EP1237851A2 - SALTS OF i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID - Google Patents

SALTS OF i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID

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Publication number
EP1237851A2
EP1237851A2 EP00989266A EP00989266A EP1237851A2 EP 1237851 A2 EP1237851 A2 EP 1237851A2 EP 00989266 A EP00989266 A EP 00989266A EP 00989266 A EP00989266 A EP 00989266A EP 1237851 A2 EP1237851 A2 EP 1237851A2
Authority
EP
European Patent Office
Prior art keywords
cyclopentyloxy
cyano
methoxyphenyl
cyclohexane
carboxylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00989266A
Other languages
German (de)
French (fr)
Other versions
EP1237851A4 (en
Inventor
Guishu Kris Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1237851A2 publication Critical patent/EP1237851A2/en
Publication of EP1237851A4 publication Critical patent/EP1237851A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/09—Diamines
    • C07C211/10—Diaminoethanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

Salts of Cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylate are disclosed herein.

Description

Salts of C; 4-Cvano-4-[3- (cvclopentyloxy)-4-methoxyphenyHcyclohexane-l- carboxylic acid Area of the Invention
This invention relates to certain salts of a carboxylic acid useful for treating diseases treatable by inhibiting the PDE4 enzyme. Background of the Invention
Cyclic nucleotide phosphodiesterases (PDEs) represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3 ',5 '-monophosphate (cAMP) and guanosine 3 ',5 '-monophosphate (cGMP) to their corresponding inactive 5 - monophosphate metabolites. At least ten distinct classes of PDE isozymes are believed to exist, each possessing unique physical and kinetic characteristics and each representing a product of a different gene family. These are distinguished using Arabic numerals 1 - 10. The enzyme targeted in this invention is the PDE4 isozyme in all its various forms and in the full domain of its distributions in all cells. It is a low Km (cAMP Krn=l-5μM) cAMP-selective enzyme that has little activity against cGMP (Km>100μM).
Current PDE inhibitors used in treating inflammation and as bronchodilators, drugs like theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminately in all tissues. These compounds exhibit side effects, apparently because they non-selectively inhibit all PDE isozyme classes in all tissues. The targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states.
A new approach toward improving the side effect profile of PDE inhibitors is to design a new generation of compounds that inhibit only a single PDE isozyme, i.e., the PDE isozyme that predominates in the tissue of cell of interest. The predominate cAMP PDE isozyme in immune and inflammatory cells is PDE4. It is also a major regulator of cAMP content in airway smooth muscle. Thus, selective inhibition of PdE4 elevates cAMP content in immune and inflammatory cells, as well as in airway smooth muscle. This leads to anti-inflammatory effects as well as bronchodilation. One or both of these therapeutic actions are useful in treating a variety of diseases, including, but not limited to asthma and COPD. PDE4 inhibitors, particularly PDE4-specific inhibitors are useful also in treating other diseases in the area of inflammation, (e.g., asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, rheumatoid arthritis), affects related to tumor necrosis factor and to cognition impairment (e.g., multi-infarct dementia, cognitive dysfunction, or stroke). Although in theory isozyme-selective PDE inhibitors should represent an improvement over non-selective inhibitors, the selective inhibitors tested to date are not devoid of side effects produced as an extension of inhibiting the isozyme of interest in an inappropriate or untargeted tissue, or because they may have cross-reactivity with other PDE isozymes. For example, clinical studies with the selective PDE4 inhibitor rolipram, which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis. Indications are that side effects of denbufylline, another PDE4 inhibitor targeted for the treatment of multi-infarct dementia, may include pyrosis, nausea and emesis as well. These side effects are thought to occur as a result of inhibiting PDE4 in specific areas of the central nervous system and the gastrointestinal system.
While to date no one has been able to identify a compound which is completely without unwanted side effects at all possible dosage levels, at least one compound has been identified that appears to be better tolerated than previous PDE4 inhibitors, namely c(5-4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l-carboxylic acid. Ariflo® is the registered trademark for this compound. This invention provides unique and useful salts of this acid. Summary of the Invention
This invention relates to the following salts of *-4-cyano-4-[3- (cyclopentyloxy)- 4-methoxyphenyl]cyclohexane-l-carboxylic acid: sodium, ethylene diamine and tris(hydroxymethy)aminomethane.
This invention also relates to methods for making these salts Detailed Description of the Invention
The preparation of c 5*-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane-l-carboxylic acid is described in several publications, for example U.S patent 5,552,438 issued 03 September 1996 and PCT application number PCT/US98/02749 and published on 13 August 1998 as WO 98/34584.
Salts of this acid were prepared and characterized as per the following examples.
Example 1
1 (a) 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 cis-4- cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane- 1 -carboxylic acid and 20ml of ethyl acetate at room temperature under N2 atmosphere. The resulting mixture was warmed up to 55-60 °C over a period of 20 minutes to obtain 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 ethyl acetate slowly over 2 minutes period while maintaining the reaction temperature between 50-60 °C. The contents of the reaction 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 stirred at room temperature for one hour. The contents of the reaction vessel were filtered through a sintered funnel and the cake was rinsed with 2x10ml of ethyl acetate. This crude product was dried under Hi-vac for 24 hours to a constant weight.
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) Recrystallization: A 25 ml 3 neck round bottom flask was equipped with thermometer, reflux condenser, addition funnel and an N2 inlet, and then charged with 0.606 g (1.654 mmoles) of crude c/s-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane-l-carboxylic acid sodium salt and 4.5 ml of acetonitrile at room temperature with stirring. To this thick suspension was added deionized water dropwise with heating up to 60 °C, with total of 0.3 ml water added. The mixture turned to a clear pale yellow solution. It was air cooled to 45 °C, seeded with 2 mg of seed crystal and cooled further to 35 °C over 5 minutes. Some cloudiness was noticed. It was cooled further with an ice-water bath to 0 °C with vigorous stirring. More precipitation formed. The suspension was placed in the freezer (-8 °C) for 16 hours. The contents of reaction flask were filtered through sintered funnel and the filter cake was rinsed with 2x1.5 ml of acetonitrile. The product was dried under Hi-vac for 24 hours to constant weight. M. P. : >240 °C (turned to brown tar at 260 °C).
DSC showed two small endotherms at 162.1 °C and 189.2 °C and one major endotherm at 232.7 °C, followed by probable decomposition at 333.0 °C.
IR(KBr) was identical to the crude product.
Karl Fisher : 2.9 %; this material upon exposed to air at room temperature for 1 week had 22.9 % water content on Karl Fisher, indicating fairly high hydroscopic nature of this salt.
Recrystallization from isopropanol gave similar crystal form (in terms of M. P. , DSC, KF, IR and 1H NMR).
Example 2 Ethylene Diamine salt
2(a) A 100 ml 3 neck round bottom flask was equipped with a reflux condenser, thermometer, magnetic stirrer and an N inlet. This flask was charged with 6.15 g (16.51 mmoles) of c/s-4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l- carboxylic acid and 55 ml of isopropanol at room temperature under N2 atmosphere. The resulting suspension was heated up to 60 °C with stirring giving a clear light 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 mixture was allowed to cool to 45 °C over 20 minutes and seeded with 2 mg of seed crystal. In few second the salt started to precipitate. The cooling was continued to room temperature then to 0 °C over 45 minutes. The suspension was stirred at 0 °C for additional 2 hours then was filtered through sintered funnel. The filter cake was rinsed with 2 X 2.0 ml cold isopropanol. The product was dried under Hi-Nac for 20 hours to a constant weight.
Η ΝMR was satisfactory; M. P. : 158-161 °C; Karl Fisher : 0.15 %; DSC one 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" 1. 2(b) Recrystallization: A 25 ml 3 neck round bottom flask equipped with thermometer, reflux condenser, addition funnel and N2 inlet was charged with 1.02 g of crude ethylene diamine salt (2.74 mmoles) and 12.0 ml of isopropanol at room temperature (18-20 °C). The resulting mixture was heated up to reflux at 90-92 °C over a period of 30 minutes to obtain a clear brown solution. The heating was removed and the contents of the reaction flask was air cooled to 63-65 °C over 30 minutes. The solution was seeded pure ethylene diamine carboxylate crystals. After a few minutes crystallization began. The solution was cooled to room temperature 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 2X2.0 ml isopropanol. The product was dried under Hi-vac at room temperature for 20 h or to constant weight.
Karl Fisher : 0.075 %; M. P. : 156-159 °C. 1H 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 isopropanol/H?O (91.0 %), EtOAc/MeOH ( 74.8 %) with similar quality of crystal.
Example 3 Preparation of Tris(hvdroxymethyl)aminomethane Salt
3(a) A 50 ml three neck round bottom flask was equipped magnetic stirrer, reflux condenser, addition funnel, thermometer and N2 inlet. It was charged with 3.0 g (8.735 mmoles) of c«-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane-l-carboxylic 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, tris(hydroxymethyl)aminomethane (1.10 g (9.091 mmoles, 1.04 equivalents) was added in a mixture of 8.0 ml of MeOH and 1.0 ml of deionized water. Some heating was required to obtain a clear solution of the 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, heavy precipitation formed. The slurry was diluted with 15 ml of isopropanol, then was transferred to a sintered funnel under vacuum. The filter cake was rinsed with 2 X 5.0 ml of cold isopropanol (0-5 °C). The product was dried under Hi-vac for 72 hours.
1H 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, 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: A 25 ml three neck round bottom flask equipped with magnetic stirrer, reflux condenser, addition funnel, thermometer and N2 inlet was charged with 1.0 g of crude tris salt prepared in 3(a) and 7 ml of isopropanol at room temperature under N2 atmosphere. The resulting mixture was heated to reflux under N2 at 80-82 °C. After approximately 20 minutes , the mixture became a clear yellow solution. The heating was removed and allowed to cool. Upon reaching 60 °C rapid precipitation was observed. 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 chilled to 0-5 °C for 30 minutes in an ice water bath. The product was isolated by filtration through sintered funnel and the cake was rinsed with 2 X 2 ml of cold isopropanol 2 X 2.0 ml. The wet solid was dried under Hi-vac. for 24 hours yielding the tris salt of cis- 4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l-carboxylic acid. 1H 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. Recrystallization was also done in EtOAc/isopropanol and acetone/isopropanol.

Claims

What is claimed is:
1. Sodium c/s-4-cyano-4-[3- (cyclopentyloxy )-4- methoxyphenyljcyclohexane- 1 -carboxylylate.
2. Ethylene diamine m-4-cyano-4-[3- (cyclopentyloxy )-4- methoxyphenyl]cyclohexane-l-carboxylate.
3. Tris(hydroxymethyl)aminomethane cw-4-cyano-4-[3- (cyclopentyloxy)- 4-methoxyphenyl]cyclohexane- 1 -carboxylate.
EP00989266A 1999-12-15 2000-12-15 SALTS OF i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID Withdrawn EP1237851A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US17097799P 1999-12-15 1999-12-15
US170977P 1999-12-15
PCT/US2000/033966 WO2001043692A2 (en) 1999-12-15 2000-12-15 SALTS OF Cis-4-CYANO-4-[3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID

Publications (2)

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EP1237851A2 true EP1237851A2 (en) 2002-09-11
EP1237851A4 EP1237851A4 (en) 2004-06-23

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EP (1) EP1237851A4 (en)
JP (1) JP2003534238A (en)
WO (1) WO2001043692A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR024076A1 (en) * 1999-05-25 2002-09-04 Smithkline Beecham Corp CIS- [4-CIANO-4- (3-CICLOPENTILOXI-4-METOXIFENIL) CICLOHEXAN-1-CARBOXYLATE SALTS]
RS53777B1 (en) * 2008-12-08 2015-06-30 Glaxosmithkline Llc 8-chloro-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-amino-2-(hydroxymethyl)-1,3-propanediol anhydrate for the treatment of diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018793A1 (en) * 1997-10-10 1999-04-22 Smithkline Beecham Corporation Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
WO2000071114A1 (en) * 1999-05-25 2000-11-30 Smithkline Beecham Corporation Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY25338A1 (en) * 1998-01-07 2001-08-27 Smithkline Beecham Corp METHOD FOR TREATING COPD

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018793A1 (en) * 1997-10-10 1999-04-22 Smithkline Beecham Corporation Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
WO2000071114A1 (en) * 1999-05-25 2000-11-30 Smithkline Beecham Corporation Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0143692A2 *

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WO2001043692A2 (en) 2001-06-21
JP2003534238A (en) 2003-11-18
EP1237851A4 (en) 2004-06-23
WO2001043692A3 (en) 2002-03-07

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