NO915122L - N-substituerte cykloalkyl- og polycykloalkyl- alfa-substituerte trp-phe- og fenetylamin-derivater - Google Patents

N-substituerte cykloalkyl- og polycykloalkyl- alfa-substituerte trp-phe- og fenetylamin-derivater

Info

Publication number
NO915122L
NO915122L NO91915122A NO915122A NO915122L NO 915122 L NO915122 L NO 915122L NO 91915122 A NO91915122 A NO 91915122A NO 915122 A NO915122 A NO 915122A NO 915122 L NO915122 L NO 915122L
Authority
NO
Norway
Prior art keywords
substituted
agents
treatment
phe
polycycloalcyl
Prior art date
Application number
NO91915122A
Other languages
English (en)
Other versions
NO915122D0 (no
NO301831B1 (no
Inventor
David Christopher Horwell
Martyn Clive Pritchard
Reginald Stewart Richardson
Edward Roberts
Julian Aranda
Original Assignee
Warner Lambert Co
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 Warner Lambert Co filed Critical Warner Lambert Co
Publication of NO915122D0 publication Critical patent/NO915122D0/no
Publication of NO915122L publication Critical patent/NO915122L/no
Publication of NO301831B1 publication Critical patent/NO301831B1/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Peptides Or Proteins (AREA)
NO915122A 1989-06-29 1991-12-27 N-substituerte cykloalkyl- og polycykloalkyl-<alfa>-substituerte Trp-Phe- og fenetylamin-derivater NO301831B1 (no)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US37432789A 1989-06-29 1989-06-29
US42248689A 1989-10-16 1989-10-16
US53081190A 1990-06-05 1990-06-05
PCT/US1990/003553 WO1991000274A1 (en) 1989-06-29 1990-06-28 N-substituted cycloalkyl and polycycloalkyl alpha-substituted trp-phe- and phenethylamine derivatives

Publications (3)

Publication Number Publication Date
NO915122D0 NO915122D0 (no) 1991-12-27
NO915122L true NO915122L (no) 1992-02-27
NO301831B1 NO301831B1 (no) 1997-12-15

Family

ID=27409174

Family Applications (1)

Application Number Title Priority Date Filing Date
NO915122A NO301831B1 (no) 1989-06-29 1991-12-27 N-substituerte cykloalkyl- og polycykloalkyl-<alfa>-substituerte Trp-Phe- og fenetylamin-derivater

Country Status (17)

Country Link
EP (2) EP0479910A1 (no)
JP (1) JP2972331B2 (no)
KR (2) KR0167315B1 (no)
CN (1) CN1049165A (no)
AT (1) ATE275546T1 (no)
AU (1) AU644088B2 (no)
CA (2) CA2060652C (no)
DE (1) DE69034162T2 (no)
DK (1) DK0405537T3 (no)
ES (1) ES2229202T3 (no)
FI (1) FI106197B (no)
IE (1) IE902347A1 (no)
IL (1) IL94903A0 (no)
NO (1) NO301831B1 (no)
NZ (1) NZ234264A (no)
PT (1) PT94543B (no)
WO (1) WO1991000274A1 (no)

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162336A (en) * 1990-06-21 1992-11-10 Rhone-Poulenc Rorer Pharmaceuticals Inc. Tetrahydro-pyrido-indoles as cholecystokinin and gastrin antagonists
DE69132805T2 (de) * 1990-08-31 2002-10-24 Warner-Lambert Co., Ann Arbor Pro-medikamente für cck-antagonisten
NZ239595A (en) * 1990-08-31 1994-06-27 Warner Lambert Co Cholecystokinin antagonistic compounds ; pharmaceutical compositions and use thereof
US5244915A (en) * 1990-08-31 1993-09-14 Warner-Lambert Company Amico acid derivatives cyclized at the c-terminal
US5340825A (en) * 1990-08-31 1994-08-23 Warner-Lambert Company Pro drugs for CCK antagonists
US5593967A (en) * 1990-08-31 1997-01-14 Warner-Lambert Company Cholecystokinin antagonists, their preparation and therapeutic use
US5264420A (en) * 1990-09-27 1993-11-23 Merck & Co., Inc. Fibrinogen receptor antagonists
WO1992019254A1 (en) * 1991-04-24 1992-11-12 Warner-Lambert Company α-SUBSTITUTED POLYPEPTIDES HAVING THERAPEUTIC ACTIVITY
HUT68769A (en) * 1991-05-07 1995-07-28 Merck & Co Inc FIBRINOGéN RECEPTOR ANTAGONIST COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AS EFFECTIVE SUBSTANCE
EP0594692A1 (en) * 1991-07-12 1994-05-04 Warner-Lambert Company Cholecystokinin antagonists useful in the treatment of panic attacks
US5217957A (en) * 1991-08-20 1993-06-08 Warner-Lambert Company Cholecystokinin antagonists useful for treating depression
US5153191A (en) * 1991-08-20 1992-10-06 Warner-Lambert Company Cholecystokinin antagonists useful for treating depression
US5389631A (en) * 1991-10-29 1995-02-14 Merck & Co., Inc. Fibrinogen receptor antagonists
US5272158A (en) * 1991-10-29 1993-12-21 Merck & Co., Inc. Fibrinogen receptor antagonists
DE4137490A1 (de) * 1991-11-14 1993-05-19 Goedecke Ag Synthese von tricyclo(3.3.1.13,7)dec-2.yl(r-(r*,r*))-3- (1h-indol-3-yl-methyl)-3-methyl-4,9-dioxo- 7,11-diphenyl-10-oxa-2,5,8-triaza-undecanat
US6492531B1 (en) 1992-02-18 2002-12-10 Warner-Lambert Company Method of treating cognitive disorders
GB9316722D0 (en) * 1993-08-12 1993-09-29 Black James Foundation Bicyclo (2.2.2)octane derivatives
US5514683A (en) * 1992-02-20 1996-05-07 James Black Foundation Limited Bicyclo 2,2,2!octane derivatives
JPH07504184A (ja) * 1992-02-20 1995-05-11 ジェイムズ・ブラック・ファウンデーション・リミテッド コレストシストキニン抑制剤としてのビシクロ［２，２，２］オクタン誘導体
US5227490A (en) * 1992-02-21 1993-07-13 Merck & Co., Inc. Fibrinogen receptor antagonists
AU4348993A (en) * 1992-06-19 1994-01-24 James Black Foundation Limited Bicyclooctane and bicycloheptane derivatives
US5380872A (en) * 1992-07-14 1995-01-10 Glaxo Inc. Modulators of cholecystokinin
US5922681A (en) * 1992-09-14 1999-07-13 Warner-Lambert Company Endothelin antagonists
ATE188379T1 (de) * 1992-10-14 2000-01-15 Merck & Co Inc Fibrinogenrezeptor-antagonisten
US5340798A (en) * 1992-10-14 1994-08-23 Merck & Co., Inc. Fibrinogen receptor antagonists
US5358956A (en) * 1992-10-14 1994-10-25 Merck & Co., Inc. Fibrinogen receptor antagonists
AU674553B2 (en) * 1992-10-14 1997-01-02 Merck & Co., Inc. Fibrinogen receptor antagonists
AU675689B2 (en) * 1992-12-01 1997-02-13 Merck & Co., Inc. Fibrinogen receptor antagonists
FR2700540B1 (fr) * 1993-01-15 1995-02-17 Irj alpha-méthyl-(R)-tryptophyl-arylcycloalkylalkylamides ligands aux récepteurs des gastrines, leur préparation et leur utilisation en thérapeutique.
US5441952A (en) * 1993-04-05 1995-08-15 Merck & Co., Inc. Fibrinogen receptor antagonists
US5334596A (en) * 1993-05-11 1994-08-02 Merck & Co., Inc. Fibrinogen receptor antagonists
US5397791A (en) * 1993-08-09 1995-03-14 Merck & Co., Inc. Fibrinogen receptor antagonists
US5821241A (en) * 1994-02-22 1998-10-13 Merck & Co., Inc. Fibrinogen receptor antagonists
DE69530081T2 (de) * 1994-05-27 2003-12-24 James Black Foundation Ltd., London Gastrin- und cck-antagonisten
US5719144A (en) * 1995-02-22 1998-02-17 Merck & Co., Inc. Fibrinogen receptor antagonists
US5852045A (en) * 1995-10-19 1998-12-22 Merck & Co., Inc. Fibrinogen receptor antagonists
US5789421A (en) * 1995-10-26 1998-08-04 Merck & Co., Inc. Fibrinogen receptor antagonist
US5780480A (en) * 1996-02-28 1998-07-14 Merck & Co., Inc. Fibrinogen receptor antagonists
US5889023A (en) * 1996-05-10 1999-03-30 Merck & Co., Inc. Fibrinogen receptor antagonist
US5981584A (en) * 1997-02-06 1999-11-09 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US7375093B2 (en) 2002-07-05 2008-05-20 Intrexon Corporation Ketone ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
BRPI0606228A2 (pt) 2005-01-05 2009-06-09 Abbott Lab inibidores de enzima 11-beta-hidroxiesteróide desidrogenase tipo 1
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
JP5078621B2 (ja) 2005-01-05 2012-11-21 アボット・ラボラトリーズ １１−β−ヒドロキシステロイドデヒドロゲナーゼ１型酵素の阻害薬としてのアダマンチル誘導体
JP5736098B2 (ja) 2007-08-21 2015-06-17 アッヴィ・インコーポレイテッド 中枢神経系障害を治療するための医薬組成物
AU2018251687B2 (en) * 2017-04-10 2021-07-29 The Regents Of The University Of Michigan Covalent small molecule DCN1 inhibitors and therapeutic methods using the same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482567A (en) * 1982-10-07 1984-11-13 Research Foundation For Mental Hygiene, Inc. N-hexanoyl to n-heptadecanoyl 5-hydroxy tryptophan-5-hydroxytryptophanamides and use as analgesics
US4757151A (en) * 1985-11-14 1988-07-12 Warner-Lambert Company 2-substituted-[2-substituted-amino]-N-arylalkyl-3-[indol-3-yl]
US4814463A (en) * 1985-12-31 1989-03-21 Biomeasure, Inc. CCK antagonists

Also Published As

Publication number Publication date
PT94543A (pt) 1991-03-20
KR920702678A (ko) 1992-10-06
ATE275546T1 (de) 2004-09-15
AU5962890A (en) 1991-01-17
KR0180539B1 (en) 1999-05-01
CN1049165A (zh) 1991-02-13
EP0479910A1 (en) 1992-04-15
EP0405537B1 (en) 2004-09-08
DK0405537T3 (da) 2005-01-10
CA2060652A1 (en) 1990-12-30
CA2344707A1 (en) 1991-01-10
JPH04506079A (ja) 1992-10-22
PT94543B (pt) 1997-04-30
NO915122D0 (no) 1991-12-27
JP2972331B2 (ja) 1999-11-08
CA2060652C (en) 2001-08-21
DE69034162D1 (de) 2004-10-14
FI106197B (fi) 2000-12-15
EP0405537A1 (en) 1991-01-02
DE69034162T2 (de) 2005-09-22
IE902347L (en) 1990-12-29
KR0167315B1 (ko) 1999-01-15
NZ234264A (en) 1993-05-26
FI916060A0 (fi) 1991-12-20
CA2344707C (en) 2002-07-30
WO1991000274A1 (en) 1991-01-10
IE902347A1 (en) 1991-01-16
NO301831B1 (no) 1997-12-15
AU644088B2 (en) 1993-12-02
ES2229202T3 (es) 2005-04-16
IL94903A0 (en) 1991-04-15

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