CZ397091A3 - Azaspirane derivatives and pharmaceutical preparations containing thereof - Google Patents

Abstract

Analogs of spivogermani compounds that are applied in an effective amount, has an immunomodulatory effect animals in need and pharmaceuticals compositions containing such compounds.

Description

Field of the Invention .Ρ; · [;

i; z

The invention relates to a spiro-germanium analog comprising non-metals, pharmaceutical compositions comprising the same 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., U.S. Patent 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-gennanspiro) 4.5 / dean; N- (3-dimethylaminopropyl) -2-aza-8,8-diethyl-8-germanspiro [4.5] decane;

N- (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 31, 1987, claims a method for treating multiple sclerosis, comprising treating an affected patient with multiple sclerosis with an effective amount of spirogermania selected from the group consisting of:

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;

N- (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.

Rice et al., J. Heterocycl. Chem., 10 (5), 731-735 (1973), (Rice I) discloses 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 and N- (3-dimethylaminopropyl) -9,9-propyl-3-aza2 spiro (5.5) undecane and N- (3-dimethylaminopropyl) -9,9-diethyl-3-azaspiro [5,5] -undecane. Rice I shows that the biological evaluation of these amines shows significant inhibition of cancer cell growth in human cancer cells grown in tissue culture.

There is no discovery or suggestion in Rice I that such amines have antiarthritic action.

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

Rice et al. No. 3,256,277 published

June 14, 1966 (Rice III) claims a compound selected from the group consisting of compounds of Formula (I)

wherein A is a ring with at least 5 ring atoms, all ring atoms being carbon atoms except r 1, R 2 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; cyclic lower alkyl groups and monocarbocyclic groups; B is a saturated ring of 5 to 6 ring atoms, the ring atoms other than the nitrogen atom are carbon atoms; Y is selected from the group consisting of an alkyl group and an alkenylene group of up to 6 carbon atoms; n is 0-1; and R is selected from the group consisting of lower alkyl, lower aikenyl, cyclonic lower alkyl and alkenylamino, saturated heterocyclic groups selected from morpholino, piperidinone, pyrrolidine, piperazine, tetrahydrofuryl and its lower alkyl and alkenyl substituted derivatives, monocarbocyclic aryl, naphthyl, cuinolyl, furvl 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 the nervous and cardiovascular systems. There is no discovery or suggestion in Rice III that such compounds have an antiarthritic effect.

Rice et al. U.S. Pat. No. 3,282,947, published Nov. 1, 1966 (Rice IV), claims compounds of the formula

wherein R a are each selected differently from the group consisting of: ...

(a) hydrogen (b) lower alkyl

Aralkyl-1-selected from the group consisting of pyridyl, lower alkyl and phenyl-lower-alkyl-ene; - (d) di-lower alkylamino lower alkylene skupir * ^ or (e) hydroxy lower alkylene / Rice IV states that such compounds are valuable as intermediates and that they also have undefined farm koTo'gickě ^- effects. V ^- Ric E IV are no disclosure or suggestion that such amines have antiarthritic activity.

Rice et al., J. Med. Chem., 6, 388-402 (1963) discloses preparations of a broad group of X-dialkylaminoalkylazaspiroalkanes and reports that strong (but undefined) pharmacology activity has been observed in the group and that some observations have been made on the known growth inhibitory effects Certain members of the group (e.g., 3- (3-dimethylaminopropyl-9-tert-butyl-3-azaspiro [5.3] undecane)) on cancer cells in tissue cultures and objective clinical effects in human cancer cells. discovery or presumption of antiarthritic effects ·

Rice et al., J. Heterocycl. Chem., 1 (3), 125-127 (1964), (Rice VI) discloses synthetic procedures for various symmetrical and asymmetric 3,9-diazaspiro (5,5) -undecanes. There is no discovery or suggestion in Rice VI that such compounds have any biological activity.

Rice et al. U.S. Patent No. 3,825,546, published July 23, 1974 (Rice VII), claims a compound

in which

12.

R and R are the same or different alkyl groups Λ

1-4 carbon atoms

X is silicone or germanium

And they are the same and both are

II

CH 2 or C n is Ο or 1

Β is CH ₃ when n is one and B is the same as A when n is zero

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

45.

R and R are the same or different lower alkyls having 1-4 carbon atoms, lower alkenyls having 3-4 carbon atoms, or cyclized together to form a heterocyclic group selected from morpholine, pyrrolidine, piperidine and lower alkyl (1-4 carbon atoms) piperazines. a new group in which said lower alkyl is attached to the terminal nitrogen atom. Rice VII reports that bisquaternary salts of such compounds exhibit antihypertensive effects and are particularly useful in blocking ganglionic activity in dogs and other animals. There is no discovery or suggestion _in Rice VII that such compounds have antiarthritic effects.

Sanwa KK, European Patent Application Publication Number EO, 186,505 A2, published July 2, 1986, proposes a formulation formed by an organo-germanium compound represented by the formula

R R

I-I Ge-CC-COOH 1-5n (S) in which one is greater than or equal ^to 1? R is hydrogen, alkyl-1-, COOH-, -COOR-, -phenylene-1- (3-carboxylic acid);

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

<

the.

or regulating action.

Di Martino et al., J. Pharmacol., Exp. Therapeut., 235, 103-110. (1986) report on the ability of spirogermania to induce suppressor cells.

Badger et al., Immunopharmacol., 10, 201-207 (1935) report on the generation of suppressor cells in normal spirogermanium-treated rats.

Australian National University, PCT Patent Application Publication Number WO 85/05031, published Nov. 21, 1985, claims a method of modulating or suppressing an immune response in an animal by administering an effective amount of at least one .alpha.-J-film capable of modifying cell surface interaction its surface properties such that it inhibits or modifies antigen recognition by the affected cells. Preferably, am1 Lifile is a cationic surfactant, such as a double-chained quaternary ammonium surfactant.

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

-i i

c NR ¹ -NN R ¹ (CH 2 -C ¹ ) wherein A- is a mono or bi-cyclic carbon ring of at least 5 carbon atoms, Z is selected from one or more hydrogen, alkyl and alkoxy, n is 0 or 1, R is an alkylene chain of 2 or 6 carbon atoms or an alkylene chain of 2 to 6 carbon atoms substituted by a hydroxyl group on carbon atom 2 in at least the beta or nitrogen position, and R is a dialkyl of which each alkyl group has 1; -a-6-atoms-carbon-carbon or alkylene chain forming, together with the nitrogen atom to which it is attached, a morpholino, a non-eridine, a pyrrolidine or a piperazine ring, or an alkyl-substituted derivative of any of them, containing from 1 to The 6-carbon atoms in the substituent group and their non-toxic acid addition salts.

N- (3-dimethylaminopropyl) -9-tert-butyl-3-azaspiro- (5,5) undecane.

The Gerschchter 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 relates to a compound of the formula:

R,

Rz (CH 1) - N (CH 1?

'in.

in which:

n is 3-7;

m is, l · or 2; ...: ..... ....... ·. .

and R 6 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 ₂ and R ₂ , when taken together, is 4-10 ; or R and R ₂ are joined together to form cyclic alkyl sk-up-and-ny-containing d-C ^ 3--7 -atomů-uhTíku? ------ "

R 6 and R 6 are the same or different and are selected from hydrogen or a straight chain alkyl having 1 to 3 carbon atoms; or R 1 and R 2 are joined together to form a cyclic alkyl group containing R 3 and R 3

4-7 carbon atoms; provided that when R ₇ and R 6 are R 6 and R 6 are CH 2 and -b is 1 or 2, n is other than 3, and further provided that when R _{2 3} ^H 1 R ₁ is (CH 3) R 4 ^and R 4 are CH 4 and m is 2, n is no more than 3, or a pharmaceutically acceptable salt thereof, hydrate or solvate thereof.

This invention:

X ^ í ·. Ca) z also refers to a compound of the formula

Rj /

X \

R4

2;

in which: n is 3-7; m is 1 or R 1, R ₂ , R 5 ^and R 6 are the same or different and are selected from hydrogen or methyl;

And R are identical or different and are selected from hydrogen or straight chain alkyl containing .1 = 3-carbon-carbon-U- ·; -or-RY-Ar-R-sou -j ^- ^ together spiro

To form a cyclic alkyl group containing 4-7 carbon atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

and

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

R) (CHi) here in which:

n is 3-7; m 'is 1 or 2;

R 6a 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 2, when taken together, is 4-10; or R1 and R2 are taken together to form a cyclic alkyl group containing 3-7 carbon atoms; i, and R _Ro _jsou same or different and are selected from a -___ _{_} ___4 of thanks or straight chain alkyl containing .1-3 carbon atoms; or R 6 and R 6 are joined together to form a cyclic alkyl group containing 4-7 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 formula (XI).

The invention also relates to a method of treating an animal in need of immunomodulation which remains in the administration of such an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

It will be apparent to those skilled in the art 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, with Compound // 02 of Table 1 being particularly preferred.

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.

R i

Compounds of formula (I) and formula (II) may be produced by the methods described in the Examples below.

All compounds of formula (I) and formula (II) are useful for treating animals, including humans in need of immunomodulation. Such immunomodulatory activity is determined using an arthritic adjuvant-induced test in rats, the results are summarized in Table I, and / or a suppressor cell activity assay, the results of which are summarized in Table II.

TABLE 1

The activity of the compounds of formula (I) and formula (II) in the adjuvant-induced arthritis assay

R «

»(Fa). ro Π R | Ri R) fU (b) (C) 01 1 3 CHjCHi ch ₃ ch ₂ ch ₃ CHj 0.57 30 02 / 1 3 CH ₂ CH ₂ CH ₂ ch ₂ ch ₂ ch ₂ CHj CHj 1.35 30 03 / 1 3 CHjfCHíhCHi CH ₃ (CH ₃ ) ₂ CH ₂ CHj CHj 0.3S 30 04 / 1 3 CH ₃ (CH 2) ₃ CH ₃ CH _{(CH2) 2} JCH CHj CHj 0.4 30 OJ 1 3 (CH ₂ CHCH ₂ (CH ₃ hCHCH ₂ ch ₃ CHj 0.97 30 .06 2 3 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CHj. CHj 0.90 30 07 / 1 3 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ H H 1.52 30 OS 1 3 'CHjCH ₂ CH ₂ ch ₂ ch ₂ ch ₂ CHj _r . H 1.02 09 / 1 3 CH 3 CH 2 (CH 3) CH CHj CHj CHj 1.27 30 10 1 3 CHj CH ₃ CH ₂ (CH ₃ ) CH, CHj CHj 2.84 60 11 1 3 CHjCHi CH ₂ (CH ₂ ) ₂ CH ₂ CHj CHj l.U AT 12 l , 3 CH 2 CHOiCHi CH ₂ CH ₂ CHj .CHj 4.00 .30 13 1 3 H CH3 (CH3) ₃ CH3 ch ₃ CHj 0.78 30 - and 3 H '’' · cvclohejcvl ‘ ... CH ₃ / ch ₃ . ’.019.8. .130 ... 1J 3 H (CH3) jC ch ₃ CHj 0.31 30 , 6 1 3 (CH3) ₃ C H ch ₃ CHj 0.90 30 17 1 3 —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - CHj CHj 1.70 60 13 1 3 CH ₂ CH ₂ CH ₂ ch ₂ ch ₂ ch ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1.42 30 19 Dec 1 3 CHjCHiCH: CH ₃ CH ₂ CH ₂ —CH ₂ (CH ₃ ) j CH ₂ - 1.39 30 20 May AND 4 CHjCHjCHi CH ₃ CH ₂ CH ₂ CHj ch ₃ 0.4J 30 21 l WITH CH ₂ CH ₂ CH ₂ ch ₂ ch ₂ ch ₂ CHj CHj 0.S1 30 22nd l 6 CH ₂ CH ₂ CH ₂ ch ₃ ch ₃ ch ₂ CHj ch ₃ 1.2S 30 23 1 7 CH ₂ CH ₂ CH ₂ ch ₂ ch ₂ ch ₂ CHj CH] 1.57 30 24 1 3 Spiroadamintan CHj CHj 0.76 30 25 3 Adanunun CHj CHj 0.33 30 26 1 3 BicvClo (3.3.1) nonan-9-one. CHi CHi 0.92. .30 " 27 Mar: 3 CH ₂ CH ₂ CH ₂ CHjCHjCHí -CHKCHíhCHí- 1.03 30 23 1 6 ch ₂ ch ₂ ch ₂ CH ₂ CH ₂ CH ₂ -CH ₂ CH ₂ - ₂ CH ₂ - .63 30 29 6 ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ —CHKCH ^ jCHj— n, t. 30 1 3 ch ₃ ch ₂ CH ₂ CH ₂ —CH ₂ (CH ₂ ) ₁ CH ₂ - m.p. 31 1 3 ch ₃ ch ₂ CH ₂ CH ₂ —CH (CH ₂ )] CH - n.l, 32 1 3 chjCH ₂ ch ₃ ch ₂ CHjCHi CHjCHj

m.p. = not tested (a) ir compound number. The numbers of compounds 01 to 23 and 27 to 32 are those of the compounds of formula (I) (b) AA Rats% right paw inhibition (day 16) g relative to spirogermanium. (d, e) i (c) dose (mg / kg) (d) test development / modification

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 foot. The injected paw becomes inflamed (its volume increases) and reaches its maximum size over time

3-5 days (primary forest). Animals show a decrease in weight gain during this initial period. Adjuvant arthritis (secondary forest). ’Appears after a delay of approximately 10 days and is marked by inflammation of the uninjected side (right hind paw), weight loss and a further increase in injected hind paw volume. Test compounds are administered daily starting on the day of adjuvant injection either after days 4, 5, 11 and 12 for 11 consecutive days or 17 consecutive days. The effect of the drugs on the primary (left paw - day 3) and secondary (right hind paw - day 16) forests is determined by comparing the volume of the paws of the treatment group to the control arthritic (veicic) group. The volumes of the hind legs are measured by immersing the bags in the mercury of the water reservoir and recording them. Even the subsequent displacement. I • (e) Definition of significant activity ()

A compound is considered to have anti-arthritic activity when 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 as compared to arthritic contexts. The balance of the 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 compared to the control group. The% inhaled compound of formula (I) and formula (II) on day 16 is divided by spirogermanium activity on day 16 to obtain a relative activity profile. Note: In some of the experiments, compound rr 2 of Table 1- was used as a standard instead of spirogermania. ++ Compound 2 L _R 35 times more potent than SG AAkrysím modelu.- Therefore, the efficiency of Nin The osmolality normalized to SG multiplying three meters .to_f.ak .to no m -. ·

TABLE 2

Suppressor cell activity of compounds of formula (I) and _p of formula (II) ^c Compound Suppressor cell- number dose ná activity ^b 1. 30 mg / kg 88 2. 30 mg / kg 172 3. 30 mg / kg 176 4. 7.5 mg / kg 118 5. 30 mg / kg 162 6. 30 mg / kg 158 7. 30 mg / kg 217 8. 15 mg / kg 67 9. 30 mg / kg 132 10. 30 mg / kg 112 11. 15 mg / kg 139 12. 15 mg / kg 172 13. 15 mg / kg 96 14. n. t. 15 Dec n. t. 16. m.p. 17. n. t. 18. 30 mg / kg 201 19 Dec 30 mg / kg 241 20 May 30 mg / kg 178 21. 30 mg / kg 177 22nd 15 mg / kg 141 23. 30 mg / kg 146 24. 30 mg / kg 84 25. n. t. 26. 30 mg / kg 7 27 Mar: n. t. 28. m.p. 29. m.p. 30. m.p. 31. n. t. 32. m.p.

m.p. = Not tested (a) See Table 1 for the structure of Compound (b) The suppressor cell activity is calculated as follows. The percent suppression plot (dependent variable) versus the logarithm (base e) of the number of suppressor cells (independent variable) was generated and the area under the curve represented by the data points of this plot was determined by the trapezoidal rule. The trapezoidal rule provides the area under the curve by means of the summation of trapezoid areas whose verticals are located at adjacent values of an independent variable. All data are normalized to spirogermanium (SG). In some experiments, Compound // 2 of Table 1 was used as a standard instead of spiroger-mannium. Compound-2-is-1-, 7-2-king-better-than-SG- in the assay. suppressor cells. Therefore, all activities were normalized to SG by multiplying by this factor (i.e., SG = 100, compound // 2 = 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). The rats were grown with water and normal rat food and were .....

used 6-8 weeks (160-180 g). During any given experiment, only rats of the same

The strain and the strain Goncanava-A-Gon-A were obtained from Pharmacia Fine-Chem.cal. (.P.is.cataway _, .__...

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 min) fetal calf dims. This medium is hereinafter referred to as RPMHO. 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 5X. 10 µl / ml. Co-culture experiments to determine suppressor cells were performed by first adding a different number of putative suppressor cells (0.15 to 5 x 10 ³ ) to 96 round bottom wells, microtiter plates (Linbro, Flow Labs) in 100 µΐ RPMI-10. These cells were then irradiated (2000 Rad) in a 137 Cs source Gamma chamber 40.

To these cultures were added 5 x ^{10 5} normal cells and optimal Con A concentration (5 ng / ml) and the final volume was adjusted to 200 µl. Cell cultures were incubated for 72 hours at 37 ° C in a 5% CO- atmosphere, pulse-modulated with 5 · 0.5 µCi (H) thymidine (specific activities 1.9 · Ci / mmol; Schwarz / Mann, Orangenburg, NY) for at least 16 hours of culture. Cells were collected on an automated multiple sample collector and cell-associated radioactivity counted in a Beckman liquid scinetillation counter. Suppressive activity is determined by comparing the cpm of co-cultured cultures containing untreated cells to those containing the affected cells by the Student's t test.

The above Table 2 shows the action of the compounds of formula (I) and formula (II) in the generation of suppressor cells in vivo. by generation of suppressor cells, it is meant that the compound induces suppressor cell activity, i.e., the cell is capable of suppressing the immune function of a normal cell in an in vitro co-culture assay, such as that of Rich and Pierce, J. Exp.Med., 137, 649 (1973). Spleen cells from treated animals were stored at varying concentrations with normal cells: these suppressor cells are also capable of inhibiting mixed lymphocyte reactions, 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. common practices. Such procedures may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired formulation.

The 1-6-f-a-rmae-eut-1-e-1-s-1-e can be either 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 retarder. well known in the art such as. is glycerol monostearate or glyceryl distearate non-wax / ethylcellulose hydroxypropylmethylcellulose with methyl methacrylate and the like.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or ^- pěletbvaňe ^- form ^- form or lozenge to dissolve in the mouth or oral administration. The amount of solid carrier will vary widely, but will range from about 25 mg to 1.0 g. When a liquid carrier is used, the formulation will take the form of a syrup, emulsion, soft gelatin capsule, sterile, injection or suspension in an ampoule or vial, or a non-aqueous liquid suspension.

To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II) is dissolved in an aqueous solution of an organic or inorganic acid such as a 0.3M acid solution (succinic or preferably citric).

If nerj, the available soluble salt form, the compound of formula (I) or formula (II) is dissolved in. a suitable co-solvent or a combination 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 0-60% of the total volume. Preferably, each parenteral 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 .v to about 1000 mg;

i ¹ '' · Λ «

The compounds of formula (i) and formula (II) are all active. As immunomodulatory agents in animals, including humans in need of such immunomodulation, when such compounds are administered to such animals according to the method of administration. of the invention. The term immunomodulatory agent is s?

each compound of formula (I) or formula (II) is capable of inducing immune suppression by inducing surpesor cell activity (as evidenced by their activity in the suppressor cell assay described in Table 2) and / or by causing a statistically significant decrease in inflammation immune system i

mediated secondary forest responses in the 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 multiple sclerosis _______________________ acute, acute, transplant - graft ------------------------- 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

This invention also relates to-the use of compounds of formula (I) or formula (II), · in the treatment of animals in need of immunomodulation, including humans and other mammals · which ^- forms application ^- such animals ^- effective amount of a compound of formula (I) or formula ( II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. By treatment is meant prophylactic or therapeutic use. The compound of formula (I) or (II) is administered to animals in need of immunomodulatory treatment in a 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 mixing a compound of formula (I) or formula (II) with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. Those of skill will YASNA ~ that ~ -form and properties pharmaceutically acceptable nos Ic ^- or ^- Thinner ^{- ye_} determined by ván'a "mn'o'ž'st in £ m ^- akti'v = Ni component with to be combined by the administration route and other well known variables.

The route of administration of a compound of formula (I) or formula (II) may be t-oral, parenteral, inhalation-or-local. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. In general, for parenteral administration, administration by subcutaneous and intramixcular routes is preferred. The daily parenteral dosage regimen will preferably be from about 0.1 mg to about

1000 mg per day. The daily oral dosage regimen will be higher much from about 1 mg to about 2000 mg. ·

The compounds of formula (I) and formula (II) may also be administered topically.

The amount of the compound of formula (I) or formula (II) (hereinafter referred to as the active ingredient) required for a therapeutic effect in topical application will vary with the selected compound, the nature and severity of the inflammatory conditions and the animals undergoing treatment. a suitable immunomodulatory dose of the compound of formula (I) or of formula (II) is from 1.5 µg to 500 mg base per kg body weight for topical administration, the most preferred dosage is 1 µg to 50 mg / kg body weight ¹ For example, an animal of, for example, 5 µg to 25 mg / kg administered two to three times a day. For application to the skin from 1 µg to several milligrams of active ingredient, it can be administered per administration, preferably from 1 µg. 10 µg do. 100 jig per application.

By topical administration is meant non-systemic administration and involves the application of the compound of formula (I) and formula (II) externally to the epidermis, into the oral cavity, and installing ¹ such compound in the ear, eye and nose and where the compound does not significantly enter the bloodstream.

By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

Whenever the active ingredient can be administered alone, as a raw chemical, it is preferable to administer it as a pharmaceutical. The active ingredient may comprise, for topical application, from 0.001% to 10% (w / w), e.g. up to 1% to 2% (w / w) of the formulation, although it may constitute up to 10% (w / w) but preferably does not exceed 5% more preferably from 0.1% to 1% (by weight) of the composition. ’

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). The carrier must be acceptable ^'1 in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations suitable for topical application include liquid or semi-liquid preparations suitable for penetration through the skin. to a place in need of treatment such as: liniments, 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 ”keeping-m-at- * 40 ——— 10 0— ^? é - half an hour in Alternativo —----------..- it-is-a-flow-can.es-teriliso-va.t-fil-trac.-a-asep-ticko The technique can be transferred into a container. Examples of bactericidal and fungicidal agents suitable for inclusion in drops are phenyl mercuric nitrate or acetate (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 eye wash 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 desiccants and skin cooling agents such as alcohol or acetone, and / or humectants such as glycerol or castor or peanut oil.

The creams, ointments and pastes of the invention are semi-solid formulations 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, with the aid of a suitable greasy or non-greasy base apparatus. The base may comprise 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, or wool derivatives, or fatty acids such as stearic or oleic together with an alcohol such as propylene glycol or macrogols. The composition may also include any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives- or inorganic materials such as silicon oxides, and other ingredients such as lanolin may also be included.

It will be appreciated by those skilled in the art that the optimal amount and division of the individual dosage of a compound of formula (I) or formula (II) will depend on the nature and extent of the conditions to be treated, the form, route and location of administration, and in particular the animal to be treated. such optimums can be determined by conventional techniques. It will also be appreciated by those skilled in the art that the optimal course of treatment, i.e. the number of doses of a compound of formula (I) or formula (II) per day, for a defined number of days, can be determined by one skilled in the art.

It is believed that one skilled in the art will, using the foregoing description, utilize the invention to its fullest extent without further elaboration. The following examples are therefore designed. as an illustrative and non-limiting scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

1. Formulation examples

EXAMPLE A - CAPSULAR PRODUCT

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

EXAMPLE B - INJECTION PARENTERAL

The pharmaceutical composition of the invention in a form suitable for injection is prepared by stirring

1.5% by weight of a compound of formula (I) or formula (II) in 10% (v / v) propylene glycol and water. The solution is sterilized by filtration.

EXAMPLE C - MEAT PRODUCT

Compound 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 tu / γ is then filled with the dispersion.

EXAMPLE D - LOCAL CREAM PREPARATION

Compound of formula (I) or formula (II) 1.0 g Polawax GP 200 20.0 g Lanolin anhydrous 2.0 g White beeswax 2.5 g Methylhydroxybenzoate 0.1 g Distilled water ad 100.0 g

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

EXAMPLE E - LOCAL WASH

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. ad 100.0 g

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 the compound of formula (I) or formula (II) is added as a suspension in the remaining water. The total suspension is stirred until homogeneous.

----- EXAMPLE “F” “EYE'S DROPPER *

Compound of Formula (I) or Formula (II)

0.5 g

0.01 g

0,04 g

Methylhydroxybenzoate Propylhydroxybenzoate Purified water B.P.

ad

100.0 ml (B.P. = British Pharmacopea)

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

EXAMPLE G - PREPARATION FOR INHALATION APPLICATION

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

EXAMPLE H - PREPARATION FOR. INHALATION APPLICATION

For an aerosol container with a capacity of 15-20 ml: Dissolve 10 mg of a compound of formula (I) or formula (II) in 6-8 ml of ethanol, add 0.1-0.2% of a lubricant such as polysorbate 85 or oleic acid; and dispersed in a propellant gas such as freon, preferably a mixture of 1 - (- 1, 2-dithloride for fluorine ethane) and difluorochloromethane and filled into a suitable gas. aerosol cans adapted for either intranasal or oral inhalation.

II, Synthetic examples

In the following steps or breaths, it is in degrees Celsius (C). Elemental analyzes and melting points of compounds of formula (I) and formula (II) prepared according to the method of the following synthetic examples are given 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-cyclohexylcyclohex & non , valeraldehyde, allyl bromide, dodecanal, 2,3-dimethylvaleraldehyde, 2-ethyibutyryialdehyde,

2-ethylhexana, adamantanone, bicyclo (3.3.1) nonan-9-one,

3-dimethylaminopropylamine, 3-diethylaminopropylamine, diisobutylamine, 2,6-dimethylheptan-4-one, cycloheptbenzoic 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 reduction of 1-piperidine propionitrile (Aldrich Chemicals; Milwaukee, Wis., USA).

4-dimethylaminobutylamine and 6-dimethylaminohexylamine were purchased from Pfaltz and Bauer (Waterbury, Conn., USA). 5-dimethylaminoperitylamine and 7-dimethylaminoheptyl amine were purchased from Karl 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.

Section 1: Synthesis of 4,4-disubstituted cyclohexanone

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

R2 ((CHibS

NaH. OMSO

Schemítl

Continuation Scheme 1

Triton 3 methyl vinyl acetate. teitucanq | »I. X X * methyl vinyl Itetoni H2SO4 (cet) o

II

EXAMPLES EXAMPLES 1-5 p_op.is.u-spec-i-i-c-k-y-synthesis

4,4-dipropylcyclohexanone from 4-one heptane, but this method was used to produce the following cyclohexanes starting from the commercially available ketones ketone cyclohexanone

2,6-dimethylheptan-4-one nonan-5-one undecan-6-one cycloheptanone 2-adamantanone

4,4 bis (2-methylpropyl4,4-dibutyl4,4-pipenylspiro (5,6) docan-3-one spiro (cyclohexane-1,2'-tricyclo ('3', 3 ', 7', 4 ')) dean-4 -he

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

aldehyde cyclohexanone

2-ethylbutyraldehyde

2-ethylhexanal

4,4-diethyl-4-butyl-4-ethyl28

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 postuoys are set forth in Examples 5 and 6.

(1) H 1 O 2

Example 1: 2-PROPYL-1,2-EPOXYPENTANE

Dimethylsulfoxide (1 L / 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 is formed and upon completion of gas evolution, heptan-4-one (0.4 equivalents) is added and the reaction mixture is heated to 75 ° C for 3-24 hours.

The reaction mixture was poured into water (3-5 volumes) and extracted with ethyl acetate. The organic extract was dried with 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-2-epoxypentane>} (1 equivalent), prepared as described in Example 1, in benzene cooled to 0, was added a solution of boron trifluoride etherate Florida (0.5 equivalents) in benzene. The reaction mixture was stirred for 1 minute and quenched by the addition of water. After separation of the phases, the organic kelp was washed with a saturated aqueous solution of sodium bicarbonate and water, dried with magnesium sulfate, filtered and concentrated to give a colorless oil. The oil was distilled to give the desired product as a colorless oil;

-7-5 -% - yield of the heat-reflux ^_ "^ 0 6 63''7 Ό7Γ ^- mm)

Example 3: 4,4 DIPROPYLCYCLOHEX-2-ENON

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) in tert-butanol. during 1 hour so that the temperature is kept below 15 '.

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 0.5 M sodium hydroxide solution, dried, dried over gentian on Iran, filtered and filtered. It is concentrated to give the desired product after Kugelrohr distillation, boiling point 75-80 / 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 equilibrated 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. Dry the organic phase with magnesium sulfate, filter and concentrate, b

The oil is distilled according to Kugelrohr to give the desired product as a colorless oil, boiling point 75-85 * / 0.075 mm, yield 65-75%.

Example 4: 4,4-DIPROPYLCYCLOHEXANONE. To a suspension of 10% palladium on charcoal (0.1 equivalent) (4,4-dipropylcyclohex-2-one prepared as described in Example 3 was added in ethyl acetate). The catalyst was removed by filtration through Celite and the filtrate was concentrated to give the desired product as a colorless oil, and was used without further purification in 98% yield.

Example 5: 2-PROPYLPENT-4-ENAL

Toluene, valeraldehyde (1 equivalent) and diisobutylamine (1 equivalent) were mixed and heated to reflux using a Dean-Stark trap. Heating was continued until the water had stopped collecting in the separator (1 equivalent of water was collected). The reaction mixture was cooled to room temperature and the 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 was refluxed for 16-24 hours.

The reaction mixture was treated with a buffer solution of acetic acid (60 ml) / sodium acetate (3.0 g) / water. (300 ml / mol) .______ and refluxed for 5 hours The black orange-brown solution was cooled to room temperature and ethyl acetate (300 ml / mol) and saturated sodium chloride solution (150 ml / mol) were added. The organic extract was dried over magnesium sulphate, filtered and concentrated to give a brown oil. The oil was fractionated to give the desired product, and the organic layer was dried over MgSO4, washed with 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine. boiling point 68-73 * / 30 mm, yield 50%.

Example 6: 2-PROPYLPENTANAL

The Parr hydrogenation flask was charged with 10% palladium on activated carbon (0.1 equivalent) and ethyl acetate. A solution of 2-propylpent-4-enal prepared as a solution was added.

In Example 5, in ethyl acetate. The mixture was hydrogenated at 300 N / m ^{2 of} hydrogen in a Parr hydrogenation apparatus at room temperature until the uptake of hydrogen ceased. 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.

SECTION 1A: SYNTHESIS OF 4-SUBSTITUTED CYCLOHEXANONE.

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

Example 7; SYNTHESA 4-DECYLCYKLP.BEXANONE- · A mixture of potassium carbonate (1 equivalent) and morpholine (3.3 equivalents) is cooled to -5% under an inert atmosphere and dodecanal (1 equivalent) is added dropwise over 30 minutes. ). The reaction mixture was allowed to warm to warm or-the-m-i-shnosti ^- and ^{- _} stirring was continued for 3-6 hours Addition to ether followed by filtration and concentration gave crude morpholine enamine. The residue is distilled to give the desired product, bp 103-108 * / 0.07 mm, yield 74%.

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 heated to reflux 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 / 0.22 mm; 40% yield.

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

Section 2: COMPOUNDS OF Formula (I) IN WHICH IS 1

4, R, 4z R. ARE OTHER THAN H 3 4

Scheme 3 depicts a generic synthesis of azaspirane analogs of formula (I) wherein m is 1; R ₄ and R ₄ together are other than hydrogen and m, and R 6 are as defined above, starting from suitably substituted cyclohexanones.

- 33 o

Scheme 3

Examples 8-12 below describe the synthesis of 2- (3-dimethylaminopropyl) -8,8-diethyl-2-azaspiro (4,5) 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- Dibutylcyclohexynone

4,4- dipentylcyclohexanone

4,4-bis (2-methylpropyl) cyclohexanone

4-ethyl-4-butylcyclohexynone

4-methyl-4- (1-methylpropyl) cyclohexynone

4-Cyclohexylcyclohexynone

4-decylcyclohexynone

4- (1,1-dimethylethyl) cyclohexynone

Example 11 'describes the reaction of an anhydride with dimethylaminopropylamine to obtain the desired imide. In a similar way. 4,4-dipropylcyclohexane-1-carboxy-1-acetic anhydride condenses with:

4-dimethylaminobutylamine

5-dimethylaminopentylamine

6-dimethylaminohexylamine

7- dimethylaminoheptylamine

3-diethylaminopropylamine

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 give the desired product upon formation of 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 azaspirane analog.

Example 8: ETHYL-X-CYANO- <X - (4,4-DIETHYLCYCLOHEXYLIDENE) ACETATE

To a solution of 4,4-diethylcyclohexynone (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 solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue is purified by Kugelrohr distillation to give the desired product as a colorless oil, bp 92-98 * / 0.15nm; yield 80-95%. "

Example 9: 4,4-DIETHYLCYCLOHEXAN-1-CARBOXY-1-ACETIC ACID

To a solution of ethyl 4-cyano- (4,4-diethylcyclohexilidene) acetate (1 equivalent) prepared as described above in ethanol was added a solution of potassium cyanide (1.15 equivalents) in water. The reaction mixture was heated to 50-85'C for 3-9 hours and then concentrated to dryness.

The residue was treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in a mixture of acetic acid / hydrochloric acid / water (4.5%, 2L / 0; žinol) and heated to reflux for 2-5 days. The volatiles were removed under reduced pressure and the solid residue was partitioned between water and ethyl acetate. The organic extract was dried with magnesium sulfate, filtered and concentrated to give the desired dibasic acid as a white solid. Recrystallisation from ethyl acetate to give krystaričká solid ^- solid, mp 150-152 ', yield 75-85%.

Example 10: 4,4-Diethylcyclohexane-1-CARBOXY-1-ACETIC ACID ANHYDRIDE

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

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

Example 11: 2- (3-DIMETHYLAMINOPROPYL) -8,8-DIETHYL-2-

AZASPIRO / 4 5 / DECAN-1,3-DION .......

To a solution of 4,4-diethylcyclohexane-1-carboxy-1-acetic anhydride (1 equivalent) in toluene is added

3-dimethylaminopropylamine (1.05 equivalents) and reaction.

=> i: »

The mixture was heated to reflux using a Dean-Star separator. After collecting water (1 equivalent) in the trap, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. without further cleaning.

Example 12: 2- (3-DIMETHYL-AMINOPROPYL) DIHYDROCHLORIDE

-8,8-DIETHYL-2-AZASPIRO / 4,5 / -DECATE

A solution of lithium aluminum hydride in an equivalent amount in diethyl ether is added dropwise

2- (3-dimethylaminopropyl) -8,8-diethyl-2-azaspiro [4,5] decane-1,3 dione (1 equivalent), prepared as described in Example 11, in diethyl ether. The reaction mixture was stirred for 2-6 hours after the addition was complete. The excess hydride is quenched with sodium sulfate decahydrate and the resulting mixture is filtered and the filtrate is concentrated.

37 to give the desired amine as a colorless oil, yield 90-95%.

Dissolve the oil in a minimum of anhydrous ethanol and add a cooled solution of hydrogen chloride in ethanol. Upon addition of a large volume of ether, a white precipitate is formed which is isolated by filtration. The white solid was recrystallized from ethanol, m.p. 293-299 (dec.), Yield 90%.

Section 3; COMPOUNDS OF Formula (I) IN WHICH IS 1

A R_ A R, ARE HYDROGEN 3 4

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

Scheme 4

h;

.2HC1

Examples 13 and 14 describe the synthesis of 2- (3-aminopropyl) -8,8-dipropyl-2-azaspiro (4,5) decane dihydrochloride

z-anh-y-d-r-id-u-y-se-1-i-n-y-4, 4-d-i-p-petroleum-1-cycl-1-ohex-a-n-1-carbox-y

-1-acetic.

Similarly suitably substituted cyclohexynones and the previously derived anhydrides described above can be reacted with s-aminoalkynitriles (n = 4-7) as in Examples 13 and 14 to synthesize the desired azaspiranes in which = R = H

Example 13: 2- (2-CYANOETHYL) -8,8-DIPROPYL-2-AZASPIRO. '· ../4,5/-DEKAN-l,3-DION

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 was added 3-aminopropanenitrile (1.1 equivalents) and toluene. The reaction mixture was heated to reflux using a Dean-Stark trap. After collecting water (1 equivalent), the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate-2/1) to give a white solid, mp 117-117.5 ', yield 95%.

Example 14: 2- (3-AMINOPROPYL) -8,8-DIPROPYL-2-A2ASPIRO / 4,5 / -DECANDIHYDROCHLORIDE

To a mixture of lithium aluminum hydride (4 equivalents) in diethyl ether was added dropwise a solution of 2- (2-cyanoethyl) -8,8-dipropyl-2-azaspiro / 4,5-decane-1,3-dione (1 equivalent) prepared as 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 in 73% yield.

The oil is dissolved in a minimum amount of anhydrous ethanol and a solution of hydrogen chloride in ethanol is added.

The solution was concentrated to give a white solid, mp 245-249 * (dec.), 95% yield.

Section 4: COMPOUNDS OF Formula (I) IN WHICH IS 1 AND R ^ IS OTHER THAN HYDROGEN AND R ^ IS HYDROGEN

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

Scheme 5

Rs

Ra

Example 15 and 16 describe the synthesis dihydrochloride (U-měthyiaminopropyl) -8,8-dipropyl-2-azaspiro / 4,5 / de- ...... k -z anu- acid anhydride ^ ^_ 474-dip ' trans-cyclohexane-1-carboxy-1-acetic acid.

In a similar manner, the appropriately substituted cyclohexanones previously described and the anhydrides derived therefrom may be reacted as described in Examples 15 and 16 of the alkylamino (n = 4-8) alkynyl derivatives to afford azaspirane derivatives, in wherein R ₃ = alkyl and R = H.

Example 15; 2- (3-MZTHYLAMINOPRGPYL) -3,3-3IPRGPYL-2-AZASPIRO / 4,5 / DECAN-1,3-DION

To a solution of toluene and 4,4-dipropylcyclohexane-1-carbonyloxy-1-acetic acid (1 equivalent), 1.05 equivalents of aminopropylamine was added. 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. Evaporate

I take it without further cleaning.

• Example 16

2- (3-METHYLAMINOPROPYL) -3,8-DIPROPYL-2-AZASPIRO / 4,5 / DECANDYYHROCHLORIDE

To a mixture of lithium aluminum hydride (4 equivalents) in diethyl ether was added dropwise a solution of 2- (3-methylaminopropyl) -8,8-dipropyl-2-azaspiro / 4,5 / decane-1,3-dione (1 equivalent) prepared as The product was purified by column chromatography (strong gel, 0.5% ammonium hydroxide in methanol) to give a colorless oil, yield 67%.

Dissolve the oil in a minimum of anhydrous ethanol and add a solution of hydrogen chloride in ethanol.

The white precipitate formed upon cooling is isolated by filtration, mp 258-260 * (dec.), Yield 84%.

Section 5: COMPOUNDS OF FORMULA (I) WHICH IS 2

Scheme 6 describes the pathway of alkyl substituted azaspiro [5.5] undecane analogs starting from substituted cyclohexanones. ---------------------------- ------------------ 41

Examples 17-21 below describe the preparation of (3-dimethylamino) propyl-9,9-dipropyl-3-azaspiro [5,5] undecane dihydrochloride from 4,4-dipropylcyclohexanone.

In a similar manner appropriately substituted previously described Cyclo-ohexanony ^- (see-section ^- L ~ iA ^- A ^- 2j ^- and ^- by ^- one ^- derived 'anhydrides as described in this section may be reacted with:

(a) dialkylaminoalkylamines as described in the synthetic examples section to provide azaspirane derivatives in which R 1 = R 1 = alkyl.

(b) aminoalkyl nitriles as described in section 3 of the synthetic examples to provide azaspirane derivatives wherein R 1 -R 1 = H.

(c) alkylaminoalkylamines as described in section 4 of the synthetic examples to provide azaspirane derivatives wherein R 1 = alkyl and R 1 = H.

Example 17: 9,9-DIPROPYL-1,5-DIKYANO-3-AZASPIRO / 5,5 / UNDEKAN-2,4-DION

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

AND*

Example 18: 4,4-DIPR0PYLCYKL0HEXAN-1,1-DIOCTIC 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 solution of concentrated hydrochloric acid / acetic acid / water (4/7). (1) The solution was refluxed for 2-3 days. The reaction mixture was cooled to room temperature and the volatile materials were removed on a rotavap (rotary evaporator). The residue was partitioned between water and ethyl acetate. The organic phase was washed with saturated. sodium chloride solution, dried with magnesium sulphate, filtered and concentrated to give

43 of the desired acid, which is recrystallized from ethyl acetate / hexane, yield 35-50%.

Example 19: 4,4-DIPROPYLCYCLOHEXAN -1,1-DIOCTIC ACID ANHYDRIDE

4,4-Dipropylcyclohexane-1,1-diacetic acid, prepared as described in Example 18, was dissolved in acetic anhydride and refluxed for 1-6 hours. Excess acetic anhydride was removed by distillation of 5 a. Under reduced pressure and the residue was recrystallized from hexanes, mp 91-93 ° C, yield 90-95%.

Example 20: 3- (3-DIEMTHYLAMINOPROPYL) -9,9-DIPROPYL3-AZASPIRO / 5.5 / UNDEKAN-2,4-DION

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

Example 21: 3- (3-DIMETHYLAMINOPROPYL) -9,9-DIPROPYL. -3-AZASPIRO / 5,5 / UNDEKANDIHYDROCHLORIDE - ...

The amine was prepared by reduction of 3- (dimethylamino) propyl-9,9-dipropyl-3-azaspiro [5,5] undecane-2,4-dione, prepared as described in Example 16 with lithium aluminum hydride, in a manner similar to that described in Example 16. The crude white solid was precipitated by addition of ether and recrystallized from ethanol, m.p. 320 (dec.), Yield 85-90%.

- .44

Section 6: SYNTHESIS OF POLYCYCLIC AZASPIRAN DERIVATIVES OF Formula (II)

The 2-adamantanone is converted to 4,4-spiro-substituted cyclohexanone as described in section 1 and then converted to the desired azaspirane analog using the procedure described in section 2 (Examples 8-12), mp 329-330. .

2-Adamantanone is converted to the desired azaspirane derivative using the procedures described in Section 2 (Examples)

8-12), mp 300-302 *.

·>

2-adamantanone may also be reacted as described in section 5 to provide azaspirane derivatives in which m = .2.

In a similar manner, the 2-adamantanone anhydride synthesized either as described in Section 2 or Section 5 can be reacted with:. (A) dialkylaminoalkylamines, as described in Section 2 of the Synthetic Examples, to provide azaspirano derivatives wherein R 1 = R 1 = alkyl.

(b) aminoalkyl nitriles as described in section 3 of the synthetic examples, to provide. derivatives in which R ^ 'R ^ = H.

(c) alkylaminoalkylamines, as described in Section 4 of the Synthetic Examples, to provide azaspirane derivatives wherein R ₄ = alkyl and R ₄ = H.

The bicyclo [3.3.1] nonan-9-one is similarly reacted as in Section 2 to give the desired azaspirane derivative, mp 303-304 ’. This ketone can be modified as 2-adamantanone to provide 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)

Likewise, the reaction may be reacted as described above for the starting system.

Chan's dissertation is a publicly available document and is readily available from the ϋ-Μ-Σ-Dissertation Information Service, 300 N. Zeeb Road, Ann Arbor, Mich. 48 106, telephone (800)521-0600 or (313) 761-4700. In Chan dissertation 3,3,7,7-tetramethylbicyclo [3.3.1] nonan-9-one, synthesize as follows:

3,3,7,7-tetramethylbicyclo [3.3.1] nonan-9-one (1) was synthesized for the construction study of bicyclo (3.3.1) nonane systems. Both the resulting compound (1) and 3,3-dimethylbicyclo [3.3.1] non-nano-9-one were found to be in double boat form at room temperature.

The resulting compound (1) is prepared as follows:

CHO = 0) = 0

OCOR

AND

The isobutylaldehyde is alkylated with methyl vinnyl ketone via its pyrrolidinino enamine, cyclized in acid and then hydrogenated to give 4,4-dimethylcyclohexanone (2). Ketone 2 is alkylated with acrolein via its morpholine enamine, then hydrolyzed to give 2- (2-oxocyclohexyl) propanal (3) Crude 3 is then purified over its diketal, cyclized in 7N hydrochloric acid and esterified to give 7.7 -dimethylbicyclo / 3.3. 1-nonan-9-one-2-yl pivalate (4). Ketalisation, 4 followed by alkaline hydrolysis, CrO, -pyridine oxidation and alkylation with iodomethane and potassium tert-butoxide affords 3,3,7,7-tetramethyl-9,9-ethylenedioxybicyclo [3.3.1] nonan-2-one (5). When various efforts of the Wolf-Kishner reduction have failed, it 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-methanesulfoline (6). Lithium-ammonia reduction 6, followed by acid hydrolysis, affords the title compound (1).

TABLE 3

The melting points (based) of the compounds of formula (I) and formula (II) prepared according to the methods of the synthetic examples

melting point (C) rt to

300- 302 299-300 299-301

301- 302 297-29S 243-249 233-240

295- 296

296-298 239-291 303-304 306-307

TABLE 3 - continued

melting point (* C)

13 297-298 14 326-328 if 325-326 lů 334-335 17 305-307 13 • 2Í2-254 19 Dec 235-236 20 May 266-269 21 274-276 22nd 239-261 23 245-246 24 329-330 23 308-310 26 323-325 27 Mar: 234-236 '23 287-289 '29 -293-296 30 271-272 31 275-278 . J2 24 ^ 243

Note:

(and)

See Table 1 for structure

TABLE 4

Elemental analysis of compounds of formula (I) and formula (II) prepared according to the methods of the synthetic examples

Molecule- Mass Calculated

n lami formula ^: for: Found: C: H: N: WHOSE: C: H: N: Cl: ot CijHnNiCti 353.5 61.17 10.33 7.92 20.06 60.98 10.73 7.64 20.01 02 / CwHrtNzCli 331.5 62.97 11. to 7.14 18.59 62.73 10.97 7.32 18.42 03 / CuřiuN ^ Ch 409.5 64.52 11.32 6.34 17.31 64.69 11.34 6.32 O CmHjoNiCli 437.6 65.33 11.52 6.40 16.20 66.04 11.42 6.31 16.39 05 / Goal & laIli 409.5 64.52 1122 6.34 17.31 64.23 11.32 6.76 17.23 06 / CijHjgNiCli 353.4 61.17 10.34 7.93 19.30 61.03 10.90 7.35 19.97 07 / C 18 H 18 N 1 Cl 2 367.4 6111 10.97 7.62 19.30 62.06 10.99 7.58 19.33 08 / CuftuNiCb 395.5 63.73 11.21 7.08 17.93 63.63 11.07 7.03 13.12 09 / CiíKíoNiGi 367.4 6111 10.97 7.62 19.30 62.06 10.98 7.61 19.J5 10 C19H40N2G2 367.4 6111 10.97 7.62 19.30 61.99 11.01 7.53 19.36 11 C 10 H 11 NiCl 3 381.5 6197 11.10 7.34 18.59 62.92 11.11 7.30 13.64 12  CmíLiNíCh 331.5 6197 11.10 7J4 13.59 62.38 11.13 7.31 13.65 13 CíbljoNiCk 437.6 65.33 11.52 6.40 16.20 65.39 11.52 6.38 16.17 14 C10H40N2G1 379.5 63.31 10.62 7.38 13.69 63.24 10.64 7.37 18.63 AT CisHjgNiCh 353.4 61.17 10.34 7.93 20.06 61.10 10.77 8.02 20.07 16 C) gH] gNiCl1 353.4 61.17 10.34 7.93 20.06 61.16 10.36 7.92 19.94 17 C20H40N2G2 379.5 63.31 10.62 7.38 18.69 63.22 10.67 7.35 18.70 1S CnfWhCh 409.5 64.52 11.32 6.34 17.31 64.42 11.32 6.32 17.39 19 Dec CufLbkdi 421.5 65.53 11.00 6.65 16.82 65.42 11.03 6.64 16.39 20 May CiiHmíůCIi 395.5 63.73 11.21 7.08 17.93 63.64 10.99 6.96 21 C22H44N2Cl2 409.5 64.52 11.32 6.34 17.31 64.59 ' 11.30 6.78 17.30 22nd CuHtgNjCk 423.6 65.22 11.42 6.61 16.74 65.05 11.29 6.57 23 CuJíjoNtCti 437.6 65.33 11.52 6.40 16.20 65.91 11.48 6.37 16.19 24 CuíhoNiCli 417.5 66.17 10.14 6.71 1628 66.21 10.16 6.67 16.94 25 CigHuNjCh 349.4 61.33 9.81 8.02 20.29 61.30 9.70 7.35 26 C17H2 * N2Cl2 337.4 60.52 10.16 3.30 21.02 60.55 10.12 3.31 27 Mar: CuřLxNíCh 407.5 64.34 10.38 6.37 17.40 64.75 10.39 6.87 17.34 23 CuHjoNiCh 449.6 66.79 11.21 6.23 15.77 66.68 11.31 6.30 15.67 29 ClíHnNxCh 463.6 67.36 11.30 6.04 15.29 67.39 11.29 6.03 15.24 30 CioHiořhCh 379.5 63.31 10.62 7.33 18.69 63.24 10.65 7.35 18.65 31 CiiřU2N2a2 393.5 64.10 10.76 7.12 18.02 60.01 10.31 7.10 17.93 32 C2DH42N2Cl2 331.5 62.97 11.10 7.34 13.59 62.33 11.11 7.31 13.52

Note:

Compounds 03, 20, 22, 25 and 26 were not analyzed for chloride composition.

While the above descriptions and examples fully describe the invention and its preferred embodiments, it is necessary. . Note that the invention is not limited to certain described embodiments falling within the scope of the following claims:

Claims (22)

PATENT CLAIMS An azaspirane derivative of formula (IA). n is 3-7; m is 1 or 2; , and R ₂ are the same or different and are selected from hydrogen. or a straight-chain, branched-chain alkyl or ^- cyclic ^- alkyl, having a "preactivity" of ^{- the} total number of carbon atoms contained in R 1 and R ₂ when taken together is 5-10; or R 1 and R ₂ are. taken together to form a cyclic alkyl group having 3-7 carbon atoms; R 6 and R 6 are the same or different and are selected from hydrogen or a straight chain alkyl having 1-3 carbon atoms; or R 6 and R 6 are taken together to form a cyclic alkyl group having 4-7 carbon atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. * Compound according to claim 1, of the formula:. ... ... í í and The compound of claim 1, which is selected from compounds of formula; s \ -t 1- x, · ^ H N H \ '' —S N Continuation: 51a The azaspirane compound of formula II In which: n is 3-7? m is 1 or 2; ^R 1, R ₂ , R ₅ and R 8 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 1-3 carbon atoms; or R 6 and R 6 are taken together to form a cyclic alkyl group containing 4-7 carbon atoms or a pharmaceutically acceptable salt, hydrate or solvate thereof. A compound according to 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 the formula: Formula (IA) in which: n is 3-7; m is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or 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 5-10; or and R6 are taken together to form a cyclic alkyl group having 3-7 carbon atoms; R 3 and R 6 are the same or different and are selected from hydrogen or a straight chain alkyl having 1-3 carbon atoms; or R ₄ and R ₄ are taken together to form a cyclic alkyl group having 4-7 carbon atoms; Continuation: Pharmaceutical composition according to Claim 6, characterized in that it contains as active compound: Pharmaceutical composition according to claim 6, characterized in that the active compound is selected from the group consisting of: 1 ·. Η · r ~ \ r ι, ** · ’* '/ Ν \ ΐ i Λ. 9. A pharmaceutical composition according to claim 6 in a dosage form suitable for oral administration. 10. A pharmaceutical composition according to claim 6 in a dosage form suitable for parenteral administration. application. 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 for topical application. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent. and the immunomodulatory effective amount of the compound. , formulas: or ί *; νΛ * i. ¹ ? Λ ?! wherein n is 3 to 7, m is 1 or 2; ^R 5 ^{and R} 5 are the same or different and are selected from hydrogen or methyl; and R 6 are the same or different and are selected from hydrogen or a straight chain alkyl having 1-3 carbon atoms; or and R 6 are taken together to form a cyclic alkyl group containing 4-7 carbon atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof. The pharmaceutical composition of claim 13, wherein the compound is selected from: 15. A pharmaceutical composition according to claim 13, wherein the dosage form is suitable for oral administration. 16. A pharmaceutical composition according to claim 13 which is in a dosage form suitable for use as a parenteral agent. 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. ΐ 19. A method of treating animals in need of immunomodulation, comprising administering such V · ^f 'animals / immunomodulatory effective amount of a compound of formula: R: Jt In which: n is 3-7; i m / is 1 or 2; Ri and R2 are the same or different and are selected from hydrogen or C \ straight or branched chain '\, Hebo cyclic alkyl, provided that the total ./počet carbon atoms contained in R and R2 when _Z; taken together, is 4-1 * 0; or and R 2 'are taken together to form a cyclic alkyl group containing 3-7 carbon atoms; R 6 and R 6 are the same or different and are selected from hydrogen or a straight chain alkyl having 1-3 carbon atoms; or R 6 and R 6 are taken together to form a cyclic alkyl group containing 4-7 atoms; carbon; or a pharmaceutically acceptable salt, hydrate or solvate thereof. The method of claim 19, wherein the compound is: wherein the compound is a compound. The method of claim 19, wherein the security is selected from: / \ N AND HiiCio The method of claim 19, wherein the compound is administered orally. 23. The method of claim 22, wherein from 1 to 1000 mg of compound per day is administered. 24. The method of claim 19 wherein the compound is parenterally applied. F The method of claim 24, wherein from 0.1 to 1000 mg of compound per day is administered. 2S. The method of claim 19, wherein the compound is administered by inhalation. The method of claim. 26 characterized in that 29. administer from 10 to 1% of the compound per day. The method of claim 19 wherein the compound is administered topically. The method of claim 28 wherein the compound is administered in an amount of from about 1.5 mg / kg to about 500 mg / kg of body weight per day. A method for treating animals in need of immunomodulation, comprising administering to such animals an immunomodulatory effective amount of a compound of the formula: Formula II Rj -64 wherein: n is 3-7; m is 1 or 2; ΐ R 1, R ₂ , R ₅ and R 8 are the same or different and are selected from hydrogen or methyl; in R 6 and R 6 are the same or different and are selected from hydrogen * or a straight chain alkyl having 1-3 carbon atoms; or R 1 and R 2 are taken together to form a cyclic alkyl group having 4-7 carbon atoms; or a pharmaceutically acceptable salt, hydrate or solvate thereof, The method of claim 30, wherein the compound is selected from: ^r 32. The method of claim 30 wherein the compound is administered orally. 33. The method of claim 32, wherein the method is: -ap-1-i-ku-is-1-to-2-000-mg-s-1-en-i-n-y-per-day ------- 34. The method of claim 30, wherein the compound is administered prerereally. 35. The method of claim 34, wherein from about 1 to about 1000 mg of compound per day is administered. L ¹ l. AND Η 33. 39. The method of claim 30, wherein the compound is administered by inhalation. The method of claim 36, wherein from 10 to 100 mg of compound per day is administered. The method of claim 70, wherein the compound is an ocular. * \ The method of claim 33, wherein the compound is administered in an amount of from 1.5 mg / kg to 500 mg / kg body weight per day.