WO1992007829A1 - Indole-3-methanamines utilisees en tant qu'agents antidiabetiques, antiobesite et antiatherosclerotiques - Google Patents

Indole-3-methanamines utilisees en tant qu'agents antidiabetiques, antiobesite et antiatherosclerotiques Download PDF

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Publication number
WO1992007829A1
WO1992007829A1 PCT/US1991/007785 US9107785W WO9207829A1 WO 1992007829 A1 WO1992007829 A1 WO 1992007829A1 US 9107785 W US9107785 W US 9107785W WO 9207829 A1 WO9207829 A1 WO 9207829A1
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WO
WIPO (PCT)
Prior art keywords
phenylmethyl
methoxy
indole
methyl
mmol
Prior art date
Application number
PCT/US1991/007785
Other languages
English (en)
Inventor
Chiu-Hong Lin
John Charles Sih
Steven Paul Tanis
Original Assignee
The Upjohn Company
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 The Upjohn Company filed Critical The Upjohn Company
Publication of WO1992007829A1 publication Critical patent/WO1992007829A1/fr

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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
    • 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
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention provides novel compounds . More particularly, the present invention provides novel indole-3-methaanamines which are useful in treating or preventing certain metabolic disorders of human and animal metabolism, e.g. hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia, excess adiposity or hyperlipidemia. BACKGROUND OF THE INVENTION
  • the above disease states could be treated by either ameliorating or preventing the metabolic and biochemical disorders.
  • humans and animals which have not been diagnosed as having one of the above disease states but evidencing some or all of the disorders described above, could be benefitted by preventing the development of a currently recognized disease state. Therefore, a compound that is useful in the treatment of hyperglycemia, impaired glucose tolerance, hyperinsulinemia and insulin insensitivity could also be used to treat or prevent NIDDM, obesity, hypertension, or atherosclerosis.
  • IR (nujol): 3185, 2957, 2927, 2856, 1627, 1497, 1471, 1442, 1422, 1282, 1211, 1076, and 712cm -1 .
  • the solid is purified by recrystallization from absolute ethanol to give the target indole as a white powdery solid.
  • the mother liquor is concentrated in vacuo to give a viscous yellow oil which is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, EtOAc-hexanes 1:2, 400 mL fractions).
  • IR 1655, 1527, 1478, 1431, 1406, 1252, 1161, 1043, 824, and 732cm -1 .
  • the suspended solids are removed by filtration through a pad of celite.
  • the filter cake is rinsed with EtOAc (0.5L) and the combined filtrates are concentrated in vacuo to yield the crude benzyl ether as a tan solid.
  • the solid is dissolved in hot EtOAc (0.5L) and the solution is diluted with hexanes (1.0L). The mixture is cooled to room temperature overnight and deposited the target ether as a white solid (133.3 g).
  • the mother liquor is concentrated in vacuo to give a tan solid which is recrystallized from hexanes-EtOAc (2:1).
  • IR (nujol): 2952, 2925, 1598, 1510, 1481, 1467, 1357, 1329, 1297, 1192, 1170, 1111, 855, 851 and 838cm -1 .
  • the enamine solution is hydrogenated (30 psi) in a Parr shaker (2.0L) over Raney nickel (3.0 g, 50% slurry, washed 3X10mL with absolute EtOH) until hydrogen uptake ceases (5 hours).
  • the catalyst is removed by filtration through a pad of celite, the filter cake is rinsed with EtOAc (1.0L) and the combined filtrates (clear, pale yellow solution) are dried (Na 2 SO 4 ).
  • IR (nujol): 3235, 2954, 2925, 2855, 1655, 1636, 1617, 1528, 1496, 1462, 1452, 1283, 1220, 1137, and 1127cm -1 .
  • IR (nujol): 2956, 2925, 2854, 1646, 1602, 1535, 1494, 1469, 1453, 1418, 1262, 1230, 1172, 1055, and 779cm -1 .
  • the organic phase is separated, dried (N a 2 SO 4 ), and concentrated in vacuo to give the indole as a pale yellow solid which is purified by recrystallizationfrom Et 2 O-hexanes to give 5-phenylmethoxy-1-phenylmethyl-1H-indole as white crystals.
  • the mother liquor is concentrated in vacuo to give an oily yellow solid which is recrystallized to afford an additional amount of the target compound as a white crystalline solid.
  • TLC provide a clear, pale yellow, viscous oil.
  • Example 3 According to the general procedure described in Example 3, treatment of the crude imine derived from [4S, 5S]-2,2-dimethyl-4-phenyl-5-amino-1,3-dioxane (2.07 g, 10 mmol) and 1 -methyl- 1H-indole-3-carboxaldehyde (1.31 g, 8.2 mmol) with NaBH 3 CN (0.67 g, 10.7 mmol) provide a crude viscous yellow oil.
  • the crude material is purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm OD, ethyl acetate-hexanes 50:50, 450 mL fractions) using the flash technique. Fractions homogenous by TLC provide a clear, pale yellow, viscous oil.
  • Example 11 1 -Phenylmethyl-5-methoxy-N-((S)- 1 -phenyl)ethyl-3-indolemethanamine
  • IR (nujol): 1706, 1481, 1444, 1285, 1254, 1238, 1115, and 706cm -1 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux composés utilisés dans le traitement du diabète sucré indépendant de l'insuline (NIDDM), de l'obésité, de l'hypertension ou de l'athérosclérose. L'invention comprend un composé de formule (I), dans laquelle R1-R6 représentent toute une variété de substituants, ainsi qu'un procédé de traitement des conditions pathologiques susmentionnées.
PCT/US1991/007785 1990-11-02 1991-10-29 Indole-3-methanamines utilisees en tant qu'agents antidiabetiques, antiobesite et antiatherosclerotiques WO1992007829A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60815990A 1990-11-02 1990-11-02
US608,159 1990-11-02

Publications (1)

Publication Number Publication Date
WO1992007829A1 true WO1992007829A1 (fr) 1992-05-14

Family

ID=24435314

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/007785 WO1992007829A1 (fr) 1990-11-02 1991-10-29 Indole-3-methanamines utilisees en tant qu'agents antidiabetiques, antiobesite et antiatherosclerotiques

Country Status (2)

Country Link
AU (1) AU8876591A (fr)
WO (1) WO1992007829A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506245A (en) * 1992-10-12 1996-04-09 Adir Et Compagnie Thiazolidinedione compounds
US5981599A (en) * 1996-05-01 1999-11-09 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
US6001884A (en) * 1991-08-23 1999-12-14 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
EP1189583A1 (fr) * 1999-05-27 2002-03-27 Neurim Pharmaceuticals (1991) Limited Derives d'indole
WO2003035061A1 (fr) * 2001-10-23 2003-05-01 Biovitrum Ab Utilisation de derives d'indole et d'indoline pour le traitement de l'obesite ou la reduction de l'apport alimentaire
WO2007093880A3 (fr) * 2006-02-15 2007-11-01 Neurim Pharma 1991 Nouveaux dérivés d'indolopyrone et leur procédé de préparation
US9101613B2 (en) 2006-02-15 2015-08-11 Neurim Pharmaceuticals (1991) Ltd. Methods for treating neurological disease

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0530149A1 (fr) * 1991-08-30 1993-03-03 Ciba-Geigy Ag Parasiticide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459767A (en) * 1965-08-10 1969-08-05 Pfizer & Co C Aminomethylindoles
EP0375133A1 (fr) * 1988-11-14 1990-06-27 The Upjohn Company Acides alpha-amino-indole-3-acétiques, utiles comme agents antidiabétiques, antiobésité et antiartériosclérotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459767A (en) * 1965-08-10 1969-08-05 Pfizer & Co C Aminomethylindoles
EP0375133A1 (fr) * 1988-11-14 1990-06-27 The Upjohn Company Acides alpha-amino-indole-3-acétiques, utiles comme agents antidiabétiques, antiobésité et antiartériosclérotiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 110, 1989, (Columbus, Ohio, US), S.R. Dhaneshwar et al.: "Synthesis and anti-inflammatory activities of some N-acetyl-2-phenylindole Mannich bases", see page 726, abstract 192587f, & Indian J. Pharm. Sci. 1988, 50(3), 165-7 (RN 120239-54-5) *
Chemical Abstracts, vol. 84, 1976, (Columbus, Ohio, US), see abstract 121647j, & ES,A, 407703 (S. SOTO et al.) 16 October 1976 (RN56972-16-8; RN 56972-12-4; RN 56972-08-8; RN 56972-04-4) *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6001884A (en) * 1991-08-23 1999-12-14 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US5506245A (en) * 1992-10-12 1996-04-09 Adir Et Compagnie Thiazolidinedione compounds
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US6710088B2 (en) 1996-05-01 2004-03-23 Nps Pharmaceuticals, Inc. Inorganic ion receptor-active compounds
US5981599A (en) * 1996-05-01 1999-11-09 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
US6342532B1 (en) 1996-05-01 2002-01-29 Nps Pharmaceuticals, Inc. Inorganic ion receptor active compounds
EP1189583A4 (fr) * 1999-05-27 2004-04-14 Neurim Pharma 1991 Derives d'indole
EP1189583A1 (fr) * 1999-05-27 2002-03-27 Neurim Pharmaceuticals (1991) Limited Derives d'indole
US6858642B1 (en) 1999-05-27 2005-02-22 Neurim Pharmaceuticals (1991) Ltd. Indole derivatives
US7355054B2 (en) 1999-05-27 2008-04-08 Neurim Pharmaceuticals (1991) Ltd. Indole derivatives
CN100425592C (zh) * 1999-05-27 2008-10-15 纽里姆药品(1991)有限公司 吲哚衍生物
WO2003035061A1 (fr) * 2001-10-23 2003-05-01 Biovitrum Ab Utilisation de derives d'indole et d'indoline pour le traitement de l'obesite ou la reduction de l'apport alimentaire
WO2007093880A3 (fr) * 2006-02-15 2007-11-01 Neurim Pharma 1991 Nouveaux dérivés d'indolopyrone et leur procédé de préparation
US7635710B2 (en) 2006-02-15 2009-12-22 Neurim Pharmaceuticals (1991) Ltd. Pyrone-indole derivatives and process for their preparation
EA015605B1 (ru) * 2006-02-15 2011-10-31 Ньюрим Фармасьютикалз (1991) Лтд. Производные пирониндола, фармацевтическая композиция и способы лечения
US8242163B2 (en) 2006-02-15 2012-08-14 Neurim Pharmaceuticals (1991) Ltd. Pyrone-indole derivatives and process for their preparation
KR101207736B1 (ko) 2006-02-15 2012-12-03 뉴림 파머슈티칼스 (1991) 리미티드 신규한 피론-인돌 유도체들 및 그 제조 공정
US8569355B2 (en) 2006-02-15 2013-10-29 Neurim Pharmaceuticals (1991) Ltd. Pyrone-indole derivatives and process for their preparation
US9101613B2 (en) 2006-02-15 2015-08-11 Neurim Pharmaceuticals (1991) Ltd. Methods for treating neurological disease

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Publication number Publication date
AU8876591A (en) 1992-05-26

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