NZ515169A

NZ515169A - Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate] and pharmaceuticals thereof

Info

Publication number: NZ515169A
Application number: NZ515169A
Authority: NZ
Inventors: Guishu Kris Huang
Original assignee: Smithkline Beecham Corp
Priority date: 1999-05-25
Filing date: 2000-05-24
Publication date: 2003-05-30
Also published as: CA2375543A1; CN1351491A; HUP0201265A3; MXPA01012048A; NO20015699D0; EP1194142A4; TR200103238T2; AU5304900A; NO20015699L; WO2000071114A8; HK1046630A1; EP1194142A1; ZA200109624B; WO2000071114A1; JP2003500356A; CZ20014186A3; KR20020010669A; BR0010483A; AR024076A1; PL351945A1

Abstract

The sodium salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]. Also described is the ethylene diamine salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]. Also described is the tris(hydroxymethyl)aminomethane salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]. Also described is a pharmaceutical composition comprising the sodium salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and a pharmaceutically acceptable excipient. Also described is a pharmaceutical composition comprising the ethylene diamine salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and a pharmaceutically acceptable excipient. Also described is a pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of cis-[-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and a pharmaceutically acceptable excipient.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 515169 WO 00/71114 1 PCT/US00/14855 Salts of ci'i-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate] Field of Invention The present invention relates to salts of a 4,4-5 disubstitutedphenylcyclohexanoic acid which are useful in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF). Background of the Invention It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) 10 isozyme, PDE 4, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast 15 cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE 4 inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE 4 inhibitors would be effective in the treatment of a number of diseases involving the pulmonary system. 20 One compound of interest in treating PDE 4-modulated diseases is cis-[4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylate]. It is described in U.S. patent 5,552,438. This compound has been effective in treating several forms of asthma, chronic obstructive pulmonary disease, and various other conditions modulated by drugs which inhibit PDE 4. 25 Summary of the Invention This invention covers certain salts of c«-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] and the method for preparing these salts, namely the sodium salt, the ethylene diamine salt and the 30 tris(hydroxymethyl)aminomethane salt. This invention also relates to the pharmaceutical compositions comprising these salts combined with a pharmaceutically acceptable carrier or diluent. Detailed Description of the Invention 35 The carboxylic acid, cw-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate] is prepared by the method described in WO 00/71114 2 PCT/USOO/14855 U.S. patent 5,552,438 as well as by other route set forth in the likes of PCT application as W098/34584 published 13 August 1998. The salts of this invention and their preparation are described in the following examples. Examples Example 1A Formation and Recrvstallization of Sodium Salt 1(a) Formation of salt: A 50 ml 3 necked round bottom flask equipped with thermometer, reflux condenser, addition funnel and N2 inlet was charged with 2.01 g (5.85 mmoles) of m-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] and 20ml of ethyl acetate at room temperature under a nitrogen atmosphere. The resulting mixture was warmed up to 55-60 °C over a period of 20 minutes and gave a clear colorless solution. To this solution was added a pre-made solution of 1.16 g (7.03 mmoles, 1.2 equivalents) of sodium hexanoate in 8.0 ml of ethyl acetate slowly over a 2 minute period while maintaining the reaction temperature between 50-60 °C. The contents of the flask were cooled to room temperature (18-20 °C) over a period of 30 minutes. Precipitation started at around 25-30 °C. The suspension was kept stirred at room temperature for one hour. The contents of flask were then filtered through a sintered funnel and the cake was rinsed with 2 x 10ml of ethyl acetate. This crude product was dried under Hi-vac for 24 hours to give 1.64 g (76.5% yield) of the captioned sodium salt. M. P.: 238 °C. Karl Fisher: 1.64%. ]H NMR was satisfactory. DSC indicated three small endotherms at 154.4 °C, 185.1 °C_and 212.0 °C, one major endotherm at 230 °C and probable decomposition at 324.3 °C. IR (KBr pellet): 3420, 2953, 2232, 1559, 1519, 1415, 1260, 1241, 1167, 1148,1027,992,805 cm-1. 1(b) Recrvstallization of Sodium Salt: A 25 ml 3 neck round bottom flask equipped with thermometer, reflux condenser, addition funnel and N2 inlet was charged with 0.606 g (1.654 mmoles) of crude sodium salt product from Example 1(a) and 4.5 ml of acetonitrile at room temperature with stirring. To this thick suspension was added dionized water dropwise with heating up to 60 °C; a total of 0.3 ml water was added. The mixture changed to a clear pale yellow solution. The solution was air cooled to 45 °C, seeded with 2 mg of seed crystal and cooled further to 35 °C over 5 minutes. It was then placed in the freezer (-8 °C) for 16 hours. The contents of flask were then filtered through a sintered funnel and the filter cake was rinsed with 2 x 1.5 ml of acetonitrile. The product was dried under Hi-vac for 24 hours. Recovery from the recrystallization step was 0.568 g (93.56%). M. P.: >240 °C (turned to brown tar at 260 °C). DSC showed two small endotherms at 162.1 °C WO 00/71114 PCT/US00/14855 3 and 189.2 °C and one major endotherm at 232.7 °C, followed by probable decomposition at 333.0 °C. This profile was identical to the crude product; Karl Fisher : 2.9%. This material, when exposed to air at room temperature for 1 week, had a 22.9% water content (Karl Fisher) indicating this salt is hydroscopic. 5 Recrystallization was also done using isopropyl alcohol with a 50% recovery and similar form of crystal (in terms of M. P., DSC, KF, IR and 'H NMR) Example 2 Preparation of an Ethylene Diamine Salt 10 2(a) Formation of Salt: A 100 ml 3 neck round bottom flask equipped with a reflux condenser, thermometer, magnetic stirrer and N2 inlet was charged with 6.15 g (16.51 mmoles) of cis-[4-cyano-4-(3-cycIopentyIoxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and 55 ml of isopropanol at room temperature under a N2 atmosphere. The resulting suspension was heated up to 60 °C with stirring, giving a clear light 15 brown solution. To this mixture was added 0.60 ml (0.54 g, 8.96 mmoles, 0.51 equivalents ) of ethylene diamine in one portion. The resulting solution was kept at 60 °C for 15 minutes. The solution was then allowed to cool to 45 °C over 20 minutes and seeded with 2 mg of seed crystal. In a few seconds the salt started to precipitate. The cooling was continued to room temperature and then to 0 °C over 45 20 minutes. The suspension was stirred at 0 °C for an additional 2 hours after which it was filtered through a sintered glass funnel. The filter cake was rinsed with 2 x 2.0 ml of cold isopropyl alcohol. The product was dried under Hi-Vac for 20 hours. The isolated weight was 5.989 g (45.74% recovery, 50% in theory, 98.61% Wt/Wt assay). *H NMR was satisfactory; M. P.: 158-161 °C; Karl Fisher : 0.15%; DSC one 25 small endotherm at 77.4 °C , one major at 167.4 °C and probable decomposition at >180 °C; IR(KBr): 3379, 2959, 2860,2638,2229, 1617, 1519, 1414, 1268, 1234, 1148, 1024, 988,936, 807,739, 634 cm-*. 2(b) Recrvstallization: A 25 ml 3 neck round bottom flask equipped with thermometer, reflux condenser, addition funnel and N2 inlet was charged with 1.02 g 30 of crude ethylene diamine salt (2.74 mmoles) prepared in 2(a) and 12.0 ml of isopropanol at room temperature (18-20 °C). The resulting mixture was heated to reflux at 90-92 °C over a period of 30 minutes, giving a clear brown solution. Heating was stopped and the content of the reaction flask was air cooled to 63-65 °C over 30 minutes. The solution was seeded with pure ethylene diamine salt. 35 Crystallization started after a few minutes. The mixture was further cooled to room temperature and then further chilled to 0 °C in an ice water bath for 1.0 h. The solid was isolated by filtration and the filter cake was rinsed with 2 x 2.0 ml of isopropyl alcohol. The product was dried under Hi-vac at room temperature for 20 h. WO 00/71114 PCT/US00/14855 4 Recovery was 90.1% (Wt=0.919 g). Karl Fisher: 0.075%; M. P.: 156-159 °C; NMR was satisfactory; DSC showed minor sharp endotherm at 81.46 °C and major sharp endotherm at 166.68 °C. IR(KBr) was identical to the crude product. Recrystallization was also done in 99/1 isopropyl alcohol/E^O (91.0%), 5 EtOAc / MeOH (74.8%) and gave a similar quality crystal. Example 3 TrisChvdroxvmethvDaminomethane salt 3(a) Salt Formation: A 50 ml three neck round bottom flask equipped with magnetic stirrer, reflux condenser, addition funnel, thermometer and N2 inlet was 10 charged with 3.0 g (8.735 mmoles) of the acid and 30 ml of isopropanol at room temperature. The mixture was heated to 70 °C with vigorous stirring to obtain a clear solution. While maintaining the reaction temperature at 70 °C, there was added tris (hydroxymethyl)aminomethane (1.10 g, 9.091 mmoles, 1.04 equivalents) in a mixture of 8.0 ml of MeOH and 1.0 ml of deionized water (some heating was 15 required to obtain a clear aqueous solution of amine). The resulting clear solution was stirred and cooled to room temperature for 2.0 hours without precipitation. Upon stirring overnight (16 hours) at room temperature, a heavy precipitation formed. The slurry was diluted with 15 ml of isopropyl alcohol and transferred to a sintered funnel under house vacuum. The filter cake was rinsed with 2 x 5.0 ml of 20 cold isopropyl alcohol (0-5 °C). The filter cake was dried under Hi-vac for 72 hours yielding 2.713 g of white solid, i.e., crude tris salt of cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] (66.9%). *H NMR was satisfactory, M.P.: 143-147 °C; Karl Fisher: 1.73%; DSC had two sharp endotherm at 127.8 °C, 140.9 °C and probable decomposition at 185 °C; IR(KBr pellet): 3513, 25 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) Recrvstallization: A 25 ml three neck round bottom flask was equipped with a magnetic stirrer, reflux condenser, addition funnel, thermometer and N2 inlet. It was charged with 1.0 g of crude tris salt and 7 ml of isopropanol at room 30 temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux under nitrogen at 80-82 °C. After approximately 20 minutes, the mixture became a clear yellow solution. Heating was removed and the flask allowed to air cool. Upon reaching about 60 °C, rapid precipitation was observed. An additional 2.0 ml of isopropyl alcohol was added to facilitate a proper stirring. The solution was further 35 cooled to room temperature over 45 minutes and then further chilled to 0-5 °C for 30 minutes in an ice water bath. The product was isolated by filtration through a sintered glass funnel and the cake was rinsed with 2 x 2 ml of cold isopropyl alcohol. The wet solid was dried under Hi-vac for 24 hours yielding 0.888 g of recrystallized </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/71114 5 PCT/US00/14855 tris salt of cij-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] (recovery was 88.8%). NMR was satisfactory, M. P. : 145-148 °C; Karl Fisher: 0.32%; DSC indicated one sharp major endotherm at 147.1 °C and one shoulder at 153.2 °C. IR (KBr) was identical to the crude product. The recrystallization was also done in ethyl acetate/isopropyl alcohol (Y= 81.3%) and acetone isopropyl alcohol (Y = 50.50%). 515169 What is claimed is:

1. The sodium salt of c«'j-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylate].

2. The ethylene diamine salt of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylate].

3. The tris (hydroxymethyl)aminomethane salt of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carboxylate].

4. A pharmaceutical formulation comprising sodium cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] and a pharmaceutically acceptable excipient.

5. A pharmaceutical formulation comprising ethylene diamine cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] and a pharmaceutically acceptable excipient.

6. A pharmaceutical formulation comprising tris (hydroxymethyl)aminomethane ci5-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate] and a pharmaceutically acceptable excipient. INTELLECTUAL PROPERTY OFFICE OF N.Z. - 5 DEC 2002 received </div>