EP1237851A2 - SELS D'ACIDE CARBOXYLIQUE i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1 - Google Patents

SELS D'ACIDE CARBOXYLIQUE i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1

Info

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Withdrawn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)
English (en)
Other versions
EP1237851A4 (fr
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1237851A2 publication Critical patent/EP1237851A2/fr
Publication of EP1237851A4 publication Critical patent/EP1237851A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • This invention relates to certain salts of a carboxylic acid useful for treating diseases treatable by inhibiting the PDE4 enzyme.
  • Cyclic nucleotide phosphodiesterases 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.
  • PDE isozymes 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.
  • 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.
  • 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).
  • diseases in the area of inflammation e.g., asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, rheumatoid arthritis
  • cognition impairment e.g., multi-infarct dementia, cognitive dysfunction, or stroke.
  • 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.
  • 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.
  • Salts of this acid were prepared and characterized as per the following examples.
  • 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
  • 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.
  • 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.
  • ⁇ ⁇ MR 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 .
  • 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.
  • 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.
  • DSC indicated one sharp major endotherm at 147.1 °C and one shoulder at 153.2 °C.

Landscapes

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

Abstract

L'invention concerne des sels de cis-4-cyano-4-[3-(cyclopentyloxy)-4-méthoxyphényl]cyclohexane-1-carboxylate.
EP00989266A 1999-12-15 2000-12-15 SELS D'ACIDE CARBOXYLIQUE i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1 Withdrawn EP1237851A4 (fr)

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 (fr) 1999-12-15 2000-12-15 SELS D'ACIDE CARBOXYLIQUE Cis-4-CYANO-4-[3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1

Publications (2)

Publication Number Publication Date
EP1237851A2 true EP1237851A2 (fr) 2002-09-11
EP1237851A4 EP1237851A4 (fr) 2004-06-23

Family

ID=22622045

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00989266A Withdrawn EP1237851A4 (fr) 1999-12-15 2000-12-15 SELS D'ACIDE CARBOXYLIQUE i Cis /i -4-CYANO-4- 3-(CYCLOPENTYLOXY)-4-METHOXYPHENYL]CYCLOHEXANE-1

Country Status (3)

Country Link
EP (1) EP1237851A4 (fr)
JP (1) JP2003534238A (fr)
WO (1) WO2001043692A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR024076A1 (es) * 1999-05-25 2002-09-04 Smithkline Beecham Corp Sales de cis-[4-ciano-4-(3-ciclopentiloxi-4-metoxifenil) ciclohexan-1-carboxilato]
CA2746316C (fr) * 2008-12-08 2017-01-03 Glaxosmithkline Llc Sel de tris(hydroxymethyl)aminomethane de 8-chloro-3-pentyl-3,7-dihydro-1h-purine-2,6 dione et son utilisation therapeutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018793A1 (fr) * 1997-10-10 1999-04-22 Smithkline Beecham Corporation Procede de preparation d'acides 4-phenyl-4-cyanocyclohexanoiques substitues
WO2000071114A1 (fr) * 1999-05-25 2000-11-30 Smithkline Beecham Corporation Sels de cis-¢4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyle) cyclohexane-1-carboxylate!

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY25338A1 (es) * 1998-01-07 2001-08-27 Smithkline Beecham Corp Método para tratar copd

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018793A1 (fr) * 1997-10-10 1999-04-22 Smithkline Beecham Corporation Procede de preparation d'acides 4-phenyl-4-cyanocyclohexanoiques substitues
WO2000071114A1 (fr) * 1999-05-25 2000-11-30 Smithkline Beecham Corporation Sels de cis-¢4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyle) cyclohexane-1-carboxylate!

Non-Patent Citations (1)

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

Also Published As

Publication number Publication date
EP1237851A4 (fr) 2004-06-23
JP2003534238A (ja) 2003-11-18
WO2001043692A2 (fr) 2001-06-21
WO2001043692A3 (fr) 2002-03-07

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