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WO2004063147A1 - Sels et solvates d'antagonistes de glucagon - Google Patents

Sels et solvates d'antagonistes de glucagon Download PDF

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Publication number
WO2004063147A1
WO2004063147A1 PCT/DK2004/000013 DK2004000013W WO2004063147A1 WO 2004063147 A1 WO2004063147 A1 WO 2004063147A1 DK 2004000013 W DK2004000013 W DK 2004000013W WO 2004063147 A1 WO2004063147 A1 WO 2004063147A1
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Prior art keywords
alkyl
aryl
hydrogen
independently
alkenyl
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Inventor
Karol Horvath
Anette Frost Jensen
Kaare Gyberg Rasmussen
Finn Broni Junager
Ole Ekelund
Claus Christophersen
Hanne Tøfting KORNØ
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Novo Nordisk AS
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61P3/08—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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D277/32—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 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • 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
    • 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

Definitions

  • the present invention relates to salts and solvates of glucagon antagonists.
  • the invention relates to glucagon antagonist as previously disclosed in published patent ap- plications WO 99/01423, WO 00/39088, WOOO/42026, WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446, WO03/048109, WO03/51357, WO03/53938, WO03/97619 (Novo Nordisk A/S) disclose glucagon antagonists and other glucagon antagonists.
  • the compounds areuseful as glucagon antagonist and in the treatment of hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism, such as dyslipidemia, and obesity as well as in treatment of other diseases.
  • an active compound with properties such as for example good stability, non-hygroscopicity, high melting point, good bioavail- ability, good handling properties, high degree of crystallinity and a reproducible crystalline form.
  • the present invention thus provides suitable salts and solvates of the compounds of the invention.
  • the salts and solvates of the invention provide stable compounds under storage and accelerated storage conditions as a model for long term stability.
  • the invention provides a composition comprising a salt or a solvate of a glucagon antagonist.
  • a composition comprising a salt of a glucagon antagonist and a pharmaceutically acceptable base
  • the glucagon antagonists are described in the published applications WO 99/01423, WO 00/39088, WOOO/42026, WO 00/69810, WO 02/00612, WO 02/40444.
  • the basic counter ion are derived from ammonium or imidazole or the metal ions of lithium, sodium, potassium, magnesium, calcium, zinc, or the basic amino acids L-arginine, L-lysine, L-histidine, and L-omithine; or alkylated ammonium derivatives such as di-ethylamine, tert-butylamine (erbumine), 1 ,2-ethylenediamine, [si(phenylmethyl)-benzeneethaneamine (benethamine) or N,N'-dibenzylethylenediamine (benzathine); or hydroxyalkylated ammonium derivatives trishydroxymethylaminomethane (tris, tromethamine), N-methyl-D-glucamine (meglumine), choline, monoethanolamine (2- aminoethanol, olamine), di-ethanolamine (2,2'-iminobis(ethanol)), tri-ethanolamine (2,2',2"- nitrilotr
  • composition comprising a solvate of a glucagon antagonist.
  • the solvate is formed from a class III solvent (ICH Guidelines Q3C; "Impurities: Guidelines for Residual Solvents", 1997).
  • the solvate is formed from one of the solvents: ethanol, 2-propanol, 2- methyl-1-propanol, n-butanol, 2-butanol, 3-methyl-1-butanol, diethyl ether, terf-butyl- methylether, tetrahydrofuran, anisol, acetone, 2-butanon, methylacetate, ethylacetate, n- propylacetate and toluene.
  • the present invention also relates to a process for the preparation and pharmaceutical compositions containing the compounds.
  • the present invention provides compounds as novel materials, in particular in pharmaceutically acceptable form.
  • Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • C ⁇ -alkyl or “lower alkyl” as used herein 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, tetf-butyl, n- pentyl, isopentyl, neopentyl, terf-pentyl, n-hexyl, isohexyl and the like.
  • C 2 _ ⁇ -alkenyl or “lower alkenyl” as used herein 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-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
  • C 2 - 6 -alkynyl or “lower alkynyl” as used herein 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 ⁇ -alkoxy or “lower alkoxy” as used herein refers to the radical -O-Ci- ⁇ -alkyl, wherein C ⁇ -alkyl is as defined above.
  • Representative examples are methoxy, ethoxy, n- propoxy, isopropoxy, butoxy, sec-butoxy, terf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C ⁇ _ 6 -alkanoyl or “lower alkanoyl” as used herein denotes a group -C(O)H or -C(O)-C ⁇ . 5 -alkyl. Representative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
  • C 3 ⁇ -cycloalkyl or “cycloalkyl” as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobu- tyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C ⁇ -cycloalkenyl or "cycloalkenyl” as used herein 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-cyclo- octadienyl 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 hydro- genated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • aroyl denotes a group -C(O)-aryl, wherein aryl is as defined above.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • 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.
  • heteroaryl represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furanyl, 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 ,2,4-thiadiazolyl
  • 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 ⁇ _ 6 -alkyl means C ⁇ - 6 -alkyl or C 2 -e-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • Crystalline salts with a well defined structure are preferred salts due to their stability.
  • the salts may form in different ratios between compound and salt. The ratio depend on the nature of the basic counter ion and of the compound.
  • salts are formed in a 1 :1 ratio of compound to salt.
  • the salts are formed in a 2:1 ratio of compound to salt.
  • composition as above wherein the pharmaceutically acceptable basic counter ion are derived from ammonium or imidazole or the metal ions of lithium, sodium, potassium, magnesium, calcium, zinc, or the basic amino acids L-arginine, L-lysine, L-histidine, and L- omithine; or alkylated ammonium derivatives such as di-ethylamine, tert-butylamine (erbumine), 1,2-ethylenediamine, N-(phenylmethyl)-benzeneethaneamine (benethamine) or N,N'-dibenzylethylenediamine (benzathine); or hydroxyalkylated ammonium derivatives trishydroxymethylaminomethane (tris, tromethamine), N-methyl-D-glucamine (meglumine), choline, monoethanolamine (2-aminoethanol, olamine), di-ethanolamine (2,2'- iminobis(ethanol)), tri-ethanolamine (2,2',2"-nitri
  • the basic counter ions are selected from calcium, zinc, the amino acids L-arginine, L-lysine, L-histidine, and L-omithine; N-methyl-D-glucamine (meglumine), choline, monoethanolamine (olamine), di-ethanolamine, tri-ethanolamine (trolamine), 2-diethylaminoethanol, tri-ethylamine, trishydroxymethylaminomethane (tris, tromethamine), 1,2-ethylenediamine or N,N'-dibenzylethylenediamine (benzathine).
  • the basic counter ion is selected from: L-lysine, L-arginine, L-histidine, tert-butylamine (erbumine), monoethanolamine (olamine), 1 ,2-ethylenediamine or N,N'-dibenzylethylenediamine (benzathine).
  • the basic counter ion is selected from : L-arginine, tert- butylamine (erbumine), or N,N'-dibenzylethylenediamine (benzathine). In an embodiment of the invention the basic counter ion is N,N'-dibenzylethylenediamine (benzathine).
  • the ratio of compound to counter ion is 2:1 when the counter ion is N,N'- dibenzylethylenediamine (benzathine) or 1 ,2-ethylenediamine.
  • Solvates between the parent compound and the following solvents are to be considered as being administrable to subjects: pentane, heptane, cumene, 1-propanol, dimethylsulfoxide, ethanol, ethyl formiate, formic acid, acetic acid, methyl acetate, ethyl acetate, n-propyl acetate, isopropylacetate, n-butylacetate, iso-butylacetate, methyl-isobutyl- ketone, 1-butanol, 2-butanol, 2-propanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1- pentanol, diethyl ether, terf-butyl methyl ether, te
  • Stable solvates are arranged in stable conformations of solvent and parent compound which can be defined as a ratio of the parent compound to the solvate.
  • the specific ratio between the two components is in the context of this invention not a limiting feature.
  • 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 com- pounds 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. 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.
  • 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 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 prepara- tion 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 progression from IGT to Type 2 diabetes. In yet another preferred embodiment of the invention 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 disorders 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 combination 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 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 828 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro 829 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 828 human insulin, Lys 828 Pro 829 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 828 human insulin, Lys 828 Pro 829 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 com- bination 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. Reddy's Research Foundation) and
  • WO 00/23425 WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S).
  • 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 meglitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitin
  • 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- uptake inhibitors, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR ⁇ agonists.
  • MSH melanocyte-stimulating hormone
  • MCH melanocyte-
  • 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. In another embodiment of the invention 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, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being 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 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, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non- aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile pow- ders 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.
  • 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 dos- ages 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 administra- tion.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical earners 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 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 gela- tine 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:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • Polacrillin potassium NF tablet disintegrant, Rohm and Haas. * Acylated monoglyceride used as plasticizer for film coating.
  • 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 below.
  • X is a valence bond, -CR 1 R 2 - or -NR 1 -,
  • Y is >CR 3 - or >N-
  • R 1 , R 2 and R 3 independently are hydrogen or C ⁇ -alkyl, or R 1 and R 3 on adjacent atoms may be combined to form a double bond,
  • Y is -S-, -O- or -NR 9 -
  • R 8 is hydrogen, d-e-alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C ⁇ -alkyl, d-e-alkoxy, d- ⁇ -thioalkyl, -CF 3l -OCF 3 , -SCF 3 , -OCHF 2 , -SCHF 2 , -SO 2 CF 3 and -SO 2 -d-6-alkyl,
  • R 9 is hydrogen or Ci-e-alkyl
  • D is aryl or heteroaryl
  • R 8 is as defined above.
  • R 4 and R 5 are as defined above.
  • R 4 is hydrogen and R 5 is d- ⁇ -alkyl, d-e-alkoxy, cyclohexyl, halogen, -CF 3 or cyclo-
  • R 10 , R 11 , R 12 , R 15 , R 16 , R 17 and R 18 are as defined above.
  • R , R and R 12 are as defined above
  • the invention provides the compounds as above, wherein R 10 , R 11 and R 12 independently are hydrogen, halogen, -OCF 3 , -CF 3 , -NO 2 , di-d-e-alkylamino, d- 10 -alkyl, d- ⁇ -alkoxy or -CN,
  • R 10 , R 11 and R 12 in adjacent positions form a bridge -O-CH 2 -O-, -O-CH 2 -CH 2 -O- or -O-CH 2 -CH 2 -CH 2 -O-.
  • the invention provides the compounds as above, wherein one of R 10 , R 11 and R 12 represent hydrogen. In another embodiment the invention provides the compounds as above, wherein one or two of R 10 , R 11 and R 12 is hydrogen, and the remaining is independently selected from halogen, - OCF 3 , -CF 3 , -NO 2 , di-d-e-alkylamino, d- 10 -alkyl, C ⁇ -6-alkoxy or -CN. In another embodiment the invention provides the compounds such as
  • the invention provides the compounds such as 3-(4- ⁇ [[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5,6,7,8-tetrahydronaphthalen-2-yl)amino]methyl ⁇ - benzoylamino)propionic acid as a salt with tert-butylamine.
  • the invention provides the compound 3-(4- ⁇ [[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with L-lysine.
  • the invention provides the compound3-(4- ⁇ [[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with L-histidine.
  • the invention provides the compound3-(4- ⁇ [[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with monoethanolamine.
  • the invention provides the compound3-(4- ⁇ [[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with tert-butylamine.
  • the invention provides the compound3-(4- ⁇ [[4-chlorophenyl)thiazol-2- yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with 1 ,2- ethylenediamine.
  • the invention provides the compound 3-(4- ⁇ [[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ benzoylamino)propionic acid as a salt with N.N'-dibenzylethylenediamine.
  • the invention provides glucagon antagonists of the formula (I):
  • V is -C(O)OR 2 , -C(O)NR 2 R 3 , -C(O)NR 2 OR 3 , -S(O) 2 OR 2 ,
  • R 2 and R 3 independently are hydrogen or d- 6 -alkyl
  • R 4 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 5 , -NR 5 R 6 or d- ⁇ -alkyl,
  • R 5 and R 6 independently are hydrogen or d-e-alkyl
  • b is 0 or 1 ,
  • n 0, 1 , 2 or 3
  • R 7 is hydrogen, C ⁇ -6-alkyl or Cs-e-cycloalkyl-d-e-alkyl,
  • R 8 and R 9 independently are hydrogen or d-e-alkyl
  • Y is -C(O)-, -S(O) 2 -, -O- or a valence bond
  • Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R 46 and R 47 selected from hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 10 , -NR 0 R 11 and d-e-alkyl,
  • R and R independently are hydrogen or d-e-alkyl
  • R is hydrogen or d-e-alkyl
  • r is 0 or 1 ,
  • R q and s independently are 0, 1 , 2 or 3
  • R , R , R 14 and R 15 independently are hydrogen or d-e-alkyl
  • R 16 , R", R 18 and R ⁇ a independently are
  • cyclic moieties optionally may be substituted with one or more sub- stituents selected from
  • aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -OS(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 21 , -NR 21 R 22 , -SR 21 , -NR 21 S(O) 2 R 22 , -S(O) 2 NR 21 R 22 , -SfOJNR ⁇ R 22 , -S(O)R 21 , -S(O) 2 R 21 , -OS(O) 2 R 21 , -CfOJNR ⁇ R 22 , -OC(O)NR 21 R 22 , -NR 21 C(O)R 22 , -CH 2 C(O)NR 21 R 22 ,
  • R 21 and R 22 independently are hydrogen, -CF 3 , d-e-alkyl, tri-d- ⁇ -alkylsilyl, C 3 - ⁇ -cyclo- alkyl, C 3 _ 8 -cycloalkyl-d-e-alkyl, aryl, aryl-d-e-alkyl or heteroaryl,
  • 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 het- eroatoms 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 1 ⁇ ' , R 17' , R 18' and R 19' independently are hydrogen, d-e-alkyl or halogen
  • R 20 and R 20' independently are hydrogen, C ⁇ - 6 -alkyl, C 3 -8-cycloalkyl or Cs- ⁇ -cycloalkyl-d-e- alkyl
  • E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two double bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R 23 and R 24 may be attached to the same or different ring carbon atoms and wherein a group R 31 may be attached to a ring nitrogen atom when present, or
  • n and p independently are 0, 1 , 2, 3 or 4, with the proviso that when both m and p are present in the same formula at least one of m and p is different from 0, R 23 and R 24 independently are
  • aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
  • R and R independently are hydrogen, d-e-alkyl or aryl
  • the aryl moiety optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 38 , -NR ⁇ R 39 and d-e-alkyl,
  • R and R independently are hydrogen or d-e-alkyl
  • R 36 and R 37 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 23 and R 24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH 2 ) r CR 40 R 41 -(CH 2 ) r O-, -(CH 2 ) r CR 40 R 41 -(CH 2 ) r or -S-(CH 2 )rCR 40 R 41 -(CH 2 ) r S-,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 40 and R 41 independently are hydrogen or Ci-e-alkyl
  • R 25 to R 30 independently are hydrogen, halogen, -CN, -CF 3 , -NO 2 , -OR 42 , -NR ⁇ R 43 , Ci-e-alkyl, Qj-e-cycloalkyl or d-e-cycloalkenyl,
  • R 42 and R 43 independently are hydrogen or Ci-e-alkyl, or
  • R 42 and R 43 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 31 , R 32 and R 33 independently are hydrogen or Ci-e-alkyl
  • R 34 and R 35 independently are
  • aryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 44 , -NR ⁇ R 45 and d- ⁇ -alkyl,
  • R 44 and R 45 independently are hydrogen or d-e-alkyl, or
  • R 34 and R 35 when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, or R 34 and R 35 when attached to a 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 or sulfur, and optionally containing one or two double bonds,
  • the invention provides compounds, wherein V is -C(O)OH or 5-tetrazolyl.
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein Y is -C(O)-,
  • the invention provides compounds.wherein Z is
  • the invention provides compounds, wherein R 1 is hydrogen or methyl.
  • the invention provides compounds, wherein 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)-.
  • the invention provides compounds, wherein D is
  • R 16 R 17 and R 18 are hydrogen and the remaining is independently se- lected from -OCF 3 , -SCF 3 -CF 3 , -S(O) 2 CH 3 , phenyl, halogen, d-e-alkyl, nitro, -S-Ci-e-alkyl or -S(O) 2 NR 21 R 22 , wherein R 21 is Ci-e-alkyl and R 22 is phenyl.
  • E is
  • R 23 is hydrogen and R 24 is Ci-e-alkyl such as terf-butyl or Qj- ⁇ -cycloalkyl such as cyclohexyl, wherein R 23 and R 24 are both d-e-alkyl or wherein R 23 and R 24 together form the radical -(CH 2 ) 5 -.
  • E is
  • R 25 is -OCF 3 , -CF 3 , Ci-e-alkyl such as terf-butyl, phenyl, piperidyl, Qj- ⁇ -cycloalkyl such as cyclohexyl or d- ⁇ -cycloalkenyl such as cyclohexenyl.
  • the invention provides compounds, wherein the compound is any of the following
  • the invention provides the compound N-[4-( ⁇ 4-(1-cyclohexen-1-yl)[(3,5- dichloroanilino)carbonyl]anilino ⁇ methyl)benzoyl]- ?-alanine as a salt with and tert-butylamine. In an embodiment the invention provides the compound N-[4-( ⁇ 4-(1-cyclohexen-1-yl)[(3,5- dichloroanilino)carbonyl]anilino ⁇ methyl)benzoyl]-;ff-alanine as a salt with L-arginine.
  • the invention provides a glucagon antagonist represented by the general formula (I):
  • R 1 , R 2 , R 3 , R 4 and R 5 independently are hydrogen or Ci-e-alkyl
  • A is -C(O)-, -CH(OR 6 )- or -CHF-,
  • R 6 is hydrogen or Ci-e-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, 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 d-e-alkyl,
  • R 9 and R 10 independently are hydrogen or Ci-e-alkyl
  • r is O or 1 ,
  • q and s independently are 0, 1 , 2 or 3,
  • R , R , R and R independently are hydrogen, Ci-e-alkyl or C 3 - ⁇ -cycloalkyl, D is
  • R 10 , R 10 , R 1 ' and R 10 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 ⁇ -alkyl,
  • R 21 and R 22 independently are hydrogen, Ci-e-alkyl, aryl-Ci-e-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, Ci-e-alkyl or fluorine,
  • R 19 and R 20 independently are hydrogen, Ci- ⁇ -alkyl, C 3 - 8 -cycloalkyl or C 3 -e-cyclo- alkyl-Ci-e-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 Ci-e-alkyl,
  • R 32 and R 33 independently are hydrogen or d-e-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
  • Ci-e-alkyl C 2 -e-alkenyl or C 2 . 6 -alkynyl
  • 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 ⁇ R 35 and
  • R 34 and R 35 independently are hydrogen, Ci-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 31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH 2 ) r CR 36 R 37 -(CH 2 ) r O-, -(CH 2 ) t -CR 36 R 37 -(CH 2 )r 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 38 and R 37 independently are hydrogen or Ci-e-alkyl
  • An embodiment of the invention provides compounds, wherein R ⁇ R 2 , R 3 , R 4 and R 5 are hydrogen.
  • An embodiment of the invention provides compounds, wherein A is -CHF-.
  • An embodiment of the invention provides compounds, wherein A is -CH(OR 6 )-, wherein R 6 is as defined above.
  • An embodiment of the invention provides compounds, wherein A is -CH(OH)-.
  • An embodiment of the invention provides compounds, wherein Z is
  • R 7 and R 8 are as defined above.
  • An embodiment of the invention provides compounds, wherein Z is
  • An embodiment of the invention provides compounds, wherein X is -C(O)NH-, -C(O)NHCH 2 -, -C(O)NHCH(CH 3 )-, -C(O)CH 2 - or -C(O)-.
  • An embodiment of the invention provides compounds, wherein X is -C(O)NH-.
  • An embodiment of the invention provides compounds, wherein D is
  • R 15 , R 16 and R 17 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 or Ci- ⁇ - alkoxy.
  • An embodiment of the invention provides compounds, wherein E is
  • R 29 and R 31 are both hydrogen, and R 30 is cyclohexenyl
  • ⁇ which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2l -OR 34 , -NR ⁇ R 35 and d-e-alkyl,
  • R 34 and R 35 independently are hydrogen, Ci-e-alkyl or aryl
  • R 34 and R 35 when attached to the same nitrogen atom together with the said ni- trogen 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 independent- ly are hydrogen, Ci-e-alkyl, phenyl, C 3 - 8 -cycloalkyl or C 4 _ ⁇ -cycloalkenyl.
  • An embodiment of the invention provides compounds, wherein R 29 and R 31 are both hydrogen and R 30 is Ci-e-alkyl, C3_8-cycloalkyl or C 4 _e-cycloalkenyl
  • the invention provides the compounds as below: (R)-3- ⁇ 4-[1-(4-Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoyl- amino ⁇ -2-hydroxypropionic acid (R)-3- ⁇ 4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino ⁇ -2-hydroxypropionic acid
  • the invention provides the compound (R)-[3- ⁇ 4-[1-(4-Cyclohex-1- enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid as an L-arginine salt.
  • the invention provides the compound (R)-[3- ⁇ 4-[1-(4-Cyclohex-1- enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid as a salt with N,N'-dibenzylethylenediamine.
  • the invention provides the compound (R)-[3- ⁇ 4-[1-(4-Cyclohex-1- enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid as a salt with N.N'-dibenzylethylenediamine as a 2:1 ratio between compound and N,N'- dibenzylethylenediamine.
  • the invention provides the compound (2R)-N-[4-( ⁇ [1,1'-biphenyl]-4-yl[(3,5- dichloroanilino)carbonyl]amino ⁇ methyl)benzoyl]-2-hydroxy- ⁇ -alanine and benzathine.
  • the invention provides the compound (2R)-N-[4-( ⁇ [1 ,1'-biphenyl]-4-yl[(3,5- dichloroanilino)carbonyl]amino ⁇ methyl)benzoyl]-2-hydroxy- ?-alanine and benzathine as a 2:1 ratio between compound and N.N'-dibenzylethylenediamine.
  • the invention provides the compound ((2R)-N-[4-( ⁇ 4-cyclohexyl[(3,5- dichloroanilino) ⁇ rbonyl]anilino ⁇ methyl)benzoyl]-2-hydroxy- ?-alanine as a salt with N,N'- dibenzylethylenediamine.
  • the invention provides the compound ((2R)-N-[4-( ⁇ 4-cyclohexyl[(3,5- dichloroanilino)carbonyl]anilino ⁇ methyl)benzoyl]-2-hydroxy- ⁇ -alanine as a salt with N,N'- dibenzylethylenediamine in a 2:1 ratio of compound to N.N'-dibenzylethylenediamine.
  • a glucagon antagonist represented by the general formula (I):
  • R is hydrogen or Ci-e-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 Ci-e-alkyl,
  • R 9 and R 10 independently are hydrogen or Ci-e-alkyl
  • r is O or 1 ,
  • q and s independently are 0, 1 , 2 or 3,
  • R 11 , R 12 , R 13 and R 14 independently are hydrogen or Ci-e-alkyl
  • R ⁇ a , R 10 , R" and R 1B independently are
  • Ci-e-alkyl C 2 -e-alkenyl or C 2 .e-alkynyl
  • 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 21 R 22 and d-e-alkyl,
  • R 21 and R 22 independently are hydrogen, Ci-e-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 , R , R ⁇ and R ⁇ ° independently are hydrogen, d ⁇ -alkyl or fluorine,
  • R and R independently are hydrogen, Ci-e-alkyl, Qj-e-cycloalkyl or C 3 _e-cyclo- alkyl-Ci-e-alkyl, E is
  • R 27 and R 28 independently are
  • cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and Ci-e-alkyl,
  • R l 32 a __nd J R D33 independently are hydrogen or C ⁇ _ ⁇ -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 ⁇ R 35 and
  • R 34 and R 35 independently are hydrogen, d-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 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 )»-CR 36 R 37 -(CH 2 )r or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) r S-,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 36 and R 37 independently are hydrogen or Ci-e-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
  • the invention provides a compound, wherein R 2 is hydrogen.
  • the invention provides a compound, wherein Z is
  • R 7 and R 8 are as defined as above.
  • the invention provides a compound, wherein Z is
  • the invention provides a compound, wherein X is
  • R 12 and R 13 independently are hydrogen or Ci-e-alkyl.
  • the invention provides a glucagon antagonist as represented by the general formula (I):
  • 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 2 is hydrogen, d-e-alkyl, Ci-e-alkanoyl, aryl or aryl-Ci-e-alkyl,
  • R 3 , R 4 and R 5 independently are
  • the cyclic moieties may optionally be substituted with one or more substituents selected from fluoro, -C(O)OR 6 , -CN, -CF 3 , -OCF 3 , -OR 7 , -NR 6 R 7 and Ci-e-alkyl,
  • cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR 6 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 7 , -NR 6 R 7 and Ci-e-alkyl,
  • R 6 and R 7 independently are hydrogen or Ci-e-alkyl
  • R 6 and R 7 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,
  • t 1 or 2
  • R , R , R and R independently are hydrogen, Ci-e-alkyl or fluoro,
  • p 0, 1 , 2, 3 or 4,
  • Q 1 is-CH 2 -or-NH-
  • q 2, 3, 4, 5 or 6
  • R 12 , R 13 and R 14 independently are
  • the cyclic moieties may optionally be substituted with one or more substituents selected from fluoro, -C(O)OR 17 , -CN, -CF 3 , -OCF 3 , -OR 17 and -NR 17 R 18 ,
  • cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR 17 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 17 , -NR 17 R 18 and d-e-alkyl,
  • R 17 and R 18 independently are hydrogen or Ci-e-alkyl
  • R 17 and R 18 when attached to the same nitrogen atom together with the said nitro- gen 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,
  • x 0, 1 or 2
  • R 19 , R 20 , R 21 and R 22 independently are hydrogen, d-e-alkyl or fluoro,
  • R 15 and R 16 independently are hydrogen, halogen, -CN, -CF 3 , -OR 23 , -NR 23 R 24 , d- ⁇ -alkyl, C ⁇ -cycloalkyl, d- 8 -cycloalkenyl, aryl or aryl-Ci-e-alkyl,
  • cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 23 , -NR 23 R 24 and Ci-e-alkyl,
  • R 23 and R 24 independently are hydrogen or C ⁇ _ ⁇ -alkyl, or
  • R 23 and R 24 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 25 and R 26 independently are hydrogen or d- 6 -alkyl, or
  • R 25 and R 26 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,
  • Z is -(CR 27 R 28 ) V -(O) W -(CR 29 R 30 ) 2 -,
  • v and z independently are 0, 1 or 2
  • R 27 , R 28 , R 29 and R 30 independently are hydrogen or Ci-e-alkyl
  • the invention provides a compound, wherein A is o HO (CH 2 ) n ⁇ wherein n is as defined above.
  • the invention provides a compound.wherein A is
  • the invention provides a compound, wherein A is
  • the invention provides a compound, wherein B is
  • R 3 to R 5 are as defined above.
  • the invention provides a glucagon antagonist as represented by the gen- eral formula (I):
  • n 0 or 1
  • n 0, 1 , 2 or 3
  • R 4 is hydrogen, halogen or -(CH 2 ) 0 -OR 5 ,
  • o 0 or 1
  • R 5 is hydrogen, Ci-e-alkyl, C ⁇ - 6 -alkanoyl, aryl or aryl-d-e-alkyl,
  • R 1 and R 2 independently are hydrogen, halogen or Ci-e-alkyl, or R 1 and R 2 are combined to form a double bond,
  • R 3 is hydrogen, Ci-e-alkyl or halogen, or R 3 and R 2 are combined to form a double bond to oxygen,
  • X is arylene or heteroarylene, which may optionally be substituted with one or two groups R 6 and R 7 selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -NO 2 , -OR 8 , -NR 8 R 9 and Ci-e-alkyl, R 8 and R 9 independently are hydrogen or Ci-e-alkyl,
  • Y is -C(O)-, -O-, -NR 10 -, -S-, -S(O)-, -S(O) 2 - or -CR 11 R 12 -,
  • R 10 is hydrogen or C ⁇ _6-alkyl
  • R 11 and R 12 independently are hydrogen, Ci-e-alkyl or hydroxy, or R 11 is combined with R 1 to form a double bond, and R 12 is hydrogen, C ⁇ _e-alkyl or hydroxy,
  • Z is -C(O)-(CR 13 R 14 ) p -, -O-(CR 13 R 14 )p-, -S-(CR 13 R 4 ) P -, -S(O)-(CR 13 R 14 ) p -, -S(O) 2 -(CR 13 R 14 ) p -, -NR 15 -(CR 13 R 14 ) p - or -(CR 13 R 14 ) P -,
  • p 0, 1 or 2
  • R 13 and R 14 independently are selected from hydrogen, -CF 3 , -OCF 3 , -OCHF 2 and Ci-e-alkyl,
  • R 15 is hydrogen or Ci-e-alkyl
  • D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R 6 , R 17 , R 8 , R 19 , R 20 and R 21 , wherein
  • R 16 , R 17 , R 18 and R 19 independently are
  • Ci-e-alkyl C 2 _ ⁇ -alkenyl or C 2 . 6 -alkynyl
  • aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -C(O)OR 22 , -CN, -CF 3 , -OCF 3 ,
  • R 22 and R 23 independently are hydrogen, d-e-alkyl, aryl-Ci-e-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, Ci-e-alkyl or fluoro,
  • R 20 and R 21 independently are hydrogen, Ci-e-alkyl, d- ⁇ -cycloalkyl or C ⁇ -cyclo- alkyl-d-e-alkyl,
  • R 28 and R 29 which are independently selected from • hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OR 33 , -NR ⁇ R 34 , Ci-e-alkyl, C M - cycloalkyl, d-e-cycloalkenyl, heteroaryl and aryl,
  • heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -NO 2 , -OR 33 , -
  • R 33 and R 34 independently are hydrogen or Ci-e-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,
  • aryl, heteroaryl, aryl-C 2 -e-alkenyl or aryl-C 2 - 6 -alkynyl of which the aryl and heteroaryl moieties may optionally be substituted with one or more substitutents R 28 , R 29 , R 30 , R 31 and R 32 ,
  • R 28 and R 29 are as defined above, and R 30 , R 31 and R 32 are independently selected from
  • R 35 and R 36 independently are hydrogen, C ⁇ _ 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 when attached to the same ring carbon atom or adjacent ring carbon atoms together may form a bridge - ⁇ -(CH ⁇ t -CR ⁇ R 38 - (CH 2 ),-O-, -(CH 2 ),-CR 37 R 38 -(CH 2 ) ⁇ - 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 Ci-e-alkyl
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein X is monocyclic arylene or heteroarylene, which may optionally be substituted as defined above.
  • the invention provides compounds, wherein X is
  • R 6 and R 7 are as defined above.
  • the invention provides compounds, wherein X is
  • R 6 and R 7 are as defined above.
  • the invention provides compounds, wherein E is
  • R 30 , R 31 and R 32 are as defined above.
  • the invention provides compounds, wherein R 30 , R 31 and R 32 independently are • hydrogen,
  • Ci-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 ,
  • 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 ⁇ R 36 and Ci-e-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 d-e-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 , _ NR35R 36 and C ⁇ .glky ⁇
  • R 35 and R 38 independently are hydrogen or d-e-alkyl.
  • the invention provides compounds, wherein E is
  • the invention provides compounds, wherein R 1 and R 2 are both hydrogen. In an embodiment the invention provides compounds, wherein R 1 and R 2 are combined to form a double bond.
  • the invention provides compounds, wherein R 3 is hydrogen. In an embodiment the invention provides compounds, wherein Z is NH or -C(O)-. In an embodiment the invention provides compounds, wherein D is
  • R 16 , R 17 and R 18 are as defined above.
  • the invention provides compounds, wherein R 6 , R 17 and R 18 independently are
  • the invention provides compounds such as (Z)-3- ⁇ 4-[4-Biphenyl-4-yl-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoylamino ⁇ propionic acid
  • glucagon antagonists as represented by the general formula (I):
  • 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 2 is hydrogen, Ci-e-alkyl, C ⁇ _6-alkanoyl, aryl or aryl-Ci-e-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 ⁇ _6-alkyl or aryl
  • s and t independently are 0 or 1 ;
  • R 6 , R 7 and R 8 independently are selected from hydrogen, Ci-e-alkyl and aryl;
  • D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R , R 17 , R 18 , R 19 , R 20 and R 21 , wherein
  • R 16 , R 17 , R 18 and R 19 independently are
  • Ci-e-alkyl C 2 -e-alkenyl or C 2 -e-alkynyl
  • 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 22 R 23 and d-e-alkyl, R 22 and R 23 independently are hydrogen, d-e-alkyl, aryl-Ci-e-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, d-e-alkyl or fluoro
  • R 20 and R 21 independently are hydrogen, Ci-e-alkyl, C3- ⁇ -cycloalkyl or C ⁇ -cyclo- alkyl-Ci- 6 -alkyl,
  • heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -NO 2 , -OR 33 , -NR 33 R 34 and d-e-alkyl,
  • R 33 and R 34 independently are hydrogen or Ci-e-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, aryl, heteroaryl, aryl-C 2 -e-alkenyl or aryl-C 2 -e-alkynyl, of which the cyclic moieties may optionally be substituted with one to three substitutents R 30 , R 31 and R 32 , which are independently selected from
  • heterocy- clyl-C 2 -e-alkenyl heterocyclyl-C 2 -e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- C ⁇ -e-alkyl, aryl-C 2 - ⁇ -alkenyl, aryl-C 2 .e-alkynyl, heteroaryl, heteroaryl-C ⁇ _ ⁇ -alkyl, hetero- aryl-C 2 ⁇ -alkenyl and heteroaryl-C 2 -e-alkynyl,
  • 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 Ci-e-alkyl,
  • R and R independently are hydrogen, Ci-e-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 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 ),-CR 37 R 38 -(CH 2 ) r or -S-(CH 2 ),-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 Ci-e-alkyl
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein A is
  • the invention provides compounds, wherein D is
  • R 16 , R 17 and R 18 independently are
  • R , R , R 31 and R are independently selected from
  • Ci-e-alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3l -OR 35 and -NR 35 R 36 ,
  • 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 Ci-e-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 Ci-e-alkyl.
  • the invention provides a compound which is 3- ⁇ 4-[(4-Cyclohexylbenzyl)-(4-trifluoromethoxybenzyl)amino]benzoylamino ⁇ propionic acid.
  • the invention provides a glucagon antagonist represented by the general formula (I):
  • R ⁇ R 2 , R 3 and R 4 independently are hydrogen, halogen, -CN, -CF 3 , -NO 2 , -OR 5 , lower alkyl, -SR 5 , -S(O) 2 NR 5 R e , -S(O)NR 5 R 6 , -S(O) 2 R 5 , -S(O)R 5 , -C(O)NR 5 R 6 , -CH 2 OR 5 , -CH 2 NR 5 R 6 , -NR 5 R 6 , -C(O)R 5 or -C(O)OR 5 ,
  • R 5 and R 6 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloal- kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower
  • D is hydrogen, halogen, -CN, -CF 3 , -NO 2 , -OR 7 , -NR 7 R 8 , lower alkyl, aryl, -C(O)NR 7 R 8 , -CH 2 OR 7 , -CH 2 NR 7 R 8 or -C(O)OR 7 ,
  • R 7 and R 8 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alky
  • R 9 , R 9a and R 9b independently are hydrogen, lower alkyl, lower alkenyl, lower al- kynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl- lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, hetero
  • R and R 3 9d ° independently are hydrogen or lower alkyl
  • n, r independently are 0, 1 , 2, 3 or 4,
  • a and B independently are hydrogen, halogen, -CF 3 , -CF 2 CF 3 , -CN, -NO 2 , lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH 2 OH, -NO 2 , -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH 3 , -C(O)NH 2 , -OCH 2 C(O)NH 2 , -NH 2 , -N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 and -OCF 3 ,
  • p 1, 2 or 3
  • G is -CR 18a R 18b -, -N + O ' -, -NR 19 -, -O- or -S-,
  • K is -CR 18c R 18d -, -NR 20 , -O- or -S-,
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 18a , R 18b , R 18c and R 18d independently are hydro- gen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -NO 2 , -OR 21 , -NR 21 R 22 , lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl- lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkenyl, cycl
  • R 21 and R 22 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alky
  • R 9 and R 20 independently are hydrogen, -OR 23 , -NR 23 R 24 , lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower
  • R 23 and R 24 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alky
  • q 1, 2 or 3
  • s is O, 1, 2 or 3,
  • a and B may be connected and together form a C 2 -3-alkylene radical
  • M represents a group wherein n or r is 0, B is not halogen, -CN or -NO 2 ,
  • glucagon antagonists represented by the general formula (I):
  • R 1 is chloro, fluoro, nitro or cyano
  • K is -C(O)-(CH 2 ) d -, -CH 2 -CH 2 -O- or -CHR 2 -;
  • d is 0 or 1 ;
  • R 2 is hydrogen or Ci-e-alkyl
  • Q is -O- or -S-;
  • R 3 , R 4 , R 5 , R 6 and R 7 independently are hydrogen, Ci-e-alkyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, halogen, carboxamido, hydroxy methyl, phenyl, dimethylamino, Ci- ⁇ -alkoxy or nitro;
  • the invention provides a glucagon antagonist of the general formula (I):
  • R 2 is hydrogen or C ⁇ _ ⁇ -alkyl
  • A is a valence bond, -(CR 3 R 4 )-, or -(CR 3 R 4 )(CR 5 R 6 )-,
  • R 1 , R 3 , R 4 , R 5 and R 6 independently are hydrogen or Ci-e-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 d-e-alkyl,
  • R 9 and R 10 independently are hydrogen or Ci-e-alkyl
  • q and s independently are 0, 1 , 2 or 3,
  • R 11 , R 12 , R 13 and R 14 independently are hydrogen or Ci-e-alkyl, D is
  • R_°, R TM R ⁇ / and R TM independently are
  • Ci-e-alkyl C 2 -e-alkenyl or C 2 . 6 -alkynyl
  • 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 21 R 22 and Ci-e-alkyl,
  • R 21 and R 22 independently are hydrogen, C ⁇ _ ⁇ -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, Ci-e-alkyl or fluorine,
  • R 19 and R 20 independently are hydrogen, Ci-e-alkyl, Cs-e-cycloalkyl or C 3 _ ⁇ -cyclo- alkyl-d-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 , -OCF 3 , -NO 2 , -OR 32 , -NR 32 R 33 and d-e-alkyl,
  • R 32 and R 33 independently are hydrogen or Ci-e-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 het- eroatoms 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 se- lected from halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 34 , -NR ⁇ R 35 and Ci-e-alkyl,
  • R 34 and R 35 independently are hydrogen, Ci-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 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 ) ⁇ -O-, -(CH 2 ),-CR 36 R 37 -(CH 2 ) ⁇ - or -S-(CH 2 ) t -CR 36 R 37 -(CH 2 ) r S-,
  • t and I independently are 0, 1 , 2, 3, 4 or 5,
  • R 36 and R 37 independently are hydrogen or Ci-e-alkyl
  • n O, 1, 2 or 3
  • R 4 is hydrogen, fluoro or -(CH 2 ) p -OR 5 ,
  • p 0 or 1
  • R 5 is hydrogen, C ⁇ _ 6 -alkyl, aryl or aryl-Ci-e-alkyl,
  • R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, Ci-e-alkyl, C ⁇ -alkoxy, hydroxy, Ci-e-alkylthio, Ci-e-alkylsulfonyl, trifluoromethylsulfonyl or -NR 6 R 7 ,
  • R 6 and R 7 independently are hydrogen or d-e-alkyl
  • R 8 , R 9 , R 13 and R 14 independently are hydrogen, halogen, trifluoromethyl, d-e-alkyl or C ⁇ _6-alkoxy,
  • R 10 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, Ci-e-alkyl, methylthio or Cs-e-cycloalkyl,
  • R and R independently are hydrogen or Ci-e-alkyl
  • q 0, 1 , 2 or 3;
  • R 3 is hydrogen or C ⁇ _ 8 -alkyl
  • R >16 a corpenndJ o R17 independenly are hydrogen or Ci-e-alkyl, • aryl or heteroaryl, which may optionally be substituted with
  • halogen trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, Ci-e-alkyl, d-e-alkoxy, hydroxy, Ci-e-alkylthio, Ci-e-alkylsulfonyl, trifluoromethylsulfonyl or -NR 18 R 19 ,
  • R 18 and R 19 independenly are hydrogen or C ⁇ _ ⁇ -alkyl
  • R 20 and R 21 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, C ⁇ . 6 -alkyl, aryl, methylthio, methylsulfonyl, trifluoromethylsulfonyl, -NR 23 R 24 , d- ⁇ -cycloalkyl or -S(O) 2 -N(C ⁇ -alkyl)(aryl),
  • R 23 and R 24 independently are hydrogen or d-e-alkyl
  • R 22 is hydrogen, Ci-e-alkyl, dj- ⁇ -cycloalkyl or Cs- ⁇ -cycloalkyl-Ci-e-alkyl,
  • the invention provides a compound, wherein A is
  • the invention provides a compound, wherein A is
  • the invention provides a compound, wherein R 1 and R 2 are both hydrogen. In an embodiment the invention provides a compound, wherein B is
  • R 8 , R 9 , R 11 and R 12 are as defined above.
  • the invention provides a compound, wherein R 8 and R 9 are both hydrogen. In an embodiment the invention provides a compound, wherein B is
  • R 10 is as defined in above.
  • the invention provides a compound, wherein R 3 is hydrogen.
  • the invention provides a compound, wherein D is
  • R , R and R 22 are as defined above.
  • the invention provides a compound, wherein R 20 and R 21 independently are hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and R 22 is Ci-e-alkyl.
  • the invention provides solvates of compounds as described above.
  • the invention provides 3- ⁇ 4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino ⁇ propionic acid in a solvate form.
  • the invention provides 3- ⁇ 4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid in a solvate form.
  • the invention provides 3- ⁇ 4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid as a solvate with one of the following solvents ethanol, 2-propanol, 2-methyl-1-propanol, n-butanol, 2-butanol, 3- methyl-1-butanol, diethyl ether, terf-butyl-methylether, tetrahydrofuran, anisol, acetone, 2- butanon, methylacetate, ethylacetate, n-propylacetate and toluene.
  • the invention provides ⁇ /-[4-( ⁇ 4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)- carbonyl]anilino ⁇ methyl)benzoyl]- ?-alanine as a solvate with acetone, butanol, ethanol or propanol.
  • the invention provides 3- ⁇ 4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R-hydroxypropionic acid as a solvate with 2- butanol, 3-methyl-1 -butanol and 2-methyl-1 -propanol.
  • the invention provides a process for the preparation a solvate of 3- ⁇ 4-[1- (4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino ⁇ -2R- hydroxypropionic acid comprising the steps of :
  • the invention provides the process of claim 4 wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient a compound according to the invention as a solvate or as a salt as describedn above together with pharmaceutically acceptable carriers and/or diluents
  • the invention provides a pharmaceutical composition according to the above in a unit dosage form comprising from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg compound as described above.
  • the invention provides a pharmaceutical composition useful in the treatment and/or prevention of conditions mediated by glucagon receptors, the composition comprising a compound as a salt or as a solvate according to the above together with a pharmaceutically acceptable carrier or diluent.
  • a method for the treatment and/or prevention of conditions mediated by glucagon receptors which method comprises administering to a subject in need thereof an an effective amount of a compounds according to the above as a solvate or as a salt.
  • a method for the treatment and/or prevention of diabetes and/or obesity which method comprises administering to a subject in need thereof an effective amount of a compound according to the above.
  • the invention provides the use of a compound according to the above as a salt or as a solvate for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by glucagon receptors.
  • the invention provides the use of a compound according to the above for the preparation of a medicament useful in the treatment and/or prevention of diabetes and/or obesity.
  • PXRD Powder X-ray Diffraction
  • DSC Differential Scanning Analysis
  • Thermo gravimetric Analysis (TGA) experiments were conducted on a TA Hi Res Thermo gravimetric Analyser, Model 2959. Samples (approximately 6-12 mg) were heated in an open platinum pan from 25°C to 250°C at a rate of 10°C/min. The TGA measuring chamber was continuously purged with dry nitrogen during the runs and the instrument was routinely calibrated with indium and aluminium.
  • Example 1 [3- ⁇ 4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino ⁇ -2 ?-hydroxypropionic acid:/V,_V-dibenzylethylenediamine (1 :0.5)]
  • Example 7 3- ⁇ 4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino ⁇ propionic acid : L-arginine:
  • Example 8 N3-(4- ⁇ [[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5,6,7,8-tetrahydronaphthalen-2- yl)amino]methyl ⁇ benzoylamino)propionic acid :tert-butylamine (erbumine) (1:1)
  • Example 11 3-(4- ⁇ [[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)- amino]methyl ⁇ benzoylamino)propionic acid : monoethanolamine (olamine) (1 :1)
  • Example 12 3-(4- ⁇ [[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)- amino]methyl ⁇ benzoylamino)propionic acid: tert-butylamine (1:1)
  • Example 13 3-(4- ⁇ [[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trif luoromethylphenyl)- amino]methyl ⁇ benzoylamino)propionic acid: ethylenediamine (2:1) 33.7 mg of 3-(4- ⁇ [[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl ⁇ - benzoylamino)propionic acid was dissolved in 1 mL of ethylacetate while shaking. 510 ⁇ L of 0.118 M ethylenediamine in ethylacetate was added in three portions, during which a precipitate formed. The solution was allowed standing at room temperature. After a few days a white voluminous precipitate formed. This was suspended in 300 ⁇ L of ethylacetate. After some days a white, solid precipitate was formed. The precipitate was analysed.
  • the parent compound as a free acid, an ester derivative or optionally as a solvate was dissolved in a suitable solvent.
  • the solvent may the same solvent as the solvate to be obtained or it may be a different solvent.
  • the temperature was elevated to dissolve the compound.
  • the pH may be adjusted for ensuring the compound was dissolved.
  • the solvent to form solvates with the compound as above was added in surplus amount and the formed solvate was isolated and dried, optionally in vacuo, at elevated temperature.
  • PXRD Powder X-ray Diffraction
  • the evaporation residue was added ethyl acetate (500 ml) and further stripping of water conducted by removal of the solvent under reduced pressure.
  • the crude material was dissolved in ethyl acetate (500 ml) and heated to 40 °C for 1 hour. The solution was cooled to room temperature. After stirring over night a precipitate was formed and the slurry was cooled to 0°C prior to filtration. The filter cake was washed with cooled (2 °C) ethyl acetate (100 ml) and dried in vacuo at 40 °C for 2 hours followed by drying at room temperature in the air. The title compound (92.8 g) was isolated in 91% yield.

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Abstract

L'invention concerne des sels et des solvates d'antagonistes de glucagon.
PCT/DK2004/000013 2003-01-10 2004-01-12 Sels et solvates d'antagonistes de glucagon Ceased WO2004063147A1 (fr)

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WO2006074262A1 (fr) * 2005-01-05 2006-07-13 Rigel Pharmaceuticals, Inc. Inhibiteurs d'ubiquitine-ligases
US7381736B2 (en) 2004-09-02 2008-06-03 Metabasis Therapeutics, Inc. Thiazole and thiadiazole inhibitors of tyrosine phosphatases
WO2010071750A1 (fr) * 2008-12-19 2010-06-24 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon
US7794965B2 (en) 2002-03-13 2010-09-14 Signum Biosciences, Inc. Method of identifying modulators of PP2A methylase
US7923041B2 (en) 2005-02-03 2011-04-12 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
US8076374B2 (en) * 2005-11-18 2011-12-13 Eli Lilly And Company Glucagon receptor antagonists, preparation and therapeutic uses
US8221804B2 (en) 2005-02-03 2012-07-17 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
US8809342B2 (en) 2010-12-23 2014-08-19 Pfizer Inc. Glucagon receptor modulators
US8859591B2 (en) 2011-02-08 2014-10-14 Pfizer Inc. Glucagon receptor modulators
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
WO2015145371A1 (fr) * 2014-03-27 2015-10-01 Piramal Enterprises Limited Modulateurs de ror-gamma et leurs utilisations
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US9394287B2 (en) 2010-11-05 2016-07-19 Senomyx, Inc. Compounds useful as modulators of TRPM8
US9486441B2 (en) 2008-04-21 2016-11-08 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
US9732071B2 (en) 2015-10-01 2017-08-15 Senomyx, Inc. Compounds useful as modulators of TRPM8
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2
US11976052B2 (en) 2019-01-11 2024-05-07 Naegis Pharmaceuticals Inc. Leukotriene synthesis inhibitors

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WO1998022109A1 (fr) * 1996-11-20 1998-05-28 Merck & Co., Inc. Imidazoles a substitution triaryle en tant qu'antagonistes du glucagon
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US7794965B2 (en) 2002-03-13 2010-09-14 Signum Biosciences, Inc. Method of identifying modulators of PP2A methylase
US7381736B2 (en) 2004-09-02 2008-06-03 Metabasis Therapeutics, Inc. Thiazole and thiadiazole inhibitors of tyrosine phosphatases
WO2006074262A1 (fr) * 2005-01-05 2006-07-13 Rigel Pharmaceuticals, Inc. Inhibiteurs d'ubiquitine-ligases
US8221804B2 (en) 2005-02-03 2012-07-17 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
US7923041B2 (en) 2005-02-03 2011-04-12 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
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
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US9486441B2 (en) 2008-04-21 2016-11-08 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
US10583119B2 (en) 2008-04-21 2020-03-10 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
WO2010071750A1 (fr) * 2008-12-19 2010-06-24 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon
US9422282B2 (en) 2010-04-01 2016-08-23 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US10953007B2 (en) 2010-11-05 2021-03-23 Firmenich Incorporated Compounds useful as modulators of TRPM8
US10016418B2 (en) 2010-11-05 2018-07-10 Seaomyx, Inc. Compounds useful as modulators of TRPM8
US9394287B2 (en) 2010-11-05 2016-07-19 Senomyx, Inc. Compounds useful as modulators of TRPM8
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
US9073871B2 (en) 2011-02-08 2015-07-07 Pfizer Inc. Glucagon receptor modulators
US9452999B2 (en) 2011-02-08 2016-09-27 Pfizer Inc. Glucagon receptor modulators
US8859591B2 (en) 2011-02-08 2014-10-14 Pfizer Inc. Glucagon receptor modulators
US9139538B2 (en) 2011-07-22 2015-09-22 Pfizer Inc. Quinolinyl glucagon receptor modulators
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
WO2015145371A1 (fr) * 2014-03-27 2015-10-01 Piramal Enterprises Limited Modulateurs de ror-gamma et leurs utilisations
AU2015237788B2 (en) * 2014-03-27 2021-03-11 Piramal Enterprises Limited ROR-gamma modulators and uses thereof
US11084784B2 (en) 2014-03-27 2021-08-10 Piramal Enterprises Limited ROR-gamma modulators and uses thereof
US9732071B2 (en) 2015-10-01 2017-08-15 Senomyx, Inc. Compounds useful as modulators of TRPM8
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11976052B2 (en) 2019-01-11 2024-05-07 Naegis Pharmaceuticals Inc. Leukotriene synthesis inhibitors
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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