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WO2000071114A1 - Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] - Google Patents

Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] Download PDF

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Publication number
WO2000071114A1
WO2000071114A1 PCT/US2000/014855 US0014855W WO0071114A1 WO 2000071114 A1 WO2000071114 A1 WO 2000071114A1 US 0014855 W US0014855 W US 0014855W WO 0071114 A1 WO0071114 A1 WO 0071114A1
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Prior art keywords
cyclohexan
cyclopentyloxy
methoxyphenyl
carboxylate
cyano
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Ceased
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PCT/US2000/014855
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French (fr)
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WO2000071114A8 (en
Inventor
Guisha Kris Huang
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
Priority to KR1020017015036A priority Critical patent/KR20020010669A/en
Priority to AU53049/00A priority patent/AU5304900A/en
Priority to JP2000619421A priority patent/JP2003500356A/en
Priority to NZ515169A priority patent/NZ515169A/en
Priority to BR0010483-3A priority patent/BR0010483A/en
Priority to IL14621300A priority patent/IL146213A0/en
Priority to CA002375543A priority patent/CA2375543A1/en
Priority to MXPA01012048A priority patent/MXPA01012048A/en
Priority to HK02106898.8A priority patent/HK1046630A1/en
Priority to EP20000937937 priority patent/EP1194142A4/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to PL00351945A priority patent/PL351945A1/en
Publication of WO2000071114A1 publication Critical patent/WO2000071114A1/en
Publication of WO2000071114A8 publication Critical patent/WO2000071114A8/en
Priority to NO20015699A priority patent/NO20015699D0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C261/00—Derivatives of cyanic acid
    • 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
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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

Definitions

  • the present invention relates to salts of a 4,4- disubstitutedphenylcyclohexanoic acid which are useful in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
  • TNF Tumor Necrosis Factor
  • PDE 4 cyclic nucleotide phosphodiesterase
  • 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.
  • PDE 4 inhibitors would be effective in the treatment of a number of diseases involving the pulmonary system.
  • One compound of interest in treating PDE 4-modulated diseases is cis- ' - cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -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. Summary of the Invention
  • This invention covers certain salts of cw-[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 tris(hydroxymethyl)aminomethane salt.
  • This invention also relates to the pharmaceutical compositions comprising these salts combined with a pharmaceutically acceptable carrier or diluent.
  • the carboxylic acid, c/s-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l -carboxylate] is prepared by the method described in U.S. patent 5,552,438 as well as by other route set forth in the likes of PCT application as WO98/34584 published 13 August 1998.
  • Example 2 Preparation of an Ethylene Diamine Salt 2(a) Formation of Salt: A 100 ml 3 neck round bottom flask equipped with a reflux condenser, thermometer, magnetic stirrer and N 2 inlet was charged with 6.15 g (16.51 mmoles) of s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carboxylate] and 55 ml of isopropanol at room temperature under a N 2 atmosphere. The resulting suspension was heated up to 60 °C with stirring, giving a clear light brown solution.
  • the isolated weight was 5.989 g (45.74% recovery, 50% in theory, 98.61% Wt/Wt assay).
  • ⁇ NMR 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;
  • Example 3 Tris(hvdroxymethyl)aminomethane 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 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

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

Description

Salts of cw-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate]
Field of Invention
The present invention relates to salts of a 4,4- 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) 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 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. One compound of interest in treating PDE 4-modulated diseases is cis-' - cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -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. Summary of the Invention
This invention covers certain salts of cw-[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 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
The carboxylic acid, c/s-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l -carboxylate] is prepared by the method described in U.S. patent 5,552,438 as well as by other route set forth in the likes of PCT application as WO98/34584 published 13 August 1998.
The salts of this invention and their preparation are described in the following examples. Examples
Example IA Formation and Recrystallization of Sodium Salt 1(a) Formation of salt: A 50 ml 3 necked round bottom flask equipped with thermometer, reflux condenser, addition funnel and N inlet was charged with 2.01 g (5.85 mmoles) of cw-[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%. Η 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 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 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. 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 Η NMR)
Example 2 Preparation of an Ethylene Diamine Salt 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 s-[4-cyano-4-(3-cyclopentyloxy-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 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 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). Η NMR 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) 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. 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. Recovery was 90.1% (Wt=0.919 g). Karl Fisher : 0.075%; M. P. : 156-159 °C; Η NMR was satisfactory; DSC showed minor shaφ 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/H2O (91.0%), EtOAc / MeOH ( 74.8%) and gave a similar quality crystal.
Example 3 Tris(hvdroxymethyl)aminomethane 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 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 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 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%). 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 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 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 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 tris salt of e-_.-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- carboxylate] (recovery was 88.8%). 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.
The recrystallization was also done in ethyl acetate/isopropyl alcohol (Y= 81.3%) and acetone isopropyl alcohol (Y = 50.50%).

Claims

What is claimed is:
1. the sodium salt of c/5-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -carboxylate] .
2. The ethylene diamine salt of c-5-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -carboxylate] .
3. The tris (hydroxymethyl)aminomethane salt of s-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carboxylate] .
4. A pharmaceutically formulation comprising sodium cw-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -carboxylate] and a pharmaceutically acceptable excipient.
5. A pharmaceutically formulation comprising ethylene diamine cis-[4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carboxylate] and a pharmaceutically acceptable excipient.
6. A pharmaceutically formulation comprising tris (hydroxymethyl)aminomethane c/s-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -carboxylate] and a pharmaceutically acceptable excipient.
PCT/US2000/014855 1999-05-25 2000-05-24 Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] Ceased WO2000071114A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
HK02106898.8A HK1046630A1 (en) 1999-05-25 2000-05-24 Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate
JP2000619421A JP2003500356A (en) 1999-05-25 2000-05-24 Salt of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]
NZ515169A NZ515169A (en) 1999-05-25 2000-05-24 Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate] and pharmaceuticals thereof
BR0010483-3A BR0010483A (en) 1999-05-25 2000-05-24 Cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate salts]
IL14621300A IL146213A0 (en) 1999-05-25 2000-05-24 Sales of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxilate
CA002375543A CA2375543A1 (en) 1999-05-25 2000-05-24 Salts of cis-¬4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate|
MXPA01012048A MXPA01012048A (en) 1999-05-25 2000-05-24 Salts of cis.
KR1020017015036A KR20020010669A (en) 1999-05-25 2000-05-24 Salts of Cis-[4-Cyano-4-(3-Cyclopentyloxy-4-Methoxyphenyl) Cyclohexan-1-Carboxylate]
AU53049/00A AU5304900A (en) 1999-05-25 2000-05-24 Salts of CIS-(4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate)
EP20000937937 EP1194142A4 (en) 1999-05-25 2000-05-24 Salts of cis -4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate!
PL00351945A PL351945A1 (en) 1999-05-25 2000-05-24 Salts of cis [4-cyano-4-(cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylan]
NO20015699A NO20015699D0 (en) 1999-05-25 2001-11-22 Salts of cis- (4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13573299P 1999-05-25 1999-05-25
US60/135,732 1999-05-25

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WO2000071114A1 true WO2000071114A1 (en) 2000-11-30
WO2000071114A8 WO2000071114A8 (en) 2001-05-25

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EP (1) EP1194142A4 (en)
JP (1) JP2003500356A (en)
KR (1) KR20020010669A (en)
CN (1) CN1351491A (en)
AR (1) AR024076A1 (en)
AU (1) AU5304900A (en)
BR (1) BR0010483A (en)
CA (1) CA2375543A1 (en)
CO (1) CO5170527A1 (en)
CZ (1) CZ20014186A3 (en)
HK (1) HK1046630A1 (en)
HU (1) HUP0201265A3 (en)
IL (1) IL146213A0 (en)
MX (1) MXPA01012048A (en)
NO (1) NO20015699D0 (en)
NZ (1) NZ515169A (en)
PL (1) PL351945A1 (en)
TR (1) TR200103238T2 (en)
WO (1) WO2000071114A1 (en)
ZA (1) ZA200109624B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1237851A4 (en) * 1999-12-15 2004-06-23 Smithkline Beecham SALTS OF i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID

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Publication number Priority date Publication date Assignee Title
JP2015510947A (en) * 2012-03-22 2015-04-13 トランステック・ファーマ，エルエルシー Tris (hydroxymethyl) aminomethane salt of small molecule GLP1R agonist and pharmaceutical composition and use thereof

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US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

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UY25338A1 (en) * 1998-01-07 2001-08-27 Smithkline Beecham Corp METHOD FOR TREATING COPD
WO2001043692A2 (en) * 1999-12-15 2001-06-21 Smithkline Beecham Corporation SALTS OF Cis-4-CYANO-4-[3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1237851A4 (en) * 1999-12-15 2004-06-23 Smithkline Beecham SALTS OF i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1-CARBOXYLIC ACID

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EP1194142A4 (en) 2002-10-25
ZA200109624B (en) 2002-09-11
MXPA01012048A (en) 2002-05-06
CN1351491A (en) 2002-05-29
HK1046630A1 (en) 2003-01-24
CO5170527A1 (en) 2002-06-27
EP1194142A1 (en) 2002-04-10
PL351945A1 (en) 2003-07-14
KR20020010669A (en) 2002-02-04
CA2375543A1 (en) 2000-11-30
BR0010483A (en) 2002-02-13
CZ20014186A3 (en) 2002-04-17
AU5304900A (en) 2000-12-12
HUP0201265A3 (en) 2003-03-28
NO20015699L (en) 2001-11-22
NO20015699D0 (en) 2001-11-22
IL146213A0 (en) 2002-07-25
HUP0201265A2 (en) 2002-08-28
TR200103238T2 (en) 2002-02-21
AR024076A1 (en) 2002-09-04
NZ515169A (en) 2003-05-30
WO2000071114A8 (en) 2001-05-25
JP2003500356A (en) 2003-01-07

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