EP1296942A1 - Antagonistes/agonistes inverses du glucagon - Google Patents

Antagonistes/agonistes inverses du glucagon

Info

Publication number
EP1296942A1
EP1296942A1 EP01943189A EP01943189A EP1296942A1 EP 1296942 A1 EP1296942 A1 EP 1296942A1 EP 01943189 A EP01943189 A EP 01943189A EP 01943189 A EP01943189 A EP 01943189A EP 1296942 A1 EP1296942 A1 EP 1296942A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound according
hydrogen
independently
cycloalkyl
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Withdrawn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
EP01943189A
Other languages
German (de)
English (en)
Inventor
Anker Steen Joergensen
Inge Thoeger Christensen
Janos Tibor Kodra
Peter Madsen
Carsten Behrens
Christian Sams
Jesper Lau
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1296942A1 publication Critical patent/EP1296942A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/42—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • 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
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to agents that act to antagonize the action of the glucagon pep- tide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
  • Glucagon is a key hormonal agent that, in co-operation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
  • Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.
  • Diabetes mellitus is a common disorder of glucose metabolism.
  • the disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin-dependent in character.
  • Subjects with Type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
  • absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state.
  • glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional antihyperglycemia treatment of diabetes.
  • the action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent glucagon- induced responses.
  • the antagonist can be peptidic or non-peptidic in nature.
  • Native glucagon is a 29 amino acid peptide having the sequence:
  • Glucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al., Science 259, 1614, (1993)).
  • the receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
  • Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred.
  • non-peptide glucagon antagonists a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)).
  • WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
  • US patent No 4,359,474 discloses the glucagon antagonistic properties of 1-phenyl pyrazole derivatives.
  • US patent No 4,374,130 discloses substituted disilacyclohexanes as glucagon antagonists.
  • WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists.
  • WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity.
  • Madsen et al. J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol-2-ylthio)-1-(3,4- dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists.
  • WO 99/01423 and WO 00/39088 (Novo Nordisk A/S) disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists.
  • Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • C 1-6 -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, terf-pentyl, n-hexyl, isohexyl and the like.
  • C 2-6 -alkenyr represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1 ,3-butadienyl, 1-but- enyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-penten- yl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.
  • C 2 - 6 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
  • C ⁇ -6 -alkoxy refers to the radical -O-C 1-6 -alkyl, wherein C 1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, ferf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • d-e-alkanoyl denotes a group -C(O)H or -C(O)-C 1-5 -alkyl. Represen- tative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
  • C 3-8 -cycloalkyl as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 4-8 -cycloalkenyl represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.
  • Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1 ,4-cyclooctadienyl and the like.
  • heterocyclyl represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds.
  • Representative examples are pyrrolidinyl, piperidyl, piperaz- inyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • arylene as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, pentalenylene, azulenylene and the like.
  • Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydro- naphthylene, 1 ,4-dihydronaphthylene and the like.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • aroyl denotes a group -C(O)-aryl, wherein aryl is as defined above.
  • heteroaryl as used herein is intended to include heterocyclic aromatic ring sys- tems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3- thiadiazolyl, 1
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • Aryl-C 1-6 -alkyl means C 1-6 -alkyl or C 2-6 -alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • the present invention is based on the unexpected observation that the compounds of the general formula (I) disclosed below antagonize the action of glucagon.
  • the compounds are advantageous by being selective towards the glucagon receptor and show a higher binding affinity for the glucagon receptor compared to the binding affinity for the structurally relatedGIP (Gastric Inhibitory Peptide) receptor and GLP-1 receptor.
  • R 1 , R 2 , R 3 , R 4 and R 5 independently are hydrogen or C ⁇ -alkyl
  • A is -C(O)-, -CH(OR 6 )- or -CHF-,
  • R 6 is hydrogen or C 1-6 -alkyl
  • Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
  • R 7 and R 8 which may optionally be substituted with one or two groups R 7 and R 8 selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl,
  • R 9 and R 10 independently are hydrogen or C ⁇ -6 -alkyl
  • r is 0 or 1 ,
  • q and s independently are 0, 1 , 2 or 3,
  • R 11 , R 12 , R 13 and R 14 independently are hydrogen, C 1-6 -alkyl or C 3 - 8 -cycloalkyl,
  • R ⁇ o , R lb , R 1 ' and R 1B independently are
  • cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR 21 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl,
  • R 21 and R 22 independently are hydrogen, C 1-e -alkyl, aryl-C 1-6 -alkyl or aryl,
  • R 21 and R 22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • a 0, 1 or 2
  • c 1 or 2
  • R 23 , R 24 , R 25 and R 26 independently are hydrogen, C 1-6 -alkyl or fluorine,
  • R 19 and R 20 independently are hydrogen, C ⁇ -6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo- alkyl-d-e-alkyl, E is
  • R and R independently are
  • aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and d. 6 -alkyl,
  • R 32 and R 33 independently are hydrogen or C ⁇ -alky!, or
  • R 32 and R 33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R 29 , R 30 and R 31 independently are
  • cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 3 R 35 and
  • R 34 and R 35 independently are hydrogen, C 1-6 -alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • R 29 , R 30 and R 31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH 2 ) t -CR 36 R 37 -(CH 2 ) r O-, -(CH 2 ) t -CR 36 R 37 -(CH 2 ) r or -S-(CH 2 )rCR 36 R 37 -(CH 2 ) r S-, wherein
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 36 and R 37 independently are hydrogen or C 1-6 -alkyl
  • R ⁇ R 2 , R 3 , R 4 and R 5 independently are hydrogen or C 1-6 -alkyl
  • A is -C(O)-, -CH(OR 6 )- or -CHF-,
  • R 6 is hydrogen or C ⁇ -6 -alkyl
  • Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
  • R 7 and R 8 which may optionally be substituted with one or two groups R 7 and R 8 selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl,
  • R 9 and R 10 independently are hydrogen or Cve-alkyl, X is
  • r is 0 or 1 ,
  • q and s independently are 0, 1 , 2 or 3,
  • R , R , R 13 and R 14 independently are hydrogen, C 1-6 -alkyl or C 3-8 -cycloalkyl,
  • R 15 , R 16 , R 17 and R 18 independently are
  • cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR 21 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 and C 1-6 -alkyl,
  • R and R independently are hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl or aryl,
  • R 21 and R 22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • a 0, 1 or 2
  • c 1 or 2
  • R 23 , R 24 , R 25 and R 26 independently are hydrogen, C ⁇ -6 -alkyl or fluorine,
  • R 19 and R 20 independently are hydrogen, C ⁇ -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo- alkyl-C 1-6 -alkyl, E is
  • aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and C 1-6 -alkyl,
  • R 32 and R 33 independently are hydrogen or C -6 -alkyl, or
  • R 32 and R 33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R 29 , R 30 and R 31 independently are
  • cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and
  • R 34 and R 35 independently are hydrogen, C 1-6 -alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • R 29 , R 30 and R 31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH 2 ) t -CR 36 R 37 -(CH 2 )i-O-, -(CH 2 ) t -CR 36 R 37 -(CH 2 ) ⁇ - or -S-(CH 2 ) r CR 36 R 37 -(CH 2 ),-S-, wherein
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 36 and R 37 independently are hydrogen or C 1-6 -alkyl
  • R 1 , R 2 , R 3 , R 4 and R 5 independently are hydrogen or C 1-6 -alkyl
  • A is -C(O)-, -CH(OR 6 )- or -CHF-,
  • R 6 is hydrogen, C 1-6 -alkyl or halogen
  • Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
  • R 7 and R 8 which may optionally be substituted with one or two groups R 7 and R 8 selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 9 , -NR 9 R 10 and C 1-6 -alkyl,
  • R 9 and R 10 independently are hydrogen or C ⁇ -6 -alkyl, X is
  • r is 0 or 1 ,
  • q and s independently are 0, 1 , 2 or 3,
  • R , R 12 , R 13 and R 14 independently are hydrogen or C 1-6 -alkyl
  • R 1b , R ⁇ , R 1 ' and R 1B independently are
  • the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 21 , -NR 2 R 22 and C 1-6 -alkyl,
  • R and R independently are hydrogen, C 1-6 -alkyl or aryl
  • R 21 and R 22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • a 0, 1 or 2
  • c 1 or 2
  • R 23 , R 24 , R 25 and R 26 independently are hydrogen, C ⁇ -6 -alkyl or fluorine,
  • R 19 and R 20 independently are hydrogen, C ⁇ -alky!, C 3 . 8 -cycloalkyl or C 3-8 -cyclo- alkyl-C-i-e-alkyl, E is
  • R 27 and R 28 independently are
  • aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and C 1-6 -alkyl,
  • R 32 and R 33 independently are hydrogen or C 1-6 -alkyl, or
  • R 32 and R 33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • R 29 , R 30 and R 31 independently are
  • the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl,
  • R 34 and R 35 independently are hydrogen, C ⁇ -6 -alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
  • R 29 , R 30 and R 31 when attached to the same ring carbon atom or differ- ent ring carbon atoms together may form a radical -O-(CH 2 ) t -CR 36 R 37 -(CH 2 ) r O-, -(CH 2 ) r CR 36 R 37 -(CH 2 )r or -S-(CH 2 ),-CR 36 R 37 -(CH 2 ),-S-,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 36 and R 37 independently are hydrogen or C 1-6 -alkyl
  • R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.
  • A is -CHF-.
  • A is -CH(OR 6 )-, wherein R 6 is as defined for formula (I), such as -CH(OH)-.
  • Z is
  • R 7 and R 8 are as defined for formula (I), such as
  • X is
  • R 12 and R 13 independently are hydrogen or C 1-6 -alkyl.
  • X is -C(O)NH-, -C(O)NHCH 2 -, -C(O)NHCH(CH 3 )-, -C(O)NHCH 2 CH 2 -, -C(O)CH 2 -, -CH 2 -, -C(O)- or -NHC(O)-.
  • X is -C(O)NH-, -C(O)NHCH 2 -, -C(O)NHCH(CH 3 )-, -C(O)CH 2 - or -C(O)-, such as -C(O)NH-.
  • D is
  • R 15 , R 16 , R 7 , R 18 , R 19 and R 20 are as defined for formula (I).
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R , R and R are as defined for formula (I).
  • R 15 , R 16 and R 17 are independently hydrogen, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -SCF 3 , C 1-6 -alkyl, C 1-6 -alkoxy, -S-C ⁇ -6 -alkyl, -C(O)OR 21 , -C(O)R 21 , -CH 2 OR 21 , -C(O)NR 21 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -S(O) 2 CF 3 , -S(O) 2 NR 21 R 22 , C 3 . 8 -cycloalkyl, C 3-8 -cycloalkyl- d- 6 -alkoxy or C 3-8 -cycloalkyl-C 1-6 -thioalkyl, or
  • aryl heteroaryl or aryloxy, which may optionally be substituted with -CF 3 , -OCF 3 , C 1-6 -alkyl, halogen or -C(O)OR 21 , or
  • R 21 and R 22 independently are hydrogen or C -6 -alkyl, and a, c, R 23 , R 24 , R 25 and R 26 are as defined for formula (I).
  • R , R lb and R are independently hydrogen, halogen, -CN, -CF 3
  • R 15 , R 16 and R 17 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 or d- 6 -alkoxy.
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R , R ⁇ a and R 2 ⁇ are as defined for formula (I).
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 15 and R 16 are both hydrogen and R 9 is C ⁇ -alkyl, C 3 . 8 -cycloalkyl or C 3-8 -cycloalkyl- C 1-6 -alkyl.
  • D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 1 ° and R 1 are both hydrogen and R 19 and R 20 are both C 1-6 -alkyl
  • E is
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl or phenyl, wherein the phenyl group is optionally substituted as defined for formula (I).
  • R 27 and R 28 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C . 8 -cycloalkenyl.
  • R 27 is hydrogen and R 28 is C 1-6 -alkyl or C 3-8 -cyc)oalkyl, such as fe/if-butyl, cyclohexyl or cyclohexenyl.
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 29 , R 30 and R 31 are as defined for formula (I).
  • R 29 , R 30 and R 31 are as defined for formula (I).
  • R 29 , R 30 and R 31 are independently
  • R 34 and R 35 independently are hydrogen, C ⁇ e-alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 29 , R 30 and R 3 are independently
  • R 34 and R 35 are as defined for formula (I), or
  • R 29 , R 30 and R 31 are independently
  • R 29 , R 30 and R 31 are independently
  • ⁇ which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 3 R 35 and C ⁇ -alky!,
  • R 34 and R 35 independently are hydrogen, C 1-6 -alkyl or aryl, or R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R and R are both hydrogen, and R is different from hydrogen.
  • R 29 and R 31 are both hydrogen, and R 30 is C 3-8 -cycloalkyl or C 4 . 8 -cycloalkenyl,
  • ⁇ which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2) -OR 34 , -NR 34 R 35 and C ⁇ -alky!,
  • R and R independently are hydrogen, C 1-6 -alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 29 and R 31 are both hydrogen, and R 30 is C 4-8 -cycloalkenyl,
  • ⁇ which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR 34 R 35 and C 1-6 -alkyl,
  • R 34 and R 35 independently are hydrogen, C 1-6 -alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 29 and R 31 are both hydrogen, and R 30 is cyclohexenyl
  • R 34 and R 35 independently are hydrogen, C 1-6 -alkyl or aryl,
  • R 34 and R 35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
  • R 30 is substituted with one C 1-6 -alkyl substituent, such as ferf-butyl or methyl.
  • R 29 , R 30 and R 31 are independently hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl.
  • R 29 and R 31 are both hydrogen and R 30 is C-
  • the invention relates to a compound of the general formula ( ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, D and E are as defined for formula (I) or in any one of the preceding embodiments.
  • the invention relates to a compound of the general formula (l 2 ):
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , D and E are as defined for formula (I) or in any one of the preceding embodiments.
  • the invention relates to a compound of the general formula (l 3 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15 , R 16 , R 17 , R 29 , R 30 , and R 31 are as defined for formula (I) or in any one of the preceding embodiments.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen.
  • the invention relates to a compound of the general formula (l 4 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , X, D and E are as defined for formula (I) or in any one of the preceding embodiments.
  • the invention relates to a compound of the general formula (l 5 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , D and E are as defined for formula (I) or in any one of the preceding embodiments.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are hydrogen.
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.
  • geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane- sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, terf-butyl-, tetramethylammonium salts and the like.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
  • the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
  • prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required com- pound of the formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bund- gaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment and/or prevention of disorders and diseases in which such an antagonism is beneficial.
  • the present compounds may be applicable for the treatment and/or prevention of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, Type 1 diabetes, Type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipo- proteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.
  • they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secretions and to reverse intestinal hypomobility due to glucagon administration.
  • the invention relates to a compound according to the invention for use as a medicament.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredi- ent, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the invention.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disorder or disease, wherein a glucagon antagonistic action is beneficial.
  • the invention also relates to a method for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
  • the present compounds are used for the preparation of a medicament for the treatment and/or prevention of hyperglycemia.
  • the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from IGT to Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 1 diabetes.
  • Such treatment and/or prevention is normally accompanied by insulin therapy.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of disor- ders of the lipid metabolism, such as dyslipidemia.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of an appetite regulation or energy expenditure disorder.
  • the present compounds are combined with diet and/or exercise.
  • the present compounds are administered in combina- tion with one or more further active substances in any suitable ratios.
  • Such further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
  • Suitable antidiabetic agents comprise insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg Asp B28 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro B29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on the ATP-dependent potassium channel of the ⁇ -cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthas
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro B29 human insulin, Lantus, or a mix- preparation comprising one or more of these.
  • insulin an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro B29 human insulin, Lantus, or a mix- preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide or glicazide.
  • a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide eg metformin.
  • the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
  • the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).
  • a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and
  • the present compounds may be administered in combination with an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr.
  • an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS- 67582, repaglinide or nateglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS- 67582, repaglinide or nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothy- roxine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothy- roxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glibenclamide or glyburide; a sulphonylurea and acarbose; metformin and a meglitinide such as repaglinide; acarbose and metformin; a sulfonylurea, metformin and troglitazone; a sulfonylurea, metformin and pioglitazone; a sulfonylurea, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a me- glitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitin and a me
  • WO 00/63189 or WO 97/41097 insulin and lovastatin; an insulin analogue or derivative, metformin and a meglitinide such as repaglinide; an insulin analogue or derivative, metformin and a sulfonylurea; an insulin analogue or derivative and troglitazone; an insulin analogue or derivative and pioglitazone; an insulin analogue or derivative and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; an insulin analogue or derivative and lovastatin; etc.
  • the compounds according to the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceu- tical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracistemal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred.
  • suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracistemal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred.
  • the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syr- ups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non- aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot in- jectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is a base addition salt of a compound having the utility of a free acid.
  • a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho- lipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl mono- stearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl mono- stearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be presented as dis- crete units such as capsules or tablets, each containing a predetermined, amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain:
  • the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • HOAt 3-hydroxy-3H-[ ,2,3]triazolo[4,5- ⁇ ]pyridine, also denoted 1- hydroxy-7-azabenzotriazole
  • EGTA ethylene glycol bis( ⁇ -aminoethyl ether) ⁇ /, ⁇ /, ⁇ /' ⁇ /'-tetracetic acid
  • the Sciex Sample control software running on a Macintosh PowerPC 7200 computer was used for the instrument control and data acquisition.
  • the HPLC pump was connected to four eluent reservoirs containing: acetonitrile water
  • samples contain approximately 500 ⁇ g/mL of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)
  • an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof.
  • the analysis was performed at room temperature by injecting 20 ⁇ L of the sample solution on the column, which was eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions were used.
  • the eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 ⁇ L/min through approx. 1 m. 75 ⁇ fused silica capillary to the API interface of API 100 spectrometer.
  • the remaining 1.48 mL/min was passed through the UV detector and to the ELS detector.
  • the detection data were acquired concurrently from the mass spec- trometer, the UV detector and the ELS detector.
  • the HPLC pump was connected to two eluent reservoirs containing: A: 0.01 % TFA in water
  • HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
  • the HPLC pump was connected to two eluent reservoirs containing:
  • the analysis was performed at room temperature by injecting an appropriate volume of the sample (preferably 1 ⁇ L) onto the column that was eluted with a gradient of acetonitrile.
  • an appropriate volume of the sample preferably 1 ⁇ L
  • the HPLC conditions, detector settings and mass spectrometer settings are given in the following table.
  • Step A (RH2,2-Dimethyl-5-oxo-H .3ldioxolan-4-vDacetic acid
  • D-(+)-malic acid 15. O g, 0.1119 mol
  • 2,2-dimethoxypropane 50 mL, 0.392 mmol
  • the mixture was refluxed at 100 °C for 2 hours and evaporated in vacuo.
  • the residue was dissolved in diethyl ether (150 mL) and subjected to flash column chromatography using diethyl ether as eluent (200 mL).
  • Step B (R)-(2,2-Dimethyl-5-oxo-f1 ,31dioxolan-4-ylmethyl)carbamic acid benzyl ester
  • (R)-(2,2-dimethyl-5-oxo-[1 ,3]dioxolan-4-yl)acetic acid (10.0 g, 57.41 mmol)
  • triethylamine (10 mL, 68.89 mmol)
  • diphenylphosphoryl azide 14 mL, 63.15 mmol
  • Step E (R)-lsoserine ethyl ester hvdrochloride
  • Step A (S)-(2,2-Dimethyl-5-oxo-H ,31dioxolan-4-yl)acetic acid
  • Step C (S)-2.2-Dimethyl-5-oxo-F1 ,31dioxolan-4-ylmethylammonium trifluoroacetate
  • the crude (S)-(2,2-dimethyl-5-oxo-[1 ,3]dioxolan-4-ylmethyl)carbamic acid benzyl ester (976 mg, 3.5 mmol) was dissolved in ethanol (14 mL), and palladium (10% on activated charcoal, 300 mg) and 1 ,3-cyclohexadiene (2.8 g, 35 mmol) were added and the reaction was stirred for 1 hour at room temperature, and heated to 40 °C for 10 min.
  • the above (R)-2-methoxysuccinic acid 1 -methyl ester (5.0 g, 30.8 mmol) was dissolved in thionyl chloride (16 mL), and heated to reflux for 2 hours Thionyl chloride and traces thereof was removed by rotary evaporation followed by co-evaporation with acetonitrile.
  • the residual oil was further purified by column chromatography using 20 % ethyl acetate/heptane as eluent. Pure fractions (TLC plates were stained with ammonium molybdate/cerium sul- phate/sulphuric acid) were pooled and taken to dryness. The final yield of 3-fe/t-butoxy- carbonylamino-2(R)-methoxypropionic acid methyl ester was 600 mg (9 %).
  • HNO 3 5 mL fuming, 100%
  • Methyl 2-(trifluoromethoxy)benzoate 5 g, 22.7 mmol
  • the reaction was then stirred at 60 °C for 1 hour and 2 hours at room temperature.
  • the mixture was added to ice water and an oil separated.
  • the oily residue was added water (50 mL), neutralised with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate (25 mL).
  • Step B 5-Amino-2-trifluoromethoxybenzoic acid methyl ester
  • This compound is commercially available (e.g. from Lancaster or Avocado).
  • 4-(4-terf-Butylcyclohex-1-enyl)aniline was prepared in analogy to procedure for preparation of building block 1 1 using 4-ferf-butylcyclohexanone (0.59 mol) and aniline.
  • Step 1 4-((4-Cvclohexylphenylamino)methyl)benzoic acid methyl ester 4-Formylbenzoic acid methyl ester (6.65 g, 40.5 mmol) was dissolved in hot methanol (175 mL). To this mixture, 4-cyclohexylaniline (7.1 g, 40.5 mmol) was added. To the resulting suspension, more methanol (75 mL) was added and the mixture was heated at reflux for 1 hour.
  • Step 2 4-f 1 -(Cvclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyllbenzoic acid methyl ester
  • Step 2a 4-f1 -(Cvclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyllbenzoic acid 4-[1 -(Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid methyl ester (3.0 g ) was dissolved in absolute ethanol (50 mL), sodium hydroxide (4 N, 15 mL) was added and the reaction mixture was stirred at room temperature for 16 hours.
  • Step 3 (R)-3- ⁇ 4-ri-(4-Cyclohexylphenv ⁇ -3-(3-methoxy-5-trifluoromethylphenyl)ureidomethvn- benzoylamino)-2-hydro ⁇ ypropionic acid ethyl ester
  • Step 4 (R)-3- ⁇ 4-[1-(4-Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoyl- amino ⁇ -2-hydroxypropionic acid ethyl ester was dissolved in ethanol (15 mL) and sodium hydroxide (2 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 60 min. Then ethanol was removed in vacuo, water (50 mL) was added and pH was adjusted with 4 N hydrochloric acid to acidic reaction. Filtration and washing with water (5 x 5 mL) and drying in vacuo afforded 460 mg of the title compound as a crystalline solid.
  • Step 2 4-r3-(3.5-Bis(trifluoromethyl)phenv ⁇ -1-(4-cvclohexylphenyl)ureidomethvnbenzoic acid methyl ester
  • Step 2a 4-r3-(3,5-Bis(trifluoromethvDphenyl)-1 -(4-cvclohexylphenvOureidomethv ⁇ benzoic acid
  • aqueous phase was extracted twice with ethyl acetate (75 mL and 25 mL) and the combined organic phases were washed with water (3 x 15 mL), dried (magnesium sulphate) and concentrated in vacuo to afford 4-[3-(3,5-bis(trifluoromethyl)- phenyl)-1 -(4-cyclohexylphenyl)ureidomethyl]benzoic acid.
  • Step 3 (R)-3-f4-r3-(3.5-Bis(trifluoromethyl)phenyl)-1 -(4-cyclohexylphenyl)ureidomethyll- benzoylamino)-2-hydroxypropionic acid ethyl ester
  • the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL).
  • the aqueous phase was extracted with ethyl acetate (10 mL).
  • the combined organic phases were washed with hydrochloric acid (0.2 N, 3 x 10 mL) and water:saturated sodium chloride (1 :1), dried (magnesium sulphate) and concentrated in vacuo.
  • aqueous phase was extracted twice with ethyl acetate (25 mL and 10 mL) and the combined organic phases were washed with saturated sodium chloride:water (1 :1), dried (magnesium sulphate) and concentrated in vacuo to afford 0.21 g of the title compound.
  • Step 1 4-[(4-Cvclohexylphenylamino)methyllbenzoic acid
  • Step 2 4-r3-(3-BromophenvO-1-(4-cvclohexylphenyl)ureidomethvHbenzoic acid 3-Bromoaniline (1.4 g, 8.1 mmol) was dissolved in diethyl ether (50 mL) and 3.5 M dry HCI in ethyl acetate (2.3 mL) was added. The mixture was concentrated in vacuo. The residue was added toluene (100 mL) and concentrated in vacuo. The residue was added toluene (100 mL) and diphosgene (8.1 g, 41 mmol) and the resulting mixture was refluxed for 1.5 hour. After cooling, the mixture was concentrated in vacuo.
  • Step 3 (R)-3- ⁇ 4-r3-(3-Bromophenyl)-1 -(4-cvclohexylphenvDureidomethv ⁇ benzoylamino)-2- hydroxypropionic acid ethyl ester 4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.20 g, 0.39 mmol) was dissolved in DMF (2.5 mL) and EDAC (0.12 g, 0.6 mmol) and HOBt (0.089 mg, 0.6 mmol) were added and the mixture was stirred at room temperature for 10 min.
  • Step 4 (R)-3-f4-r3-(3-Bromophenyl)-1 -(4-cvclohexylphenyl)ureidomethv ⁇ benzoylamino)-2- hydroxypropionic acid
  • Step 2 4-[3-(3-Bromophenyl)-1-(4-cvclohex-1-enylphenv ⁇ ureidomethyllbenzoic acid methyl ester
  • Step 1 f/-ans-4-f(4-tetf-butylcvclohexylamino)methvnbenzoic acid methyl ester
  • the mother liquid was taken to dryness to leave 4.2 g (22%) white solid, which according to NMR consisted mainly of the imino cis isomer.
  • Step 2 Trans-4- ⁇ l -(3,5-bis(trifluoromethyl)phenyl)-3-(4-te/ -butylcvclohexyl)ureidomethv ⁇ - benzoic acid methyl ester
  • Step 2a rrans-4-[1-(3,5-bis(trifluoromethyl)pheny ⁇ -3-(4-te/f-butylcvclohexyl)ureidomethvn- benzoic acid
  • Step 1 4-ri-(4-fe/f-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyllbenzoic acid
  • 4-Formylbenzoic acid methyl ester (10.6 g, 64 mmol) was dissolved in methanol (200 mL).
  • 4-fe/f-Butylaniline (9.61 g, 64 mmol) was added and the resulting suspension was refluxed for 15 min.
  • TFA 5.18 mL, 68 mmol
  • sodium cyanoborohydride 3.26 g, 52 mmol
  • Step 2 The above benzoic acid methyl ester (0.73 g, 2.44 mmol) was dissolved in acetonitrile (7 mL) and 4-trifluoromethoxyphenylisocyanate (405 ⁇ L, 2.68 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours and then refluxed for 1.5 hour.
  • Step 3 (RS)-3- ⁇ 4-H -(4-fe/ ⁇ -Butylpheny ⁇ -3-(4-trifluoromethoxyphenyl)ureidomethy ⁇ benzoyl- amino ⁇ -2-hydroxypropionic acid ethyl ester
  • Step 3 (RS)-3-(4-[1 -(4-Cvclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethvnbenzoyl- aminoV2-hvdroxypropionic acid ethyl ester Yield: 0.33 g (89%).
  • Step 4 (RS)-3- ⁇ 4-H -(4-Cyclohex-1 -enylphenyl)-3-(3.5-dichlorophenyl)ureidomethvnbenzoyl- amino)-2-hvdroxypropionic acid
  • Step 3 (R)-3-(4-H -(4-Cvclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl1benzoyl- amino>-2-hvdroxypropionic acid ethyl ester
  • Step 4 A solution of (R)-3- ⁇ 4-[1 -(4-cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino ⁇ -2-hydroxypropionic acid ethyl ester (0.60 g, 0.98 mmol) in ethanol (5 mL) and THF (5 mL) was stirred and 4 N sodium hydroxide (0.76 mL, 2.94 mmol) was added. The solution was stirred for 3 hours at room temperature and then acidified with 1 N hydrochloric acid. Evaporation in vacuo afforded an oil, which was partitioned between ethyl acetate, wa- ter and brine.
  • aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine. Drying (magnesium sulphate), filtration, and evaporation in vacuo afforded 0.43 g (73%) of the title compound as a solid.
  • Steps 1 and 2 4-ri-(4-Cvclohex-1-enylphenyl)-3-(3.5-dichlorophenyl)ureidomethyllbenzoic add
  • Step 3 (RS)-3-(4-H -(4-Cvclohex-1 -enylphenv0-3-(3,5-dichlorophenyl)ureidomethyribenzoyl- aminol-2-fluoropropionic acid methyl ester
  • Step 2 4-H -(4-Cvclohexylphenv ⁇ -3-(4-trifluoromethylsulfanylphenyl)ureidomethvnbenzoic acid methyl ester
  • Step 2a 4-H -(4-Cvclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethvnbenzoic acid
  • Step 3 (R)-3-f4-M -(4-Cvclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyll- benzoylaminol-2-hvdroxypropionic acid methyl ester
  • reaction mixture was transferred to a separatory funnel with ethyl acetate (30 mL) and water (15 mL) and extracted.
  • the aqueous phase was extracted once more with ethyl acetate (15 mL) and the combined organic phases were washed with hydrochloric acid (0.2 N, 3 x 10 mL) and an aqueous solution of saturated sodium chloride (3 x 10 mL), dried over magnesium sulphate, filtered and concentrated in vacuo.
  • Step 3 (R)-3- ⁇ 4-ri-(4-cvclohexen-1-ylphenyl)-3-(3-methanesulfonyl-4-trifluoromethoxy- phenyl)ureidomethyllbenzoylamino)-2-hvdro ⁇ ypropionic acid methyl ester
  • This intermediate was prepared using general procedure (A) (steps 1 , 2, 2a, and 3).
  • Steps 1 and 2 rra ?s-4-r3-(3.5-bis(methyl)phenyl)-1-(te/ -butylcvclohexyl)ureidomethyl1- benzoic acid methyl ester
  • Step 2a Trans-4-]3-(3.5-bis(methyl)phenyl)-1-(tetf-butylcvclohexyl)ureidomethyl1benzoic acid
  • the compound was prepared by hydrolysis of frans-4-[3-(3,5-bis(methyl)phenyl)-1-(fert-butyl- cyclohexyl)ureidomethyl]benzoic acid methyl ester.
  • Step 3 Trans-(R -3-f4-r-3-(3.5-bis(methyl)phenvn-1 -(4-ferf-butylcvclohexynureidomethvH- benzoylamino>-2-hvdroxypropionic acid methyl ester:
  • This compound was prepared from rans-4-[3-(3,5-bis(methyl)phenyl)-1-(tet ⁇ -butylcyclo- hexyl)ureidomethyl]benzoic acid.
  • Methyl 4-formylbenzoate (47 g, 285 mmol) was dissolved in methanol (400 mL) and a solution of 4-cyclohexylaniline (50 g, 0.285 mmol) in methanol (200 mL) is slowly added with mechanical stirring. More methanol (1 L) was added and the suspension was stirred at room temperature for 3 days. Filtration, washing and drying in vacuo afforded 90.7 g (99%) of 4- [(4-cyclohexylphenylimino)methyl]benzoic acid methyl ester. This was dissolved in N- methylpyrrolidone (855 mL) and methanol (45 mL).
  • This compound was prepared similarly as described in example 35 from ⁇ /-chlorocarbamoyl- 4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl es- ter hydrochloride. Hydrolysis afforded the title compound.
  • Step 1 is performed using the same method as in general procedure (A).
  • Step 2 4- ⁇ fterf-ButoxycarbonvH4-cvclohexylphenyl)aminolmethyl)benzoic acid methyl ester 4-((4-Cyclohexylphenylamino)methyl)benzoic acid methyl ester (2.0 g, 6.18 mmol) was sus- pended in sodium hydroxide (1 N, 6.18 mL) and a solution of di-te f-butyldicarbonate (1.67 g, 7.42 mmol) in THF (10 mL) was added dropwise.
  • reaction mixture was stirred overnight and was concentrated in vacuo to a solid residue, which was redissolved in diethyl ether (50 mL) and washed with water (25 mL) added sodium hydroxide (1.3 mL, 1 N). The aqueous phase was extracted again with diethyl ether (25 mL) at pH 11-12. The combined organic phases were washed with sodium hydrogen sulphate (30 mL, 10%) and water (3 x 20 mL), dried with magnesium sulphate and concentrated in vacuo.
  • Step 3 4-frfe -Butoxycarbonyl-(4-cvclohexylphenyl)amino1methyl)benzoic acid 4- ⁇ [ferf-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl ⁇ benzoic acid methyl ester was suspended in ethanol (30 mL) and sodium hydroxide (4 N, 8.1 mL) was added. The reaction mixture was stirred overnight. The mixture was concentrated to dryness, suspended in water (100 mL), acidified with hydrochloric acid (8.5 mL, 4 N) and extracted with ethyl acetate (100 mL).
  • Step 4 (R)-3-(4- ⁇ rte/ ⁇ -Butoxycarbonyl-(4-cvclohexylphenyl)aminolmethyl ⁇ benzoylamino)-2- hydroxypropionic acid methyl ester 4- ⁇ [terf-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl ⁇ benzoic acid was dissolved in DMF (10 mL) and HOBt (0.40 g, 2.93 mmol) and EDAC (0.52 g, 2.73 mmol) were added. The reaction mixture was stirred for 45 min.
  • Step 6 (R -3- ⁇ 4-r3-(4-Cyano-3-trifluoromethylphenv ⁇ -1-(4-cyclohexylphenyl)ureidomethv ⁇ - benzoylamino)-2-hvdroxypropionic acid methyl ester
  • Step 7 (R)-3- ⁇ 4-[3-(4-Cyano-3-trifluoromethylphenyl)-1 -(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino ⁇ -2-hydroxypropionic acid methyl ester (0.07 g, 0.124 mmol) was suspended in ethanol (3 mL) and sodium hydroxide (4 N, 0.19 mL, 0.742 mmol) was added. The reaction mixture was stirred for 1.5 hour, and concentrated to remove the ethanol. The residue was diluted with water (10 mL) and acidified with hydrochloric acid (4 N, 0.21 mL).
  • Step 6 (R 3-f4- r 3-(3-ferf-Butylphenvn-1 -(4-cvclohexylphenyl)ureidomethyl1benzoylamino)-2- hvdroxypropionic acid methyl ester
  • 3-( ert-Butyl)aniline (0.054 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL) and added dry hydrogen chloride in ethyl acetate twice (3.5 M, 3 mL + 2.5 mL). After 15 min the mixture was concentrated to dryness and co-evaporated three times from toluene (3 x 5 mL). The residue was added toluene (2.5 mL) and flushed with nitrogen for about 10 min, before diphosgene (0.43 mL) was added. Then the mixture was gently refluxed for 1 hour under a nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. This was repeated twice to remove excess of diphosgene.
  • the mixture was concentrated to dryness and co- evaporated three times from toluene (5 mL each time). The residue was concentrated to dryness and co-evaporated twice from toluene. Then it was redissolved in toluene (2.5 mL) and flushed with nitrogen for about 10 min, before diphosgene (0.43 mL) was added. The mixture was gently refluxed under nitrogen for 1 hour. After cooling, the mixture was concentrated and co-evaporated twice from toluene to remove excess diphosgene to afford 3-fert-butyl- phenyl isocyanate.
  • Step 6 (R)-3-(4-r3-r3-(te/ ⁇ f-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenvn-1 -(4- cvclohexylphenvDureidomethvHbenzoylamino)-2-hvdroxypropionic acid methyl ester
  • Bis(trichloromethyl)carbonate (triphosgene) (0.09 g, 0.31 mmol) was dissolved in DCM (2 mL) and cooled in an ice-bath under nitrogen.
  • 3-(ferf-Butyldimethylsilanyloxymethyl)-4- trifluoromethoxyaniline 0.3 g, 0.93 mmol was evaporated twice from toluene to remove any moisture and then dissolved in DCM (2 mL) and diisopropylethylamine (0.32 mL) was added. This solution was added to the cooled triphosgene solution and the mixture was stirred at 20 °C for 2.5 hours.
  • R 2 , R 3 , R 4 , R 5 , A, Z, D and E are as defined for formula (I),
  • X is -C(O)NH- or -C(O)NHCR 12 R 13 - wherein R 12 and R 13 are as defined for formula (I), and
  • Resin is a polystyrene resin loaded with a 2-chlorotrityl linker.
  • Step 1 Resin bound (R)-Fmoc-isoserine
  • the resin was filtered and washed with ⁇ /-methyl-2-pyrrolidinone:1 ,2-dichloropropane (1:1, 2 x 1 mL).
  • ⁇ /-methyl-2-pyrrolidinone (500 ⁇ L) and 1,2-dichloropropane (500 ⁇ L) were added followed by 150 ⁇ mol (R)-Fmoc-isoserine and 100 ⁇ L diisopropylethylamine.
  • Step 2 Resin bound (RV3-(4-FormylbenzoylaminoV2-hvdroxypropionic acid
  • resin bound (R)-Fmoc-isoserine 500 ⁇ L of a 20% solution of pipe dine in DMF.
  • N- methyl-2-pyrrolidinone 6 x 1 mL.
  • Step 3 Resin bound (R)-3- ⁇ 4-r(4-fe/f-butylphenylamino)methyl1benzoylamino)-2- hvdroxypropionic acid
  • Step 4 Resin bound (R)-3-f4-f1-(4-te/ -butylphenvn-3-(3.4-dichlorophenyl)ureidomethvn- benzoylamino)-2-hydroxypropionic acid
  • Step 5 (R)-3- ⁇ 4-H -(4-ferf-butylphenv0-3-(3,4-dichlorophenyl)ureidomethyl1benzoylamino)-2- hydroxypropionic acid

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Abstract

L'invention concerne une nouvelle classe de composés servant à antagoniser l'action de l'hormone appelée glucagon, sur le récepteur du glucagon. Etant donné leur effet antagoniste du récepteur du glucagon, ces composés sont appropriés au traitement et/ou à la prévention de tout trouble ou pathologie dans lequel une action antagoniste du glucagon est souhaitable, tel que l'hyperglycémie, les diabètes de type 1 et 2, des troubles du métabolisme lipidique, et l'obésité.
EP01943189A 2000-06-23 2001-06-21 Antagonistes/agonistes inverses du glucagon Withdrawn EP1296942A1 (fr)

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US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
AU2002365622A1 (en) * 2001-12-03 2003-06-17 Novo Nordisk A/S Novel glucagon antagonists
US7081473B2 (en) 2002-05-22 2006-07-25 Sanwa Kagaku Kenkyusho Co., Ltd. Agent for preventing/ameliorating obesity comprising methylidene hydrizide compound as active ingredient
EP1519723A1 (fr) * 2002-06-27 2005-04-06 Novo Nordisk A/S Nouveaux antagonistes/agonistes inverses du glucagon
AU2003291959A1 (en) * 2002-12-20 2004-07-14 Novo Nordisk A/S Novel glucagon antagonists
WO2004063147A1 (fr) * 2003-01-10 2004-07-29 Novo Nordisk A/S Sels et solvates d'antagonistes de glucagon
ATE490244T1 (de) 2003-01-27 2010-12-15 Merck Sharp & Dohme Substituierte pyrazole, zusammensetzungen,die solche verbindungen enthalten, und anwendungsverfahren
WO2004101505A1 (fr) * 2003-05-14 2004-11-25 Novo Nordisk A/S Nouveaux composes pour le traitement de l'obesite
PL1656139T3 (pl) * 2003-07-21 2012-03-30 Merck Serono Sa Arylodikarboksyamidy
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WO2006102067A1 (fr) 2005-03-21 2006-09-28 Merck & Co., Inc. Derives d'aryle et d'heteroaryle substitues
JP2008534593A (ja) 2005-03-30 2008-08-28 メルク エンド カムパニー インコーポレーテッド グルカゴン受容体アンタゴニスト化合物、そのような化合物を含む組成物、及びその使用方法
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