WO2004056763A2 - Nouveaux antagonistes du glucagon - Google Patents

Nouveaux antagonistes du glucagon Download PDF

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WO2004056763A2
WO2004056763A2 PCT/DK2003/000903 DK0300903W WO2004056763A2 WO 2004056763 A2 WO2004056763 A2 WO 2004056763A2 DK 0300903 W DK0300903 W DK 0300903W WO 2004056763 A2 WO2004056763 A2 WO 2004056763A2
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alkyl
aryl
compound according
general procedure
benzoylamino
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WO2004056763A3 (fr
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Janos Tibor Kodra
Carsten Behrens
Peter Madsen
Anker Steen JØRGENSEN
Inge Thøger Christensen
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Novo Nordisk A/S
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Publication of WO2004056763A2 publication Critical patent/WO2004056763A2/fr
Publication of WO2004056763A3 publication Critical patent/WO2004056763A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C237/36—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 the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
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    • 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
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—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 carboxyl groups bound to the same carbon skeleton
    • C07C323/62—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 carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to agents that act to antagonize the action of the glu- cagon peptide 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 ho- meostatic 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.
  • 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.
  • removal of circulating glucagon with selective and specific antibodies has resulted in reduction of the glycemic level.
  • glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent gluca- gon-induced responses.
  • the antagonist can be peptidic or non-peptidic in nature.
  • Native glucagon is a 29 amino acid peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH
  • Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family.
  • the receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
  • DesHis 1 ,Phe 6 [Glu 9 ]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) and NLeu 9 ,Ala 11,16 -glucagon amide (Unson et al., J. Biol. Chem. 269 (17), 12548 (1994)).
  • 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 quinoxa- line 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 Chem. Lett. 2(9):915-918 (1992)).
  • WO 94/14426 (The Wellcome Foundation Limited) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
  • US 4,359,474 (Sandoz) discloses the glucagon inhibiting properties of 1 -phenyl pyrazole derivatives.
  • US 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibiting agents.
  • WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists.
  • US 5,776,954 discloses substituted pyridyl pyrroles as gluca- gon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and US 5,880,139 (Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. Furthermore, WO 97/16442 and US 5,837,719 (Merck & Co., Inc.) disclose 2,5-substituted aryl pyrroles 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 ac- , tivity.
  • 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 disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists.
  • WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446 disclose further classes of glucagon antagonists.
  • A. L. Handlon et al. (GlaxoSmithKline) recently published aminooxadiazoles as glucagon antagonists (226 th ACS National Meeting, Division of Medicinal Chemistry (poster no. 164)).
  • WO 03/064404 discloses 2-furancarboxylic acid hydrazides as glucagon antagonists. These known glucagon antagonists differ structurally from the present compounds.
  • Halogen designates an atom selected from the group consisting of F, CI, 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, terf-butyl, n-pentyl, isopentyl, neopentyl, ferf-pentyl, n-hexyl, isohexyl and the like.
  • C 2-6 -alkenyl represents a branched or straight hydrocarbon, group having from 2 to 6 carbon atoms and at least one double bond.
  • Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-buta- dienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pent- enyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
  • C 2 ⁇ -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • Examples of such ' 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 ⁇ -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, iso- propoxy, butoxy, sec-butoxy, ferf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 3-8 -cycloalkyl 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-cyclobutenyl, 2-cyclobutenyl, 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, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems.
  • Aryl is also intended to include the 5 partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1,4- dihydronaphthyl, indanyl and the like.
  • arylene as used herein is intended to include divalent, carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, ,0 divalent, carbocyclic, aromatic ring systems. Representative examples are phenylene, bi- phenylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, az- , ulenylene and the like.
  • Arylene is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydro- .
  • genated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 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.
  • C 1-6 -alkanoyl denotes a group -C(O)-C -6 -alkyl, wherein C ⁇ 0 6 -alkyl is as defined above.
  • heteroaryl as used herein is intended to include aromatic, heterocyclic . ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen 5 , and sulfur.
  • Representative examples are 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 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazoIyl, tetrazolyl, thiadiazinyl
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, 5 pyrazolinyl, indolinyl, oxazoiidinyl, oxazolinyl, oxazepinyl and the like.
  • heteroarylene as used herein is intended to include divalent, aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro- benzofuranylene, pyrrolinylene, pyrazolinylene, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.
  • Aryl-Ci-e-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:
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • n 0 or 1
  • n 0, 1 , 2 or 3
  • R 1 is hydrogen, fluoro or -(CH 2 ) 0 -OR 2 ,
  • o 0 or 1
  • R is hydrogen, C 1-6 -alkyl, C 1-6 -alkanoyl , aryl or aryl-C 1-6 -alkyl,
  • X is N, CH or C with a double bond to one substituent
  • R 3 , R 4 and R 5 are independently selected from hydrogen, C 1-6 -alkyl or aryl,
  • s and t independently are 0 or 1 ;
  • R 6 , R 7 and R 8 independently are selected from hydrogen, C 1-6 -alkyl and aryl;
  • linkers Y and Z are to be understood as optionally attached in either direction,
  • D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R 16 , R 17 , R 18 , R 19 , R 20 and R 21 , wherein
  • R 1b , R 1 ', R 1S and R 19 independently are
  • cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR 22 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 22 , -NR ⁇ R 23 and d-e-alkyl,
  • R 22 and R 23 independently are hydrogen, C ⁇ -6 -alkyl, aryl-C 1-6 -aIkyl or aryl, or R 22 and R 23 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 is O, 1 or 2
  • c 1 or 2
  • R 24 , R 25 , R 26 and R 27 independently are hydrogen, C 1-6 -alkyl or fluoro,
  • R 20 and R 21 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo- alkyl-C 1-6 -alkyl,
  • R 33 and R 34 independently are hydrogen or C 1-6 -alkyl
  • R 33 and R 34 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,
  • the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -SCF 3 , -NO 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • R and R independently are hydrogen, C 1-6 -alkyl or aryl, or R 35 and R 36 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 , R 31 and R 32 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH 2 ) t -CR 37 R 38 - (CH 2 ) ⁇ -O-, -(CH 2 ) t -CR 37 R 38 -(CH 2 )r or -S-(CH 2 ) t -CR 37 R 38 -(CH 2 ) r S-,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 37 and R 38 independently are hydrogen or C ⁇ -6 -alkyl
  • R 1b , R 1 ', R 1B , R ⁇ a , R ⁇ u and R ⁇ 1 are as defined in claim 1.
  • R 16 , R 17 and R 18 are as defined in claim 1.
  • R 16 , R 17 and R 18 independently are • hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 22 , -NR ⁇ R 23 , -SR 22 , -NR 22 S(O) 2 R 23 , -S(O) 2 NR 22 R 23 , -S(O)NR 22 R 23 , -S(O)R 22 , -SfOfeR 22 , -C(O)NR 22 R 23 , -OC(O)NR 22 R 23 , -NR 22 C(O)R 23 , -CH 2 C(O)NR 22 R 23 , -OC ⁇ C ⁇ JNR ⁇ R 23 , -CH 2 OR 22 ,
  • C 1-6 -alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 22 and -NR 22 R 23 ,
  • aryl or aryloxy which may optionally be substituted with one or more substituents selected from halogen, -C(O)OR 22 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 22 , -NR 22 R 23 and C 1-6 -alkyl,
  • R 22 and R 23 independently are hydrogen, C 1-6 -alkyl, aryl-C ⁇ -alkyl or aryl, or R 22 and R 23 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 24 , R 25 , R 26 and R 27 independently are hydrogen, C 1-6 -alkyl or fluoro.
  • R 16 , R 17 and R 18 independently are
  • R , R , R d1 and R** are as defined in claim 1.
  • R , R and R ⁇ are as defined in claim 1.
  • R 30 , D R31 a are
  • d-e-alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 ,
  • R 35 and R 36 independently are hydrogen, C 1-6 -alkyl or aryl
  • R 35 and R 36 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 , R 31 and R 32 independently are
  • C 1-6 -alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 ,
  • cyclohexyl or cyclohex-1-enyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF 3 , -OCF 3> -NO 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
  • phenoxy or benzyloxy of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 35 ,
  • R 35 and R 36 independently are hydrogen or d ⁇ -alkyl.
  • R 30 and R 32 are both hydrogen, and R 31 is different from hydrogen.
  • the compound as above has an IC 50 value of no greater than 5 ⁇ M as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the compound has an IC 50 value of less than 1 ⁇ M, preferably of less than 500 nM and even more preferred of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the compound is an agent useful for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, type 2 diabetes, type 1 diabetes, dyslipidemia and obesity.
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
  • diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the 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, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino- benzoic, 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-, ferf-butyl-, tetramethylammonium salts, benzatine or benzatine derivatives 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 ap-litiste 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. In general, such prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required compound 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. Bundgaard, 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 of disorders and diseases in which such an antagonism is beneficial.
  • the compounds according to the present invention preferably have an IC 50 value of no greater than 5 ⁇ M, more preferably of less than 1 ⁇ M, even more preferred of less than 500 nM, such as of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the present compounds may be applicable for the treatment 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.
  • glucagon receptors 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. They may also be useful as tool or reference molecules in labelled form eg radio- labelled in binding assays to identify new glucagon antagonists.
  • 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 ingredient, 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 inven- tion.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of a disorder or disease, wherein a glucagon antagonistic ' action is beneficial.
  • the invention also relates to a method for the treatment 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 of any glucagon-mediated conditions and diseases.
  • the present compounds are used for the preparation of a medicament for the treatment of hyperglycemia.
  • the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
  • the present compounds are effective in lowering the blood glucose, both in the fasting and the postprandial stage.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT. In still another embodiment, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression 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 of type 1 diabetes.
  • Such treatment is normally accompanied by insulin therapy.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of obesity.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of disorders of the lipid metabolism, such as dyslipidemia.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of an appetite regulation or energy expenditure disorder.
  • pounds is combined with diet and/or exercise.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratio(s).
  • further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobe- sity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (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®, all of which are incorporated herein by reference, GLP-1 and 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 hypoglycemic agents.
  • the orally active hypoglycemic agents include 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), all of which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, insulin secretagogues, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
  • PTPase inhibitors inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, activators of glucokinase (GK) such as those disclosed in WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478.WO 01/85706, WO 01/85707 and WO 02/08209 (Hoffman-La Roche), which are incorporated herein by reference, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.
  • GK glucokinase
  • PPAR peroxisome proliferator-activated receptor
  • RXR
  • 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 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) human insulin, Lantus, or a mix-preparation comprising one or more of these.
  • insulin or an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) 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, glimepride or glicazide.
  • a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepride 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, pioglitazone, 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).
  • 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, LY465608, MBX-102, CLX-0940, GW-501516, tesaglitazar (AZ 242) or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (-)DRF 2725) (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, LY465608, MBX-102
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor, eg voglibose, emiglitate, miglitol or acarbose.
  • 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 combina- tion with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • 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 sul- fonylurea, metformin and troglitazone; a sulfonylurea, metformin and pioglitazone; a sulfony- lurea, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a meglitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitinide such as
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, H3 histamine 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 cita- lopram, serotonin
  • 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 compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the phar- maceutical 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 sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that 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 appropri- ate, 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, syrups and elixirs.
  • Pharmaceutical 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 injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • 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.
  • 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, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil 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 admini- stration.
  • 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, phospholipids, 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 monostearate or glyceryl distearate, alone or mixed with a wax.
  • compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically ac- ceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete 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 con- tain:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • 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.
  • DABCO 1 ,4-diazabicyclo[2.2.2.]octane
  • DCM dichloromethane, methylenechloride
  • DIPEA ⁇ /, ⁇ /-diisopropylethylamine
  • the Sciex Sample control software running on a Macintosh Power G3 computer was used for the instrument control and data acquisition.
  • the HPLC pump was connected to two eluent reservoirs containing: A: Acetonitrile containing 0.05% TFA
  • the requirements for the samples are that they contain approximately 500 ⁇ g/ml of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetoni- trile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)
  • 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 0.05% TFA
  • 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 AP1 150 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 spectrometer, the UV detector and the ELS detector.
  • the instrument was controlled by HP Chemstation software.
  • the HPLC pump was connected to two eluent reservoirs containing:
  • the analysis was performed at 40 °C by injecting an appropriate volume of the sample (preferably 1 ⁇ L) onto the column, which was eluted with a gradient of acetonitrile.
  • HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
  • E and D independently are aryl or heteroaryl and are both optionally substituted as defined above.
  • This reaction is generally known (F.Z. D ⁇ rwald, "Organic Synthesis on Solid Phase", 1 st Edi- tion Wiley-VCH: Weinheim, 2000, p. 239-241 ), and is achieved by using an excess of aldehyde, sodium cyano borohydride and a proton source such as acetic acid.
  • the reaction is performed at 20-100°C preferable at 40-80°C in a polar organic solvent such as DMF or NMP.
  • Steps 5 The formation of carbamoyl chlorides from amines tethered on solid support is a know reaction (Wang, G. T. et al.; Tetrahedron Lett, 1997, 38 (11), 1895-1898, Scicinski, J. J.; Barker, M. D.; Murray, P. J.; Jarvie, E. M.; Bioorg Med Chem Lett 1998, 8 (24), 3609-3614), and is generally performed by adding phosgene (or a synthetic equivalent such as bis(trichloromethoxy)carbonate or trichloromethoxycarbonyl chloride) to resin bound primary or secondary amine in the presence of base.
  • phosgene or a synthetic equivalent such as bis(trichloromethoxy)carbonate or trichloromethoxycarbonyl chloride
  • an organic amine such as triethylamine, pyridine, or DIPEA can be used.
  • the reaction is preferably performed at 0-20°C, in an inert aprotic solvent such as DCM, toluene, DCP, THF or the like.
  • This step is analogous to the corresponding transformations described in WO 00/69810 and WO 02/00612.
  • Stepl Fmoc- ⁇ -Ala-Wang resin (5.0 g, 0.31 mmol/g, 1.55 mmol) was treated with piperidine (20% in NMP, 20 ml) for 30 min and the resin was drained. This was repeated once. The resin was then washed with DMF (5x).
  • Step 2 A solution of DIPEA (3 ml) in NMP (17 ml) was added, followed by slow addition of a solution of p-nitrobenzoylchloride (2.88 g; 15.5 mmol, 10 eq.) in NMP (20 ml). The mixture was shaken for 3h, then drained. The resin was washed with DMF (5x). Step 3: Then a solution of SnCI 2 .2H 2 O (10,5 g; 46.5 mmol, 30 eq.) in NMP (30 ml) was added. The mixture was shaken at room temperature for 16h. The resin was drained and washed with DMF (3x) and DCM (10x), then dried under vacuum for 16h to give 5.20 g of resin bound 4-aminobenzoyIaminopropanoic acid.
  • Step 4 The dry resin (100 mg; 54 umol; 0.54 mmol/g) prepared as described in step 3, was swelled in DCM for 30 min. Fluorene-2-carboxaldehyde (194.5 mg; 1 mmol) dissolved in DMF (1 ml) was added followed by a solution of sodium cyano borohydride (138 mg; 2 mmol) in DMF - acetic acid (1.2 ml, 5:1). The reaction mixture was heated to 80°C over night.
  • Step 5 Resin bound 3- ⁇ 4-[(9H-fluoren-2-ylmethyl)amino]benzoylamino ⁇ propionic acid (100 mg; 0.54 mmol/g) was suspended in DCM (500 ul) and DIPEA (100 ul) was added. A solution of bis(trichloromethyl)carbonate (44 mg; 0.15 mmol) in DCM (500 ul) was then added. The reaction was shaken for 60 min.
  • Step 6 To resin bound 3- ⁇ 4-[chlorocarbonyl-(9H-fluoren-2-ylmethyl)amino]benzoylamino ⁇ propionic acid, was added a solution of 4-f-butylphenol (75 mg; 0.5 mmol) in DMF (500 ul) followed by a solution of DABCO (100 mg) in DMF (500 ul). The reaction was stirred over- night at ambient temperature, then washed with DMF (3x), 10% HOAc - MeOH (3x) and DCM (1 Ox).
  • Step 7 The product was cleaved from the resin using 50% TFA in DCM. Solvent was removed by speed evacuation to give 10-12 mg of pure title material.
  • HPLC-MS Method (B): m/z: 563 (M+1 ), Rt: 5.20 min.
  • R are C 1-6 -alkyl
  • E and D independently are aryl or heteroaryl and are both op- tionally substituted as defined above.
  • carbamoyl chlorides from amines is a known reaction (Heusler, K.; Helv. Chim. Ada, 1972, 55, 388), and is generally performed by adding phosgene (or a synthetic equivalent such as bis(trichloromethoxy)carbonate or trichloromethoxycarbonyl chloride) to a secondary amine in the presence of base.
  • phosgene or a synthetic equivalent such as bis(trichloromethoxy)carbonate or trichloromethoxycarbonyl chloride
  • base an organic amine such as triethylamine, pyridine, or DIPEA can be used.
  • the reaction is preferably performed at 0-20°C, in an inert aprotic solvent such as DCM, toluene, DCP, THF or the like.
  • This reaction is known (Wuest, H. M.; Sakal, E. H.; J Am Chem Soc, 1951, 73, 1210.) and is performed by reacting carbamoyl chlorides with aryl - or hetero aryl alcohols in the presence of base.
  • base an organic amine such as triethylamine, pyridine, DIPEA or 1 ,4- diazabicydo[2.2.2.]octane (DABCO) can be used.
  • DABCO 1 ,4- diazabicydo[2.2.2.]octane
  • the reaction is performed at 0-80°C, preferably at ambient temperature in an inert aprotic polar solvent such as DMF, THF or NMP.
  • Steps 5 is an ester hydrolysis, and is performed analogue to similar transformations de- scribed in WO 00/69810.
  • 3-(4-Aminobenzoylamino)propionic acid ethyl ester (12.0 g; 50.8 mmol) was dissolved in ethanol (200 ml). Then a solution of fluorene-2-carboxaldehyde (9.86 g; 50.8 mmol) in etha- nol (100 ml) was added to give a clear yellow solution. The solution was heated for reflux for 10 min. then cooled to room temperature. Acetic acid (30 ml) and solid sodium cyano borohydride (3.5 g; 50.7 mmol) were added. The mixture was refluxed for 30 min; then slowly allowed to cool to room temperature.
  • D, E, m, n and R 1 are as defined for formula (I), and Resin is a polystyrene resin loaded with a Wang-linker.
  • This reaction is known (Wang S.J., J. Am. Chem. Soc. 95, 1328, 1973) and is generally per- formed by stirring polystyrene resin loaded with a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in the presence of a catalyst such as DMAP.
  • a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
  • the esterification is carried out in solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • the reactions are performed between 0 °C and 80 °C, preferably between 20 °C to 40 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • Step 2 ⁇ -Fluorenylmethylcarbonyl protecting group is removed by treating the resin bound derivative with a 20%-50% solution of a secondary amine such as piperidine in a polar solvent such as DMF or NMP (Carpino L, Han G., J. Org. Chem. 37, 3404, 1972).
  • the reaction is performed between 20 °C to 180 °C, preferably between 20 °C to 40 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with solvent used in the reaction.
  • the resulting resin bound intermediate is acylated with acid.
  • the acylation is known (The combinatorial index, Ed. Bunin B. A., 1998, Acedemic press, p.
  • acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
  • the reactions are performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • This reaction is a modification of previously described procedures for aldol condensation on solid support (U. Sensfuss, Tetrahedron Lett.44, 2371-2374 (2003)).
  • the reaction is carried out by reacting polystyrene-linked benzaldehydes with methyl ketones in presence of co- balt(ll) or zinc acetate 2,2'-bipyridine complexes and an amidine base at elevated temperature to give resin-bound (EJ-enones.
  • the reaction is carried out in a polar aprote solvent like DMF or NMP.
  • the reactions are performed 40 °C to 120 °C preferreably at 70 °C-80 °C.
  • excess of reagent is removed by filtration.
  • the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • aldehydes to activated double bonds is generally carried out by stirring the aldehyde with a compound that contains an activated dobbelt bond such as a substituted propenone in the presence of a catalyst such as sodium or potassium cyanide or thiazolium salts such as 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-benzyl-5-(2-hydroxyethyl)- 4-methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium bromide or vitamin Bi.
  • a catalyst such as sodium or potassium cyanide or thiazolium salts
  • 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide 3-benzyl-5-(2-hydroxyethyl)- 4-methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl
  • a non-nucleophilic amine base such as triethyl amine, ⁇ /,/V-diisopropylethylamine or DBU is added.
  • the addition is carried out in a solvent such as dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
  • the reactions are performed between 50 °C to 120 °C, preferably between 50 °C to 80 °C.
  • excess of reagent is removed by filtration.
  • the resin is suc- cessively washed with the solvent used in the reaction, followed by washing with methanol.
  • the resin bound product can be further dried and analyzed.
  • step 21 is generally performed by stirring the resin bound intermediate obtained in step 3 with a 50-95 % solution of TFA.
  • the final cleavage is carried out in a solvent such as THF, DCM, 1 ,2 dichloroethane, 1 ,3-dichloropropane, toluene or a mixture or more of these.
  • the reactions are performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
  • the product is removed by filtration.
  • the resin is successively washed with DCM.
  • the product and washings are collected.
  • the solvent is removed and the product is dried in vacou.
  • Step 1 and Step 2 Resin bound 3-(4-formylbenzoylamino)propionic acid
  • Step 3 Preparation of resin bound 3-(4-(3-(4-cvclohexylphenyl)-3-oxopropenyl)- benzoylamino)propionic acid
  • the above resin bound 3-(4-formylbenzoylamino)propionic acid (1 g resin) was suspended in DMF (20 mL) for 30 min and filtered.
  • 4-cyclohexylacetophenone (4.05 g, 20 mmol) was dissolved in DMF (10 mL) and added to the resin.
  • Zinc(ll)acetate dihydrate (220 mg, 1 mmol) and 2,2'-bipyridine (156 mg, 1 mmol) was dissolved in DMF (10 mL) and added.
  • DBU (2 mmol) was added and the suspension was shaken at 70 °C for 16 hours.
  • the resin was iso- lated by filtration and washed with methanol (1 x 20 mL) and NMP (2 x 20 mL
  • Step 4 and Step 5 Preperation of 3-(4-r3-(4-Cvclohexylphenyl)-3-oxo-1-(4- trifluoromethoxybenzoyl)propyllbenzoylamino>propionic acid
  • the resin was isolated by filtration and washed with methanol (1 x 20 mL), DCM containing 5 % acetic acid (1 x 20 mL) followed by DCM (3 x (20 mL).
  • the resin bound 3- ⁇ 4-[3-(4- cyclohexylphenyl)-3-oxo-1-(4-trifluoromethoxybenzoyl)propyl]benzoylamino ⁇ propionic acid was treated with 50% TFA in DCM (20 mL) for 0.5 hour at 25 °C.
  • the mixture was filtered and the resin was washed with DCM (20 mL).
  • the combined filtrates were concentrated in vacuo to afford an oil which was purified on silica gel column eluted with DCM/ethanol (95:5) to afford the title compound.
  • Steps 1 to 2 These steps are analogous to the corresponding steps described in WO 00/69810 and WO 02/00612.
  • This reaction is generally known (F.Z. D ⁇ rwald, "Organic Synthesis on Solid Phase", 1 st Edi- tion Wiley-VCH: Weinheim, 2000, p. 239-241), and is achieved by using an excess of aldehyde, sodium cyano borohydride and a proton source such as acetic acid.
  • the reaction is performed at 20-100°C preferable at 40-80°C in a polar organic solvent such as DMF or NMP.
  • Steps 5a This reaction is known (see WO 00/69810 and WO 02/00612), and is generally performed by reacting solid phase tethered amine with alkyl or aryl isocyanates in organic solvents. The reaction is performed at 20-100°C preferable at 20-40 ° C in an aprotic organic solvent such as toluene, DCP or DCM depending on the temperature.
  • an aprotic organic solvent such as toluene, DCP or DCM depending on the temperature.
  • Steps 5b The formation of urea can alternatively be performed via chlorocarbamoylation followed by reaction with amines.
  • the formation of carbamoyl chlorides from amines tethered on solid support is a know reaction (Wang, G. T. et al.; Tetrahedron Lett, 1997, 38 (11), 1895-1898, Scicinski, J. J.; Barker, M. D.; Murray, P. J.; Jarvie, E.
  • Step 1 Fmoc- ⁇ -Ala-Wang resin (5.0 g, 0.31 mmol/g, 1.55 mmol) was treated with piperidine (20% in NMP, 20 ml) for 30 min., and the resin was drained. This was repeated once. The resin was then washed with DMF (5x).
  • Step 2 A solution of DIPEA (3 ml) in NMP (17 ml) was added, followed by slow addition of a solution of p-nitrobenzoylchloride (2.88 g; 15.5 mmol, 10 eq.) in NMP (20 ml). The mixture was shaken for 3h, then drained. The resin was washed with DMF (5x). Step 3: Then a solution of SnCI 2 .2H 2 O (10,5 g; 46.5 mmol, 30 eq.) in NMP (30 ml) was added. The mixture was shaken at room temperature for 16h. The resin was drained and washed with DMF (3x) and DCM (10x), then dried under vacuum for 16h.
  • Step 4 Dry resin (100 mg; 54 umol; 0.54 mmol/g) prepared as described above, was swelled in DCM for 30 min. 4-Cyclohexylbenzaldehyde (188.2 mg; 1 mmol) dissolved in DMF (1 ml) was added followed by a solution of sodium cyano borohydride (138 mg; 2 mmol) in DMF - acetic acid (1.2 ml, 5:1). The reaction mixture was heated to 80°C over night.
  • the resin was drained for solvent and reactants, and subsequently washed with MeOH (3x), DMF (5x) and DCM (4x) to give resin bound 3- ⁇ 4-[(4-cyclohexylphenylmethyl)amino]benzoylamino ⁇ propi- onic acid.
  • Step 5a Resin bound 3- ⁇ 4-[(4-cyclohexylphenylmethyl)amino]benzoylamino ⁇ propionic acid (100 mg; 0.54 mmol/g) was suspended in DCP (1.0 ml) and 3,5-bis(trifluoromethyl)phenyl isocyanate (255 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 48h, then washed with DMF (3x) and DCM (10x). Step 6: The product was cleaved from the resin using 50% TFA in DCM. Solvent was removed by speed evacuation to give 10-12 mg of pure title material.
  • Step 5b Resin bound 3- ⁇ 4-[(4-cyclohexylphenylmethyl)amino]benzoylamino ⁇ propionic acid (100 mg; 0.54 mmol/g), prepared as in the above example (step 1-4) was suspended in DCM (500 ul) and DIPEA (100 ul) was added. A solution of bis(trichloromethyl)carbonate (44 mg; 0.15 mmol) in DCM (500 ul) was then added. The reaction was shaken for 60 min.
  • Step 6 The product was cleaved from the resin using 50% TFA in DCM. Solvent was removed by speed evacuation to give 10-12 mg of pure title compound.
  • Step l
  • step 3 If the product from step 2 is a benzoic acid ester, then the ester is hydrolysed (step 3). This step is similar to similar transformations described in WO 00/69810.
  • Steps 4 & 5 are coupling of the benzoic acid with a ⁇ -alanine ester or R-isoserine ester followed by hydrolysis of the ester. These steps are similar to similar transformations described in WO 00/69810.
  • the general procedure (E) is further illustrated in the following example:
  • E and D independently are aryl or heteroaryl and are both optionally substituted as defined previously.
  • This reaction is generally known (F.Z. D ⁇ rwald, "Organic Synthesis on Solid Phase", 1 st Edition Wiley-VCH: Weinheim, 2000, p. 239-241), and is achieved by using an excess of aide- hyde, sodium cyano borohydride and a proton source such as acetic acid.
  • the reaction is performed at 20-100°C preferable at 40-80°C in a polar organic solvent such as DMF or NMP.
  • Steps 5 This reaction is generally known (A.P. Shawcross & S.P. Stanforth, Tetrahedron,
  • This step is analogous to the corresponding transformations described in WO 00/69810 and WO 02/00612.
  • Step 1 Fmoc- ⁇ -Ala-Wang resin (5.0 g, 0.31 mmol/g, 1.55 mmol) was treated with piperidine (20% in NMP, 20 ml) for 30 min and the resin was drained. This was repeated once. The resin was then washed with DMF (5x).
  • Step 2 A solution of DIPEA (3 ml) in NMP (17 ml) was added, followed by slow addition of a solution of p-nitrobenzoylchloride (2.88 g; 15.5 mmol, 10 eq.) in NMP (20 ml). The mixture was shaken for 3h, then drained. The resin was washed with DMF (5x).
  • Step 3 A solution of SnCI 2 .2H 2 O (10,5 g; 46.5 mmol, 30 eq.) in NMP (30 ml) was added to the resin. The mixture was shaken at room temperature for 16h. The resin was drained and washed with DMF (3x) and DCM (10x), then dried under vacuum for 16h.
  • Step 4 Dry resin (100 mg; 54 umol; 0.54 mmol/g) prepared as described above, was swelled in DCM for 30 min. Fluorene-2-carboxaIdehyde (194.5 mg; 1 mmol) dissolved in DMF (1 ml) was added followed by a solution of sodium cyano borohydride (138 mg; 2 mmol) in DMF - acetic acid (1.2 ml, 5:1). The reaction mixture was heated to 80 ° C over night.
  • the resin was drained for solvent and reactants, and subsequently washed with MeOH (3x), DMF (5x) and DCM (4x) to give resin bound 3- ⁇ 4-[(9H-fluoren-2-yImethyl)amino]benzoylamino ⁇ propionic acid.
  • Step 5 Resin bound 3- ⁇ 4-[(9r/-fluoren-2-ylmethyl)amino]benzoylamino ⁇ propionic acid (50 mg; 27 umol; 0.54 mmol/g) was washed twice with propionitril.
  • DIPEA 55 ul, 0.3 mmol
  • Step 6 The product was cleaved from the resin using 50% TFA in DCM. Solvent was removed by speed evacuation to give 10-12 mg of pure title material. HPLC-MS (Method (B)): m/z: 561 (M+1), Rt: 5.11 min.
  • R are d-e-alkyl
  • E and D independently are aryl or heteroaryl and are both optionally substituted as defined previously.
  • Step l The reductive amination steps are analogous to the corresponding steps described in WO 00/69810.
  • This reaction is generally known (A.P. Shawcross & S.P. Stanforth, Tetrahedron, 45(22), 1989, 7063-7076) and is performed by adding alkyl halides to anilines in the presence of base.
  • Steps 4 & 5 are coupling of the derivatized benzoic acid with a ⁇ -alanine ester followed by hydrolysis of the ester. These steps are similar to similar transformations described in WO
  • R are C 1-6 -alkyl
  • E and D independently are aryl or heteroaryl and are both optionally substituted as defined previously.
  • Step l
  • the step is similar to transformations described in WO 00/69810
  • Step 2 The reductive amination steps are analogous to the corresponding steps described in WO 00/69810.
  • This reaction is generally known (A.P. Shawcross & S.P. Stanforth, Tetrahedron, 45(22), 1989, 7063-7076) and is performed by adding alkyl halides to anilines in the presence of base.
  • Steps 4 is an ester hydrolysis similar to those described in WO 00/69810.
  • the general procedure (H) is illustrated in the following example:
  • 3-(4-Aminobenzoylamino)propionic acid ethyl ester (12.0 g; 50.8 mmol) was dissolved in ethanol (200 ml). Then a solution of fluorene-2-carboxaldehyde (9.86 g; 50.8 mmol) in etha- nol (100 ml) was added to give a clear yellow solution. The solution was heated for reflux for 10 min. then cooled to room temperature. Acetic acid (30 ml) and solid sodium cyano borohydride (3.5 g; 50.7 mmol) were added. The mixture was refluxed for 30 min; then slowly allowed to cool to room temperature.
  • R are hydrogen or C 1-6 -alkyl
  • This reaction is known (see Albright, J., D. et al., J. Med. Chem. 1983, 26 (10), 1378-1393) and is performed by reacting carbonyl chlorides with arylamines in the presence of base.
  • base an organic amine such as triethylamine, pyridine, DIPEA or 1,4- diazabicyclo[2.2.2.]octane (DABCO) can be used.
  • DABCO 1,4- diazabicyclo[2.2.2.]octane
  • the reaction is performed at 0-80°C, pref- erably at ambient temperature in an inert aprotic polar solvent such as DCM, DMF, THF or NMP.
  • step 3 If the product from step 2 is a benzoic acid ester, then the ester is hydrolysed (step 3). This step is similar to similar transformations described in WO 00/69810.

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Abstract

L'invention concerne des nouveaux composés permettant d'antagoniser l'action de l'hormone peptidique glucagon sur le récepteur du glucagon. Plus particulièrement, l'invention concerne des antagonistes ou des agonistes inverses du glucagon.
PCT/DK2003/000903 2002-12-20 2003-12-18 Nouveaux antagonistes du glucagon WO2004056763A2 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058845A2 (fr) * 2003-12-19 2005-06-30 Novo Nordisk A/S Nouveaux antagonistes/agonistes inverses du glucagon
WO2007114855A3 (fr) * 2005-11-18 2007-11-29 Lilly Co Eli Antagonistes du récepteur du glucagon, préparation et utilisations thérapeutiques
US7598398B2 (en) 2005-10-13 2009-10-06 Merck & Co., Inc. Acyl indoles, compositions containing such compounds and methods of use
US7696248B2 (en) 2005-11-17 2010-04-13 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US7807702B2 (en) 2005-11-23 2010-10-05 Eli Lilly And Company Substituted thiophene carboxylic amide glucagon receptor antagonists, preparation and therapeutic uses
US7816557B2 (en) 2004-06-14 2010-10-19 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US7863329B2 (en) 2005-11-17 2011-01-04 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US7935713B2 (en) 2006-05-16 2011-05-03 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7989472B2 (en) 2006-03-23 2011-08-02 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US8318760B2 (en) 2005-03-21 2012-11-27 Merck Sharp & Dohme Corp. Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
WO2012162407A1 (fr) * 2011-05-23 2012-11-29 Janssen Pharmaceutica Nv Dérivés d'acide picolinamido-propanoïque utiles en tant qu'antagonistes du récepteur du glucagon
WO2012162409A1 (fr) * 2011-05-23 2012-11-29 Janssen Pharmaceutica Nv Dérivés de biphényle utiles en tant qu'antagonistes de récepteurs du glucagon
US8507533B2 (en) 2011-02-08 2013-08-13 Pfizer Inc. Glucagon receptor modulators
US8691856B2 (en) 2005-11-22 2014-04-08 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US8809342B2 (en) 2010-12-23 2014-08-19 Pfizer Inc. Glucagon receptor modulators
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
US9649294B2 (en) 2013-11-04 2017-05-16 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US9944687B2 (en) 2011-07-04 2018-04-17 Imperial Innovations Limited Compounds and their effects on feeding behaviour

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069810A1 (fr) * 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002000612A1 (fr) * 2000-06-23 2002-01-03 Novo Nordisk A/S Antagonistes/agonistes inverses du glucagon
WO2002040444A1 (fr) * 2000-11-17 2002-05-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002040445A1 (fr) * 2000-11-17 2002-05-23 Novo Nordisk A/S Agonistes de glucagon/antagonistes inverses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069810A1 (fr) * 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002000612A1 (fr) * 2000-06-23 2002-01-03 Novo Nordisk A/S Antagonistes/agonistes inverses du glucagon
WO2002040444A1 (fr) * 2000-11-17 2002-05-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002040445A1 (fr) * 2000-11-17 2002-05-23 Novo Nordisk A/S Agonistes de glucagon/antagonistes inverses

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WO2005058845A3 (fr) * 2003-12-19 2005-10-20 Novo Nordisk As Nouveaux antagonistes/agonistes inverses du glucagon
WO2005058845A2 (fr) * 2003-12-19 2005-06-30 Novo Nordisk A/S Nouveaux antagonistes/agonistes inverses du glucagon
US7816557B2 (en) 2004-06-14 2010-10-19 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US8609892B2 (en) 2004-06-14 2013-12-17 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US8318760B2 (en) 2005-03-21 2012-11-27 Merck Sharp & Dohme Corp. Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
US7598398B2 (en) 2005-10-13 2009-10-06 Merck & Co., Inc. Acyl indoles, compositions containing such compounds and methods of use
US7863329B2 (en) 2005-11-17 2011-01-04 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US7696248B2 (en) 2005-11-17 2010-04-13 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US8076374B2 (en) 2005-11-18 2011-12-13 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
AU2006341392B2 (en) * 2005-11-18 2012-05-17 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
JP2009519227A (ja) * 2005-11-18 2009-05-14 イーライ リリー アンド カンパニー グルカゴン受容体アンタゴニストおよびその製造及び治療用途
WO2007114855A3 (fr) * 2005-11-18 2007-11-29 Lilly Co Eli Antagonistes du récepteur du glucagon, préparation et utilisations thérapeutiques
US8691856B2 (en) 2005-11-22 2014-04-08 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US7807702B2 (en) 2005-11-23 2010-10-05 Eli Lilly And Company Substituted thiophene carboxylic amide glucagon receptor antagonists, preparation and therapeutic uses
US7989472B2 (en) 2006-03-23 2011-08-02 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7935713B2 (en) 2006-05-16 2011-05-03 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US9056834B2 (en) 2010-12-23 2015-06-16 Pfizer Inc. Glucagon receptor modulators
US8933104B2 (en) 2010-12-23 2015-01-13 Pfizer Inc. Glucagon receptor modulators
US8809342B2 (en) 2010-12-23 2014-08-19 Pfizer Inc. Glucagon receptor modulators
US8507533B2 (en) 2011-02-08 2013-08-13 Pfizer Inc. Glucagon receptor modulators
US8859591B2 (en) 2011-02-08 2014-10-14 Pfizer Inc. Glucagon receptor modulators
US9452999B2 (en) 2011-02-08 2016-09-27 Pfizer Inc. Glucagon receptor modulators
US9073871B2 (en) 2011-02-08 2015-07-07 Pfizer Inc. Glucagon receptor modulators
US9045389B2 (en) 2011-05-23 2015-06-02 Janssen Pharmaceutica Nv Biphenyl derivatives useful as glucagon receptor antagonists
WO2012162409A1 (fr) * 2011-05-23 2012-11-29 Janssen Pharmaceutica Nv Dérivés de biphényle utiles en tant qu'antagonistes de récepteurs du glucagon
US8748624B2 (en) 2011-05-23 2014-06-10 Janssen Pharmaceutica Nv Picolinamido-propanoic acid derivatives useful as glucagon receptor antagonists
WO2012162407A1 (fr) * 2011-05-23 2012-11-29 Janssen Pharmaceutica Nv Dérivés d'acide picolinamido-propanoïque utiles en tant qu'antagonistes du récepteur du glucagon
CN103547570A (zh) * 2011-05-23 2014-01-29 詹森药业有限公司 可用作胰高血糖素受体拮抗剂的吡啶甲酰胺基-丙酸衍生物
JP2014515370A (ja) * 2011-05-23 2014-06-30 ヤンセン ファーマシューティカ エヌ．ベー． グルカゴン受容体拮抗薬として有用なピコリンアミド−プロパン酸誘導体
US9944687B2 (en) 2011-07-04 2018-04-17 Imperial Innovations Limited Compounds and their effects on feeding behaviour
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
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US9649294B2 (en) 2013-11-04 2017-05-16 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use

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