SK397091A3 - Azaspirane derivatives, pharmaceutical compositions containing thereof and use thereof - Google Patents

Abstract

Azaspirane derivatives of the general formula are described (I) wherein n is 3 to 7, m is 1 to 2, R 1 and R 2 are the same or different and are selected from hydrogen or alkyl straight chain, branched chain or z cyclic alkyl provided that the total number of atoms the carbon contained in R1 and R2 together are 5 to 10, or R 1 and R 2 are joined to form a cyclic alkyl C 3 -C 7. R3 and R4 are the same or different and are selected from hydrogen or straight-chain alkyl or from 3 to 4 carbon atoms, or R 3 and R 4 are linked to form a cyclic alkyl group of 4 to 7 or a pharmaceutically acceptable salt thereof or hydrates, or solvates. Pharmaceutical compositions are described below compositions containing them and their use for immunomodulation in animals and humans.

Description

Technical field

The invention relates to a spiro-germanium analog comprising non-metals, pharmaceutical compositions comprising such an analog and a pharmaceutically acceptable carrier or diluent, and to a method of treating rheumatoid arthritis in an animal in need thereof comprising administering an effective amount of such an analog to such animals.

BACKGROUND OF THE INVENTION

Geschichter et al. No. 4,468,393, published Sep. 28, 1984, claims a method of treating arthritis using various germanium-containing spiro-germanium analogues, including: N - (3-dimethylaminopropyl) -2-aza-8,8-dimethyl-8-germanspiro [4,5] decane; N- (3-dimethylaminopropyl) -2-aza-8,8-diethyl-8-germanspiro [4,5] decane; / V- (3-dimethylaminopropyl) -2-aza-8,8-dipropyl-8-germanspiro [4,5] decane; and N- (3-dimethylaminopropyl) -2-aza-8,8-dibutyl-8-germanspiro [4.5] decane.

Tenoso et al., U.S. Pat. No. 4,654,333, published March 32, 1987, claims a method of treating multiple sclerosis, which comprises treating an affected patient with multiple sclerosis with an effective amount of spirogermania selected from the group consisting of:

A / - (3-dimethylaminopropyl) -2-aza-8,8-dimethyl-8-germanspiro [4,5] decane; / V- (3-dimethylaminopropyl) -2-aza-8,8-diethyl-8-germanspiro- [4.5]; A / - (3-dimethylaminopropyl) -2-aza-8,8-dipropyl-8-germanspiro [4,5] decane; N - (3-dimethylaminopropyl) -2-aza-8,8-dibutyl-8-germanspiro [4,5] decane.

Rice et al., J. Heterocycl. Chem., 10 (5), 731-735 (1973), (Rice I) describes the synthesis of N - (2-dimethylaminopropyl) -8,8-dimethyl-2-azaspiro [4.5] decane; N - (2-dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4,5] decane, N - (3-dimethylaminopropyl) -9,9-dimethyl-3-azaspiro [5,5] undecane, and / V- (3-dimethylaminopropyl) -9,9-diethyl-3-azaspiro [5.5] undecane. Rice I describes that it shows a biological evaluation of these amines

- significant inhibition of cancer cell growth in human cancer cells grown in tissue culture. There is no finding in Rice I that such amines have anti-arthritic action.

Rice et al., J. Heterocycl. Chem., 10 (5), 737-741 (1973) (Rice II) describes the synthesis of N - (2-dimethylaminopropyl) -8,8-dimethyl-8-sila-2-azaspiro [4,5] decane and Λ N- (3-dimethylaminopropyl) -9,9-dimethyl-9-sila-3-azaspiro [5,5] undecane and further notes that biological evaluation of such compounds indicates a cytotoxic action against human cancer cells grown in tissue culture. There is no finding or suggestion in Rice II that such compounds have an anti-arthritic effect.

Rice et al., U.S. Pat. No. 3,256,277, published June 14, 1966 (Rice III), claims (1) a compound selected from the group consisting of compounds of Formula IA

(IA) in which

A is a ring with at least 5 ring atoms, all ring atoms being carbon atoms except R ¹ . R ¹ is selected from the group consisting of oxygen and sulfur; X is selected from the group consisting of at least one of hydrogen, lower alkoxy, lower alkyl, lower alkenyl; a lower cycloalkyl group and a monocarbocyclic aryl; B is a saturated ring of 5 to 6 ring atoms, wherein the ring atoms other than the nitrogen atom are carbon atoms; Y is selected from the group consisting of alkylene and alkenylene of up to 6 carbon atoms; n is 0 to 1; and R is selected from the group consisting of lower alkyl, lower alkenyl, lower cycloalkyl and alkenylamino, a saturated heterocyclic group selected from the group consisting of morpholine, piperidine, pyrrolidine, piperazine, tetrahydrofuryl and their lower alkyl and alkenyl substituted derivatives, pyridyl, monocarbocyclic, quinolyl, fury and lower alkoxy; (2) non-toxic acid addition salts (1); and (3) non-toxic quaternary salts (1). Rice III notes that such compounds are characterized by their pharmacological activity on nerve and cardiovascular

-3systém. There is no finding or suggestion in Rice III that such compounds have an anti-arthritic effect.

Rice et al., U.S. Pat. No. 3,282,947, published November 1, 1966 (Rice IV), claims compounds of the formula wherein R 1 and R ¹ are each selected differently from the group consisting of:

(a) hydrogen

b) lower alkyl;

c) aralkyl selected from the group consisting of pyridyl, lower alkyl and phenyl-lower alkyl;

d) a di-lower alkylamino-lower alkylene group; or

e) a hydroxy-lower alkylene group.

Rice IV notes that such compounds are valuable as intermediates and that they also have undefined pharmacological effects. In Rice IV there are no findings or suggestions that such amines have antiarthritic effects.

Rice et al., J. Med. Chem., 6, 388-402 (1963) (Rice V) describes preparations of a broad group of N -dialkylaminoalkylazaspiroalkanes and reports that strong (but undefined) pharmacological activity has been observed in the group and that some observations have been made about the significant growth inhibitory effects of certain group members (e.g., 3- (3-dimethylaminopropyl-9-tert-butyl-3-azaspiro [5,5] undecane)) on cancer cells in tissue cultures and objective clinical effects in human cancer cells. believed that these compounds would have anti-arthritic effects.

Rice et al., J. Heterocycl. Chem., 1 (3), 125-127 (1964), (Rice VI) discloses synthetic methods for producing various symmetrical and asymmetric 3,9-diazaspiro [5.5] undecanes. In Rice VI, there is no finding or suggestion that such compounds have any biological activity.

-4Rice et al., U.S. Pat. No. 3,825,546, published July 23, 1974 (Rice VII), claims a compound having the structural formula:

/

in which

R ¹ and R ² are the same or different C 1 -C 4 alkyl groups, X is silicon or germanium,

A and A ¹ are the same or both are

ABOUT

II

CH ₂ or C n is 0 or 1,

B is CH3 when n is 1 and B is the same as A when n is 0,

R ³ is alkylene or alkenylene, y is 2 to 6 when R ³ is alkylene and 3 to 4 when R ³ is alkenylene,

R ⁴ and R ⁵ are the same or different lower C 1 -C 4 alkyl, lower C 3 -C 4 alkenyl, or cyclize together to form a heterocyclic group selected from morpholine, pyrrolidine, piperidine and lower alkyl (C 1 -C 4) atoms a piperazine group wherein said lower alkyl is attached to a terminal nitrogen atom. Rice VII states that the bisquaternary salts of such compounds exhibit antihypertensive effects and are particularly useful for blocking ganglionic activity in dogs and other animals. There is no finding or suggestion in Rice VII that such compounds have anti-arthritic effects.

Sanwa KK, European Patent Application Publication No. EO, 186,505 A2, published July 2, 1986, discloses a composition comprising an organo-germanium compound represented by the formula

-5 wherein n is an integer of R 1, R is hydrogen, alkyl, -COOH, -COOR ', phenyl'>

_c or on R 'is a lower alkyl group and high molecular weight carrier for pharmaceutical agents. Sanwa KK discloses that such compounds do not have an immune-enhancing action, but instead have an immune-modifying or regulating action.

Di Martino et al., J. Pharmacol., Exp. Therapeut., 236, 103-110 (1986) report on the ability of spirogermania to induce suppressor cells.

Badger et al., Immunopharmacol., 10, 201-207 (1985) report on the generation of suppressor cells in normal spiro-germanated rats.

The Australian National University, PCT Patent Application Publication Number WO 85/05031, published November 21, 1985, claims a method of modulating or suppressing an immune response in an animal comprising administering an effective amount of at least one amphiphil that is capable of modifying its surface properties by interaction on the cell surface. thus, it inhibits or modifies antigen recognition by the affected cells. Preferably, the amphiphil is a cationic surfactant, for example a double-chained quaternary surfactant.

Gerschichter Fund, British Patent Application No. 929,739, published June 26, 1967, discloses azaspirane compounds of the formula

wherein A is a mono or bicyclic carbon ring of at least 5 carbon atoms, X is selected from one or more hydrogen, alkyl and alkoxy, n is 0 or 1, R ¹ is an alkylene chain of 2 to 6 carbon atoms or an alkylene chain of 2 up to 6 carbon atoms substituted by a hydroxyl group on a carbon atom, at least in the beta or nitrogen position, and R ² is a dialkyl, each alkyl group having 1

-6 to 6 carbon atoms, or an alkylene chain forming, together with the nitrogen atom to which it is attached, a morpholine, piperidine, pyrrolidine or piperazine ring, or an alkyl-substituted derivative of any of them, containing from 1 to 6 carbon atoms in the substituted group and their non-toxic addition salts with acids. The Gerschichter patent also specifically discloses N - (3-dimethylaminopropyl) -9-tert-butyl-3-azaspiro [5.5] undecane.

The Gerschichter patent also discloses that such compounds are useful for their pharmacological effects on the nervous and cardiovascular systems.

SUMMARY OF THE INVENTION

The present invention provides azaspirane derivatives of formula (I)

d) 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 or cyclic alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² , when taken together, is 4 to 10 , or R ¹ and R ² when taken together to form a cyclic alkyl group containing 3 to 7 carbon atoms,

R ³ and R ⁴ are the same or different and are selected from hydrogen or a straight chain alkyl having 1 to 3 carbon atoms, or R ³ and R ⁴ are joined together to form a cyclic alkyl group having 4 to 7 carbon atoms, provided that: that when R ¹ and R ² are CH ³ CH 2, R ³ and R ⁴ are CH 3 and m is 1 or 2, n is other than 3, and further provided that when R ² is H, R ¹ is (CH 3) 3 C, R ³ and R ⁴ are CH ₃ and m is 2, n is other than 3, or pharmaceutically acceptable salts, hydrates or solvates thereof.

The present invention also relates to a compound of formula II

(H)

wherein n is 3-7, ^R _Ri, m is 1 or 2,

R ¹ , R ² , R ⁵ and R ⁶ are the same or different and are selected from hydrogen or methyl,

R ³ and R ⁴ are the same or different and are selected from hydrogen or a straight chain alkyl having 1 to 3 carbon atoms, or R ³ and R ⁴ are joined together to form a cyclic alkyl group having 4 to 7 carbon atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

This invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula

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

-8R ¹ and R ² are the same or different and are selected from hydrogen, straight or branched chain alkyl or cyclic alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² , when taken together, is 4 to 10, or

R ¹ and R ² are joined together to form a cyclic alkyl group containing 3 to C atoms,

R ³ and R ⁴ are the same or different and are selected from hydrogen or a straight chain alkyl of 1 to 3 carbon atoms, or R ³ and R ⁴ are joined together to form a cyclic alkyl group of 4 to 7 carbon atoms, or a pharmaceutical thereof an acceptable salt, hydrate or solvate.

This invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula II.

The invention also relates to the use of a compound of the invention for the manufacture of a pharmaceutical composition for the treatment of animals in need of immunomodulation and which comprises administering to such animals an effective amount of a compound of formula I or formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Those skilled in the art will recognize that all compounds of formula IA are included within the scope of formula I. Preferred compounds of formula I and formula II are listed in Table 1 below, a particularly preferred compound is compound # 02 of Table 1.

Pharmaceutically acceptable salts and their preparation are well known to those skilled in the art. Preferred pharmaceutically acceptable salts of the compounds of Formula I and Formula II include, but are not limited to, hydrochlorides, dihydrochlorides, citrates, maleates, lactates, hydrobromides, and sulfates. The dihydrochloride salt is particularly preferred.

The compounds of formula I and II may form hydrates or solvates. It is known to those skilled in the art that charged compounds form hydrate species when lyophilized with water or form solvate species when concentrated in solution with a suitable organic solvent.

Compounds of formula I and formula II can be prepared by the methods described in the Examples below.

All compounds of Formula I and Formula II can be used in the manufacture of a medicament for the treatment of animals, including humans in need of immunomodulation. Such immunomodulatory efficacy is assessed using an adjuvant-induced arthritis assay

-9µ rats, the results are summarized in Table 1 and / or using a suppressor cell activity assay, the results of which are summarized in Table 2.

Table 1

Efficacy of compounds of formula I and formula II in the adjuvant-induced arthritis assay

R)

FROM

N / - (CHi) n

# (A) m n R ¹ R ^z R ^J R ⁴ (B) (C) 01 1 3 CH3CH2 CH3CH2 ch ₃ ch ₃ 0.57 30 02 1 3 CH3CH2CH2 CH ₃ CH ₂ CH ₂ ch ₃ ch ₃ 1.35 30 03 1 3 CH ₃ (CH ₂ ) ₂ CH ₂ CH ₃ (CH ₂ ) ₂ CH ₂ ch ₃ ch ₃ 0.88 30 04 1 3 CH ₃ (CH ₂ ) ₃ CH ₂ CH ₃ (CH 2) ₃ CH 2 ch ₃ ch ₃ 0.41 30 05 1 3 (CH ₃ ) ₂ CHCH ₂ (CH ₃ ) ₂ CHCH ₂ ch ₃ ch ₃ 0.97 30 06 2 3 CH3CH2CH2 ch ₂ ch ₂ ch ₂ ch ₃ ch ₃ 0.90 30 07 1 3 CH3CH2CH2 ch ₂ ch ₂ ch ₂ H H 1.52 30 08 1 3 CH3CH2CH2 ch ₂ ch ₂ ch ₂ ch ₃ H 1.02 30 09 1 3 CH ₃ CH ₂ (CH ₃ ) CH ch ₃ ch ₃ ch ₃ 1.27 30 10 1 3 ch ₃ CH ₃ CH ₂ (CH ₃ ) CH ch ₃ ch ₃ 2.84 60 11 1 3 CH3CH2 CH ₃ (CH ₂ ) ₂ CH ₂ ch ₃ ch ₃ 1.15 15 12 1 3 CH ₃ (CH ₂ ) ₂ CH ₂ ch ₃ ch ₂ ch ₃ ch ₃ 4.00 30 13 1 3 H CH ₃ (CH ₂ ) ₃ CH ₂ ch ₃ ch ₃ 0.78 30 14 1 3 H cyclohexyl ch ₃ ch ₃ 0.98 30 15 1 3 H (CH _{3) 3} C ch ₃ ch ₃ 0.31 30 16 1 3 (CH _{3) 3} C H ch ₃ ch ₃ 0.90 30

17 1 3 -CH2CH2CH2CH2CH2CH2- ch ₃ ch ₃ 1.70 60 18 1 3 CH3CH2CH2 CH3CH2CH2 CH3CH2 CH3CH2 1.42 30 19 1 3 CH3CH2CH2 CH3CH2CH2 -CH ₂ (CH _{2 3} ch ₂ - 1.89 30 20 1 4 CH3CH2CH2 CH3CH2CH2 ch ₃ ch ₃ 0.45 30 21 1 5 CH ₃ CH ₂ CH ₂ CH3CH2CH2 ch ₃ ch ₃ 0.82 30 22 1 6 CH3CH2CH2 CH3CH2CH2 ch ₃ ch ₃ 1.28 30 23 1 7 CH3CH2CH2 CH3CH2CH2 ch ₃ ch ₃ 1.57 30 24 1 3 spiroadamantan ch ₃ ch ₃ 0.76 30 25 1 3 adamantane ch ₃ ch ₃ 0.33 30 26 1 3 [3.3.1] nonane-9-one ch ₃ ch ₃ 0.92 30 27 1 3 CH3CH2CH2 CH3CH2CH2 -CH ₂ (CH ₂ CH2CH2- 1.03 30 28 1 6 CH3CH2CH2 CH3CH2CH2 -CH ₂ (CH ₂ ) ₂ CH ₂ - 0.63 30 29 1 6 CH3CH2CH2 CH3CH2CH2 -CH ₂ (CH ₂ ) ₃ CH ₂ - amp; 30 1 3 CH3CH2 CH3CH2 -CH ₂ (CH ₂ ) ₂ CH ₂ - amp; 31 1 3 CH3CH2 CH3CH2 -CH ₂ (CH ₂ ) ₃ CH 2 - amp; 32 1 3 CH3CH2 CH3CH2 ch ₃ ch ₂ ch ₃ ch ₂ amp;

amp; not tested # compound number. Compound numbers 01 to 23 and 27 to 32 include those of Formula I (b) AA rats% right paw inhibition (day 16) relative to spirogermania (d, e) (c) dose (mg / kg) (d) elaboration / modification test

Adjuvant arthritis is induced by a single intradermal injection of 0.75 mg M. butyricum suspended in white paraffin oil (light N.F.) into the left hind paw. The injected paw is inflamed (its volume increases) and reaches its maximum size within 3-5 days (primary lesion). Animals show a decrease in weight gain during this initial period. Adjuvant arthritis (secondary lesion) appears delayed after approximately 10 days and is characterized by inflammation of the uninjected side (right hind paw), weight loss and further increase in injected hind paw volume. Test compounds are administered

-11 daily, starting on the day of adjuvant injection for either 17 days, with the exception of days 4, 5, 11 and 12 for 11 consecutive days or 17 consecutive days. The effect of the pharmaceutical composition on the primary (left paw - day 3) and secondary (right paw - day 16) lesions is determined by comparing the paw volumes of the treatment group to the control arthritis (vehicle) group. The hindpaw volumes are measured by immersing the paw in the mercury of the water reservoir and recording the subsequent displacement.

(e) definition of significant activity (*)

A compound is considered to have anti-arthritic activity if it produces a statistically significant (p < 0.05) decrease of thirty percent (£ 30%) or more volumes of inflamed hindpaws and / or arthritic scores of treatment groups compared to arthritic controls. The level of significant difference between the treatment groups and the control group is determined by the Student's "t" test. Changes in body weight from day 0 are also statistically compared to the arthritic control group. The% inhibition of the compound of formula I and formula II at day 16 is divided by spiro-germanium activity

Day 16 to obtain a relative activity profile.

Note: In some experiments, Compound # 02 of Table 1 was used as a standard instead of spirogermation, Compound # 02 is 1.35 times more potent than SG in the AA-rat model. Therefore, the potencies of all compounds were normalized to SG by multiplying by this factor.

Table 2

Suppressor Cell Activity of Compounds of Formula I and Formula Ii ^(c)

Compound ^ιa, dose Suppressor cell number [Mg / kg] activity ^(b> 1 30 88 2 30 172 3 30 176 4 7.5 118 5 30 162 6 30 158

7 30 217 8 15 67 9 30 132 10 30 112 11 15 139 12 15 172 13 15 96 14 amp; 15 amp; 16 amp; 17 amp; 18 30 201 19 30 241 20 30 178 21 30 177 22 15 141 23 30 146 24 30 84 25 amp; 26 30 7 27 amp; 28 amp; 29 amp; 30 amp; 31 amp; 32 amp;

amp; - untested (a) - see Table 1 for the structure of compound (b) - Suppressor cell activity is calculated as follows. Plot of percent suppression (dependent variable) versus logarithm (base e) count

The 1313 suppressor cells (independent variable) were generated and the area under the curve represented by the data points of this diagram was determined by the trapezoidal rule path. The trapezoidal rule provides the area under the curve by the summation of trapezoidal surfaces whose verticals are located at adjacent values of the independent variable. All data are normalized to spiro-germanium (SG). In some experiments, compound # 02 of Table 1 was used as a standard instead of spirogermany. Compound # 02 is 1.72 times better than SG in the suppressor cell assay. Therefore, all activities were normalized to SG by multiplying by this factor (i.e., SG = 100, compound # 02 = 172).

(c) - The assay used to test compounds of Formula I and Formula II for the ability to generate suppressor cells is the same as described by Badger et al., Immunopharmacology, 10, 201-207 (1985). Briefly, male inbred Lewis rats were obtained from Charles River Laboratories (Wilmington, MA, OSA). Rats were bred by administration of water and normal rat food and used at 6 to 8 weeks of age (160 to 180 g). Only rats of the same age, strain and sex are used during any given experiment. Concanavalin A (Con A) was obtained from Pharmacia Fine Chemicals (Piscataway, NJ) and dissolved in RPMI-1640 (Flow Laboratories, Rockville, MD) supplemented with penicillin, streptomycin and L-glutamine (Grand Island Biological Co., Grand Island) , NY) and 10% heat inactivated (56 ° C, 30 minutes) fetal calf serum. This medium is hereinafter referred to as RPMI-10. For in vivo treatment, the compounds were dissolved in 0.5% tragacanth and administered orally once daily. Spleen cells from animals treated with compounds of Formula I and Formula II were stabilized in RPMI-10 at 5 x 10 ⁶ / ml. Co-culture experiments to determine suppressor cells were performed by first adding a different number of putative suppressor cells (0.15 to 5.10 ⁵ ) to 96 well round bottom microtiter plates (Linbro, Flow Lbas) in 100 μΙ RPMI-10. These cells were then irradiated (2000 Rad) in a Gamma chamber for 40 seconds with a 137 Cs source. To these cultures, ⁵ x ^{10 5} normal cells and an optimal Con Con concentration (5 µg / ml) were added and the final volume was adjusted to 200 µΙ. Cell cultures were incubated for 72 hours at 37 ° C in a 5% CO ₂ atmosphere, pulsed with 0.5 pCi ( ³ H) thymidine (specific activities 1.9 Ci / mmol; Schwarz / Mann, Orangenburg, NY) for at least 16 hours. hours of cultivation. The cells were

Collected on an automatic multiple sample collector and cell-associated radioactivity was counted in a Beckman liquid scintillation counter. Suppressive activity is determined by comparing cpm of co-cultured cultures containing untreated cells to those containing the affected cells

Student's t test.

Table 2 above shows the action of compounds of Formula I and Formula II in the generation of suppressor cells in vivo. By "generation of suppressor cells" is meant that the compound induces suppressor cell activity, i. the cell is capable of suppressing the immune function of a normal cell in an in vitro co-activation assay, such as that of Riche and Pierce, J. Exp. Med., 137, 649 (1973). Spleen cells from treated animals were kept at varying concentrations with normal cells; these suppressor cells are also capable of inhibiting mixed lymphocyte responses, antibody synthesis, and delayed-type hypersensitivity responses.

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula I or Formula II.

The compound of Formula I or Formula II is administered in a conventional dosage form prepared by combining a therapeutically effective amount (i.e., an effective immunomodulatory amount) of a compound of Formula I or Formula II ("active ingredient") with standard pharmaceutical carriers or diluents according to conventional procedures. Such processes may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired formulation.

The pharmaceutical carriers used can be, for example, solid or liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. In addition, the carrier or diluent may include a delay agent well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax, ethylcellulose, hydroxypropylcellulose, methyl methacrylate, and the like.

A variety of pharmaceutical forms can be used. If a solid carrier is used, the preparation may be tabletted, placed in hard gelatin capsules and in powder or pellet form, or form lozenges for dissolution in the mouth or for oral administration. The amount of solid carrier will vary, but will range from about 25 mg to 1.0 g. When a liquid carrier is used, the preparation will take the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or be a non-aqueous liquid emulsion.

To obtain a stable water-soluble dosage form, the pharmaceutically acceptable salt of a compound of Formula I or Formula II is dissolved in an aqueous solution of an organic or inorganic acid, for example, in a 0.3M solution of succinic or preferably citric acid. If a soluble salt form is not available, the compound of formula I or formula II is dissolved in a suitable co-solvent or combinations thereof. Examples of such suitable co-solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. Preferably, each percent dosage unit will contain the active ingredient in an amount of from 0.1 mg to about 500 mg. Preferably, each oral dosage unit will contain the active ingredient in an amount of from about 1 mg to about 1000 mg.

The compounds of formula I and formula II are all effective as immunomodulatory agents in animals, including humans, in need of such immunomodulation when such compounds are administered to these animals by the method of the invention. By "immunomodulatory agent" is meant that each of the compounds of Formula I or Formula II is capable of inducing immune suppression by inducing suppressor cell activity (as shown by their activity in the suppressor cell assay described in Table 2) and / or by causing a statistically significant decrease in inflammation by the immune-mediated secondary lesion response in an adjuvant-induced arthritis assay (see Table 1). Indications for therapy using an immunomodulatory agent include, but are not limited to, the following disease states: rheumatoid arthritis, systemic lupus erythematosis,

-16 multiple sclerosis, acute transplant graft rejection, myasthenia gravis, progressive systemic sclerosis, multiple myeloma, atopic dermatitis, hepatitis B - antigen negative chronic active hepatitis,

Hashimoto's thyroiditis, familial Mediterranean fever,

Graves' disease, primary biliary cirrhosis, inflammatory bowel disease.

The invention also relates to the use of a compound of Formula I or Formula II for the manufacture of a pharmaceutical composition for treating animals in need of immunomodulation, including humans and other mammals, comprising administering to such animals an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, hydrate or solvate. The term "treatment" refers to prophylactic or therapeutic use. The compound of formula I or II is administered to animals in need of immunomodulatory treatment in sufficient amount to induce immunomodulation at a therapeutic or prophylactic stage. Such a compound of Formula I or Formula II may be administered to such animals in a conventional dosage form prepared by admixing a compound of Formula I or Formula II with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be appreciated by those skilled in the art that the form and properties of the pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.

The route of administration of a compound of Formula I or Formula II may be oral, parenteral, inhalation, or topical. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. In general, subcutaneous and intramuscular administration is preferred for parenteral administration. Daily parenteral dosage regimen

-17 will preferably be from about 0.1 mg to about 1000 mg per day. The daily oral dosage regimen will preferably be from about 1 mg to about 2000 mg.

The compounds of formula I and formula II can also be administered topically.

However, the amount of a compound of Formula I or Formula II (hereinafter referred to as the active ingredient) required for therapeutic effect in topical application will vary with the selected compound, the nature and severity of the inflammatory conditions in the animals undergoing treatment and the physician will ultimately decide. A suitable immunomodulatory dose of a compound of Formula I or Formula II is from about 1.5 µg to 500 mg base per kg body weight for topical application, most preferably the dosage is 1 µg to 50 mg / kg animal body weight, for example 5 µg to 25 mg / kg of body weight applied two to three times a day. For application to the skin, from 1 μ9 to several milligrams of the active ingredient may be administered, preferably from 10 μg to 100 μο ·

By topical administration is meant non-systemic administration and involves the application of a compound of Formula I and Formula II externally to the epidermis, the oral cavity and the installation of such a compound in the ear, eye, nose and where the compound does not significantly enter the bloodstream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

When the active ingredient can be administered alone as a raw chemical, it is preferable to administer it as a pharmaceutical composition. The active ingredient may comprise, for topical application, from 0.001% to 10% by weight, for example from 1% to 2% by weight of the composition, although it may comprise up to 10% by weight but preferably does not exceed 5% by weight and more preferably 0.1 to 1% by weight. preparation.

Topical formulations of the invention, for both veterinary and human medical use, form the active ingredient together with one or more acceptable carriers and optionally any other therapeutic ingredient (s). Carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the formulation.

Formulations suitable for topical application include liquid or semi-liquid preparations suitable for penetrating the skin to a site in need of treatment such as:

-18Liniments, lotions, creams, ointments or pastes and drops suitable for application to the eyes, ears or nose.

The drops of the invention may form sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any suitable preservative and preferably including a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container in which it is sealed and sterilized by autoclaving or holding at 40 to 100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to a container by aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in droplets are mercuric nitrate or phenylacetate (0.002%), bencalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for oily solutions include glycerol, dilute alcohol and propylene glycol. The lotions of the invention include formulations suitable for application to the skin or eyes. The ophthalmic lotions may contain a sterile aqueous solution optionally containing a bactericidal substance and may be prepared by methods similar to droplet preparation. Lotions or liniments for application to the skin may also include agents that accelerate and dry the skin, such as alcohol or acetone, and / or wetting agents, such as glycerol or castor or peanut oil.

The creams, ointments and paste according to the invention are semi-solid preparations of the active ingredient for external use. They can be prepared by mixing the active ingredient in finely divided or powdered form. Alone or in solution or suspension in an aqueous or non-aqueous liquid by means of a suitable oily or non-greasy base apparatus. The base may contain hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soap, mucilago, natural origin oil such as almond, corn, peanut, castor or olive oil, wool grease or derivatives thereof, or fatty acids, such as such as stearic or oily together with an alcohol such as propylene glycol or macrogols. The composition may also include any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents may also be included

Such as natural gums, cellulose derivatives or inorganic materials such as silicon oxides and other ingredients such as lanolin.

It will be appreciated by those skilled in the art that the optimum quantity and individual dose distribution of a compound of Formula I or Formula II will depend upon the nature and extent of the conditions to be treated, the form, the route and the site of administration, and in particular the animal to be treated. can be determined by conventional techniques. It will also be appreciated by those skilled in the art that the optimal course of treatment, i. the number of doses of a compound of Formula I or Formula II per day, over a defined number of days, can be determined by one of ordinary skill in the art using the routine assays determining treatment.

It is believed that one skilled in the art will utilize the invention to its fullest extent without further elaboration using the foregoing description. The following examples are, therefore, to be construed as illustrative and not limiting of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

1. Examples of preparations

Example A - Capsule formulation

The pharmaceutical composition of the invention is prepared in capsule form by filling a two-piece hard gelatin capsule with 50 mg of a compound of Formula I or Formula II in powder form, 110 mg of lactose, 32 mg of talc and 8 mg of magnesium stearate.

Example B - Parenteral Injection

A pharmaceutical composition of the invention in a form suitable for injection is prepared by mixing 1.5% by weight of a compound of formula I or formula II in 10% by volume propylene glycol and water. The solution is sterilized by filtration.

Example C - Ointment

-20Compound of Formula I or Formula II 1.0 g

White soft paraffin up to 100,0 g

The compound of Formula I or Formula II is dispersed in a small volume of vehicle and gradually incorporated into the whole of the vehicle to produce a smooth, homogeneous product. The compressible metal tubes are then filled with the dispersion.

Example D - Topical cream preparation

Compound of Formula I or Formula II 1.0 g

Polawax GP 200 20.0 g

Anhydrous lanolin 2.0 g

White beeswax 2.5 g

Methylhydroxybenzoate 0.1 g

Distilled water up to 00,0 g

Polawax, beeswax and lanolin are heated together to 60 ° C. A solution of methylhydroxybenzoate is added and homogenization is achieved using high speed stirring. The temperature was then allowed to drop to 50 ° C. The compound of formula I or formula II is then carefully added and dispersed carefully, allowing the formulation to cool at low speed with stirring.

Example E - Local wash composition

Compound of Formula I or Formula II 1.0 g

Sorbitan monolaurate 0.6 g

Polysorbate 20 0.6 g

Cetostearyl alcohol 1,2 g

Glycerin 6.0 g

Methylhydroxybenzoate 0.2 g

Purified water B.P up to 00.0 g

-21 Methylhydroxybenzoate and glycerin are dissolved in 70 ml of 75 ° C warm water. Sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75 ° C and added to the aqueous solution. The resulting emulsion is homogenized, allowed to cool with continued stirring, and a compound of Formula I or Formula II is added as a suspension in the remaining water. The total suspension is stirred until it becomes homogeneous.

Example F - Eye drops preparation

Compound of Formula I or Formula II 0.5 g

Methylhydroxybenzoate 0.01 g

Propyl hydroxybenzoate 0.04 g

Purified water B.P. up to 00,0 ml (B.P = British Pharmacopea)

The methyl and propyl hydroxybenzoates are dissolved in 70 ml of 75 ° C warm purified water and the solution is allowed to cool. The compound of formula I or formula II is then added and the solution is sterilized by filtration through a membrane filter (0.22 µm pore size) and packaged under aseptic conditions into suitable sterile containers.

Example G - Formulation for inhalation application

For an aerosol container with a capacity of 15 to 20 ml: 10 mg of a compound of formula I or formula II is mixed with 0.1 to 0.2% of a lubricant, for example polysorbate 85 or oleic acid, and dispersed in a propellant such as freon, preferably in a mixture of (1,2-dichlorotetrafluoroethane) and difluorochloromethane and filled into a suitable aerosol container adapted for either intranasal or oral inhalation administration.

Example H - Formulation for inhalation application

For an aerosol container with a capacity of 15 to 20 ml: 10 mg of a compound of formula I or formula II are dissolved in 6-8 ml of ethanol, 0.1 to 0.2% of a lubricant such as polysorbate 85 or oleic acid is added; and dispersed in a propellant such as CFC, preferably in a mixture (1,2 dichlorotetrafluoroethane) and difluorochloromethane, and filled into a suitable aerosol container adapted for either intranasal or oral inhalation administration.

2. Synthesis examples

In the following examples, the temperature is in degrees Celsius (° C). Elemental analyzes and melting points of compounds of formula I and formula II prepared by the method of the following synthetic examples are shown in Tables 3 and 4.

Sodium hydride, trimethylsulfoxonium iodide, methyl vinyl ketone, ethyl cyanoacetate, morpholine, lithium aluminum hydride, boron trifluoride etherate, heptan-4-one, nonan-5-one, undecan-6-one, 4- (1,1-dimethylethyl) cyclohexanone, 4-cyclohexylcyclohexane, 4-cyclohexylcyclohexane , allyl bromide, dodecanal, 2,3-dimethylvaleraldehyde, 2-ethylbutyrylaldehyde,

2-ethylhexanal, adamantanone, bicyclo [3.3.1] nonan-9-one, 3-dimethylaminopropylamine,

3-diethylaminopropylamine, diisobutylamine, 2,6-dimethylheptan-4-one, cycloheptanone, acid anhydride, Triton B and 3-methylaminopropylamine were purchased from Aldrich Chemicals (Milwaukee, Wis, USA). 3- (1-piperidine) propylamine was synthesized by lithium aluminum hydride by reducing 1-piperidine propionitrile (Aldrich Chemicals; Milwaukee, Wis., USA).

4-dimethylaminobutylamine and 6-dimethylaminohexylamine were purchased from Pfaltz and Bauer (Waterbury, Conn., USA). 5-Dimethylaminopentylamine and 7-dimethylaminoheptylamine were purchased from Kari Industries (Aurora, Ohio, USA).

3-Aminopropanitrile and 3- (1-pyrrolidine) propylamine were purchased from Alfa Chemicals (Danvers, Mass., USA). 6- (1-Piperidine) hexylamine was prepared in two stages by alkylation of 6-bromohexylamine (Aldrich Chemicals) with piperidine and then reduction with hydride.

6- (1-Pyrrolidine) hexylamine was similarly prepared from the desired bromonitriles and pyrrolidine.

Group 1 - Synthesis of 4,4-disubstituted cyclohexanone

Scheme 1 shows a generic synthesis of 4,4-disubstituted cyclohexanes starting from either a commercially available ketone or α, α-disubstituted aldehyde.

Scheme 1 o

^R @ 1 ((CH3) 2 S * OH - ^R @ 1 (BF) OEt) = NaH. DMSO * ^η « ^π ·

Triion B-ethyl vinyl chloride. tex-buunol triethyl vinyl ketone. HjSO «

Examples 1 to 5 below describe the specific synthesis of 4,4-dipropylcyclohexanone from heptan-4-one, but this method was used to produce the following cyclohexanes starting from the commercially available ketones.

ketone cyclohexanone 2,6-dimethylheptane-4-one 4,4-bis (2-methylpropyl nonane-5-one 4,4-dibutyl undecane-6-one 4,4-pipenyl- cycloheptanone spiro [5.6] dodecane-3-one 2-adamantanone spiro (cyclohexane-1,2'-tricyclo [3.3.1.1 ^3,7 ] decan-4-one

-24In the following cases α, α-disubstituted aldehydes were available and 4,4-disubstituted cyclohexanones were synthesized:

aldehyde cyclohexanone 2-ethyl butyraldehyde 4,4-diethyl 2-ethylhexanol 4-butyl-4-ethyl 2,3-dimethylvaleraldehyde 4-Methyl-4- (1-methylpropyl) -

A second route with better yield specifically for the synthesis of 2-propylpentanal is described in Scheme 2. The procedures are described in Examples 5 and 6.

Scheme 2

H toluene, reflux. - H2O

HN

(1) 3lvl.bromide icetomtnl (2) HjO *

Example 1

2-propyl-1,2-epoxypentane

-25 Dimethylsulfoxide (11 mol) was added slowly to a mechanically stirred mixture of sodium hydride (1.1 equivalents) and trimethylsulfoxonium iodide (1 equivalent) under an inert atmosphere. A strong evolution of hydrogen was formed and upon completion of gas evolution, heptan-4-one (0.4 equivalents) was added and the reaction mixture was heated to 75 ° C for 3 to 24 hours.

The reaction mixture was poured into water (3-5 volumes) and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and concentrated to give the desired product (85% yield) which was used without further purification.

Example 2 2-Propylpentanal

To a vigorously stirred solution of 2-propyl-1,2-epoxypentane (1 equivalent) prepared as described in Example 1 in benzene cooled to 0 ° C was added a solution of boron trifluoride etherate (0.5 equivalent) in benzene. The reaction mixture was stirred for 1 minute and quenched by the addition of water. After phase separation, the organic phase was washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. The oil is distilled to give the desired product as a colorless oil; 75% yield, bp 60-63 70.1 mm.

Example 3

4,4-Dipropylcyklohex-2-enone

Method 1

To a solution of the base (Triton B, 0.05 equivalents) in tert-butanol was simultaneously added from separate funnels 2-propylpentanal (1 equivalent), prepared as described in Example 2, and methyl vinyl ketone (1.2 equivalents) over 1 hour such that the temperature is kept below 15 ° C. Concentrated hydrochloric acid (0.02-0.2 equivalents) was then added to the reaction mixture and the solution was concentrated to a viscous oil. The oil was dissolved in ethyl acetate and washed twice with a 0.5 M solution

-26 sodium hydroxide. The organic phase is dried over magnesium sulphate, filtered and concentrated to give the desired product after Kugelrohr distillation, boiling point 75-80 ° C / 0.05 mm, yield 20-35%.

Method 2

To a solution of 2-propylpentanal (1 equivalent) and methyl vinyl ketone (1 equivalent) in benzene (400 mL / mol) was added concentrated sulfuric acid (3 mL / mol). The reaction mixture was heated to reflux using a Dean-Stark trap. The reflux was continued for 3-5 hours and no further water separation was observed. The black reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution. The organic phase was dried with magnesium sulfate, filtered and concentrated to give a dark brown oil. The oil is distilled according to Kugelrohr to give the desired product as a colorless oil, boiling point 75-85 ° C / 0.075 mm, yield 65-75%.

Example 4

4,4-Dipropylcyklohexanón

To a suspension of 10% palladium on charcoal (0.1 equivalents) in ethyl acetate was added 4,4-dipropylcyclohex-2-enone prepared as described in Example 3. The reaction mixture was hydrogenated at 300 N / m ² hydrogen in a Parr Hydrogenation at room temperature until the uptake of hydrogen has decreased (0.5 to 5 hours). The catalyst was removed by filtration through celite and the filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification. Yield 98%.

Example 5

2-propylpent-4-enal

Toluene, valeraldehyde (1 equivalent) and diisobutylamine (1 equivalent) are mixed and heated to reflux using a Dean-Stark trap. Heating was continued until the water had stopped collecting in

-27 Separators (1 equivalent of water was collected). The reaction mixture was cooled to room temperature and toluene was removed under reduced pressure. Acetonitrile (500 mL / mol) was added to the colorless residue followed by allyl bromide (1.5 equivalents). The reaction mixture is refluxed for 16-24 hours.

The reaction mixture was treated with a buffer solution (acetic acid (60 mL) / sodium acetate (30 g) / water (300 mL / mol)) and refluxed for 5 hours. The black orange-brown solution was cooled to room temperature and ethyl acetate was added. The organic phase was then washed with 10% aqueous hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic extract was dried over magnesium sulfate, filtered. The oil was fractionated to give the desired product, bp 68-73 ° C / 30 mm, 50% yield.

Example 6

2-propylpentane

A Parr hydrogenation flask was charged with 10% palladium on charcoal (0.1 equivalent) and ethyl acetate. A solution of 2-propylpent-4-enal, prepared as in Example 5, in ethyl acetate was added. The mixture is hydrogenated at 300 N / m ^{2 of} hydrogen in a Parr hydrogenation apparatus at room temperature until hydrogen uptake ceases. The catalyst was removed by filtration through celite. The filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification.

Group 1A - Synthesis of 4-substituted cyclohexanes

The synthesis of 4-decylcyclohexanone is described in Example 7. Similarly, other straight-chained, branched or cyclic-substituted aldehydes can be converted to 4-substituted cyclohexanones.

Example 7

-28Synthesis of 4-decylcyclohexanone

The mixture of potassium carbonate (1 equivalent) and morpholine (3.3 equivalents) was cooled to -5 ^{° C} under an inert atmosphere and dodecanal (1 equivalent) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3-6 hours. Addition to ether followed by filtration and concentration afforded the crude morpholine enamine. The residue was distilled to give the desired product, bp 103-108 ° C / 0.07mm, 74% yield.

Under an inert atmosphere, the above morpholine enamine (1 equivalent) and methyl vinyl ketone (1.05 equivalents) were mixed and stirred overnight at room temperature. Buffer solution (sodium acetate (70 g) / acetic acid (700 ml) / ethanol (525 ml) / water (175 ml) / mol) was added and the solution was refluxed for 4-6 hours. The volatiles were removed under reduced pressure and the thick brown oily residue was partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a light brown viscous oil. The oil gave Kugelrohr distillation the desired product as a colorless viscous oil, bp 122-135 ° C / 0.22 mm; yield 40%.

The cyclohexenone synthesized above was hydrogenated in a manner similar to that described in Example 6 to give 4-decylcyclohexanone. The product was used without further purification.

Group 2 - Synthesis of compounds of formula I wherein m is 1 and R ³ and R ⁴ are other than H

Scheme 3 shows a generic synthesis of azaspiran analogs of Formula I wherein m is 1; R ³ and R ⁴ together are other than hydrogen and m, R ¹ and R ² are as defined above, starting from suitably substituted cyclohexanones.

-29Scheme 3

COOH \ COOH

HCI / HOAc / HJO

AcjO

rl

rj

2HC1

Rx * 3

Examples 8-12 below describe the synthesis of 2- (3-dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4,5] decane dihydrochloride from 4,4-diethylcyclohexanone. In a similar manner, the following cyclic ketones were reacted to obtain analogous derivatives of compounds of formula I including:

4.4- Dipropylcyclohexanone

4.4- Dibutylcyclohexanone

4,4- dipentylcyclohexanone

4,4-bis (2-methylpropyl) cyclohexanone

Ethyl-4-butylcyclohexanone

4-methyl-4- (1-methylpropyl) cyclohexanone

4-cyklohexylcyklohexanón

4-decylcyklohexanón

4- (1,1-dimethylethyl) cyclohexanone

Example 11 describes the reaction of an anhydride with dimethylaminopropylamine to afford the desired imide. Similarly, 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride is condensed with:

4-dimethylaminobutylamine

5-dimethylaminopentylamine

6-dimethylaminohexylamine

7- dimethylaminoheptylamine

3-diethylaminopropylamino

3- (1-piperidine) propylamine

6- (1-piperidine) hexylamine

3- (1-pyrrolidine) propylamine

6- (1-pyrrolidine) hexylamine and then reduced as described in Example 12 to provide the desired product to form the hydrochloride.

In a similar manner, any anhydride derived from a suitably substituted cyclohexanone can be reacted with any of the above amines and subsequently reacted as in Example 12 to give the desired azaspiran analog.

Example 8

-31 Ethyl- (cyano-α- (4,4-diethylcyclohexylidene) acetate)

To a solution of 4,4-diethylcyclohexanone (1 equivalent) in toluene was added ethyl cyanoacetate (1 equivalent), acetic acid (0.2 equivalents) and ammonium acetate (0.1 equivalents). The mixture was heated to reflux using a Dean-Stark apparatus to collect water azeotropically removed from the reaction. After collecting 1 equivalent of water, the reaction mixture was cooled and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by distillation using a Kugelrohr apparatus to give the desired product as a colorless oil, bp 92-98 ° C / 0.15 mm; yield 80-95%.

Example 9

4,4-Diethylcyclohexane-1-carboxy-1-acetic acid

To a solution of ethyl-α-cyano-α- (4,4-diethylcyclohexylidene) acetate (1 equivalent) prepared as described above in ethanol was added a solution of potassium cyanide (1.15 equivalent) in water. The reaction mixture was heated at 50-85 ° C for 3 to 9 hours and then concentrated to dryness. The residue was treated with hydrochloric acid and the mixture was then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in acetic acid / hydrochloric acid / water (4.5 L / 2 L / 0.2 L / mol) and heated to reflux for 2 to 5 days. The volatiles were removed under reduced pressure and the solid residue was partitioned between water and ethyl acetate. Dry the organic extract with magnesium sulfate, filter and concentrate to give the desired dibasic acid as a white solid. Recrystallization from ethyl acetate gave a crystalline solid, m.p. 150-152 ° C, yield 75-85%.

Example 10

4,4-Diethylcyclohexane-1-carboxy-1-acetic acid anhydride

The 4,4-diethylcyclohexane-1-carboxy-1-acetic acid (1 equivalent) prepared as described in Example 9 was dissolved in acetic anhydride and refluxed for 1 to 6 hours. Excess acetic anhydride was removed by distillation under reduced pressure and the residue was recrystallized from hexanes, mp 91-93 ° C, yield 90-95%.

Note: In cases where the substituents at the 4-position of the starting cyclohexanone are not identical, the geometric isometric anhydrides are separated by chromatography on a Waters 500 preparation system and using hexane / ethyl acetate mixtures as eluent.

Example 11

2- (3-dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4.5] decane-1,3-dione

To a solution of 4,4-diethylcyclohexane-1-carboxy-1-acetic anhydride (1 equivalent) in toluene was added 3-dimethylaminopropylamine (1.05 equivalents) and the reaction mixture was heated to reflux using a Dean-Stark trap. After the water (1 equivalent) was collected in the trap, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was used directly without further purification.

Example 12

2- (3-Dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4,5] decane dihydrochloride

To a mixture of lithium aluminum hydride in an equivalent amount in diethyl ether is added dropwise a solution of 2- (3-dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4.5] decane-1,3-dione (1 equivalent), prepared as described above. in Example 11, in diethyl ether. The reaction mixture was stirred for 2-6 hours after the addition was complete. The excess hydride was quenched with sodium sulfate decahydrate and the resulting mixture was filtered and the filtrate concentrated to give the desired amine as a colorless oil, yield 90-95%.

The oil was dissolved in a minimum of anhydrous ethanol and a cooled solution of hydrogen chloride in ethanol was added. After addition of a large volume of ether it is formed

-33 a white precipitate which was isolated by filtration. The white solid was recrystallized from ethanol, mp 298-299 ° C (dec.), Yield 90%.

Group 3 - Synthesis of compounds of formula I wherein m is 1 and R ³ and R ⁴ are hydrogen

Scheme 4 describes a generic synthesis of azaspirane analogs of formula I wherein m is 1, R ³ and R ⁴ are hydrogen and n, R ¹ and R ² are as defined above, from suitably substituted cyclohexanones.

Scheme 4

Examples 13 and 14 describe the synthesis of 2- (3-aminopropyl) -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride from 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride.

Similarly suitably substituted cyclohexanones and anhydrides derived therefrom can be reacted with α-aminoalkynitriles (n = 4 to 7) as shown in Examples 13 and 14 to synthesize the desired azaspirals wherein R ³ = R ⁴ = H

Example 13

2- (2-cyanoethyl) -8,8-dipropyl-2-azaspiro [4.5] decane-1,3-dione

-34K To a solution of 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride (1 equivalent), prepared analogously to the 4,4-diethyl derivative prepared in Example 10, 3-aminopropanenitrile (1.1 equivalents) and toluene . The reaction mixture was heated to reflux using a Dean-Stark trap. After collection of water (1 equivalent), the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue is purified by column chromatography (hexane / ethyl acetate = 2/1) to give a white solid, m.p.

117.5 ° C, 95% yield.

Example 14

2- (3-Aminopropyl) -8,8-dipropyl-2-azaspiro [4,5] decane dihydrochloride

To a mixture of lithium aluminum hydride (4 equivalents) in diethyl ether is added dropwise a solution of 2- (2-cyanoethyl) -8,8-dipropyl-2-azaspiro [4,5] decane-1,3-dione (1 equivalent) prepared as is described in Example 13, in diethyl ether. After the addition was complete, the reaction mixture was stirred for 2-4 hours. The excess hydride was quenched with sodium sulfate decahydrate and the resulting mixture was filtered and the filtrate was concentrated. The resulting liquid was purified by preparative liquid chromatography (silica gel, 2.5% ammonium hydroxide in methanol) to give the desired amine as a colorless oil, yield 73%.

The oil was dissolved in a minimum of anhydrous ethanol and a solution of hydrogen chloride in ethanol was added. The solution was concentrated to give a white solid, mp 245-249 ° C (dec.), 95% yield.

Group 4 - Synthesis of compounds of formula I wherein m is 1 and R ³ is other than hydrogen and R ⁴ is hydrogen

Scheme 5 shows a generic synthesis of azaspirane analogs of formula I wherein m is 1, one of R ³ and R ⁴ is hydrogen, while the other is other than hydrogen and n, R ¹ and R ² are as defined above, from suitably substituted cyclohexanones.

-35Scheme 5

Examples 15 and 16 describe the synthesis of (3-methylaminopropyl) -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride from 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride.

Similarly suitably substituted cyclohexanones as described above and their anhydrides derived therefrom can be reacted as described in Examples 15 and 16 with α-alkylaminoalkylamines (n = 4 to 8) to give azaspirane derivatives wherein R ³ = alkyl and R ⁴ = H.

Example 15

2- (3-dimethylaminopropyl) -8,8-dipropyl-2-azaspiro [4.5] decane-1,3-dione

To a solution of toluene and 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride (1 equivalent) was added 1.05 equivalents of aminopropylamine. The reaction mixture was heated to reflux using a Dean-Stark trap. After collecting 1 equivalent of water, the reaction mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was used without further purification.

Example 16

2- (3-methylaminopropyl) -8,8-dipropyl-2-azaspiro [4,5] decane dihydrochloride

A solution of 2- (3-methylaminopropyl) -8,8-dipropyl-2-azaspiro [4.5] decane-1,3-dione (1 equivalent) prepared dropwise is added dropwise to a mixture of lithium aluminum hydride (4 equivalents) in diethyl ether. The product was purified by column chromatography (silica gel, 0.5% ammonium hydroxide in methanol) to give a colorless oil, yield 67%.

The oil was dissolved in a minimum of anhydrous ethanol and a solution of hydrogen chloride in ethanol was added. The white precipitate formed upon cooling is isolated by filtration, mp 258-260 ° C (dec.), Yield 84%.

Group 5 - Synthesis of compounds of formula I wherein m is 2

Scheme 6 describes a process for making alkyl-substituted azaspiro [5.5] undecane analogs starting from substituted cyclohexanones.

Scheme 6

about

II

NCCHjCOOE: NH]

W

.2HC1

Examples 17 to 21 below describe the synthesis of (3-dimethylamino) propyl-9,9-dipropyl-3-azaspiro [5.5] undecane dihydrochloride from 4,4-dipropylcyclohexanone.

In a similar manner, the appropriately substituted cyclohexanones described above (see Groups 1, 1A and 2) and the anhydrides derived therefrom as described in this group may be reacted with:

(a) dialkylaminoalkylamines as described in Group 2 of the synthetic examples to provide azaspiran derivatives wherein R ³ = R ⁴ = alkyl.

b) aminoalkyl nitriles as described in Group 3 of the synthetic examples to provide azaspiran derivatives wherein R ³ = R ⁴ = H.

c) alkylaminoalkylamines as described in Group 4 of the synthetic examples to provide azaspiran derivatives wherein R ³ = alkyl and R ⁴ = H.

Example 17

9,9-Dipropyl-1,5-dicyano-3-azaspiro [5,5] undecane-2,4-dione

To a solution of 4,4-dipropylcyclohexanone (1 equivalent) and ethyl cyanoacetate (2 equivalents) in ethanol cooled to 0 ° C was added saturated alcoholic ammonia solution. The reaction mixture is capped and allowed to react at 0 ° C for two to seven days. The precipitated ammonium salt of dicyanoimide is filtered, compressed, washed with ether and dried. The dried salt is dissolved in a minimum amount of boiling water and filtered hot. The hot filtrate was stirred and acidified with concentrated hydrochloric acid and after cooling the precipitated product was isolated by filtration to give the desired imide, yield 33%.

-38Example 18

4,4-Dipropylcyclohexane-1,1-diacetic acid

9,9-Dipropyl-1,5-dicyano-3-azaspiro [5.5] undecane-2,4-dione, prepared according to the method of Example 17, is dissolved in a concentrated hydrochloric acid / acetic acid / water solution (4 / 7/1) and the solution is refluxed for 2 to 3 days. The reaction mixture was cooled to room temperature and the volatile materials were removed on a Rotavape (rotary evaporator). The residue was partitioned between water and ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired acid, which was recrystallized from ethyl acetate / hexane, yield 35-50%.

Example 19

4,4-Dipropylcyclohexane-1,1-diacetic acid anhydride

The 4,4-dipropylcyclohexane-1,1-diacetic acid prepared as described in Example 18 is dissolved in acetic anhydride and refluxed for 1-6 hours. Excess acetic anhydride was removed by distillation under reduced pressure and the residue was recrystallized from hexanes, mp 91-93 ° C, yield 90-95%.

Example 20

3- (3-dimethylaminopropyl) -9,9-dipropyl-3-azaspiro [5.5] undecane-2,4-dione

This imide was prepared from 9,9-dipropylhexane-1,1-acetic anhydride (1 equivalent) prepared as described in Example 19 and 3-dimethylaminopropylamine (1 equivalent) in a similar manner to that described in Example 11. which is a colorless oil is used without further purification.

Example 21

3- (3-Dimethylaminopropyl) -9,9-dipropyl-3-azaspiro [5,5] -undecane dihydrochloride

-39Amin is prepared by reducing 3- (dimethylamino) propyl-9,9-dipropyl-3-aza-spiro [5,5] undecane-2,4-dione, prepared as described in Example 16, with lithium aluminum hydride, in a manner similar to the procedure as described in Example 12. The crude white solid is precipitated by addition of ether and recrystallized from ethanol, m.p.

320 DEG C. (dec.), Yield 85-90%.

Group 6 - Synthesis of polycyclic azaspiran derivatives of formula II

The 2-adamantanone is converted to the 4,4-spirosubstituted cyclohexanone as described in Group 1 and then converted to the desired azaspiran analogue using the procedures described in Group 2 (Examples 8-12), mp 329-330 ° C.

The 2-adamantanone is converted to the desired azaspiran derivative using the procedures described in Group 2 (Examples 8-12), mp 300-302 ° C.

The 2-adamantanone can also be reacted as described in Group 5 to provide azaspirane derivatives wherein m = 2.

In a similar manner, the 2-adamantanone anhydride synthesized either as described in Group 2 or Group 5 may be reacted with:

(a) dialkylaminoalkylamines as described in Group 2 of the synthetic examples to provide azaspiran derivatives wherein R ³ = R ⁴ = alkyl.

b) aminoalkyl nitriles as described in Group 3 of the synthetic examples to provide derivatives wherein R ³ = R ⁴ = H.

c) alkylaminoalkylamines as described in Group 4 of the synthetic examples to provide azaspiran derivatives wherein R ³ = alkyl and R ⁴ = H.

The bicyclo [3.3.1] nonan-9-one is similarly reacted as in Group 2 to give the desired azaspirane derivative, m.p. 303-304 ° C. This ketone can be modified as 2-adamantanone to give similarly substituted diamine derivatives.

3,3-dimethylbicyclo [3.3] nonan-9-one and 3,3,7,7-tetramethylbicyclo [3.3.1] nonan-9-one (prepared according to v. Chan, Ph. D. Dissertation, University of Utah (1972) may similarly be reacted as described above for the starting system.

-40Chan's dissertation is a publicly available document and is easily obtainable from

U-M-I-Dissertation Information Service, 300 N. Zeeb Road, Ann Arbor, Mich. 48106, (800)521-0600 or (313) 761-4700. In the Khan dissertation 3,3,7,7-tetramethylbicyclo [3.3.1] nonan-9-one is synthesized as follows:

3,3,7,7-tetramethylbicyclo [3.3.1] nonan-9-one (1) is synthesized for construction studies of bicyclo [3.3.1] nonane systems. It has been found that both the resulting compound (1) and 3,3-dimethylbicyclo [3.3.1] nonan-9-one are in double boat form at room temperature. The resulting compound (1) is prepared as follows:

->

CHO

) = O

OMI

Isobutylaldehyde is alkylated with methylvinyl ketone via its pyrrolidine enamine, cyclized in acid and then hydrogenated to give 4,4-dimethylcyclohexanone 2. Ketone 2 is alkylated with acrolein via its morpholino-41 enamine then hydrolyzed to give 2- (2). oxo-cyclohexyl) propanal

3. The crude compound 3 is then purified via its diketal, cyclized in 7N hydrochloric acid, and esterified to give 7,7-dimethyl-bicyclo [3.3.1] nonan-9-yl-2-yl-pivalate 4. Ketalization 4 followed by alkaline hydrolysis, CrO, pyridine oxidation and alkylation with iodomethane and potassium tert-butoxide afford 3,3,7,7-tetramethyl-9,9-ethylenedioxybicyclo [3.3.1] -nonan-2-one. Wolf-Kishner reduction failed, compound 5 is reduced to an alcohol with lithium ammonia, then mesylated to give 3,3,7,7-tetramethyl-9,9-ethylenedioxybicyclo [3.3.1] nonan-2-exo-yl-methanesulfone 6 Lithium-ammonia reduction 6 followed by acid hydrolysis affords the title compound 2.

Table 3

Melting points (decomposition) of compounds of formula I and formula II prepared by the methods of the synthetic examples

Melting point (° C) 01 300-302 02 299-300 03 299-301 04 301-302 05 297-298 06 245-249 07 258-260 08 295-296 09 296-298 10 289-291 11 303-304 12 306-307 13 297-298 14 326-328 15 325-326 16 334-335 17 305-307 18 252-254 19 285-286 20 266-269

21 274-276 22 259-261 23 245-246 24 329-330 25 308-310 26 323-325 27 284-286 28 287-289 29 293-296 30 271-272 31 275-278 32 240-245

note:

(a) See Table 1 for structure

Table 4

Elemental analysis of compounds of Formula I and Formula II prepared by methods of the synthetic examples

# molecular formula mass [M] C calculated found for Cl H N C H N Cl 01 C18H38N2CI2 353.5 61.17 10.83 7.93 20,06 60.98 10.78 7.64 20,01 02 C20H42N2CI2 381.5 62.97 11,10 7.34 18.59 62,73 10.97 7.32 18.42 03 C22H46N2CI2 409.5 64.52 11.32 6.84 17.31 64.69 11.34 6.82 04 C24H50N2CI2 437.6 65.88 11.52 6,40 16.20 66.04 11.42 6.31 16.39 05 C22H46N2CI2 409.5 64.52 11.32 6.84 17.31 64.23 11.32 6.76 17.28 06 C18H38N2CI2 353.4 61.17 10.84 7.93 19,30 61.03 10.90 7.85 19.97 07 C19H40N2CI2 367.4 62.11 10.97 7.62 19,30 62.06 10.99 7.58 19.33 08 C21H44N2CI2 395.5 63.78 11.21 7.08 17.93 63.68 11.07 7.08 18,12 09 C19H40N2CI2 367.4 62.11 10.97 7.62 19,30 62.06 10.98 7.61 19.35 10 C19H40N2CI2 367.4 62.11 10.97 7.62 19,30 61,99 11.01 7.58 19.36 11 C20H42N2CI2 381.5 62.97 11,10 7.34 18.59 62.92 11,11 7.30 18.64 12 C20H42N2CI2 381.5 62.97 11,10 7.34 18.59 62.88 11.13 7.31 18.65 13 C24H50N2CI2 437.6 65.88 11.52 6,40 16.20 65.89 11.52 6.38 16.17

14 C20H40N2CI2 379.5 63,31 10.62 7.38 18.69 63,24 10.64 7.37 18.68 15 C18H38N2CI2 353.4 61.17 10.84 7.93 20,06 61.10 10.77 8.02 20,07 16 C18H38N2CI2 353.4 61.17 10.84 7.93 20,06 61.16 10.86 7.92 19.94 17 C20H40N2CI2 379.5 63,31 10.62 7.38 18.69 63.22 10.67 7.35 18.70 18 C22H46N2CI2 409.5 64.52 11.32 6.84 17.31 64,42 11.32 6.82 17.39 19 C23H46N2CI2 421.5 65.53 11,00 6.65 16.82 65.42 11.03 6.64 16.89 20 C21H44N2CI2 395.5 63.78 11.21 7.08 17.93 63,64 10.99 6.96 21 C22H46N2CI2 409.5 64.52 11.32 6.84 17.31 64.59 11,30 6.78 17,30 22 C23H48N2CI2 423.6 65,22 11.42 6.61 16.74 65.05 11.29 6.57 23 C24H50N2CI2 437.6 65.88 11.52 6,40 16.20 65.91 11.48 6.37 16.19 24 C23H40N2CI2 417.5 66.17 10.14 6.71 16.98 66.21 10.16 6.67 16.94 25 C18H34N2CI2 349.4 61.88 9.81 8.02 20.29 61.30 9.70 7.85 26 C17H24N2CI2 337.4 60.52 10.16 8.30 21.02 60.55 10.12 8.31 27 C22H44N2CI2 407.5 64.84 10.88 6.87 17.40 64.75 10.89 6.87 17.34 28 C25H50N2CI2 449.6 66.79 11.21 6.23 15.77 66.68 11.31 6.30 15.67 29 C26H52N2CI2 463.6 67,36 11,30 6.04 15.29 67,39 11.29 6.03 15.24 30 C20H40N2CI2 379.5 63,31 10.62 7.38 18.69 63,24 10.65 7.35 18.65 31 C21H42N2CI2 393.5 64.10 10.76 7.12 18.02 60.01 10.81 7.10 17.93 32 C20H42N2CI2 381.5 62.97 11,10 7.34 18.59 62.83 11,11 7.31 18.52

note:

Compounds 03, 20, 22, 25 and 26 were not analyzed for chloride composition. While the above description and examples fully describe the invention and its preferred embodiments, it should be understood that the invention is not limited to certain described embodiments falling within the scope of the following claims.

Claims (39)

PATENT CLAIMS An azaspirane derivative of the 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 or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² together is 5 to 10; or R ¹ and R ² are joined to form a cyclic alkyl group having 3 to 7 carbon atoms; R ³ and R ⁴ are the same or different and are selected from hydrogen or straight chain alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are joined to form a cyclic alkyl group having 4 to 7 carbon atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. A compound according to claim 1 of the formula A compound according to claim 1, which is selected from the group of compounds of the formula: with· N A compound of formula II wherein n is 3 to 7, m is 1 or 2, R ¹ , R ² , R ⁵ and R ⁶ are the same or different and are selected from hydrogen or methyl, R ³ and R ⁴ are the same or different and are selected from hydrogen or straight chain alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are joined to form a cyclic alkyl group having 4 to 7 carbon atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. The compound of claim 4, which is selected from 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an immunomodulatory effective amount of 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 or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² together is 5 to 10; or R ¹ and R ² are joined to form a cyclic alkyl group having 3 to 7 carbon atoms; R ³ and R ⁴ are the same or different and are selected from hydrogen or straight chain alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are joined to form a cyclic alkyl group having 4 to 7 carbon atoms; / ' HnC 10 or a pharmaceutically acceptable salt or hydrate or solvate thereof. Pharmaceutical composition according to claim 6, characterized in that it contains as its active compound H FROM N H \ Pharmaceutical composition according to claim 6, characterized in that the active compound is selected from: H z N H \ - - / n. from -y \ -! In n. / WITH, H · FROM H N_ H · FROM FROM N H \ \, / \ _ M _N Pharmaceutical composition according to claim 6, characterized in that it is in a dosage form suitable for oral administration. Pharmaceutical composition according to claim 6, characterized in that it is in a dosage form suitable for parenteral administration. Pharmaceutical composition according to claim 6, characterized in that it is in a dosage form suitable for inhalation. Pharmaceutical composition according to claim 6, characterized in that it is in a dosage form suitable for topical application. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an immunomodulatory effective amount of a compound of formula -52ft or Formula II Λ ~ N V (11) wherein n is 3 to 7, m is 1 or 2, R ¹ , R ² , R ⁵ and R ⁶ are the same or different and are selected from hydrogen or methyl, R ³ and R ⁴ are the same or different and are selected from hydrogen or straight chain alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are joined to form a cyclic alkyl group having 4 to 7 carbon atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. 14. A pharmaceutical composition according to claim 13 wherein the compound is selected from: 15. A pharmaceutical composition according to claim 13 which is in a dosage form suitable for oral administration. 16. A pharmaceutical composition according to claim 13 which is in a dosage form suitable for parenteral administration. 17. A pharmaceutical composition according to claim 13 which is in a dosage form suitable for inhalation. 18. A pharmaceutical composition according to claim 13 which is in a dosage form suitable for topical administration. 19. Use of a compound of formula I: ri R 1 (CH 2 S-N, rj d) r. (Chi), -54where, 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 or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R ¹ and R ² together is 5 to 10; or R ¹ and R ² are joined to form a cyclic alkyl group having 3 to 7 carbon atoms; R ³ and R ⁴ are the same or different and are selected from hydrogen or straight chain alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are linked to form a cyclic alkyl group of 4 to 7 carbon atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a pharmaceutical composition for treating animals in need of immunomodulation. The use of claim 19, wherein the compound is The use of claim 19, wherein the compound is selected from the group of compounds: / JVÄJ \ / _ / -56 «a / K / / N \ / N \ The use of claim 19, wherein the compound is administered orally. The use of claim 22, wherein from 1 to 1000 mg of compound per day is administered. The use of claim 19, wherein the compound is administered parenterally. The use of claim 24, wherein from 0.1 to 1000 mg of the compound per day is administered. The use of claim 19, wherein the compound is administered by inhalation. The use of claim 26, wherein from 10 to 100 mg of compound per day is administered. The use of claim 19, wherein the compound is administered topically. The use of claim 28, wherein the compound is administered in an amount of from 1.5 to 500 mg / kg body weight per day. Use of a compound of formula (II) wherein n is 3 to 7, m is 1 or 2, R ¹ , R ² , R ⁵ and R ⁶ are the same or different and are selected from hydrogen or methyl, R ³ and R ⁴ are the same or different and are selected from straight chain hydrogen or alkyl of 1 to 3 carbon atoms; or R ³ and R ⁴ are linked to form a cyclic alkyl group of 4 to 7 carbon atoms, or a pharmaceutically acceptable salt or hydrate or solvate thereof, for the manufacture of a pharmaceutical composition for treating animals in need of immunomodulation. The use of claim 30, wherein the compound is selected from the group of compounds The use of claim 30, wherein the compound is administered orally. The use of claim 32, wherein from 1 to 2000 mg of the compound per day is administered. The use of claim 30, wherein the compound is administered parenterally. The use of claim 34, wherein from 0.1 to 1000 mg of the compound per day is administered. The use of claim 30, wherein the compound is administered by inhalation. The use of claim 36, wherein from 10 to 100 mg of compound per day is administered. The use of claim 30, wherein the compound is administered topically. The use of claim 38, wherein the compound is administered in an amount of from 1.5 to 500 mg / kg body weight per day.