CZ20014186A3 - Salts of cis-[4-cyan-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate] - Google Patents

Abstract

This invention relates to salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate].

Description

Salts of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate]

Technical field

The present invention relates to a phenylcyclohexanoic acid salt disubstituted at the 4,4-positions, which is useful in the treatment of allergic and inflammatory diseases and for inhibiting the formation of tumor necrosis factor (TNE).

BACKGROUND OF THE INVENTION

Certain cyclic nucleotide phosphodiesterase isoenzyme (PDE), PDE 4, has been shown to be responsible for the degradation of cAMP in airway smooth muscle and inflammatory cells. (Torphy, " Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents in New Drugs for Asthma, Barnes, published by IBC Technical Services Ltd., 1989). Research has shown that inhibition of this enzyme not only leads to relaxation of airway smooth muscle, but also suppresses mast cell degranulation, basophils and neutrophine spo together with inhibition of monocyte and neutrophil activation. In addition, the beneficial effects of PDE 4 inhibitors are greatly potentiated when target cell adenylate cyclase activity is enhanced by appropriate hormones or autocoids, as would be the case in vivo. Thus, PED 4 inhibitors would be effective in the treatment of numerous diseases affecting the pulmonary system.

One of the compounds of interest in the treatment of diseases modulated by PDE 4 is cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate]. It is described in US Patent No. 5,552,438. This compound is effective in the treatment of various forms of asthma, chronic, fcfc, fcfc, fcf, fcf Fc fc fcfc fcfcfcfc fcfc pulmonary diseases and various other drug-modulated conditions that inhibit PDE 4.

SUMMARY OF THE INVENTION

The present invention relates to certain salts of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate;

and a process for the preparation of these salts, in particular the sodium salt, the ethylenediamine salt and the tris (hydroxymethyl) aminomethane salt.

The invention also relates to pharmaceutical compositions comprising these salts in association with a pharmaceutically acceptable carrier or diluent.

Detailed description of the invention

The carboxylic acid cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] was prepared as described in U.S. Patent No. 5,552,438, as well as other procedures disclosed in the corresponding PCT application under No. WO 98/34584 published August 13, 19 93.

The salts of the present invention and their preparation are described in the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Presser 1A

Preparation and recrystallization of sodium salt 1a) Salt preparation

4 * 4 44 · 44 ·· · * ·· <4 4 4 4 · · · · 4 44 44 4 44 ·

4 44 44 44 444 4 4

444 444 444

4 44 * 44 44 4444

A 50 ml three neck round bottom flask equipped with a thermometer, reflux condenser, dropping funnel and nitrogen inlet was charged with 2.01 g (5.85 mmol) of cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane. -1-carboxylate] and 20 ml of ethyl acetate at room temperature and under a nitrogen atmosphere. The resulting mixture was heated to 55-60 ° C over 20 minutes to give a clear colorless solution. To this solution was slowly added a solution of 1.16 g (7.03 mmol, 1.2 equivalents) of sodium hexanoate in 8.0 mL of ethyl acetate slowly over 2 minutes, maintaining the reaction temperature from 50 to 60 ° C for 2 minutes. minutes.

Cool the contents of the flask to room temperature (13-20 ° C) over 30 minutes. Precipitation starts at about 25-30 ° C. The suspension was stirred at room temperature for 1 hour. The contents of the flask were then filtered through a sintered glass funnel and the filter cake was rinsed with 2 x 10 mL ethyl acetate. This crude product was dried under high vacuum for 24 hours to give 1.64 g (76.5% yield) of the collected sodium salt.

238 ° C. Karl Fisher assay: 1.64%.

K NMR is satisfactory. DSC shows 3 small endotherms at 154.4 ° C, 185.1 ° C and 212.0 ° C, 1 large endotherm at 230 ° C and probable decomposition at 324.3 ° C.

Infrared spectrum (potassium bromide pellet): 3420,

295.3, 2232, 1559, 1519, 1415, 1260, 1241, 1167, 1148,

992, 305 cm ^-1 .

lc '· Sodium salt recovery • · · • * · *

A 25 ml three-necked round-bottomed flask with a thermometer, reflux condenser, dropping funnel and nitrogen inlet was charged with stirring at room temperature with 0.606 g (1.654 mmol) of the crude sodium salt product of Example 1a) and 4.5 ml of acetonitrile. . Deionized water was added dropwise to the thick slurry while heating to 60 ° C, adding a total of 0.3 mL of water. The mixture was converted to a clear pale yellow solution. The solution was allowed to cool to 45 ° C in air, 2 mg of flocculant crystals were formed and further cooled to 35 ° C over 5 minutes. The flask is then filtered through a sintered glass funnel and the filter cake is rinsed with 2 x 1.5 ml of acetonitrile. This product is dried under high vacuum for 24 hours. step is 0.568 g (93.56%).

Melting point: greater than 240 ° C (260 ° C turns brown tar). DSC showed two small endotherms at temperatures of 162.1 ° C and 189.2 ° C and one large endotherm at 232 ° C ^Ί, nás_edovaný probable decomposition at 333.0 ° C. This profile is consistent with the crude product, Karl Fisher assay: 2.9%. This material has a water content of 22.9 ^Λ (Karl Fisher assay) when exposed to air at room temperature for 1 week, indicating that this salt is aygroscopic.

Recrystallization was also performed using isopropanol in 50% yield and a similar crystal form (with respect to melting point, DSC, KF, infrared spectrum and 1 H 2 M 2: +).

Example 2

9 · 9 9

- 4 · «·

Preparation of ethylenediamine salt

2a) Salt Preparation

A 100 ml three neck round bottom flask equipped with a reflux condenser, thermometer, magnetic stirrer and nitrogen inlet was charged with 6.15 g (16.51 mmol) of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)]. (cyclohexane-1-carboxylate) and 55 ml of isopropanol at room temperature under a nitrogen atmosphere. The resulting slurry was heated to a temperature of up to 60 ° C with stirring to give a clear pale brown solution. To this mixture was added 0.60 mL (0.54 g, 8.96 mmol, 0.51 equivalents) of ethylenediamine in one portion. The temperature of the resulting solution was maintained at 60 ° C for 15 minutes. This solution was then allowed to cool to 45 ° C over 20 minutes and 2 mg of flocculent crystals were flocculated. The salt starts to precipitate within seconds. Cooling is continued for 45 minutes to room temperature and then to 0 ° C. The suspension was stirred at 0 ° C for a further 2 hours and then filtered through a sintered glass funnel. Rinse the filter cake with 2 x 2.0 mL cold isopropanol. This product was dried under high vacuum for 20 hours. The weight of the isolated material is 5.989 g (45.74% yield, 50% theoretically, 98.61% by weight determination).

Ή NMR is satisfactory. M.p .: 158-161 ° C. Karl Fisher assay: 0.15%. DSC shows 1 small endotherm at 77.4 ° C, 1 large endotherm at 167.4 ° C, and probable decomposition above 180 ° C.

IR (potassium bromide): 3379, 2959, 2860, 2638, 2229, 1617, 1519, 1414, 1268, 1234, 1148, 1024, 988, 936, 807, 739, 634 cm ^-1 .

* ·

- 6 · · * »6 6 6 6 6 6 6 6 6

2b) Recrystallization

A 25 mL three neck round bottom flask equipped with a thermometer, reflux condenser, dropping funnel, and nitrogen inlet was charged at room temperature (18-20 ° C) with a 1.02 g (2.74 mmol ·) crude ethylenediamine salt prepared in the example. 2a) and 12.0 ml of isopropanol. The resulting mixture was heated to reflux at 90-92 ° C over 30 minutes to give a clear light brown solution. The heating was stopped and the contents of the reaction flask were allowed to cool to 63-65 ° C over 30 manutres in air. This solution was flocculated with pure diethylamine salt. Crystallization starts within minutes. The mixture was further cooled to room temperature and then further cooled to 0 ° C in an ice bath for 1.0 h. The solids were collected by filtration and the filter cake was rinsed with 2 x 2.0 mL isopropanol. This product was dried under high vacuum for 20 hours. The yield is 90.1% (weight = 0.919 g).

Kari Fisher assay: 0.075%, melting point: 156-159 ° C, ¹ H NMR satisfactory. DSC shows a small sharp endotherm at 81.46 ° C and a large sharp endotherm at 166.68 ° C. The infrared spectrum (potassium bromide) is identical to the crude product.

Recrystallization was also performed in a 99: 1 mixture of isopropanol / water (91.0%) and ethyl acetate / methanol (74.8%) to give a similar quality crystal.

Example 3

Tris (hydroxymethyl) aminomethane salt

0 00 00 00 • 0 0 · 0 · 0 ·· • 000 00 0 00 • 0000 00 0 000 0 000 000 00 • 0 0 00 0000 00

3a; Preparation of salt

A 50 ml 3-neck round bottom flask equipped with a magnetic stirrer, reflux condenser, dropping funnel, thermometer and nitrogen inlet was charged with 3.0 g (8.735 mmol) of acid and 30 ml of isopropanol at room temperature. This mixture was heated to 70 ° C replica with vigorous stirring to obtain a clear solution. While the reaction temperature is maintained at 70 ° C, 1.10 g (9.091 mmol,

1.04 equivalents) of tris (hydroxymethyl) aminomethane in a mixture of 8.0 mL of methanol and 1.0 mL of deionized water (slightly warmed to obtain a clear aqueous amine solution). The resulting clear solution was stirred for 2.0 hours and cooled to room temperature without precipitation. During the overnight stirring (16 hours) at room temperature, a strong precipitation occurred. The suspension is diluted with 15 ml of isopropanol and transferred to a sintered glass funnel under a water pump vacuum. The filter cake is rinsed with 2 x 5.0 mL cold isopropanol (0-5 ° C). The filter cake was dried under high vacuum for 72 hours to give 2.713 g of a white solid, i.e. the crude tris salt of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] (66). , 9%).

Έ NMR is satisfactory. M.p .: 143-147 ° C. Karl Fisner assay: 1.73%. DSC has 2 sharp endotherms at 127.8 ^and C and 140.9 ° C and probable decomposition at 185 ° C.

Infrared spectrum (potassium bromide pellet): 3513,

332 ^ 2954, 2865, 2233, 1590, 1519, 1409, 1197, 1258, 1244,

1192, 1147, 1122, 1095, 1063, 1048, 1028, 1002, 932

806,665,635 cm ^-1 .

»··»

0

- 8 00 00 00 00 · 0 0 · 0 0 0 0 0 0 00 00 00 00 00 00 00 00 00 00 00

3b; Recrystallization

A three-necked 25 ml round-bottomed flask is equipped! equipped with magnetic stirrer, reflux condenser, dropping funnel, thermometer and nitrogen inlet. At room temperature, 1.0 g of crude tris salt and 7 ml of isopropanol are charged under a nitrogen atmosphere. The resulting mixture was heated to reflux at 80-82 ° C under a nitrogen atmosphere. After about 20 minutes, the mixtures became a clear yellow solution. The heating is terminated and the flask does not cool in the air. A rapid precipitation is observed when the temperature reaches 60 ° C. An additional 2.0 mL of isopropanol was passed to facilitate proper mixing. The solution was further cooled to room temperature over 45 minutes and then cooled to 0-5 ° C in an ice bath for 30 minutes. The product was collected by filtration in a sintered glass funnel and the filter cake was rinsed with 2x2 mL cold isopropanol. The wet solid was dried under high vacuum for 24 hours to give 0.838 g of recrystallized cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] tris salt (yield 8.88). %).

Ή NMR is satisfactory. 145-148 ° C, Karl

Fisher assay: 0.32%, DSC shows 1 sharp endotherm at 147.1 ° C and 1 arm at 153.2 ° C.

The infrared spectrum (potassium bromide) is identical to the crude product.

Recrystallization was also carried out in ethylacenate / isopropanol (yield 81.3%) and acetone / isopropanol (yield 50.50%).

Claims (6)

PATENT CLAIMS Cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] sodium salt. 2. cis- [4-Cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate ethyl ethylenediamine salt1. 3. cis- [4-Cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] tris (hydroxymethyl) aminomethane salt. 4. A pharmaceutical composition comprising cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] sodium and a pharmaceutically acceptable excipient. 5. A pharmaceutical composition comprising the ethylenediamine salt of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] and a pharmaceutically acceptable excipient. 6. A pharmaceutical composition comprising cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] tris (hydroxymethyl) aminomethane salt and a pharmaceutically acceptable excipient.