use of the following compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of occasional infections in a mammal, including a human. Also described is a pharmaceutical composition comprising such a compound.

BACKGROUND OF THE INVENTION

Opportunistic infections are diseases that occur when the patient's immune system is compromised, for example, by an infection, another disease, or a drug. However, such infections usually do not occur if the body is healthy and not disrupted.

Occasional infections are a growing problem in medicine. Occasional infections may be caused by a wide variety of bacteria, viruses, fungi and protozoa, as described in Microbiology, 16th Ed., Appleton Crofts, New York, USA, p. 405 (1976). Of particular interest are, for example, Candida sp., Pseudomonas sp., Listeria sp., Pneumocystis 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 exceptionally concentrated in normal hosts, but under certain conditions can cause serious disease. Such conditions include, but are not limited to, extended periods of high dose antibiotic therapy, cancer chemotherapy, transplantation, and acquired immune deficiency syndrome (AIDS). In the first two cited examples, the biological response modifier (i.e., compounds with immunostimulatory activity, for example muramyl peptides) may be a complementary treatment that is selected for occasional infection (Τ H. Walsh et al., Curr Opin. Oncol. 4, 647-). 655 (1992)). In the first two cases, however, immunostimulation may be contraindicated.

In the case of transplantation, a biological response modifier may be envisaged in the patient's disease when the graft is recovered from the graft. In AIDS, simple immunostimulation can accelerate disease progression.

In general, immunomodulator compositions are not known to be capable of treating occasional infections. In addition, there are currently no ways of predicting whether a particular class of immunomodulator compositions will be of use in the treatment of opportunistic infections.

Badger et al. U.S. Pat. No. 4,963,557 to I. Badger discloses compounds of Formula I

wherein n is 3 to 7, m is 1 or 2,

R ¹ and R ² are the same or different and are selected from hydrogen, straight or branched chain alkyl, provided that the total number of carbon atoms in R ³ and R ² taken together is 5 to 10, or

R ¹ and R ² together form a C 3 -C 7 cycloalkyl group,

R ³ and R ⁴ are the same or different and are selected from hydrogen, a straight chain alkyl group containing from 1 to 3 carbon atoms, or

R ³ and R ⁴ are taken together with the nitrogen atom to form a heterocyclic group containing 5 to 8 atoms, and pharmaceutically acceptable salts, hydrates and solvates thereof.

Badger discloses compounds of formula I as a group of novel compounds which elicits an immunomodulatory effect, which is characterized by stimulation suppressing cellular activity.

Badger does not disclose the compounds of formula I as agents for the treatment of opportunistic infections.

SUMMARY OF THE INVENTION

The present invention relates to the use of a compound of formula I,

wherein n is 3 to 7, m is 1 or 2, r ³ - and R ² are the same or different and are selected from hydrogen, straight or branched chain alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² together are 5 to 10, or

R ¹ and R ² together form a C 3 -C 7 cycloalkyl group,

R ³ and R ⁴ are the same or different and are selected from hydrogen, a straight chain alkyl group containing from 1 to 3 carbon atoms, or

R ³ and R ⁴ are taken together with the nitrogen atom to form a heterocyclic group containing 5 to 8 atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of a medicament for treating occasional infections in a mammal, including a human.

Another aspect of the present invention is a pharmaceutical composition for the treatment of occasional infections in a mammal, including a human, comprising a compound of Formula I

wherein n is 3 to 7, m is 1 or 2,

R ¹ and R ² are the same or different and are selected from hydrogen, straight or branched chain alkyl, provided that the total number of carbon atoms in R ¹ and R ² taken together is 5 to 10, or

R ¹ and R ² together form a C 3 -C 7 cycloalkyl group,

R ³ and R ⁴ are the same or different and are selected from hydrogen, a straight chain alkyl group containing from 1 to 3 carbon atoms, or

R ³ and R ⁴ are taken together with the nitrogen atom to form a heterocyclic group containing 5 to 8 atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The invention is described in detail below.

The preparation of all compounds of formula I and their pharmaceutically acceptable salts, hydrates and solvates, as well as compositions comprising them, is disclosed in U.S. Pat.

No. 963,557, which is incorporated herein in its entirety.

The preferred compounds used in the novel method is the dihydrochloride salt of formula I wherein R ¹ and R ² are propyl, R ³ and R ⁴ are methyl, m is the number of ropes is 3 which is N, N-dimethyl-8 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine.

A particularly preferred compound used in the novel process is the dihydrochloride salt of a compound of formula I wherein R ¹ and R ² are propyl, R ³ and R ⁴ are ethyl, m is lan is 3, which is N, N-diethyl-8 dihydrochloride Of 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine.

A particularly preferred compound used in the novel process is the dihydrochloride salt of a compound of formula I wherein R ¹ and R ² are propyl, R ³ and R ⁴ are taken together with nitrogen to form a piperidine ring, m is lan is 3, 8,8-Dipropyl-2-azaspiro [4,5] decane-2-piperidinopropyldihydrochloride.

As used herein, Compound A refers to the dihydrochloride salt of a compound of formula I wherein R ¹ and R ² are propyl, R ³ and R ⁴ are methyl, m is lan is 3, which is N, N dihydrochloride -dimethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine.

It has now been found that the compounds of formula I and their pharmaceutically acceptable salts, hydrates or solvates are useful for treating occasional infections in mammals, including humans, in need of such treatment. By treatment is meant prophylactic or therapeutic therapy.

Compound A was tested for its ability to treat in vivo opportunistic infections in Experiment 1. To perform Experiment 1, Compound A was dissolved in saline and administered to CBA / J mice at 0, 1.5, or 15 mg / kg daily by intraperitoneal injection after for 14 days. A control group of mice receives saline. On day 8, 1x10 Candida albicans (strain B311) was injected intravenously from all mice. Survival is monitored daily until all mice die or die for human reasons. A significant increase in mean survival was observed in mice receiving a dose of 15 mg / kg. In contrast, mice that received 5 doses of dexamethasone (immunosuppressive steroid) at a dose of 50 mg / kg intraperitoneally showed a significant decrease in median survival.

Compound A is tested in an ex vivo experiment (Experiment 2) for its ability to treat opportunistic infections. In Experiment 2, Lewis rats receive an oral dose of 20 mg / kg of Compound A dissolved in tragacanth (5 doses per week) for a period of 16 days. On day 23, rats are sacrificed and alveolar macrophages are captured by bronchoalveolar lavage. Cells are dispensed into 24-well plates and the ability to kill Candida albicans is evaluated. There was a significant increase in the ability of cells treated with Compound A to kill two Candida strains (B311 and B792).

Ί

Compound A was tested in an in vitro experiment (Experiment 3) for its ability to treat occasional infections. In Experiment 3, alveolar macrophages were captured from untreated rats and incubated with compound A in vitro for 3 days. After this time, the compound is eluted and the ability of cells to kill Candida albicans (strain B792) is evaluated. Compound A exhibits a statistically significant concentration dependence on percent killing using an amount of Compound A equal to or greater than 2 mM. This effect is not due to the compound's effect on Candida albicans growth, as concentrations up to 12 μΜ have no effect on yeast.

A method of treating occasional infections in a mammal, including a human, in need of such treatment comprises administering to such mammal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof. The compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof may be administered to a mammal including a human in a conventional dosage form prepared by combining a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof with a conventional pharmaceutically acceptable carrier or diluent according to known. as described by I. Badger in U.S. Pat. 4,963,557.

One of ordinary skill in the art will recognize that the form and nature of the pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient to be combined, the route of administration and other well known variables. The compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered to a mammal, including a human, in an amount sufficient to treat occasional infections.

The route of administration of the compound of formula I (active ingredient) is not critical, but will usually be oral or parenteral, preferably oral.

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 daily parenteral dosage regimen will preferably be from about 0.01 to about 10 mg / kg body weight, more preferably from about 0.1 to about 1 mg / kg. Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 to about 100 mg.

The compounds of formula I which are active when administered orally can be formulated as liquids, for example, syrups, suspensions or emulsions, as well as tablets, capsules or lozenges.

Liquid formulations will generally consist of a suspension or solution of the compound or a pharmaceutically acceptable salt thereof in a suitable liquid carrier or carriers, for example ethanol, glycerin, a non-aqueous solvent such as polyethylene glycol, oils or water with a suspending agent, preservative, flavoring or flavoring; dye.

The composition in the form of a tablet can be prepared using any pharmaceutically acceptable carrier or carriers conventionally used in the preparation of solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Capsule compositions may be prepared by conventional routine encapsulation procedures. For example, pellets containing the active ingredient may be prepared using standard carriers and then filled into hard gelatin capsules or, in another embodiment, dispersions or suspensions may be prepared using any suitable pharmaceutically acceptable carrier or carriers, for example, aqueous solutions of gum, cellulose, silicates or oils and the dispersion or suspension is then filled into soft gelatin capsules.

The daily oral dosage regimen will preferably be from about 0.01 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 to about 100 mg.

While the active ingredient may be administered alone, it is preferred that it is present in the pharmaceutical composition.

It will be appreciated by those skilled in the art that the optimum amount and interval of single doses of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof will be determined by the nature and extent of the condition, the form, route and site of administration. This optimum can be determined by conventional techniques. One of ordinary skill in the art will also recognize that the optimal course of treatment, i.e., the number of doses of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof administered per day, can be ascertained by those skilled in the art using conventional routine tests .

A method of treating occasional infections in a mammal, including a human, comprises administering to a patient in need of such treatment an effective amount of a pharmaceutically active compound of the invention.

The pharmaceutical composition of the invention is for oral or parenteral administration.

A process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I comprises contacting a compound of formula I with a pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when the compounds of the invention are administered in accordance with the invention.

The results of testing the compounds of the present invention are presented below.

Table I shows the effect of N, N-dimethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine dihydrochloride (Compound A) on the treatment of occasional infections ex vivo from Experiment 2.

Table I

Effect of Candida activity on bronchoalveolar cells in rat

Treatment Candida strain Opsonization% killing ± germ. deviation

control B311 none 31 + 12 control B311 2% rats serum 56 + 6 20 mg / kg B311 none 67 + 9 * 20 mg / kg B311 2% rats serum 84 + 6 * control B792 none 36 + 4 control B792 2% rats serum 79 + 6 20 mg / kg B792 none 71 + 11 * 20 mg / kg B792 2% rats serum 94 + 1 *

Significantly higher than the control, P <0.001

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1 depicts the effect of N, N-dimethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine dihydrochloride (Compound A) on the treatment of occasional infections in vivo from experiment 1.

Giant. 2 shows the effect of účinek, Ν-dimethyl-8,8-dipropyl-2-azaspiro [4,5] decane-2-propanamine (compound A) dihydrochloride on the treatment of an occasional in vitro infection from the experiment

3.

The values shown in the figures and in the table of in vivo, ex vivo and in vitro experiments demonstrate the unexpected therapeutic effect of the compounds of formula I on the treatment of occasional infections.

In addition, the compounds of this invention may be co-administered with other active ingredients, such as those known for the treatment of occasional infections.

DETAILED DESCRIPTION OF THE INVENTION

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 in no way limit the scope of the invention.

Example 1 - Capsule composition

An oral dosage form for administration of compounds of Formula I is prepared by filling two standard hard gelatin capsule pieces with the ingredients in the proportions listed in Table II below.

Table II

N, N-diethyl-8,8-dipropyl- dihydrochloride

-2-azaspiro [4.5] decane-2-propanamine 25 mg lactose 55 mg talc 16 mg magnesium stearate 4 mg

Example 2: Injectable parenteral formulation

An injectable form for administering the compounds of formula I is prepared by mixing 1.5% by weight of N, N-diethyl-8,8-dipropyl-2-azaspiro [4,5] decane-2-propanamine dihydrochloride in 10% by volume. of propylene glycol in water.

Example 3 - Tablet formulation

Sucrose, calcium sulfate dihydrate and the compound of formula I, listed in Table III below, are mixed and granulated in portions with a 10% gelatin solution. The wet granules are screened, dried, mixed with starch, talc and stearic acid, re-screened and compressed into tablets.

Table III

Folders

Amount

N, N-diethyl-8,8-dipropyl- -2-azaspiroC 4,5] decane-2-propanamine 25 mg calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0 , 5 mg

While the foregoing description and examples fully describe the invention and its preferred embodiments, it is to be understood that the invention is not limited to the specific embodiments disclosed herein, which come within the scope of the appended claims.

Claims (9)

PATENT CLAIMS Use of a compound of formula (I), wherein IS is a branched atom in which n is an integer from 3 to 7, m is an integer of 1 or 2; and R ² are the same or different and are selected from hydrogen, straight-chain or ro-chain alkyl groups, provided that the total number of carbon atoms in and R 2 taken together is 5 to 10, or R ¹ and R ² together form a C 3 -C 7 cycloalkyl group, R ³ and R ⁴ are the same or different and are selected from hydrogen, a straight chain alkyl group containing from 1 to 3 carbon atoms, or R ³ and R ⁴ are joined together with the nitrogen atom to form a heterocyclic group containing 5 to 8 atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of a medicament for the treatment of occasional infections in a mammal including a human. Use according to claim 1, wherein the compound is N, N-diethyl-8,8-dipropyl-2-azaspiro [4,5] decane-2-propanamine dihydrochloride, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 3. orally. The use of claim 1 wherein the compound is administered 4. approximately Use according to claim 3, wherein from 0.01 to about 10 mg / kg of the compound is administered per day. 5. Use parenterally. according to claim 1, wherein the compound is administered 6. approximately Use according to claim 5, wherein from 0.01 to about 10 mg / kg of the compound is administered per day. A pharmaceutical composition for the treatment of occasional infections in a mammal, including a human, comprising a compound of formula I R '(CH _{2) m} -N (CH _{2) n} • N * 4 (where D is an integer 3-7; m is 1 or 2, R ₃ and R ⁶ ₃ are the same or different and are selected from hydrogen, straight or branched chain alkyl, provided that the total number of carbon atoms in R ¹ and R ² taken together is 5 to 10, or 1 2 R and R together form a C 3 -C 7 cycloalkyl group, R ³ and R ⁴ are the same or different and are selected from hydrogen, a straight chain alkyl group containing from 1 to 3 carbon atoms, or R ³ and R ⁴ are taken together with the nitrogen atom to form a heterocyclic group containing 5 to 8 atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 8. A pharmaceutical composition according to claim 7 for oral administration. A pharmaceutical composition according to claim 7 which is for parenteral administration.