JP2003534238A - Salt of cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid. - Google Patents

Abstract

  (57) [Summary] The present invention relates to cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylate.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to certain salts of carboxylic acids useful in the treatment of diseases treatable by inhibiting the PDE4 enzyme.

BACKGROUND Cyclic nucleotide phosphodiesterases invention (PDE), the second intracellular ubiquitous
Messenger, adenosine 3 ', 5'-monophosphate (cAMP) and guanosine 3', 5'-monophosphate (cGMP), are defined as enzymes that hydrolyze the corresponding inactive 5'-monophosphate metabolites. To do. At least 1
It is believed that there are zero different PDE isozymes, each with unique physical and dynamic properties, each implying the product of a different gene family. These are distinguished using the Arabic numerals 1-10. The target enzyme of the present invention is the PDE4 isoenzyme in all its various forms and its full domain distributed in all cells. It has little activity against cGMP (Km> 100 μM), low Km (cAMP Km = 1-5 μm).
M) cAMP selective enzyme.

Current PDE inhibitors used in the treatment of inflammation and as drugs such as the bronchodilators theophylline and pentoxifylline indiscriminately inhibit PDE isoenzymes in all tissues. These compounds are clearly applicable to all PD in all tissues.
Since it non-selectively inhibits the E isoenzyme species, it shows a side effect. Although the target medical condition can be effectively treated by such a compound, if an undesired secondary effect appears, and such effect can be avoided or minimized, then the whole of this method for treating certain medical conditions The therapeutic effect will increase. A new method for improving the side effect profile of PDE inhibitors is a single PD
It is designed to produce a new compound that inhibits only the E isoenzyme, that is, the PDE isoenzyme predominant in the tissue of the cell of interest. The predominant cAMP PDE isoenzyme in immune and inflammatory cells is PDE4. It is also a major regulator of airway smooth muscle cAMP content. Thus, selective inhibition of PDE4 increases cAMP content of immune and inflammatory cells, as well as airway smooth muscle. One or both of these therapeutic effects are useful in the treatment of various disorders including, but not limited to, asthma and COPD. In addition, PDE4 inhibitors, in particular PDE4 specific inhibitors, may also be found in other areas of tumor necrosis factor and cognitive impairment (eg, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, rheumatoid arthritis) and cognitive impairment (eg, , Multi-infarct dementia, cognitive impairment or stroke).

Theoretically, isoenzyme-selective PDE inhibitors should show improvement over non-selective inhibitors, whereas the selective inhibitors tested to date have demonstrated inadequate or non-targeted tissues. As a result of extending to inhibit the desired isoenzyme, or other PD
The side effects produced are not completely absent because they can cross-react with the E isoenzyme.
It does not prevent. For example, clinical studies with the selective PDE4 inhibitor rolipram, which has been developed as an antidepressant, show that it has psychotropic activity and produces gastrointestinal effects such as heartburn, nausea or vomiting. It has been shown that side effects of denbufylline, another PDE4 inhibitor, for the treatment of multi-infarction dementia can include heartburn, nausea and vomiting. These side effects are believed to result from the inhibition of PDE4 in specific areas of the central nervous system and gastrointestinal system. To date, no one has been able to identify compounds that are completely free of undesired side effects at possible dose levels, but at least one compound has been identified as a former PDE4 inhibitor, namely cis-4-cyano-4- [3 It was identified to be more acceptable than-(cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid. Ariflo® is a registered trademark for this compound. The present invention provides unique and useful salts of this acid.

SUMMARY OF THE INVENTION The present invention is directed to sodium cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid, ethylenediamine and tris (hydroxymethyl) aminomethane. Regarding salt with.

[0006] Preparation detailed description cis-4-cyano-4- INVENTION [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid, some publications, for example, 19
US Pat. No. 5,552,438 published September 3, 1996 and PCT Application No. PCT / US98 / 02749 and WO published October 13, 1998.
98/34584. The acid salt was prepared and characterized by the following examples.

Example 1 Sodium salt

[Chemical 1]

1 (a) 50 ml equipped with thermometer, reflux condenser, dropping funnel and N ₂ inlet
In a 3-necked round bottom flask of 2.01 g (5.85 mmol) of cis-4-cyano-
4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-
1-Carboxylic acid and 20 ml of ethyl acetate were charged at room temperature under N ₂ atmosphere. The resulting mixture was heated to 55-60 ° C for 20 minutes to obtain a colorless transparent solution. To this solution was added 1.16 g (7.03 m) in 8.0 ml of ethyl acetate prepared beforehand.
mol, 1.2 eq.) sodium hexanoate solution at a reaction temperature of 50-60 ° C.
And slowly added over 2 minutes. The contents of the reaction flask were cooled to room temperature (18-20 ° C) over 30 minutes, with precipitation starting around 25-30 ° C. The suspension was stirred at room temperature for 1 hour. The contents of the reaction vessel were filtered through a sinter funnel and the filter cake was washed twice with 10 ml ethyl acetate. The crude product was dried under high vacuum for 24 hours to constant weight. Melting point: 238 [deg.] C. Karl Fischer: 1.64% ¹ H NMR was satisfactory. It was estimated that DSC showed three small heat absorptions at 154.4 ° C, 185.1 ° C, and 212.0 ° C and a large heat absorption at 230 ° C and decomposed at 324.3 ° C. IR (KBr pellet): 3420, 2953, 2232, 1559, 1519, 1415, 1260, 1241
, 1167, 1148, 1027, 992, 805 cm ^-1

1 (b) Recrystallization: A 25 ml 3-neck round bottom flask was equipped with a thermometer, reflux condenser, dropping funnel and N ₂ inlet, and then 0.606 g (1.654 mmol).
Of crude cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid sodium salt and 4.5 ml of acetonitrile were charged with stirring at room temperature. To this cloudy suspension was heated to 60 ° C. and a total of 0.3 ml deionized water was added dropwise. The mixture became a clear pale yellow solution. Air cooled to 45 ° C., inoculated with 2 mg seed crystals and cooled to 35 ° C. for an additional 5 minutes. Some cloudiness was seen. Further, it was cooled to 0 ° C. with vigorous stirring in an ice water bath. More precipitate formed. The suspension was placed in the freezer (-8 ° C) for 16 hours. The contents of the reaction flask were filtered through a sinter funnel and the filter cake was washed twice with 1.5 ml acetonitrile. The product was dried under high vacuum for 24 hours to constant weight. Melting point:> 240 ° C. (converted to brown tar at 260 ° C.) DSC shows two small heat absorptions at 162.1 ° C. and 189.2 ° C. and one large heat absorption at 232.7 ° C. It was estimated to decompose at 330 ° C. IR (KBr) was consistent with the crude product. Karl Fischer: 2.9%; exposed to air for 1 week at room temperature, this material had a water content of 22.9% by Karl Fischer, suggesting the very high hygroscopic properties of this salt. Recrystallisation from isopropanol gave similar crystal forms (melting point, DSC, KF,
In terms of IR and ¹ H NMR).

Example 2 Ethylenediamine salt

[Chemical 2]

A reflux condenser, a thermometer, a magnetic stirrer, and an N ₂ inlet were provided in a 100 ml three-neck round bottom flask of 2 (a). In this flask 6.15g (16.51mmo
1) cis-4-Cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid and 55 ml isopropanol were charged at room temperature under N ₂ atmosphere. The resulting suspension was heated to 60 ° C. with stirring to give a clear light brown solution. To this mixture, 0.60 ml (0.54 g, 8
． 96 mmol, 0.51 eq) ethylenediamine was added at once. The resulting solution was kept at 60 ° C for 15 minutes. Cool the mixture to 45 ° C. for 20 minutes,
Seed with 2 mg of seed crystals. Immediately salt began to precipitate. Cooling was continued to room temperature, then to 0 ° C. for 45 minutes. The suspension was stirred at 0 ° C. for a further 2 hours and then filtered on a sinter funnel. The filter cake was washed twice with 2.0 ml cold isopropanol. The product was dried under high vacuum for 20 hours to constant weight. ¹ H NMR was satisfactory; melting point: 158-161 ° C .; curl
Fisher: 0.15%; DSC showed one small heat absorption at 77.4 ° C, a large heat absorption at 167.4 ° C and was estimated to decompose above 180 ° C; IR (KBr). ):
3379, 2959, 2860, 2638, 2229, 1617, 1519, 1414, 1268, 1234, 1148, 1024,
988, 936, 807, 739, 634 cm ^-1

2 (b) Recrystallization: Thermometer, reflux condenser, dropping funnel and 25 with N ₂ inlet.
In a ml 3-neck round bottom flask, 1.02 g of crude ethylenediamine salt (2.74 mm
ol) and 12.0 ml of isopropanol at room temperature (18-20 ° C). The resulting mixture was refluxed at 90-92 ° C for 30 minutes to give a clear brown solution. Turn off the heat and allow the contents of the reaction flask to reach 63-65 for 30 minutes.
It was air-cooled to ℃. The solution was seeded with pure ethylenediaminecarboxylate crystals. Two
After ~ 3 minutes, crystallization started. The solution was cooled to room temperature, then cooled to 0 ° C. in an ice water bath for another hour. The solid was isolated by filtration and 2.0 ml of filter cake
Washed twice with isopropanol. The product is brought to constant weight at room temperature for 20
Dried under high vacuum for hours. Karl Fischer: 0.075%; melting point: 156-159 ° C. ¹ H NMR was satisfactory. DSC showed a small sharp heat absorption at 81.46 ° C and a large sharp heat absorption at 166.68 ° C. IR (KBr) was consistent with the crude product. Recrystallization was 99/1 isopropanol / H ₂ O (91.0%), EtO.
Also performed in Ac / MeOH (74.8%) with similar crystal quality.

Example 3 Preparation of tris (hydroxymethyl) aminomethane salt

[Chemical 3]

3 (a) A 50 ml three-neck round bottom flask was equipped with a magnetic stirrer, reflux condenser, dropping funnel, thermometer, and N ₂ inlet. 3.0g (8.735mmol) to this
) -4-Cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid and 30 ml isopropanol were charged at room temperature. The mixture was heated to 70 ° C. with vigorous stirring to give a clear solution. Tris (hydroxymethyl) aminomethane (1.10 g, 9.091 mmol, 1.04 eq) was added to 8.0 ml Me while maintaining the reaction temperature at 70 ° C.
Added to a mixture of OH and 1.0 ml deionized water. Some heating was needed to get a clear solution of the amine. The resulting clear solution is stirred and left at room temperature for 2
． Cool for 0 hours without precipitation. A large amount of a precipitate formed after stirring overnight (16 hours) at room temperature. The slurry was diluted with 15 ml isopropanol and then transferred under reduced pressure to a sinter funnel. The filter cake was washed twice with 5.0 ml cold isopropanol (0-5 ° C). The product was dried under high vacuum for 72 hours. ¹ H NMR was satisfactory. Melting point: 143-147 ° C Karl Fischer: 1.73% DSC shows two sharp heat absorptions at 127.8 ° C and 140.9 ° C.
It was estimated to decompose at 85 ° C. IR (KBr pellet): 3513, 3327, 2954, 2865, 2233, 1590, 1519, 1409
, 1197, 1258, 1244, 1197, 1168, 1147, 1122, 1095, 1063, 1048, 1028, 1002
, 932, 806, 656, 635 cm ^-1

3 (b) Recrystallization: Prepared with 1.0 g of 3 (a) in a 25 ml 3-neck round bottom flask equipped with a magnetic stirrer, reflux condenser, dropping funnel, thermometer and N ₂ inlet. The crude Tris salt and 7 ml of isopropanol were added at room temperature under N ₂ atmosphere.
The resulting mixture was heated to reflux at 80-82 ° C under N ₂ atmosphere. After about 20 minutes, the mixture became a clear yellow solution. The heat was turned off and cooled. Precipitation was observed rapidly at 60 ° C. An additional 2.0 ml of isopropanol was added to facilitate stirring. The solution was further cooled to room temperature over 45 minutes. The suspension was further cooled in an ice water bath to 0-5 ° C for 30 minutes. The product was isolated by filtration on a sinter funnel and the filter cake was washed twice with 2 ml cold isopropanol. 24 wet solids
Dried under high reduced pressure for an hour to obtain tris salt of cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid. ¹ H NMR was satisfactory. Melting point: 145-148 ° C Karl Fischer: 0.32% DSC showed one large heat absorption at 147.1 ° C and one shoulder at 153.2 ° C. IR (KBr) was consistent with the crude product. Recrystallization was also performed in EtOAc / isopropanol and acetone / isopropanol.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 19/02 A61P 19/02 25/28 25/28 29/00 29/00 101 101 43/00 111 43 / 00 111 F term (reference) 4C206 AA03 HA13 KA01 KA15 MA01 MA04 NA14 ZA15 ZA59 ZA66 ZA96 ZB11 ZB15 ZC20 4H006 AA01 AA03 AB22

Claims (3)

[Claims] 1. Cis-4-cyano-4- [3- (cyclopentyloxy)-
4-Methoxyphenyl] cyclohexane-1-carboxylate sodium salt. 2. Cis-4-cyano-4- [3- (cyclopentyloxy)-
4-Methoxyphenyl] cyclohexane-1-carboxylic acid ethylenediamine. 3. Cis-4-cyano-4- [3- (cyclopentyloxy)-
4-Methoxyphenyl] cyclohexane-1-carboxylic acid tris (hydroxymethyl) aminomethane.