WO2004063147A1 - Salts and solvates of glucagon antagonists - Google Patents

Salts and solvates of glucagon antagonists 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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alkyl
aryl
hydrogen
independently
alkenyl
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PCT/DK2004/000013
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French (fr)
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Karol Horvath
Anette Frost Jensen
Kaare Gyberg Rasmussen
Finn Broni Junager
Ole Ekelund
Claus Christophersen
Hanne Tøfting KORNØ
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Novo Nordisk A/S
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Publication of WO2004063147A1 publication Critical patent/WO2004063147A1/en

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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, 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 (***e 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.

Abstract

The invention provides salts and solvated of glucagon antagonists.

Description

SALTS AND SOLVATES OF GLUCAGON ANTAGONISTS
FIELD OF INVENTION
The present invention relates to salts and solvates of glucagon antagonists.
BACKGROUND OF THE INVENTION
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.
For pharmaceutical and commercial use it is important to have 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. For example, the salts and solvates of the invention provide stable compounds under storage and accelerated storage conditions as a model for long term stability.
SUMMARY OF THE INVENTION
The invention provides a composition comprising a salt or a solvate of a glucagon antagonist.
In an aspect of the invention a composition is provided comprising a salt of a glucagon antagonist and a pharmaceutically acceptable base In an aspect of the invention 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. WO 02/40445 and WO 02/40446, WO03/048109, WO03/51357, WO03/53938 and WO03/97619 and as described in this application below.
In an embodiment of the invention 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"- nitrilotris(ethanol), trolamine), 2-diethylaminoethanol.
In an aspect of the invention a composition is provided comprising a solvate of a glucagon antagonist.
In one aspect of the invention the solvate is formed from a class III solvent (ICH Guidelines Q3C; "Impurities: Guidelines for Residual Solvents", 1997).
In another aspect 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.
Within another aspect of the present invention there is provided a method of using the compounds according to the invention for the treatment and/or prevention of diabetes and/or obesity. DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed definition of the terms used to describe the compounds of the invention:
"Halogen" designates an atom selected from the group consisting of F, Cl, Br and I.
The term "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.
The term "C2_β-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. Examples of such 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.
The term "C2-6-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. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term "C^-alkoxy" or "lower alkoxy" as used herein refers to the radical -O-Ci-β-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.
The term "Cι_6-alkanoyl" or "lower alkanoyl" as used herein denotes a group -C(O)H or -C(O)-Cι. 5-alkyl. Representative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like. The term "C3^-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.
The term "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.
The term "heterocyclyl" as used herein 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.
The term "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.
The term "aroyl" as used herein denotes a group -C(O)-aryl, wherein aryl is as defined above.
The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above.
The term "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.
The term "heteroaryl" as used herein 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 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. 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-Cι_6-alkyl", "heteroaryl-C^-alkyl", "aryl-C2^-alkenyl" or "Aryl-lower alkyl", "heteroaryl-lower alkyl", "aryl-lower alkenyl" etc. mean Cι-6-alkyl or C2-e-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
Figure imgf000006_0001
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
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. In an aspect of the invention salts are formed in a 1 :1 ratio of compound to salt. In another aspect of the invention the salts are formed in a 2:1 ratio of compound to salt.
The 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"-nitrilotris(ethanol), trolamine), 2- diethylaminoethanol.
In an embodiment of the invention 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).
In an embodiment of the invention 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).
In an embodiment of the invention 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).
In an embodiment the ratio of compound to counter ion is 2:1 when the counter ion is N,N'- dibenzylethylenediamine (benzathine) or 1 ,2-ethylenediamine.
In an embodiment of the invention is provided solvates as a novel materials, in particular in pharmaceutically acceptable form. Consequently, only solvates which are physiologically acceptable in the amount administered to the subject in need of treatment are within the scope of the invention. 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, tetrahydrofuran, anisole, acetone, 2-butanone or toluene.
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. In general, such 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.
Accordingly, 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.
Accordingly, in a further aspect 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.
Furthermore, 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.
In a preferred embodiment of 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.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of hyperglycemia.
In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of 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 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.
In a further preferred embodiment of the invention 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.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.
In yet a further preferred embodiment of the invention 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.
In still a further embodiment of the invention 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.
In a further aspect of the invention the present compounds are combined with diet and/or exercise.
In yet a further aspect of the invention 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 NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), eg Asp828 human insulin, US 5,504,188 (Eli Lilly), eg LysB28 Pro829 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 β-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 synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.
In one embodiment of the invention the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human insulin, Asp828 human insulin, Lys828 Pro829 human insulin, Lantus, or a mix- preparation comprising one or more of these.
In a further embodiment of the invention the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide or glicazide.
In another embodiment of the invention the present compounds are administered in com- bination with a biguanide eg metformin.
In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
In still another embodiment of the invention 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). In still another embodiment of the invention 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).
In a further embodiment of the invention the present compounds are administered in combination with an α-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS- 67582, repaglinide or nateglinide.
In still another embodiment of the invention 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.
In another aspect of the invention, 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 meglitinide such as repaglinide, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; insulin and a sulfonylurea; insulin and a meglitinide such as repaglinide; insulin and metformin; insulin, metformin and a meglitinide such as repaglinide; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and pioglitazone; insulin and an insulin sensitizer such as such as disclosed in WO 00/63189 or WO 97/41097; insulin and lovastatin; an insulin analogue or derivative, metformin and a meglitinide such as repaglinide; an insulin analogue or derivative, metformin and a sulfonylurea; an insulin analogue or derivative and troglitazone; an insulin analogue or derivative and pioglitazone; an insulin analogue or derivative and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; an insulin analogue or derivative and lovastatin; etc.
Furthermore, 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 (***e 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, β3 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 β agonists.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment of the invention the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment of the invention the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment of the invention the antiobesity agent is sibutramine.
In a further embodiment of the invention the antiobesity agent is orlistat. In another embodiment of the invention the antiobesity agent is mazindol or phentermine.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-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 α-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., Easton, PA, 1995.
It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
PHARMACEUTICAL COMPOSITIONS
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, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical 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.
Pharmaceutical 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.
Pharmaceutical 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.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more 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.
The formulations may conveniently be presented in unit dosage form by methods known 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.
For 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. When 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.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such 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. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho- lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, 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. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, 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.
If a solid carrier is used for oral administration, 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. If a liquid carrier is used, 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:
Core:
Active compound (as free compound or salt thereof) 5.0 mg
Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite<s>IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg
Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. * Acylated monoglyceride used as plasticizer for film coating.
If desired, 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.
In an aspect of the invention the compound is represented by the general formula (I)
Figure imgf000017_0001
wherein
A is
Figure imgf000017_0002
X is a valence bond, -CR1R2- or -NR1-,
Y is >CR3- or >N-,
R1, R2 and R3 independently are hydrogen or C^-alkyl, or R1 and R3 on adjacent atoms may be combined to form a double bond,
E is
• CLio-alkyl or C2.10-alkenyl,
• C^o-cycloalkyl, C3-10-cycloalkenyl, C7.10-bicycloalkyl, Ca-io-cycloalkyl-d-e-alkyl, 03-ιo-cycloalkenyl-C^-alkyl or C7.10-bicycloalkyl-Cι-β-alkyl, wherein the rings may optionally be substituted with one or more substituents selected from halogen, Cι_6-alkyl, C2_6-alkenyl, C^-alkoxy, d-e-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2 and -SCH F2,
• aryl, aryloxy, arylthio, heteroaryl, aryl-C^-alkyl, aryloxy-C^-alkyl, arylthio-C^-alkyl, heteroaryl-C^-alkyl, diaryl-C^-alkyl or (C1-6-alkyl)(aryl)-C1. -alkyl, wherein the non-aromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, Ci-e-alkyl, C^-alkenyl, d-β-alkoxy,
Ci-β-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2, -SCHF2, Ca-io-cycloalkyl and Ca-.o-cyclo- alkenyl, or with two substituents on adjacent positions which are combined to form a bridge C^-alkylene, C2_6-alkenylene or -O-Ci-β-alkylene-O-,
B is
- Y'-X'- ,
Figure imgf000018_0001
, -W X'-N ■ -W N-X' or
Figure imgf000018_0002
X' is -N= or -CR8=,
Y is -S-, -O- or -NR9-, R8 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-β-thioalkyl, -CF3l -OCF3, -SCF3, -OCHF2, -SCHF2, -SO2CF3 and -SO2-d-6-alkyl,
R9 is hydrogen or Ci-e-alkyl,
D is aryl or heteroaryl,
which may optionally be substituted with one or more substituents selected from
• halogen, -CF3, -OCF3, -SCF3, -CN, -NO2, Cι-ι0-alkyl, C2^-alkenyl, d-e-alkoxy,
Figure imgf000019_0001
amino, Ci-e-alkylamino, di-Ci-β-alkylamino, -SO2CF3 and -SO2-C1-e-alkyl,
• C3_β-cycloalkyl, C3_8-cycloalkenyl, aryl and aryl-d-e-alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, -CF3, -OCF3, -SCF3, -CN, -NO2, Cvio-alkyl, d-e-alkenyl, d-β-alkoxy and d-β-alkylthio, or with two substituents on adjacent positions which are combined to form a bridge -O-(CH2)m-O-(CH2)p- or -O-(CF2)m-O-(CF2)p-, wherein m is an integer of from 1 to 6, and p is 0 or 1 ,
• or with two substituents on adjacent positions which are combined to form a bridge -O-(CH2)m-O-(CH2)p- or -O-(CF2)m-O-(CF2)p-, wherein m is an integer of from 1 to 6, and p is O or 1, or a substituent on B may be combined with a substiuent on D to form a -C(=O)- bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these. In one embodiment the invention provides the compounds as above, wherein B is
Y'-X' or X'-Y'
wherein X' and Y' are as defined above.
In another embodiment the invention provides the compounds as above, wherein B is
Figure imgf000020_0001
wherein R8 is as defined above.
In another embodiment the invention provides the compounds as above, wherein E is
d-10-alkyl,
C3_ιo-cycloalkyl, which may optionally be substituted as defined above.
Figure imgf000020_0002
Figure imgf000020_0003
wherein R4 and R5 are as defined above.
In another embodiment the invention provides the compounds as above, wherein E is
Figure imgf000020_0004
wherein R4 is hydrogen and R5 is d-β-alkyl, d-e-alkoxy, cyclohexyl, halogen, -CF3 or cyclo-
> hex-1-enyl,
or R and R on adjacent positions may be combined to form a bridge Cι_6-alkylene. In another embodiment the invention provides the compounds as above, wherein D is
Figure imgf000021_0001
wherein R10, R11, R12, R15, R16, R17and R18 are as defined above.
In another embodiment the invention provides the compounds as above, wherein D is
Figure imgf000021_0002
wherein R , R and R 12 are as defined above
In another embodiment the invention provides the compounds as above, wherein R10, R11 and R12 independently are hydrogen, halogen, -OCF3, -CF3, -NO2, di-d-e-alkylamino, d-10-alkyl, d-β-alkoxy or -CN,
phenyl or phenyl-d-e-alkoxy,
or two of R10, R11 and R12 in adjacent positions form a bridge -O-CH2-O-, -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O-.
In another embodiment the invention provides the compounds as above, wherein one of R10, R11 and R12 represent hydrogen. In another embodiment the invention provides the compounds as above, wherein one or two of R10, R11 and R12 is hydrogen, and the remaining is independently selected from halogen, - OCF3, -CF3, -NO2, di-d-e-alkylamino, d-10-alkyl, Cι-6-alkoxy or -CN. In another embodiment the invention provides the compounds such as
3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid,
3-(4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5,6,7,8-tetrahydronaphthalen-2-yl)amino]methyl}- benzoylamino)propionic acid
3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoyl- amino]propionic acid,3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromethylphenyl)thiazol-2- yl]amino}methyl)benzoylamino]propionic acid or
3-[4-({(4-Trifluoromethoxyphenyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}methyl)- benzoylaminojpropionic acid,
In another embodiment 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. In another embodiment 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.
In another embodiment 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.
In another embodiment the invention provides the compound3-(4-{[[4-(4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)propionic acid as a salt with monoethanolamine.
In another embodiment 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.
In another embodiment 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. In another embodiment 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. In an embodiment the invention provides glucagon antagonists of the formula (I):
Figure imgf000023_0001
wherein
V is -C(O)OR2, -C(O)NR2R3, -C(O)NR2OR3, -S(O)2OR2,
Figure imgf000023_0002
wherein
R2 and R3 independently are hydrogen or d-6-alkyl,
R4 is hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR5, -NR5R6 or d-β-alkyl,
wherein R5 and R6 independently are hydrogen or d-e-alkyl,
A is
— (CH2)n (V)b NR7 , — -_(CH2)— NR7— , - r(CH2)n- or — ?
^^-(CH2)n '
wherein
b is 0 or 1 ,
n is 0, 1 , 2 or 3,
R7 is hydrogen, Cι-6-alkyl or Cs-e-cycloalkyl-d-e-alkyl,
R8 and R9 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 R46 and R47 selected from hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR10, -NR 0R11 and d-e-alkyl,
wherein R and R independently are hydrogen or d-e-alkyl,
or -A-Y-Z- together are
Figure imgf000024_0001
R is hydrogen or d-e-alkyl,
X is
-(CR13R14)-(CH2)S- -(CH2 2)'(q -(CR13R14) -(CH2 2)',s
Figure imgf000025_0001
— S-(CR13R14)-(CH2)S-
Figure imgf000025_0002
— N-U—ICR W,- -O-(CR13R14)— (CH2)S
R12
Figure imgf000025_0003
-(CH 2'q (CR 3R14)r-(CH2)s—
Figure imgf000025_0004
-2-(CH2)-(CR13R1Vθ-(CH2)-
Figure imgf000025_0005
O O O
^-(CH,)— S-(CR13R14)— (CH2)— or -^-(CH^— " (CR13R14) (CH2)-
wherein
r is 0 or 1 ,
q and s independently are 0, 1 , 2 or 3, R , R , R14 and R15 independently are hydrogen or d-e-alkyl,
Dis
Figure imgf000026_0001
wherein
Wis-O-,-S-,-S(O)2-or-NR
W'is=CR'u-or=N-,
R16, R", R18 and Rιa independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -SfOJNR^R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 or-C(O)OR21, • d-e-alkyl, C2-e-alkenyl or C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22,
-OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
• C3-8-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, C3_8-cycloalkyl-d-6-alkyl, C3_8-cyclo- alkyl-C^-alkoxy, C3_β-cycloalkyloxy, C3-8-cycloalkyl-d-6-alkylthio, C3-β-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3^-cycloalkyl-C2-e-alkynyl, d-β-cycloalkenyl-d-e-alkyl, C«- cycloalkenyl-C2-e-alkenyl, C4-8-cycloalkenyl-C2-8-alkynyl, heterocyclyl-d-e-alkyl, heterocy- clyl-C2-e-alkenyl or heterocyclyl-C2-β-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from
-CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR^R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
Cι.e-alkyl, C2-β-alkenyl and C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22,
-OC(O)NR 1R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
• aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-d-e-alkoxy, aryl-d-e-alkyl, aryl-C2-6-alkenyl, aryl-C2-e-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-
C2-β-alkynyl,
of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -SfOJNR^R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -CfOJNR^R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21 , -C(O)R21 and -C(O)OR21 ,
d-e-alkyl, C2-6-alkenyl and C2-e-alkynyl,
which may optionally be substituted with one or more substituents se- lected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2,
-SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
wherein R21 and R22 independently are hydrogen, -CF3, d-e-alkyl, tri-d-β-alkylsilyl, C3-β-cyclo- alkyl, C3_8-cycloalkyl-d-e-alkyl, aryl, aryl-d-e-alkyl or heteroaryl,
or R21 and R22 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR16'R17')a-O-(CR18'R19')c-O-,
wherein
a is O, 1 or 2,
c is 1 or 2,
R1β', R17', R18' and R19' independently are hydrogen, d-e-alkyl or halogen,
R20 and R20' independently are hydrogen, Cι-6-alkyl, C3-8-cycloalkyl or Cs-β-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 R23 and R24 may be attached to the same or different ring carbon atoms and wherein a group R31 may be attached to a ring nitrogen atom when present, or
Figure imgf000029_0001
Figure imgf000029_0002
wherein
m 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, R23and R24 independently are
• hydrogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -S(O)2R38, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37,
-OCH2C(O)NR36R37, -C(O)R36 or -C^JOR36,
• d-e-alkyl, C2-6-alkenyl or C2_6-alkynyl,
which may optionally be substituted with one or more substituents selected from
-CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR∞R37, -SR36, -SfOJR36, -S^JzR36, -C OJNR∞R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -CtOJR36 and -C(O)OR36,
• C3-8-cycloalkyl, C3.8-cycloalkylidene, d-β-cycloalkenyl, heterocyclyl, C3.8-cycloalkyl-
Ci-β-alkyl, C3_8-cycloalkyl-C2-6-alkenyl, C3^-cycloalkyl-C2-6-alkynyl, C^-cycloalkenyl- d-e-alkyl, C4-8-cycloalkenyl-C2-e-alkenyl, d-s-cycloalkenyl-C∑-e-alkynyl, heterocyclyl- d-e-alkyl, heterocyclyl-C2-e-alkenyl or heterocyclyl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from
-CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR∞R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C OJR36 and -C(O)OR36,
d-e-alkyl, C2-6-alkenyl and C2-6-alkynyl,
which may optionally be substituted with one or more substituents se- lected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2,
-SCF3, -OR36, -NR36R37, -SR38, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36, • aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl-d-e-alkyl, aryl-C2-e-alkenyl, aryl-C2-β-alkynyl, heteroaryl, heteroaryl-Cι-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2_β-alkynyl,
of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR36, -NR∞R37, -SR36, -NR36S(O)2R37, -SfO^NR R37, -S(O)NR36R37, -S(O)R36, -S(O)2R36, -OS(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -CHzC^NR∞R37, -CH2C(O)NR36R37, -CHzOR36, -CH2NR36R37,
-OC(O)R36, -C(O)R38 and -C^JOR36,
Ci-e-alkyl, C2_β-alkenyl and C2-β-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -SfOJR36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36,
wherein R and R independently are hydrogen, d-e-alkyl or aryl,
of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR38, -NR∞R39 and d-e-alkyl,
wherein R and R independently are hydrogen or d-e-alkyl,
or R36 and R37 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,
or R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)rCR40R41-(CH2)rO-, -(CH2)rCR40R41-(CH2)r or -S-(CH2)rCR40R41-(CH2)rS-,
wherein
t and I independently are 0, 1 , 2, 3, 4 or 5,
R40 and R41 independently are hydrogen or Ci-e-alkyl,
R25 to R30 independently are hydrogen, halogen, -CN, -CF3, -NO2, -OR42, -NR^R43, Ci-e-alkyl, Qj-e-cycloalkyl or d-e-cycloalkenyl,
wherein R42 and R43 independently are hydrogen or Ci-e-alkyl, or
R42 and R43 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,
R31, R32 and R33 independently are hydrogen or Ci-e-alkyl,
R34 and R35 independently are
• hydrogen, Ci-e-alkyl, d-e-alkoxy, Ci-e-alkanoyl, -C(O)NR44R45 or -S(O)2R45,
• aryl, aroyl, aryl-Ci-e-alkoxy, aryl-d-e-alkanoyl or aryl-Ci-e-alkyl,
of which the aryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OR44, -NR^R45 and d-β-alkyl,
wherein R44 and R45 independently are hydrogen or d-e-alkyl, or
R34 and R35 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 R34 and R35 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,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
In an embodiment the invention provides compounds, wherein V is -C(O)OH or 5-tetrazolyl.
In an embodiment the invention provides compounds, wherein A is
Figure imgf000033_0001
or
-CH.
or
-N- H
or N CH, —
In an embodiment the invention provides compounds, wherein Y is -C(O)-,
or Y is a valence bond.
In an embodiment the invention provides compounds.wherein Z is
Figure imgf000033_0002
In an embodiment the invention provides compounds, wherein R1 is hydrogen or methyl. In an embodiment the invention provides compounds, wherein X is -C(O)NH-, -C(O)NHCH2-, -C(O)NHCH(CH3)-, -C(O)NHCH2CH2-, -C(O)CH2-, -CH2-, -C(O)- or -NHC(O)-.
In an embodiment the invention provides compounds, wherein D is
Figure imgf000034_0001
wherein one or two of R16 R17 and R18 are hydrogen and the remaining is independently se- lected from -OCF3, -SCF3 -CF3, -S(O)2CH3, phenyl, halogen, d-e-alkyl, nitro, -S-Ci-e-alkyl or -S(O)2NR21R22, wherein R21 is Ci-e-alkyl and R22 is phenyl. In an embodiment the invention provides compounds, wherein E is
Figure imgf000034_0002
wherein R23 is hydrogen and R24 is Ci-e-alkyl such as terf-butyl or Qj-β-cycloalkyl such as cyclohexyl, wherein R23 and R24 are both d-e-alkyl or wherein R23 and R24 together form the radical -(CH2)5-. In an embodiment the invention provides compounds, wherein E is
Figure imgf000034_0003
wherein R25 is -OCF3, -CF3, Ci-e-alkyl such as terf-butyl, phenyl, piperidyl, Qj-β-cycloalkyl such as cyclohexyl or d-β-cycloalkenyl such as cyclohexenyl. In an embodiment the invention provides compounds, wherein the compound is any of the following
3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- propionic acid, 4-[3-(3,5-Bistrifluoromethylphenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]-N-(2H-tetrazol-5- yl)benzamide,
(S)-4-[3-[1-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5- yl)benzamide, 4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]-Λ/-(2H-tetrazol-5- yl)benzamide
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-tert-butylphenyl)ureidomethyl]-Λ -(2H-tetrazol-5- yl)benzamide,
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-Λ/-(2/--tetrazol-5- yl)benzamide,
4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]-Λ/-(2 -/-tetrazol-5-yl)- benzamide.
In an embodiment 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.
In an embodiment the invention provides a glucagon antagonist represented by the general formula (I):
Figure imgf000035_0001
wherein
R1, R2, R3, R4 and R5 independently are hydrogen or Ci-e-alkyl,
A is -C(O)-, -CH(OR6)- or -CHF-,
wherein R6 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 R7 and R8 selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and d-e-alkyl,
wherein R9 and R10 independently are hydrogen or Ci-e-alkyl,
X is
-(CH2)-(CR12R1V(CH2); -(CR12R13)-(CH2)S-
"(CH2)q-C
Figure imgf000036_0001
Figure imgf000036_0002
(CH2), M— D— M— -(CH2)-N-U-O-(CR12R13)r-(CH2)s-
2'q N- -(CR12R13)r- (CH2)—
11 -14 R11
■N-L(CR12R13)r-(CH2)- or -(CH2)q— (CR12R13)— 0-(CH2)- R11
wherein
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 C3-β-cycloalkyl, D is
Figure imgf000037_0001
Figure imgf000037_0002
wherein
R10, R10, R1' and R10 independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR^OJzR22, -SfO^NR^R22,
-S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR 1R22, -OCH^OJNR^R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
'Ci-e-alkyl, C2_6-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and d-e-alkyl,
•
Figure imgf000037_0003
C4.8-cycloalkenyl, heterocyclyl, C3_8-cycloalkyl-Cι.6-alkyl, C3_β-cyclo- alkyl-C^-alkoxy, C^-cycloalkyloxy, C^-cycloalkyl-Ci-e-alkylthio, C3-8-cycloalkylthio,
C3-8-cycloalkyl-C2-β-alkenyl, C3^-cycloalkyl-C2-e-alkynyl, d-e-cycloalkenyl-Ci-e-alkyl, d-e-cycloalkenyl-d-e-alkenyl, C^-cycloalkenyl-C^-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-e-alkenyl, heterocyclyl-C2-β-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C^-alkynyl, heteroaryl, heteroaryl-Ci-β-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2^-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR21, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C^-alkyl,
wherein R21 and R22 independently are hydrogen, Ci-e-alkyl, aryl-Ci-e-alkyl or aryl,
or R21 and R22 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,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R23, R24, R25 and R26 independently are hydrogen, Ci-e-alkyl or fluorine,
R19 and R20 independently are hydrogen, Ci-β-alkyl, C3-8-cycloalkyl or C3-e-cyclo- alkyl-Ci-e-alkyl, E is
Figure imgf000039_0001
Figure imgf000039_0002
wherein
R Ϊ27 a„n„,dJ D R28 independently are
hydrogen, halogen, -CN, -CF3, -OR32, -NR^R33, d^-alkyl, Qj-β-cycloalkyl, C^-cycloalkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -NO2, -OR32, -NR32R33 and Ci-e-alkyl,
wherein R32 and R33 independently are hydrogen or d-e-alkyl, or
R32 and R33 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, R29, R30 and R31 independently are
hydrogen, halogen, -CHF2l -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR34, -NR^R35, -SR34, -S(O)R34, -SfOJzR34, -C(O)NR34R35, -O OJNR^R35, -NR^CfOJR35, -OCH2C(O)NR34R35, -CfOJR34 or -CfOJOR34,
■ Ci-e-alkyl, C2-e-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
■ C^-cycloalkyl, d-β-cycloalkenyl, heterocyclyl, CM-cycloalkyl-Ci-e-alkyl, C3-8-cyclo- alkyl-C2-e-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, d-β-cycloalkenyl-d-e-alkyl, C«-cyclo- alkenyl-C2_e-alkenyl, C^-cycloalkenyl-C^-alkynyl, heterocyclyl-Ci-e-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2_6-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl-
Cι.6-alkyl, aryl-C2^-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-Ci-β-alkyl, hetero- aryl-C2-e-alkenyl or heteroaryl-C2^-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and
Ci-e-alkyl,
wherein R34 and R35 independently are hydrogen, Ci-e-alkyl or aryl,
or R34 and R35 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,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)rCR36R37-(CH2)rO-, -(CH2)t-CR36R37-(CH2)r or -S-(CH2)rCR36R37-(CH2)ι-S-, wherein
t and I independently are 0, 1, 2, 3, 4 or 5,
R38 and R37 independently are hydrogen or Ci-e-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
An embodiment of the invention provides compounds, wherein R\ R2, R3, R4 and R5 are hydrogen.
An embodiment of the invention provides compounds, wherein A is -CHF-.
An embodiment of the invention provides compounds, wherein A is -CH(OR6)-, wherein R6 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
Figure imgf000041_0001
wherein R7 and R8 are as defined above.
An embodiment of the invention provides compounds, wherein Z is
Figure imgf000041_0002
An embodiment of the invention provides compounds, wherein X is -C(O)NH-, -C(O)NHCH2-, -C(O)NHCH(CH3)-, -C(O)CH2- 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
Figure imgf000042_0001
wherein R15, R16 and R17 independently are hydrogen, halogen, -CN, -CF3, -OCF3 or Ci-β- alkoxy.
An embodiment of the invention provides compounds, wherein E is
Figure imgf000042_0002
wherein R29 and R31 are both hydrogen, and R30 is cyclohexenyl,
■which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2l -OR34, -NR^R35 and d-e-alkyl,
■wherein R34 and R35 independently are hydrogen, Ci-e-alkyl or aryl,
■ or R34 and R35 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.
■
An embodiment of the invention provides compounds, wherein R29, R30 and R31 independent- ly are hydrogen, Ci-e-alkyl, phenyl, C3-8-cycloalkyl or C4_β-cycloalkenyl.
An embodiment of the invention provides compounds, wherein R29 and R31 are both hydrogen and R30 is Ci-e-alkyl, C3_8-cycloalkyl or C4_e-cycloalkenyl In an embodiment 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
(R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Cyano-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Cyano-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid (R)-3-{4-[3-(3-Bromo-5-trifluoromethylphenyl)-1 -(4-cyclohex-1 -enylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(S)-rrans-3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (R)-Tra/7S-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-ter--butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
TratJS-(R)-3-{4-[3-(3-methyl-5-trifluoromethylphenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(RS)-3-{4-[1-(4-ferf-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(RS)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-
2-hydroxypropionic acid
(S)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[3-(3-Chlorophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-phenylureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(R)-3-{4-[3-Benzyl-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(RS)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl )3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- fluoropropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohexen-1-ylphenyl)-3-(3-methanesulfonyl-4-trifluoromethoxyphenyl)- ureidomethyl]benzoylamino}-2-hydroxypropionic acid Tra/7S-(R)-3-{4-[-3-(3,5-bis(methyl)phenyl)-1 -(4-te_f-butylcyclohexyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-(3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfanylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1 ,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid 3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2(R)- methoxypropionic acid:
3-(4-{3-(3,5-Dichlorophenyl)-1-[4-(2-methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoyl- amino)-2-(R)-hydroxypropionic acid and (R,S)-3-(4-{3-(3,5-dichlorophenyl)-1-[4-(6- methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoylamino)-2-(R)-hydroxypropionic acid 3-{4-[1 -[4-(4-tett-Butylcyclohex-1 -enyl)phenyl]-3-(3,5-dichlorophenyl)ureidomethyl]benzoyl- amino}-2-(R)-hydroxypropionic acid
(R,S)-3-(4-(3-(3,5-dichlorophenyl)-1 -(4-(3-methylcyclohex-1 - enyl)phenyl)ureidomethyl)benzoylamino)-2-hydroxypropionic acid
3-{4-[3-[1(S)-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)- hydroxypropionic acid 3-{4-[3-Biphenyl-2-ylmethyl-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)- hydroxypropionic acid
(R)-3-{4-[3-(4-Cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid (R)-3-{4-[3-(3-tert-Butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-hydroxymethyl-4-trifluoromethoxyphenyl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-te/ -Butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-fert-Butylcyclohexyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1 -(4-Cyclohexylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1 ,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-fert-Butylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-tert-Butylcyclohexyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-fetf-Butylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-fluoro-3-nitrophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-isopropylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[3-(4-Acetylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
3-{4-[3-[1(RS)-(4-Bromophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-
2(R)-hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-[4-({(4-tert-Butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid
(R)-3-[4-({(4-fett-Butylcyclohexyl)-[2-(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid
(R)-3-[4-({(2,2-Diphenylethyl)-[2-(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid
(R)-3-(4-{[(5-Chlorobenzo[d]thiophene-3-carbonyl)-(2,2-diphenylethyl)amino]methyl}benzoyl- amino)-2-hydroxypropionic acid (R)-3-[4-({(2,2-Diphenylethyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid
(R)-3-(4-{[(4-tetf-Butylcyclohexyl)-(5-chlorobenzo[->]thiophene-3-carbonyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-(4-{[(2,2-Diphenylethyl)-(5-trifluoromethoxy-1H-indole-2-carbonyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid (R)-3-[4-({(4-Cyclohexylphenyl)-[(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid
(R)-3-(4-{([(3,5-Bis(trifluoromethyl)phenyl)acetyl]-(4-cyclohexylphenyl)amino)methyl}benzoyl- amino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3-trifluoromethylphenyl)acetyl]amino}methyl)benzoylamino]- 2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3,4-dichlorophenyl)acetyl]amino}methyl)benzoylamino]-2- hydroxypropionic acid
(R)-3-(4-{[[(3-Bromophenyl)acetyl]-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2- hydroxypropionic acid (R)-3-(4-{[(Biphenyl-4-ylacetyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxy- propionic acid
(R)-3-(4-{[(4-Cyclohexylphenyl)-(2-naphthylacetyl)amino]methyl}benzoylamino)-2-hydroxy- propionic acid (R)-3-(4-{[(3-(3,5-Bis(trifluoromethyl)phenyl)propionyl)-(4-cyclohexylphenyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[3-(3-nitrophenyl)propionyl]amino}methyl)benzoylamino]-2- hydroxypropionic acid
(2R)-N-[4-({4-cyclohexyl[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-y-?- alanine (2R)-N-[4-({[1 , 1 '-biphenyl]-4-yl[(3,5-dichloroanilino)carbonyl]amino}methyl)benzoyl]-2- hydroxy-yff-alanineln an embodiment the invention provides the compound (R)-[3-{4-[1-(4- Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid as a tert-butylamine salt.
In an embodiment 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.
In an embodiment 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. In an embodiment 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.
In an embodiment 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.
In an embodiment 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. In an embodiment 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.
In an embodiment 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. In an embodiment the invention provides a glucagon antagonist represented by the general formula (I):
Figure imgf000048_0001
wherein
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,
which may optionally be substituted with one or two groups R7 and R8 selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and Ci-e-alkyl,
wherein R9 and R10 independently are hydrogen or Ci-e-alkyl,
X is
-(CH2)-(CR12R13)r-(CH2)s- -(CR12R13)-(CH2)S-
,
Figure imgf000049_0001
(CH2)_(CRi2Ri3)r_0_(CH2)_
Figure imgf000049_0002
wherein
r is O or 1 ,
q and s independently are 0, 1 , 2 or 3,
R11, R12, R13 and R14 independently are hydrogen or Ci-e-alkyl,
D is
Figure imgf000050_0001
Figure imgf000050_0002
wherein
Rιa, R10, R" and R1B independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22,
-S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC ONR^R22, -NR^C^R22, -CH^OJNR^R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
• Ci-e-alkyl, C2-e-alkenyl or C2.e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and Ci-e-alkyl,
• C3^-cycloalkyl, C4_8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-Cι_e-alkyl, C3-e-cyclo- alkyl-Ci-e-alkoxy, C^-cycloalkyloxy, C3.8-cycloalkyl-d-6-alkylthio, C3-e-cycloalkylthio, C3.8-cycloalkyl-C2-e-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, d-β-cycloalkenyl-d-e-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, Cwrcycloalkenyl-C2-e-alkynyl, heterocyclyl-d-e-alkyl, heterocyclyl-C2-e-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-d_e-alkoxy, aryl-Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and d-e-alkyl,
wherein R21 and R22 independently are hydrogen, Ci-e-alkyl or aryl,
or R21 and R22 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,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R , R , RΛ and R^° independently are hydrogen, d^-alkyl or fluorine,
R and R independently are hydrogen, Ci-e-alkyl, Qj-e-cycloalkyl or C3_e-cyclo- alkyl-Ci-e-alkyl, E is
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
wherein
R27and R28 independently are
hydrogen, halogen, -CN, -CF3) -OCF3, -OR32, -NR32R33, C^-alkyl, CM-cycloalkyl, C4_e-cyclo- alkenyl or aryl,
wherein the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR32, -NR32R33 and Ci-e-alkyl,
wherein
R l32 a __nd J R D33 independently are hydrogen or Cι_β-alkyl, or
R32 and R33 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,
R29, R30 and R31 independently are
■ hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH CF3, -OCF2CHF2,
-SCF3, -OR34, -NR^R35, -SR34, -S(O)R34, -S(O)2R34, -dOJNR^R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C^JR34 or -C(O)OR34, ■ d-e-alkyl, C2_e-alkenyl or C2^-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
■ Cs-a-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-Cι^-alkyl, C3_8-cyclo- alkyl-C2_β-alkenyl, d-e-cycloalkyl-d-e-alkynyl, d-e-cycloalkenyl-d-e-alkyl, C-^-cyclo- alkenyl-C2_e-alkenyl, d-β-cycloalkenyl-C^-alkynyl, heterocyclyl-Ci-e-alkyl, hetero- cyclyl-C2-6-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-β-alkoxy, aryl-
Ci-e-alkyl, aryl-C2-e-aIkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-Cι_6-alkyl, hetero- aryl-C2^-alkenyl or heteroaryl-C2_6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and
Ci-e-alkyl,
wherein R34 and R35 independently are hydrogen, d-e-alkyl or aryl,
or R34 and R35 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,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)rO-, -(CH2)»-CR36R37-(CH2)r or -S-(CH2)t-CR36R37-(CH2)rS-,
wherein
t and I independently are 0, 1 , 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or Ci-e-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
In an embodiment the invention provides a compound, wherein R2 is hydrogen.
In an embodiment the invention provides a compound, wherein Z is
Figure imgf000054_0001
wherein R7 and R8 are as defined as above.
In an embodiment the invention provides a compound, wherein Z is
Figure imgf000054_0002
In an embodiment the invention provides a compound, wherein X is
-(CH2 2v's "(CH2)- -N— (CH2 2)'(s
Figure imgf000055_0001
-(CH ■ 22)/q— N- (CH2)r -(CH2)q— N-(CH2)— O—
H
-(CH2 2's
Figure imgf000055_0002
,12
CR Η— O— (CH2)— -o-(CH2 2y's or
-N-(CR12R13)— π
wherein q is 0 or 1 , r is 0 or 1 , s is 0, 1 or 2, and R12 and R13 independently are hydrogen or Ci-e-alkyl.
In an embodiment the invention provides a glucagon antagonist as represented by the general formula (I):
Figure imgf000055_0003
wherein
A is
Figure imgf000056_0001
m is 0 or 1 ,
n is 0,1, 2 or 3,
with the proviso that m and n must not both be 0,
R1 is hydrogen, fluoro or -(CH2)0-OR2,
o is 0 or 1 ,
R2 is hydrogen, d-e-alkyl, Ci-e-alkanoyl, aryl or aryl-Ci-e-alkyl,
Xis-N=or-CH=,
Bis
Figure imgf000056_0002
V and W independently are -CH= or -N=,
Yis-O-,-S-or-NH-,
R3, R4 and R5 independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR6, -NR6R7, -SR6, -NR6S(O)2R7, -S(O)2NR8R7, -S(O)NR6R7, -S(O)R6, -S(O)2R6, -C(O)NR6R7, -OC(O)NR6R7, -NR6C(O)R7, -CH2C(O)NR6R7, -OCH2C(O)NR6R7, -OCH2C(O)OR6, -OC(O)R6, -C(O)R6 or -C(O)OR6,
• -e-alkyl, C2-e-alkenyl or C2-β-alkynyl,
which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR6 and -NR6R7,
• Qj-β-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, Cs-e-cycloalkyl-d-e-alkyl, C3_8-cyclo- alkyl-Ci-e-alkoxy, C3_β-cycloalkyloxy, Cs-e-cycloalkyl-d-e-alkylthio, C3_e-cycloalkylthio,
C3^-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-e-alkynyl, C4-β-cycloalkenyl-Cι-e-alkyl,
Figure imgf000057_0001
C -8-cycloalkenyl-C2-β-alkynyl, heterocyclyl-Ci-β-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from fluoro, -C(O)OR6, -CN, -CF3, -OCF3, -OR7, -NR6R7 and Ci-e-alkyl,
• aryl, arylthio, aryl-Cι_6-alkylthio, aryloxy, aryloxycarbonyl, aroyl, aryl-d_β-alkoxy, aryl- Ci.6-alkyl, aryl-C2-β-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, het- eroaryl-C2-6-alkenyl or heteroaryl-C2-e-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR6, -CN, -CF3, -OCF3, -NO2, -OR7, -NR6R7 and Ci-e-alkyl,
R6 and R7 independently are hydrogen or Ci-e-alkyl,
or R6 and R7 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,
or two of the groups R3 to R5 when placed in adjacent positions together may form a bridge -(CR8R9)s-O-(CR10R11)t-O-, s is 0, 1 or 2,
t is 1 or 2,
R , R , R and R independently are hydrogen, Ci-e-alkyl or fluoro,
Dis-(CH2)P-,
Figure imgf000058_0001
or-(CH2)p-O-,
p is 0, 1 , 2, 3 or 4,
Eis
Figure imgf000058_0002
X1, Z1 and W1 independently are -CH= or-N=,
Y s-O-.-S-or-NH-,
Q1is-CH2-or-NH-,
q is 2, 3, 4, 5 or 6,
ris 1,2, 3, 4 or 5,
R12, R13 and R14 independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR17, -NR17R18, -SR17, -NR17S(O)2R18, -S(O)2NR17R18, -S(O)NR17R18, -S(O)R17, -S(O)2R17, -C(O)NR17R18, -OC(O)NR17R18, -NR17C(O)R18, -CH2C(O)NR17R18, -OCH2C(O)NR17R18, -OC(O)R17, -C(O)R17 or-C(O)OR17,
• Ci-e-alkyl, C2-e-alkenyl or C.6-alkynyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR17 and -NR 7R18,
• C3-8-cycloalkyl, C«-cycloalkenyl, heterocyclyl, C3-e-cycloalkyl-Ci.6-alkyl, C3-8-cyclo- alkyl-Ci-e-alkoxy, Qj-e-cycloalkyloxy, C3-β-cycloalkyl-Cι_e-alkylthio, C^-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3^-cycloalkyl-C2-e-alkynyl, d-e-cycloalkenyl-Ci-e-alkyl, C4-8-cycloalkenyl-C2-e-alkenyl, C -8-cycloalkenyl-C2-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-e-alkenyl, heterocyclyl-C2-6-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from fluoro, -C(O)OR17, -CN, -CF3, -OCF3, -OR17 and -NR17R18,
• aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Cι.6-alkoxy,
Figure imgf000059_0001
aryl-C2-e-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2.6-alkenyl or heteroaryl-
C2-6-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR17, -CN, -CF3, -OCF3, -NO2, -OR17, -NR17R18 and d-e-alkyl,
R17 and R18 independently are hydrogen or Ci-e-alkyl,
or R17 and R18 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,
or two of the groups R12 to R14 when placed in adjacent positions together may form a bridge -(CR19R20)x-O-(CR21R22)y-O-,
x is 0, 1 or 2,
y is 1 or 2, R19, R20, R21 and R22 independently are hydrogen, d-e-alkyl or fluoro,
R15 and R16 independently are hydrogen, halogen, -CN, -CF3, -OR23, -NR23R24, d-β-alkyl, C^-cycloalkyl, d-8-cycloalkenyl, aryl or aryl-Ci-e-alkyl,
wherein the cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -NO2, -OR23, -NR23R24 and Ci-e-alkyl,
R23 and R24 independently are hydrogen or Cι_β-alkyl, or
R23 and R24 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,
or E is
d-e-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, - CN, -CF3, -OCF3, -NO2, -OR25,-SR25, -NR25R26 and Ci-e-alkyl,
R25 and R26 independently are hydrogen or d-6-alkyl, or
R25 and R26 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 -(CR27R28)V-(O)W-(CR29R30)2-,
v and z independently are 0, 1 or 2,
w is O or 1 , R27, R28, R29 and R30 independently are hydrogen or Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
In an embodiment the invention provides a compound, wherein A is o HO (CH 2 ) n ^ wherein n is as defined above.
In an embodiment the invention provides a compound.wherein A is
Figure imgf000061_0001
In an embodiment the invention provides a compound, wherein A is
Figure imgf000061_0002
In an embodiment the invention provides a compound, wherein B is
Figure imgf000061_0003
wherein R3 to R5 are as defined above.
In an embodiment the invention provides a glucagon antagonist as represented by the gen- eral formula (I):
Figure imgf000062_0001
wherein
A is
Figure imgf000062_0002
m is 0 or 1 ,
n is 0, 1 , 2 or 3,
with the proviso that m and n must not both be 0,
R4 is hydrogen, halogen or -(CH2)0-OR5,
o is 0 or 1 ,
R5 is hydrogen, Ci-e-alkyl, Cι-6-alkanoyl, aryl or aryl-d-e-alkyl,
R1 and R2 independently are hydrogen, halogen or Ci-e-alkyl, or R1 and R2 are combined to form a double bond,
R3 is hydrogen, Ci-e-alkyl or halogen, or R3 and R2 are combined to form a double bond to oxygen,
X is arylene or heteroarylene, which may optionally be substituted with one or two groups R6 and R7 selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR8, -NR8R9 and Ci-e-alkyl, R8 and R9 independently are hydrogen or Ci-e-alkyl,
Y is -C(O)-, -O-, -NR10-, -S-, -S(O)-, -S(O)2- or -CR11R12-,
R10 is hydrogen or Cι_6-alkyl,
R11 and R12 independently are hydrogen, Ci-e-alkyl or hydroxy, or R11 is combined with R1 to form a double bond, and R12 is hydrogen, Cι_e-alkyl or hydroxy,
Z is -C(O)-(CR13R14)p-, -O-(CR13R14)p-, -S-(CR13R 4)P-, -S(O)-(CR13R14)p-, -S(O)2-(CR13R14)p-, -NR15-(CR13R14)p- or -(CR13R14)P-,
p is 0, 1 or 2,
R13 and R14 independently are selected from hydrogen, -CF3, -OCF3, -OCHF2 and Ci-e-alkyl,
R15 is hydrogen or Ci-e-alkyl,
D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R 6, R17, R 8, R19, R20 and R21, wherein
R16, R17, R18 and R19 independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR^R23, -SR22, -NR22S(O)2R23,
-S(O)2NR22R23, -S(O)NR22R23, -SfOJR22, -S(0)2R22, -C^JNR^R23, -OC^JNR^R23, -NR22C(O)R23, -CH2C(O)NR22R23, -OCH2C(O)NR22R23, -CH2OR22, -CH2NR22R23, -OC(O)R22, -C(O)R22or -C(O)OR22,
• Ci-e-alkyl, C2_β-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCHF2, -OCF3, -NO2, -OR22, -NR22R23 and C^-alkyl, • Cs-e-cycloalkyl, C^-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-d-e-alkyl, C^-cyclo- alkyl-Cι.6-alkoxy, Cs-e-cycloalkyloxy, C3.8-cycloalkyl-Cι-e-alkylthio, C3-β-cycloalkylthio, C3-8-cycloalkyl-C2-e-alkenyl, C3-a-cycloalkyl-C2-e-alkynyl, d-e-cycloalkenyl-Ci-e-alkyl, C4.8-cycloalkenyl-C2-6-alkenyl, d-e-cycloalkenyl-d-β-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2_6-alkenyl, heterocyclyl-C2_e-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-d^-alkyl, aryl-C2_e-alkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2-6-alkynyl,
of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -C(O)OR22, -CN, -CF3, -OCF3,
-OCHF2, -NO2, -OR22, -NR R23 and Ci-e-alkyl,
R22 and R23 independently are hydrogen, d-e-alkyl, aryl-Ci-e-alkyl or aryl, or R22 and R23 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR24R25)a-O-(CR26R27)c-O-,
a is 0, 1 or 2,
c is 1 or 2,
R24, R25, R26 and R27 independently are hydrogen, Ci-e-alkyl or fluoro,
R20 and R21 independently are hydrogen, Ci-e-alkyl, d-β-cycloalkyl or C^-cyclo- alkyl-d-e-alkyl,
E is
d-β-cycloalkyl or d-e-cycloalkenyl, which may optionally be substituted with one or two substituents R28and R29, which are independently selected from • hydrogen, halogen, -CN, -CF3, -OCF3, -OCHF2, -OR33, -NR∞R34, Ci-e-alkyl, CM- cycloalkyl, d-e-cycloalkenyl, heteroaryl and aryl,
wherein the heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR33, -
NR∞R34 and d-e-alkyl,
R33 and R34 independently are hydrogen or Ci-e-alkyl,
or R33 and R34 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-C2-e-alkenyl or aryl-C2-6-alkynyl, of which the aryl and heteroaryl moieties may optionally be substituted with one or more substitutents R28, R29, R30, R31 and R32,
wherein R28 and R29 are as defined above, and R30, R31 and R32 are independently selected from
• hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR35, -NR35R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, -NR35C(O)R36, -OCH2C(O)NR35R36, -C(O)R35 and -C(O)OR35,
•Ci-e-alkyl, C2-e-alkenyl and C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR35, -NR35R36 and d-e-alkyl,
• C3-8-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, Cs^-cycloalkyl-d-e-alkyl, C3_e-cyclo- alkyl-C2-6-alkenyl, C3^-cycloalkyl-C2-e-alkynyl, d-β-cycloalkenyl-d-β-alkyl, C4-β-cyclo- alkenyl-C2-e-alkenyl, C4-8-cycloalkenyl-C2-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocy- clyl-C2_6-alkenyl, heterocyclyl-C2_e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- Cι-e-alkyl, aryl-C2^-alkenyl, aryl-C2-e-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, hetero- aryl-C2.6-alkenyl and heteroaryl-C2-6-alkynyl, of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OCHF2, - NO2, -OR35, -NR35R36 and Ci-e-alkyl,
wherein R35 and R36 independently are hydrogen, Cι_6-alkyl or aryl,
or R35 and R36 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,
or two of the substituents R30, R31 and R32 when attached to the same ring carbon atom or adjacent ring carbon atoms together may form a bridge -©-(CH^t-CR^R38- (CH2),-O-, -(CH2),-CR37R38-(CH2)ι- or -S-(CH2)t-CR37R38-(CH2)rS-,
t and I independently are 0, 1 , 2, 3, 4 or 5,
R37 and R38 independently are hydrogen or Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
In an embodiment the invention provides compounds, wherein A is
Figure imgf000066_0001
wherein m, n and R are as defined above.
In an embodiment the invention provides compounds, wherein A is
Figure imgf000066_0002
In an embodiment the invention provides compounds, wherein A is
Figure imgf000067_0001
In an embodiment the invention provides compounds, wherein A is
Figure imgf000067_0002
In an embodiment the invention provides compounds, wherein X is monocyclic arylene or heteroarylene, which may optionally be substituted as defined above.
In an embodiment the invention provides compounds, wherein X is
Figure imgf000067_0003
wherein R6 and R7 are as defined above.
In an embodiment the invention provides compounds, wherein X is
Figure imgf000067_0004
wherein R6 and R7 are as defined above.
In an embodiment the invention provides compounds, wherein E is
Figure imgf000067_0005
wherein R30, R31 and R32 are as defined above.
In an embodiment the invention provides compounds, wherein R30, R31 and R32 independently are • hydrogen,
• halogen, -OCF3, -OCHF2or -SCF3,
• Ci-e-alkyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35 and -NR35R36,
• cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35, -NR^R36 and Ci-e-alkyl,
• phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 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, -CF3, -OCF3, -NO2, -OR35, _NR35R36 and C^.glky^
R35 and R38 independently are hydrogen or d-e-alkyl. In an embodiment the invention provides compounds, wherein E is
Figure imgf000068_0001
Figure imgf000068_0002
In an embodiment the invention provides compounds, wherein R1 and R2 are both hydrogen. In an embodiment the invention provides compounds, wherein R1 and R2 are combined to form a double bond.
In an embodiment the invention provides compounds, wherein R3 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
Figure imgf000069_0001
wherein R16, R17 and R18 are as defined above. In an embodiment the invention provides compounds, wherein R 6, R17 and R18 independently are
• hydrogen, halogen, -CF3, -OCF3, -SCF3, Ci-e-alkyl, Ci-6-alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy,
• or two of the groups R16 to R18 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF2-O- or -O-CH2-O-.
In an embodiment the invention provides compounds such as (Z)-3-{4-[4-Biphenyl-4-yl-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoylamino}propionic acid
(Z)-3-{4-[2-Biphenyl-4-yl-4-(4-chlorophenyl)-4-oxobut-2-enoyl]benzoylamino}propionic acid
(Z)-3-{4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)but-2-enoyl]benzoylamino}- propionic acid 3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo-butyryl]benzoylamino}- propionic acid
((R)3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo- butyryl]benzoylamino}-propionic acid
(S)3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo- butyryl]benzoylamino}-propionic acid
In an embodiment the invention provides glucagon antagonists as represented by the general formula (I):
Figure imgf000070_0001
wherein
A is
Figure imgf000070_0002
m is 0 or 1 ,
n is 0, 1, 2 or 3,
with the proviso that m and n must not both be 0,
R1 is hydrogen, fluoro or -(CH2)0-OR2
o is 0 or 1 ,
R2 is hydrogen, Ci-e-alkyl, Cι_6-alkanoyl, aryl or aryl-Ci-e-alkyl,
X is N, CH or C with a double bond to one substituent,
Z is -CR3R4-, -(C=O)-(NR5)-(Cι.e-alkyl)κ-, -(C=O)-O-(C^-alkyl)K-, -(C=O)-(C^-alkyl)K-, -(Cι-e-alkyl)κ(C=O)-O-, -(C=O)-O-(C2^-alkenyl)κ-,
Figure imgf000070_0003
-(Cι-e-alkenyl)κ(C=O)-O-
wherein k is 0 or 1 ,
R3, R4 and R5are independently selected from hydrogen, Cι_6-alkyl or aryl, Y is -(Cι-β-alkyl)s-(C=O)-(Cι.e-alkyl)t-, -(C1-6-alkenyl)s-(C=O)-(Cι-6-alkyl),-, -C^-alkyl-, -C2-β- alkenyl-, or -CR6R7-
wherein s and t independently are 0 or 1 ;
wherein R6, R7 and R8 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 , R17, R18, R19, R20 and R21, wherein
R16, R17, R18 and R19 independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3. -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR^R23, -SR22, -NR22S(O)2R23, -S(O)2NR22R23, -S(O)NR22R23, -S(O)R22, -S(O)2R22, -C(O)NR22R23, -OC(O)NR22R23,
-NR22C(O)R23, -CH2C(O)NR22R23, -OCHzC OJNR^R23, -CH2OR22, -CH2NR22R23, -OdOJR22, -C(O)R22or -C(O)OR22,
• Ci-e-alkyl, C2-e-alkenyl or C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR22, -NR22R23 and Ci-e-alkyl,
• C3.8-cycloalkyl, d-β-cycloalkenyl, heterocyclyl, C3.8-cycloalkyl-Cι-e-alkyl, C^-cycIo- alkyl-Cι_β-alkoxy, C3-e-cycloalkyloxy, C3.8-cycloalkyl-Cι-e-alkylthio, C3_8-cycloalkylthio,
C3.8-cycloalkyl-C2^-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C-j-e-cycloalkenyl-d-e-alkyl,
Figure imgf000071_0001
heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-e-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2.e-alkenyl, aryl-C2.e-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR22, -CN, -CF3> -OCF3, -NO2, -OR22, -NR22R23 and d-e-alkyl, R22 and R23 independently are hydrogen, d-e-alkyl, aryl-Ci-e-alkyl or aryl, or R22 and R23 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR24R25)a-O-(CR26R27)c-O-,
a is 0, 1 or 2,
c is 1 or 2,
R24, R25, R26 and R27 independently are hydrogen, d-e-alkyl or fluoro,
R20 and R21 independently are hydrogen, Ci-e-alkyl, C3-β-cycloalkyl or C^-cyclo- alkyl-Ci-6-alkyl,
E is
C3-8-cycloalkyl or Qj-e-cycloalkenyl, which may optionally be substituted with one or two substituents R28and R29, which are independently selected from
• hydrogen, halogen, -CN, -CF3, -OR33, -NR∞R34, Ci-e-alkyl, Qj-β-cycloalkyl, C4.8-cyclo- alkenyl, heteroaryl and aryl,
wherein the heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -NO2, -OR33, -NR33R34 and d-e-alkyl,
R33 and R34 independently are hydrogen or Ci-e-alkyl,
or R33 and R34 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-C2-e-alkenyl or aryl-C2-e-alkynyl, of which the cyclic moieties may optionally be substituted with one to three substitutents R30, R31 and R32, which are independently selected from
• hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR35, -NR35R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, -NR^C^JR36, -OCHzdOJNR R36, -C(O)R35 and - O R35,
•Ci.β-alkyl, C2-β-alkenyl and C2_e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -SCF3, -NO2, -OR35, -NR35R36 and d-e-alkyl,
•C3.8-cycloalkyl, C-μβ-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-Cι^-alkyl, C^-cyclo- alkyl-C2-e-alkenyl, Cs-β-cycloalkyl-d-β-alkynyl, d-e-cycloalkenyl-d-e-alkyl, d-β-cyclo- alkenyl-C2-e-alkenyl, C4-8-cycloalkenyl-C2-e-alkynyl, heterocyclyl-Cι.6-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- Cι-e-alkyl, aryl-C2-β-alkenyl, aryl-C2.e-alkynyl, heteroaryl, heteroaryl-Cι_β-alkyl, hetero- aryl-C2^-alkenyl and heteroaryl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -SCF3, -NO2, -OR35, -NR35R36 and Ci-e-alkyl,
wherein R and R independently are hydrogen, Ci-e-alkyl or aryl,
or R35 and R36 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,
or two of the substituents R30, R31 and R32 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR37R38- (CH2),-O-, -(CH2),-CR37R38-(CH2)r or -S-(CH2),-CR37R38-(CH2)rS-, t and I independently are 0, 1 , 2, 3, 4 or 5,
R37 and R38 independently are hydrogen or Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
In an embodiment the invention provides compounds, wherein A is
Figure imgf000074_0001
wherein m, n and R4 are as defined above.
In an embodiment the invention provides compounds, wherein A is
Figure imgf000074_0002
In an embodiment the invention provides compounds, wherein A is
Figure imgf000074_0003
In an embodiment the invention provides compounds, wherein D is
Figure imgf000074_0004
wherein R16, R17 and R18 independently are
• hydrogen, halogen, CN, -CF3, -OCF3, -SCF3, -S(O) Ci-e-alkyl-, -C(O) Ci-e-alkyl-, Ci-e- alkyl, Ci-e-alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy,
• or two of the groups R16 to R18 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF2-O- or -O-CH2-O-. In an embodiment the invention provides compounds, wherein E is
Figure imgf000075_0001
wherein R , R , R , R31 and R are independently selected from
• hydrogen,
• halogen, -OCF3, -OCHF2, -SCF3, or -CF3,
• Ci-e-alkyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3l -OR35 and -NR35R36,
• cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35, -NR^R36 and Cι.β-alkyl,
• phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 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, -CF3, -OCF3, -NO2, -OR 35
-NRJ0RdB and d-e-alkyl,
• thiadiazolyl, R35 and R36 independently are hydrogen or Ci-e-alkyl. In an embodiment the invention provides compounds, wherein Y is -C=O-, -CH2-.
In an embodiment the invention provides compounds, wherein Z is -CH2-, -(C=O)-(NH), - (C=O)-O - or -(C=O)-CH2-.
In an embodiment the invention provides a compound which is 3-{4-[(4-Cyclohexylbenzyl)-(4-trifluoromethoxybenzyl)amino]benzoylamino}propionic acid.
In an embodiment the invention provides a glucagon antagonist represented by the general formula (I):
Figure imgf000076_0001
wherein
R\ R2, R3 and R4 independently are hydrogen, halogen, -CN, -CF3, -NO2, -OR5, lower alkyl, -SR5, -S(O)2NR5Re, -S(O)NR5R6, -S(O)2R5, -S(O)R5, -C(O)NR5R6, -CH2OR5, -CH2NR5R6, -NR5R6, -C(O)R5 or -C(O)OR5,
wherein R5 and R6 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, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R5 and R6 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
one of X and V is =N-, and the other is =CD- or =N-,
wherein D is hydrogen, halogen, -CN, -CF3, -NO2, -OR7, -NR7R8, lower alkyl, aryl, -C(O)NR7R8, -CH2OR7, -CH2NR7R8 or -C(O)OR7,
wherein R7 and R8 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, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R7 and R8 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl,
-C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
L and M independently are a valence bond, -(CH2)mS(CH2)n-, -(CH2)mO(CH2)n-, -(CH2)mS(O)(CH2)n-, -(CH2)mS(O)2(CH2)n-, -(CH2)mCH=CH(CH2)n-, -(CH2)mC≡C(CH2)n-, -(CH2)mCHR9(CH2)n-, -(CH2)mNR9(CH2)n-, -(CH2)mC(O)NR9(CH2)n-, -(CH2)mC(O)O(CH2)n-, -S(CH2)mC(O)O(CH2)n-, -S(O)2(CH2)π1C(O)O(CH2)n-, -S(O)2(CH2)mC(O)(CH2)n-.
-S(O)2NR9(CH2)mC(O)O(CH2)n-, -S(CH2)mC(O)NR9(CH2)n-, -(CH2)mOC(O)(CH2)n-,
-(CH2)mC(O)(CH2)n-, -(CH2)mC(NOR9)(CH2)n-, -(CH2)mNR9S(O)2(CH2)n-, -(CH2)mS(O)2NR9(CH2)n-, -(CH2)mCHOR9(CH2)n-, -(CH2)mP(O)(OR9)O(CH2)n-,
-S(O)2(CH2)mCONR9(CH2)n-, -S(O)2(CH2)mOC(O)NR9(CH2)nC(O)O(CH2)r, -NR9O(CH2)n-, -NR9NR9aC(O)NR9b(CH2)n-, -NR9(CH2)mNR9aC(O)(CH2)n- or -NR9(CR9cR9d)n-,
wherein R9, R9a and R9b 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, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
R and R 39d ° independently are hydrogen or lower alkyl,
m, n and r independently are 0, 1 , 2, 3 or 4,
A and B independently are hydrogen, halogen, -CF3, -CF2CF3, -CN, -NO2, 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, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
or A and B independently are
Figure imgf000078_0001
Figure imgf000078_0002
wherein
p is 1, 2 or 3,
X' is -N= or -CR14=,
V is -N= or -CR15=,
Z' _s -N= or -CR16=,
V' is -N= or -CR17=,
' is -N= or -CR18=,
G is -CR18aR18b-, -N+O'-, -NR19-, -O- or -S-,
K is -CR18cR18d-, -NR20, -O- or -S-,
R10, R11, R12, R13, R14, R15, R16, R17, R18, R18a, R18b, R18c and R18d independently are hydro- gen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -OCF2CHF2, -NO2, -OR21, -NR21R22, 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 al- kynyl, heteroaryl-lower alkyl, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl, -SCF3, -SR21, -CHF2, -OCHF2, -OS(O)2CF3, -OS(O)2R21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR2 R22, -S(O)2R21, -S(O)R21, -CH2C(O)NR 1R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -S(O)2NR21(CH)sC(O)OR22, -C(O)NR21(CH)sC(O)OR22 or -dOJ R^R22 where R12 and R13 furthermore independently may represent oxo, or two of the groups R10 to R18d when defined in the same ring together may form a bridge -O(CH2)qO- or -CH2O(CH2)qO-, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2> -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
wherein R21 and R22 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, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R21 and R22 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl,
-C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
R 9 and R20 independently are hydrogen, -OR23, -NR23R24, 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, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl, -C(O)NR23R24 or -C(O)OR23, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2_ -SO2NH2, -OCHF2, -CF3and -OCF3,
wherein R23 and R24 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, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R23 and R24 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C(O)OH, -O-lower alkyl, -C(O)OCH3, -C(O)NH2, -OCH2C(O)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -SO2NH2, -OCHF2, -CF3and -OCF3,
q is 1, 2 or 3,
s is O, 1, 2 or 3,
or
A and B may be connected and together form a C2-3-alkylene radical,
with the provisos that
when L represents a group wherein n or r is 0, A is not halogen, -CN or -NO2, and
when M represents a group wherein n or r is 0, B is not halogen, -CN or -NO2,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
(S)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid or (R)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
In an embodiment the invention provides glucagon antagonists represented by the general formula (I):
Figure imgf000082_0001
wherein
R1 is chloro, fluoro, nitro or cyano;
K is -C(O)-(CH2)d-, -CH2-CH2-O- or -CHR2-;
wherein
d is 0 or 1 ;
R2 is hydrogen or Ci-e-alkyl
Dis
Figure imgf000082_0002
wherein
Q is -O- or -S-;
Yis-CH=or-N=; R3, R4, R5, R6 and R7 independently are hydrogen, Ci-e-alkyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, halogen, carboxamido, hydroxy methyl, phenyl, dimethylamino, Ci-β-alkoxy or nitro;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
In an embodiment, the invention provides a glucagon antagonist of the general formula (I):
Figure imgf000083_0001
wherein
R2 is hydrogen or Cι_β-alkyl,
B is
Figure imgf000083_0002
R^is hydrogen, -S(=O)2-Cι-e-alkyl or -C(=O)-Cι-e-alkyl,
A is a valence bond, -(CR3R4)-, or -(CR3R4)(CR5R6)-,
R1, R3, R4, R5 and R6 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,
which may optionally be substituted with one or two groups R7 and R8 selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and d-e-alkyl,
wherein R9 and R10 independently are hydrogen or Ci-e-alkyl,
X is
-(CH2)-(CR12R13)r-(CH2)s— , -L(CR12R13)— (CH2)S—
Figure imgf000084_0001
■^-(CH,)— N-(CR 2R13)r-(CH2)— O- -(CH2)-N -(CR12R13)r-(CH2)s- ,
11
R11
L(CH2)-
Figure imgf000084_0002
or JL(CH2)_(CRI2RI3) _0_(CH2)_
Figure imgf000084_0003
wherein
r is O oM ,
q and s independently are 0, 1 , 2 or 3,
R11, R12, R13 and R14 independently are hydrogen or Ci-e-alkyl, D is
Figure imgf000085_0001
Figure imgf000085_0002
wherein
R_°, R™ R ι / and R™ independently are
hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
Ci-e-alkyl, C2-e-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C^-alkyl,
C3-s-cycloalkyl, C-μβ-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-d-e-alkyl, C3-β-cyclo- alkyl-d-e-alkoxy, C3_β-cycloalkyloxy, C3_^-cycloalkyl-Cι_e-alkylthio, Qj-β-cycloalkylthio, Cs-β-cycloalkyl-d-e-alkenyl, d-β-cycloalkyl-d-e-alkynyl, d-β-cycloalkenyl-d-β-alkyl, C«-cyclo- alkenyl-C2-e-alkenyl, C4.8-cycloalkenyl-C2-e-alkynyl, heterocyclyl-Cι.β-alkyl, heterocyclyl- C2^-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl- C2-e-alkenyl or heteroaryl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and Ci-e-alkyl,
wherein R21 and R22 independently are hydrogen, Cι_β-alkyl or aryl,
or R21 and R22 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,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R23, R24, R25 and R26 independently are hydrogen, Ci-e-alkyl or fluorine,
R19 and R20 independently are hydrogen, Ci-e-alkyl, Cs-e-cycloalkyl or C3_β-cyclo- alkyl-d-e-alkyl, E is
Figure imgf000087_0001
L ~TR • - / . oorr , (CnH2) _2
Figure imgf000087_0002
wherein
R27and R28 independently are
hydrogen, halogen, -CN, -CF3, -OCF3, -OR32, -NR32R33, Ci-e-alkyl, C3.8-cycloalkyl, C^-cyclo- alkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR32, -NR32R33 and d-e-alkyl,
wherein
R32 and R33 independently are hydrogen or Ci-e-alkyl, or
R32 and R33 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,
R29, R30 and R31 independently are
hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR34, -NR^R35, -SR34, -S(O)R34, -S(O)2R34, -C^JNR^R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C OJR34 or -CtOJOR34, d-e-alkyl, C2_e-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
Qj-e-cycloalkyl, C-μβ-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-d-e-alkyl, C3_β-cyclo- alkyl-C2-6-alkenyl, C^-cycloalkyl-C^-alkynyl, d-e-cycloalkenyl-d-e-alkyl, C-^-cycloalkenyl- C2-e-alkenyl, d-e-cycloalkenyl-C∑-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2_e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2-e-alkynyl, heteroaryl, heteroaryl-Cι^-alkyl, heteroaryl-C2_6-alkenyl or heteroaryl-C2^- alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
wherein R34 and R35 independently are hydrogen, Ci-e-alkyl or aryl,
or R34 and R35 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,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or differ- ent ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)ι-O-, -(CH2),-CR36R37-(CH2)ι- or -S-(CH2)t-CR36R37-(CH2)rS-,
wherein
t and I independently are 0, 1 , 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or Ci-e-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these In an embodiment the invention provides glucagon antagonist of formula (I):
Figure imgf000089_0001
wherein
A is
Figure imgf000089_0002
m is O oM ,
n is O, 1, 2 or 3,
with the proviso that m and n must not be 0 at the same time,
R4 is hydrogen, fluoro or -(CH2)p-OR5,
p is 0 or 1 ,
R5 is hydrogen, Cι_6-alkyl,
Figure imgf000089_0003
aryl or aryl-Ci-e-alkyl,
R1 and R2 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, Ci-e-alkyl, C^-alkoxy, hydroxy, Ci-e-alkylthio, Ci-e-alkylsulfonyl, trifluoromethylsulfonyl or -NR6R7,
R6 and R7 independently are hydrogen or d-e-alkyl,
B is
Figure imgf000090_0001
R8, R9, R13 and R14 independently are hydrogen, halogen, trifluoromethyl, d-e-alkyl or Cι_6-alkoxy,
R10 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 is 0, 1 , 2 or 3;
R3 is hydrogen or Cι_8-alkyl,
>15 X is =N-CN, =N-CH2R , =CH-NO2 or =CHR
Rls is
• hydrogen, cyano or trifluoromethyl,
>Cι-6-alkyl, which may optionally be substituted with
fluoro, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, d-β-alkoxy, hydroxy, Ci-e-alkylthio, Ci-β-alkylsulfonyl, trifluoromethylsulfonyl or -NR16R17,
R >16 a „„ndJ 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 -NR18R19,
R18 and R19 independenly are hydrogen or Cι_β-alkyl,
D is
Figure imgf000091_0001
R20and R21 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, Cι.6-alkyl, aryl, methylthio, methylsulfonyl, trifluoromethylsulfonyl, -NR23R24, d-β-cycloalkyl or -S(O)2-N(C^-alkyl)(aryl),
R23 and R24 independently are hydrogen or d-e-alkyl,
R22 is hydrogen, Ci-e-alkyl, dj-β-cycloalkyl or Cs-β-cycloalkyl-Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these
In an embodiment the invention provides a compound, wherein A is
Figure imgf000091_0002
In an embodiment the invention provides a compound, wherein A is
Figure imgf000092_0001
In an embodiment the invention provides a compound, wherein R1 and R2 are both hydrogen. In an embodiment the invention provides a compound, wherein B is
Figure imgf000092_0002
wherein R8, R9, R11 and R12 are as defined above.
In an embodiment the invention provides a compound, wherein R8and R9 are both hydrogen. In an embodiment the invention provides a compound, wherein B is
Figure imgf000092_0003
wherein R10 is as defined in above.
In an embodiment the invention provides a compound, wherein X is =N-CN, =CH-NO2, =N-
CH2-CF3 or =N-CH2-CN.
In an embodiment the invention provides a compound, wherein R3 is hydrogen.
In an embodiment the invention provides a compound, wherein D is
Figure imgf000092_0004
wherein R , R and R22 are as defined above. In an embodiment the invention provides a compound, wherein R20 and R21 independently are hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and R22 is Ci-e-alkyl.
In an embodiment the invention provides solvates of compounds as described above.
In an embodiment the invention provides 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}propionic acid in a solvate form.
In an embodiment the invention provides 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}-2R-hydroxypropionic acid in a solvate form.
In an embodiment 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.
In an embodiment the invention provides Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)- carbonyl]anilino}methyl)benzoyl]- ?-alanine as a solvate with acetone, butanol, ethanol or propanol.
In an embodiment 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.
In an embodiment 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 :
a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution d) isolating the precipitate e) optionally drying the obtained solvate.
In an embodiment the invention provides the process of claim 4 wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
In an embodiment the invention provides 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
In an embodiment 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.
In an embodiment 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.
Examples:
PXRD (Powder X-ray Diffraction) The PXRD measurements were conducted on a Bruker D8 Advance powder diffractometer equipped with a multilayer mirror which selects the CuK„ radiation (λ = 1.5418 A). The sample is mounted on a flat plate in reflection geometry in the center of a goniometer with a diameter of 435 mm. The diffracted beam from the sample is recorded stepwise with a scintilla- tion detector. All samples were ground in an agate mortar before measurement. Scan range in 2Θ: 2°-30° Step size: 0.03° Time per step: 10 sec
Thermal Analysis
Differential Scanning Analysis (DSC) was conducted on a MDSC 2920, TA Instruments. Samples (approximately 3 - 6 mg) were heated in pinhole crimped aluminium pans from 25°C to 280°C at a rate of 10°C/min. The DSC measuring chamber was continuously purged with dry nitrogen during the runs and the instrument was routinely calibrated with indium and tin.
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)]
Figure imgf000095_0001
17.8g (0.03 mol) 3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid, 1, was dissolved in 350 ml ethyl acetate and 88 ml tetrahydrofurane under a nitrogen atmosphere. The solution was heated to 60°C. 3.68g (0,015 mol) Λ/,Λ/'-dibenzyl-ethylenediamine was dissolved in 43 ml ethyl acetate, and added drop-wise to the hot solution over 20 minutes. When mixture became opaque, it was heated to 70°C and stirred at that temperature for 30 minutes. Then the mixture slowly cooled to room temperature, and the salt precipitated. The hemibenzathine salt was recovered and identified, after drying to constant weight.
Example 2: [3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid:ferf-butyl amine (1:1)]
Figure imgf000096_0001
1.3.4 (0.582 g) was dissolved in acetone (8 ml) and tert-butylamine (105μl, 1.0 mmol in ace- tone) was added. More acetone was added (7 ml), and the solution was left to precipitate at room temperature. The suspension was cooled to 8°C over 2h, and the tert-butylamine salt of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid was isolated. 0.51 g was isolated after drying in vacuo.
Example 3: [3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid:L-arginine (1:1)]
Figure imgf000096_0002
1 (29.15 mg, 0.050 mmole) was dissolved in methanol (1.0 mL) by heating. 520 μL (0.052 mmole) of a 0.100 M solution of L-arginine in MilliQ water was added. A fine, white precipitate was observed. The solution was stored at 4°C for 2 days, after which an apparently crystalline precipitate had formed. The mother liquor was filtered off and the precipitate was dried in a desiccator overnight. The precipitate had then become glass-like. This precipitate was analysed.
Example 4: (2R)-Λ/-[4-({4-cyclohexyl[(3,5-dichloroanilino)carbonyl]anilino}methyl)- benzoyl]-2-hydroxy-£-alanine: Λ/,/V-dibenzylethylenediamine (1 :0.5)]
Figure imgf000097_0001
(2.4 g) was dissolved in isopropyl acetate (37 ml) and Λ/,Λ/'-dibenzyl-ethylenediamine (1.6 g, 6.5 mmol) in THF (18 ml) was added at elevated temperature. The solution was left to precipitate at room temperature. The suspension was cooled to 5°C, and the hemibenzathine salt of (2R)-Λ/-[4-({4-cyclohexyl[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2- hydroxy- ?-alanine was isolated. 5.5 g was isolated after drying in vacuo.
Example 5: (2R)-W-[4-({[1, -biphenyl]-4-yl [(3,5-dichloroanilino)- carbonyl]amino}methyl)benzoyl]-2-hydroxy- ?-alanine: -V.-V-dibenzylethylenediamine (1:0.5)]
Figure imgf000097_0002
(2R)-Λ/-[4-({[1 ,1'-biphenyl]-4-yl[(3,5-dichloroanilino)carbonyl]amino}methyl)benzoyl]-2- hydroxy- ?-alanine (5.5 g) was dissolved in ethyl acetate (100 ml) and THF (28 ml) N,N'- dibenzyl-ethylenediamine (1.1 g, 4.7 mmol) in ethyl acetate (22 ml) was added at elevated temperature. The solvent was removed under reduced pressure. To the material hot methyl tert butyl ether was added, and the hemibenzathine salt of (2R)-Λ/-[4-({[1,1'-biphenyl]-4- yl[(3,5-dichloroanilino)carbonyl]amino}methyl)benzoyl]-2-hydroxy-yff-alanine precipitated. 5.7 g was isolated after drying in vacuo. Example 6: 3- 4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}propionic acid : tert-butylamine:
582 mg 3-{4-[1 -(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyϊ]- benzoylaminojpropionic acid was dissolved in 20-25 ml acetone. 0.105 ml tetf-butylamine (1 eq.) was added slowly, and the reaction mixture was stirred at ambient temperature for 4 days. The suspension (Approx. 10-15 ml) was cooled 8°C over 2 hours and filtered. The crystals were washed with cold acetone and dried under vacuum. Yield: 78%
Example 7: 3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}propionic acid : L-arginine:
566 mg. 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}propionic acid was dissolved in 15 ml 1 -propanol at reflux. 174 Mg. L-arginine was dissolved in 1 ml H2O by heating. The solution of L-arginine was slowly added to the solution of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}propionic acid. Seeding crystals were added until crystallization was observed (At ca. 60°C), and the reaction mixture was cooled to ambient temperature over VA hour. The crystals were isolated by filtration, washed with 1-propanol and dried under vacuum. Yield: 73%.
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)
35.0 mg of 3-(4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5,6,7,8-tetrahydronaphthalen-2- yl)amino]methyl}benzoylamino)propionic acid was dissolved in 2 mL ethylacetate with light heating. When dissolved, 620 μL of 0.097 M tert-butylamine in ethylacetate was added in three portions. The solution was allowed standing at room temperature a few days, during which an oily precipitate formed. This precipitate was dissolved in 1 mL THF (tetrahydrofurane) and again allowed standing at room tempe- rature. After some days a crystalline precipitate formed.
Example 9: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4- trifluoromethylphenyl)amino]methyl}benzoylamino)propionic acid: L-lysine (1:1)
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 THF while shaking. 600 μL of 0.051 M L-lysine in H2O was added in three portions. The solution was allowed standing at room temperature a few days during which the solvent evaporated and an oily precipitate formed. This was dissolved in 1 mL of absolute ethanol, and after some days a white precipitate in the solution was formed. This slurry was dried on the sample holder and analysed.
Example 10: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]- methyl}benzoylamino)propionic acid: L-histidine (1:1)
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 THF while shaking. 600 μL of 0.050 M L-histidine in H2O was added in three portions. The solution was allowed standing at room temperature a few days during which the solvent evaporated and an oily precipitate formed. This was dissolved in 1 mL of absolute ethanol, and after some days crystalline precipitate was formed on the side of the vial. The precipitate was analysed.
Example 11: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)- amino]methyl}benzoylamino)propionic acid : monoethanolamine (olamine) (1 :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. 575 μL of 0.104 M monoethanolamine in ethylacetate was added in three portions. The solution was allowed standing at room temperature. After one day a white, gel-like precipitate formed. This was suspended in 300 μL of ethylacetate. After some days a white precipitate was formed. The precipitate was analysed.
Example 12: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)- amino]methyl}benzoylamino)propionic acid: tert-butylamine (1:1)
33.6 mg of 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}- benzoylamino)propionic acid was dissolved in 1 mL of THF while shaking. 300 μL of 0.201 M tert-butylamine in ethanol was added in three portions. The solution was allowed standing at room temperature. After a few days a transparent, oily precipitate formed. This was dissolved in 1 mL of absolute ethanol. After some days a crystalline precipitate was formed. The precipitate was analysed.
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 μL 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 μL of ethylacetate. After some days a white, solid precipitate was formed. The precipitate was analysed.
Example 14: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)- amino]methyl}benzoylamino)propionic acid, dibenzylethylenediamine (benzathine) (2:1)
33.6 mg of 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}- benzoylamino)propionic acid was dissolved in 1 mL of THF while shaking. 290 μL of 0.104 M benzathine in ethanol was added in three portions. The solution was allowed standing at room temperature a few days during which the solvent evaporated and a solid, white precipi- tate formed. This was suspended in 1 mL of absolute ethanol, and after some days crystalline precipitate was formed. The precipitate was analysed.
General procedure for the preparation of solvates of the invention:
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. Optionally the temperature was elevated to dissolve the compound. Also the pH may be adjusted for ensuring the compound was dissolved. Afterwards 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.
DSC method The following instrumentation was used:
• Mettler Toledo DSC module 822
• Power Point Labplant RP 60 intra cooler
• Mettler Tolede DSC software STAR A linear heating program from 25°C to 300°C with a heating rate of 10°C/min was used. The DSC experiments were performed in open lid 40 μl aluminum crucibles.
PXRD (Powder X-ray Diffraction) The PXRD measurements were conducted on a Bruker D8 Advance powder diffractometer equipped with a multilayer mirror which selects the CuK„ radiation (λ = 1.5418 A). The sample is mounted on a flat plate in reflection geometry in the center of a goniometer with a diameter of 435 mm. The diffracted beam from the sample is recorded stepwise with a scintillation detector. All samples were ground in an agate mortar before measurement. Scan range in 2Θ: 2°-30° Step size: 0.03° Time per step: 10 sec
Examples
Example 1
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:ethyl acetate ]
Figure imgf000101_0001
To a solution of methyl 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)- ureidomethyl]benzoylamino}-2R-hydroxypropionate (112 g) dissolved in THF (2800 ml) was added an aqueous solution of lithium hydroxide mono hydrate (10.2 g in 100 ml water). The mixture was stirred for 1 hour at room temperature. Phosphoric acid (3 M) was added to pH 2.4. Ethyl acetate (400 ml) was added to the solution and the two phases were separated. The organic phase was washed with water (200 ml), and the organic solvent was removed under reduced pressure. 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.
Example 2
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:2-butanol]
Figure imgf000102_0001
1 (11.7 g) was dissolved in 2-butanol (75 ml) by heating. The 2-butanol solvate of 3-{4-[1-(4- Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid precipitated by stirring the mixture at room temperature. 7.6 g was isolated after drying the material in vacuo at 40 °C.
Example 3
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:ethanol]
Figure imgf000102_0002
2 (5.0 g) was dissolved in ethanol (14 ml) by heating. Up on cooling to room temperature the ethanol solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated. The sus- pension was filtered and washed with cold ethanol. After drying over night at room temperature 2.6g (52%) was isolated after drying the material at room temperature over night.
Example 4
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:2-propanol]
Figure imgf000103_0001
2 (5.0 g) was dissolved in 2-propanol (12 ml) by heating. The 2-propanol solvate of 3-{4-[1- (4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid precipitated by stirring the mixture at room temperature. 1.0 g was iso- lated after drying the material at room temperature over night.
Example 5
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid: 1 -butanol]
Figure imgf000103_0002
1 (5.0 g) was dissolved in 1 -butanol (5 ml) by heating to 40 °C. n-Heptane (2.2 ml) was added and the 1 -butanol solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and washed with n-heptane (2 x 10 ml) followed by drying in vacuo at 40 °C for 5 days.
Example 6
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:2-methyl-1 -propanol]
Figure imgf000104_0001
1 (25.0 g) was dissolved in 2-methyl-1 -propanol (50 ml) by heating to 40 °C. The 2-methyl-1- propanol solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and washed with 2-methyl-1 -propanol (5 ml). Drying in vacuo at 40 °C for 2 days gave 21.4 g solvate.
Example 7
[3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:3-methyl-1 -butanol]
Figure imgf000104_0002
1 (5.0 g) was dissolved in 3-methyl-1 -butanol (20 ml) by heating to 40 °C. The 3-methyl-1- butanol solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspen- sion was filtered and washed with 3-methyl-1 -butanol (10 ml) followed by drying in vacuo at 40 °C for 24 hours.
Example 8
3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:diethyl ether]
Figure imgf000105_0001
1 (5.0 g) was partly dissolved in diethyl ether (15 ml) by heating. The diethyl ether solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid precipitated by cooling to 20 - 25 °C. After drying at room temperature for several days 4.3g was isolated.
Example 9
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:ten*-butyl methyl ether]
Figure imgf000105_0002
1 (5.0 g) was dissolved in tetf-butyl methyl ether (7 ml) by heating to 40 °C. The tetf-butyl methyl ether solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)- ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and washed with n-heptane (2 x 10 ml) followed by drying in vacuo at 40 °C for 4 days.
Example 10
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:THF
Figure imgf000106_0001
1 (5.0 g) was dissolved in THF (5.0 ml) by heating to 35 °C. n-Heptane (8.0 ml) was added to the solution and the THF solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)- ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and the filter cake was dried at 20 - 25 °C for 6 days.
Example 11
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:anisole]
Figure imgf000106_0002
1 (5.0 g) was dissolved in a mixture of THF (10 ml) and anisole (90 ml) by heating to 40 °C. The anisole solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)- ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and the product was washed with n-heptane (5 ml) followed by drying at 20 - 25 °C for 5 days. Example 12
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:acetone]
Figure imgf000107_0001
1 (5.0 g) was dissolved in acetone (5.5 ml) by heating to 35 °C. n-Heptane (2.2 ml) was added to the solution and the acetone solvate of 3-{4-[1-(4-Cyclohex-1-enyiphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20 - 25 °C. The suspension was filtered and the product was dried at 20 - 25 °C for 2 days.
Example 13
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid: 2-butanone]
Figure imgf000107_0002
Methyl 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- 2R-hydroxypropionate (9.0 g) dissolved in THF (80 ml) was hydrolysed with lithium hydroxide mono hydrate (0.75 g) dissolved in water (7.5 ml). The aqueous solution was added in 5 min, and the reaction mixture was stirred at room temperature for two hours. Hydrochloric acid (3 M) was added to pH 2.2 and ethyl acetate (50 ml) was added. The two phases were separated and the organic phase was washed with water (2 x 20 ml). The organic solvent was removed under reduced pressure. Water residues were removed by stripping with 2- butanone (2 x 50 ml). The crude material was dissolved in 2-butanone (90 ml) and heated to 50°C. The solution was added n-heptane (100 ml) and cooled to 5 °C. After stirring over night a precipitate was formed, and the title compound was isolated. The material was dried at 20 - 25 °C for 4 days.
Example 14
[3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid: methyl acetate]
Figure imgf000108_0001
1 (5 g) was dissolved in methyl acetate (5 ml) at 40°C. At room temperature the methyl acetate solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated. The mixture was diluted with methyl acetate (5 ml) prior to filtration. The solvate was identified after drying at room temperature for 18 hours.
Example 15
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:n-propyl acetate]
Figure imgf000109_0001
1 (5 g) was suspended in n-propyl acetate (15 ml). The material dissolved upon heating to 40°C to 45°C. The n-propyl acetate solvate of 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5- dichlorophenyl)ureidomethyl]benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 0 - 5°C and was identified after drying at room temperature for 18 hours.
Example 16
[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid:toluene]
Figure imgf000109_0002
To a solution of methyl 3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)- ureidomethyl]benzoylamino}-2R-hydroxypropionate (72 g) dissolved in ethanol (580 ml) and toluene (56 ml) was added an aqueous solution of lithium hydroxide mono hydrate (10.2 g in
100 ml water). The mixture was stirred for 1 hour at room temperature. Phosphoric acid (3 M) was added to adjust pH to 2.4. The mixture was heated to 40 °C for Yz hour. The solution was cooled to room temperature during 2 hours and kept at this temperature for 2 hours. Stirring over night at 10 °C resulted in formation of a white precipitate. The slurry was filtered and the filter cake was washed with cooled (10 °C) ethanol/water 1/1 (v/v) (2 x 70 ml) and dried in vacuo at 40 °C for 22 hours. The title compound (72.5 g) was isolated in 88% yield. Example 17: Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)- benzoyl]-yff-alanine:acetone
Figure imgf000110_0001
Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-)9-alanine (1.0 g) was dissolved in acetone (44 ml) by heating. The acetone solvate of Λ/-[4-({4-(1- cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-i_?-alanine precipitated by stirring the mixture at room temperature. 0.62 g was isolated after drying the material.
Example 18:Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}- methyl)benzoyl]- ?-alanine:2-butanol]
Figure imgf000110_0002
Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-i-?-alanine (1.0 g) was dissolved in 2-butanol (44 ml) by heating. Up on cooling to room temperature the 2-butanol solvate of Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}- methyl)benzoyl]- ?-alanine precipitated. The material was collected by filtration. After drying at room temperature 0.98 g was isolated.
Example 19: Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)- benzoyl]-0-alanine:ethanol]
Figure imgf000111_0001
Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-^-alanine (1.0 g) was dissolved in ethanol (36 ml) by heating. Up on cooling to room temperature the ethanol solvate of Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}- methyl)benzoyl]- _ -alanine precipitated. The suspension was filtered and washed with cold ethanol. After drying for 2 days at room temperature 0.68g was isolated.
Example 20: Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)- benzoyl]-y-?-alanine:2-propanol]
Figure imgf000111_0002
Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-^-alanine (1.0 g) was dissolved in 2-propanol (56 ml) by heating. The 2-propanol solvate of Λ/-[4-({4-(1- cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-yff-alanine precipitated by stirring the mixture at room temperature. 0.58 g was isolated after drying the material at room temperature over 3 days.
Example 21 : Λ/-[4-({4-(1 -cyclohexen-1 -yl)[(3,5-dichloroanilino)carbonyl]anilino}- methyl)benzoyl]-yff-alanine: 1 -propanol]
Figure imgf000112_0001
Λ/-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-)-?-alanine (1.0 g) was dissolved in 1 -propanol (44 ml) by heating. The 2-propanol solvate of Λ/-[4-({4-(1- cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-/-?-alanine precipitated by stirring the mixture at room temperature. 0.63 g was isolated after drying the material at room temperature over 3 days.
Measurement of stability:
The stability has been observed at accelerated as well as at long term storage conditions for a time period of 33 weeks. From the apparent degradation rates observed at the different storage conditions a retest time was estimated in the cases where a significant degradation was observed.
The experiment are measured at different temperatures and humidities for example: 25°C/60 % RH, 40°C/75% RH, 60°C/ambient humidity, or with light exposure in either open containers or bulk container.

Claims

1. A composition comprising a salt of a glucagon antagonist and a pharmaceutically acceptable base. 2. The composition of claim 1 , wherein the pharmaceutically acceptable basic counter ion is 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"-nitrilotris(ethanol), trolamine),
2-diethylaminoethanol.
3. A composition according to claims 1 - 2, wherein the compound is represented by the general formula (I) below:
Figure imgf000113_0001
wherein
A is
Figure imgf000113_0002
X is a valence bond, -CR1R2- or -NR1-,
Y is >CR3- or >N-, R1, R2 and R3 independently are hydrogen or Ci-e-alkyl, or R1 and R3 on adjacent atoms may be combined to form a double bond,
E is • Cι.ιo-alkyl or C2-ιo-alkenyl,
• Qs-io-cycloalkyl, Qj-io-cycloalkenyl, C7.ι0-bicycloalkyl, Cs-io-cycloalkyl-d-e-alkyl,
Figure imgf000114_0001
or C7-ι0-bicycloalkyl-Cι_6-alkyl, wherein the rings may optionally be substituted with one or more substituents selected from halogen, C^-alkyl, C2-e-alkenyl, C^-alkoxy, d-β-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2 and - SCHF2,
• aryl, aryloxy, arylthio, heteroaryl, aryl-Cι_e-alkyl,
Figure imgf000114_0002
heteroaryl-Ci-e-alkyl, diaryl-Ci-e-alkyl or (Cι_6-alkyl)(aryl)-Cι.7-alkyl, wherein the non-aromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, Ci-e-alkyl, C2-e-alkenyl, Ci-β-alkoxy, Ci-e-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2, -SCHF2, C3-ι0-cycloalkyl and C3-ι0-cycloalkenyl, or with two substituents on adjacent positions which are combined to form a bridge Cι_e-alkylene, C2.6-alkenylene or -O-Cι-6-alkylene-O-,
B is
,N, ,N .-. sr __. ,N
Y'-XΓ' , Ύ X'-Y' , ^i X'-Ni • ^ N-X i' or Y f
X' is -N= or -CRa=,
Y is -S-, -O- or -NR 9a-, R8 is hydrogen, Ci-e-alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, Ci-e-alkyl, Ci-β-alkoxy, Ci-e-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2, -SCHF2, -SO2CF3 and -SO2-Cι^-alkyl,
R9 is hydrogen or Ci-e-alkyl,
D is aryl or heteroaryl,
which may optionally be substituted with one or more substituents selected from
• halogen, -CF3, -OCF3, -SCF3, -CN, -NO2, d-10-alkyl- C2-e-alkenyl, C^-alkoxy, Ci-e-alkylthio, amino, Cι_β-alkylamino, di-Ci-β-alkylamino, -SO2CF3 and -SO2-d-6-alkyl,
• C3.8-cycloalkyl, d-e-cycloalkenyl, aryl and aryl-Cι.β-alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, -CF3, -OCF3, -SCF3, -CN, -NO2, Cι-ι0-alkyl, C2-e-alkenyl, and Cι_6-alkylthio, or with two substituents on adjacent positions which are combined to form a bridge -O-(CH2) -O-(CH2)p- or -O-(CF2)m-O-(CF2)p-, wherein m is an integer of from 1 to 6, and p is 0 or 1 ,
• or with two substituents on adjacent positions which are combined to form a bridge -O-(CH2)m-O-(CH2)p- or -O-(CF2)m-O-(CF2)p-, wherein m is an integer of from 1 to 6, and p is O or 1 , or a substituent on B may be combined with a substiuent on D to form a -C(=O)- bridge,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
4. A compound according to claim 3, wherein B is N N
* I i I, Y'-X' or x'-r wherein X' and Y' are as defined in claim 3.
5. A compound according to claim 4, wherein B is
Figure imgf000116_0001
wherein R is as defined in claim 3.
6. A compound according to claims 3-5, wherein E is
Ci.io-alkyl,
C3-ιo-cycloalkyl, which may optionally be substituted as defined in claim 3,
Figure imgf000116_0002
Figure imgf000116_0003
wherein R4 and R5 are as defined in claim 3.
7. A compound according to claim 6 wherein E is
Figure imgf000117_0001
wherein R4 is hydrogen and R5 is d-e-alkyl, Cι_6-alkoxy, cyclohexyl, halogen, -CF3 or cyclo- hex-1-enyl,
or R4 and R5 on adjacent positions may be combined to form a bridge C^-alkylene.
8. A compound according to claims 3-7, wherein D is
Figure imgf000117_0002
wherein R10, R11, R12, R15, R16, R17and R18 are as defined in claim 3.
9. A compound according to claim 8, wherein D is
Figure imgf000117_0003
wherein R , R and R1^ are as defined in claim 3.
10. A compound according to claim 8 or 9, wherein R10, R11 and R12 independently are hydrogen, halogen, -OCF3, -CF3, -NO2,
Figure imgf000118_0001
d-io-alkyl, d-e-alkoxy or -CN,
phenyl or phenyl-Cι_6-alkoxy,
or two of R10, R11 and R12 in adjacent positions form a bridge -O-CH2-O-, -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O-.
11. A compound of claim 10 wherein one of R10, R11 and R12 represent hydrogen.
12. A compound according to claim 11, wherein one or two of R10, R11 and R12 is hydrogen, and the remaining is independently selected from halogen, -OCF3, -CF3, -NO2, di-
Cι.6-alkylamino, Cι.10-alkyl, Cι-6-alkoxy or -CN.
13. A compound according to any one of the previous claims 3-12, wherein the compounds is selected from 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid,
3-(4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5,6,7,8-tetrahydronaphthalen-2-yl)amino]methyl}- benzoylamino)propionic acid
3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoyl- amino]propionic acid,
3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}methyl)benzoylamino]- propionic acid or
3-[4-({(4-Trifluoromethoxyphenyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}methyl)- benzoylamino]propionic acid,
14. The composition according to any one of claims 1-13, comprising
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.
15. The composition according to any one of claims 1-13 comprising
3-(4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid as a salt with L-lysine.
16. The composition according to any one of claims 1-13, comprising
3-(4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid as a salt with L-histidine.
17. The composition according to any one of claims 1-13, comprising 3-(4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid as a salt with monoethanolamine.
18. The composition according to any one of claims 1-13, comprising
3-(4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid as a salt with tert-butylamine.
19. The composition according to any one of claims 1-13, comprising3-(4-{[[4- chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)propionic acid as a salt with 1 ,2-ethylenediamine.
20. The composition according to any one of claims 1-13, comprising
3-(4-{[[4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amino]methyl}benzoylamino)- propionic acid as a salt with N.N'-dibenzylethylenediamine.
21. A composition according to claims 1-2 comprising a compound represented by the general formula (I):
Figure imgf000119_0001
wherein
V is -C(O)OR2, -C(O)NR2R3, -C(O)NR2OR3, -S(O)2OR2,
Figure imgf000119_0002
wherein
R2 and R3 independently are hydrogen or Ci-e-alkyl,
R4 is hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR5, -NR5R6 or d-e-alkyl,
wherein R5 and R8 independently are hydrogen or Ci-e-alkyl,
A is
R\ /R9 R\ /R9 R\ Rβ ^ /
— (CH2)n (V)„ NR7 . _^-(cH2)n— NR7— , -^(CH.)— or — N
' (CH2)n '
wherein
b is O or l,
n is 0, 1 , 2 or 3,
R7 is hydrogen, Cι_6-alkyl or C3-e-cycloalkyl-Cι^-alkyl,
R8 and R9 independently are hydrogen or Ci-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 R46 and R47 selected from hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR10, -NR10R11 and Ci-e-alkyl,
wherein R10 and R11 independently are hydrogen or Ci-e-alkyl,
or -A-Y-Z- together are
Figure imgf000121_0001
R1 is hydrogen or d-e-alkyl,
X is
Figure imgf000122_0001
-(CH, 2)'q— N -(CR13R14)r-(CH2)s- -(CR13R14)r-(CH2)s-
,12
(CR1JR14)— (CH2)S— ,
Figure imgf000122_0002
Figure imgf000122_0003
— N -(CR13R14)r-(CH2); -O- -(CR13R14)— (CH2
I 2)'s
12
-(CH2)q— N-(CR13R14)r-(CH2)- -(CR13R14)-(CH2)S- R12 NH
12
-(CH2)-(CR13R14)r-(CH2)s— N (CR13R14)-(CH2)S—
NH
-2-(CH2) (CR13R1Vθ-(CH2)s-
Figure imgf000122_0004
o
■L(CH2)q— S-(CR13R14)— (CH2)S- or - W^ (CR13R14)r-(CH2)s-
wherein
r is 0 or 1 ,
q and s independently are 0, 1 , 2 or 3, R , R , R14 and R independently are hydrogen or Ci-e-alkyl,
Dis
Figure imgf000123_0001
wherein
Wis-O-.-S-, -S(O)2-or-NR^
Wis=CR^-or=N-,
Rιe, R1', R1B and Rιa independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3l -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR^R22, -SR21, -NR^S^^R2, -SfO^NR^R22, -StOJNR^R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -C OJNR^R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
Ci-e-alkyl, C2_e-alkenyl or C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OCfOJNR^R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
•
Figure imgf000124_0001
C4-8-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-d-e-alkyl, C3-β-cyclo- alkyl-Cι-6-alkoxy, C3_8-cycloalkyloxy, Qj-e-cycloalkyl-d-e-alkylthio, C3-8-cycloalkylthio, C3^-cycloalkyl-C2-e-alkenyl, dwrcycloalkyl-d-e-alkynyl, C-μe-cycloalkenyl-d-β-alkyl, -s- cycloalkenyl-C2-e-alkenyl, C-^-cycloalkenyl-C^-alkynyl, heterocyclyl-Cι.β-alkyl, heterocy- clyl-C2^-alkenyl or heterocyclyl-C2_e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from
-CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
d-e-alkyl, C2_e-alkenyl and C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR^R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21, • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Cι_β-alkoxy, aryl-C^-alkyl, aryl-C2-e-alkenyl, aryl- C2-e-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl- C2-e-alkynyl,
of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR^R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -CfOJNR^R22, -OCfOJNR^R22, -NR21C(O)R22, -CHzCfOJNR^R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 and -C(O)OR21,
Ci-e-alkyl, C2-β-alkenyl and C2_6-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR^R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21,
wherein R21 and R22 independently are hydrogen, -CF3, Ci-e-alkyl, tri-Ci-6-alkylsilyl, C3_β-cyclo- alkyl, C3^-cycloalkyl-d^-alkyl, aryl, aryl-Ci-e-alkyl or heteroaryl,
or R21 and R22 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR16'R17')a-O-(CR18'R19')c-O-,
wherein a is O, 1 or 2,
c is 1 or 2,
R16', R17', R18' and R19' independently are hydrogen, C^-alkyl or halogen,
R20 and R20 independently are hydrogen, Ci-e-alkyl, C3_8-cycloalkyl or Cs-β-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 R23 and R24 may be attached to the same or different ring carbon atoms and wherein a group R31 may be attached to a ring nitrogen atom when present, or
Figure imgf000127_0001
Figure imgf000127_0002
wherein
m 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 and R independently are • hydrogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 or -C(O)OR36,
• Cι_β-alkyl, C2-e-alkenyl or C2_e-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCFs, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR R37, -SR36, -S(O)R36, -S fe 36, -C(O)NR36R37, -OdOJNR R37, -NR36C(O)R37, -OCHzCtONR∞R37, -C(O)R36 and -C(O)OR36,
C3.8-cycloalkyl, C3.8-cycIoalkylidene, d-β-cycloalkenyl, heterocyclyl, C3_e-cycloalkyl- Cι-e-alkyl, C3_β-cycloalkyl-C2.6-alkenyl, d-β-cycloalkyl-d-e-alkynyl, C-μe-cycloalkenyl- Cι-6-alkyl, d-e-cycloalkenyl-d-e-alkenyl, Ct-e-cycloalkenyl-d-e-alkynyl, heterocyclyl- Ci-e-alkyl, heterocyclyl-C2-e-alkenyl or heterocyclyl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from
-CHF2, -CFs, -OCFs, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR∞R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36,
Ci-e-alkyl, C2-e-alkenyl and C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCF3, -OCHF2> -OCH2CF3, -OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -StO^R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36,
• aryl, aryloxy, aroyl, aryl-d-e-alkoxy, aryl-d-e-alkyl, aryl-C2^-alkenyl, aryl-C2-e-alkynyl, het- eroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2.6-alkenyl or heteroaryl-C2_e-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCFs, -NO2, -OR36, -NR36R37, -SR36, -NR36S(O)2R37, -S(O)2NR36R37, -S OJNR R37, -S(O)R36, -S(O)2R36, -OS(O)2R36, -C OJNR R37, -OC(O)NR36R37, -NR36C(O)R37, -CH2C(O)NR36R37, -CH2C(O)NR36R37, -CHzOR36, -CHzNR R37, -OC(O)R36, -CfOJR36 and -C(O)OR36,
Ci-e-alkyl, C2_6-alkenyl and C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from -CHF2, -CF3, -OCFs, -OCHF2, -OCH2CFs, -OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -S O^R36,
Figure imgf000129_0001
wherein R and R independently are hydrogen, Ci-e-alkyl or aryl,
of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR38, -NR38R39 and Ci-e-alkyl,
wherein R ϊ3β a „„nd_g D R39 independently are hydrogen or Ci-e-alkyl,
or R36 and R37 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,
or R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR40R41-(CH2)ι-O-, -(CH2)rCR40R41-(CH2)r or -S-(CH2)t-CR40R41-(CH2)|-S-, wherein
t and I independently are 0, 1, 2, 3, 4 or 5,
R40 and R41 independently are hydrogen or Ci-e-alkyl,
R25 to R30 independently are hydrogen, halogen, -CN, -CF3, -NO2, -OR42, -NR42R43, Ci-e-alkyl, C3-β-cycloalkyl or d-β-cycloalkenyl,
wherein R42 and R43 independently are hydrogen or Ci-e-alkyl, or
R42 and R43 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,
R31, R32 and R33 independently are hydrogen or Ci-e-alkyl,
R -rM a __ndJ D R3J50 independently are
• hydrogen, Ci-e-alkyl, C^-alkoxy, C^-alkanoyl, -C(O)NR44R4° or -S(O)2R4ϊ>,
• aryl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkanoyl or aryl-Ci-e-alkyl,
of which the aryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OR44, -NR^R45 and Ci-e-alkyl, wherein R44 and R45 independently are hydrogen or Cι_β-alkyl, or
R34 and R35 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 ni- trogen, oxygen or sulfur, and optionally containing one or two double bonds, or
R34 and R35 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,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
22. A compound according to claim
21 , wherein V is -C(O)OH or 5-tetrazolyl.
23. A compound according to claim 21 or 22, wherein A is
Figure imgf000131_0001
or
-CH *. H-
or -H-
or
-N- -CH, — H
24. A compound according to any one of the claims 21-23, wherein Y is -C(O)-,
or Y is a valence bond.
25. A compound according to any one of the claims 21 to 24, wherein Z is
Figure imgf000132_0001
26. A compound according to claims 21-25, wherein R1 is hydrogen or methyl.
27. A compound according to claims
21-26, wherein X is -C(O)NH-, -C(O)NHCH2-, -C(O)NHCH(CH3)-, -C(O)NHCH2CH2-, C(O)CH2-, -CH2-, -C(O)- or -NHC(O)-.
28. A compound according to claims 23-27, wherein D is
Figure imgf000133_0001
wherein one or two of R16 ,R17 and R18 are hydrogen and the remaining is independently selected from -OCFs, -SCF3 -CF3, -S(O)2CH3, phenyl, halogen, Ci-e-alkyl, nitro, -S-Ci-e-alkyl or -S(O)2NR21R22, wherein R21 is Ci-e-alkyl and R22 is phenyl.
29. A compound according to claim
21-28, wherein E is
Figure imgf000133_0002
wherein R23 is hydrogen and R24 is Cι_6-alkyl such as tetf-butyl or C3_β-cycloalkyl such as cyclohexyl, wherein R23 and R24 are both Ci-e-alkyl or wherein R23 and R24 together form the radical -(CH2)5-.
30. A compound according to claims
21-28, wherein E is
Figure imgf000133_0003
wherein R25 is -OCF3, -CF3, Ci-e-alkyl such as tetf-butyl, phenyl, piperidyl, C^-cycloalkyl such as cyclohexyl or C _8-cycloalkenyl such as cyclohexenyl.
31. The compound according to any one of the claims 21-30 wherein the compound is any of the following
3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- propionic acid,
4-[3-(3,5-Bistrifluoromethylphenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]-N-(2H-tetrazol-5- yl)benzamide,
(S)-4-[3-[1-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5- yl)benzamide,
4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]-Λ -(2H-tetrazol-5- yl)benzamide 4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-te/f-butylphenyl)ureidomethyl]-Λ/-(2H-tetrazol-5- yl)benzamide,
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-Λ/-(2H-tetrazol-5- yl)benzamide,
4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]-Λ/-(2 --tetrazol-5-yl)- benzamide.
32. The composition according to any one of the claims 1-2 and
21-31 comprising N-[4-({4-(1 -cyclohexen-1 -yl)[(3,5- dichloroanilino)carbonyl]anilino}methyl)benzoyl]-^-alanine and tert-butylamine.
33. The composition according to any one of the claims 1-2 and 21-31 comprising N-[4-({4-(1 -cyclohexen-1 -yl)[(3,5- dichloroanilino)carbonyl]anilino}methyl)benzoyl]- ?-alanine and L-arginine.
34. A composition according to claims 1-2 comprising a compound represented by the general formula (I):
Figure imgf000134_0001
wherein R1, R2, R3, R4 and R5 independently are hydrogen or Ci-e-alkyl,
A is -C(O)-, -CH(OR6)- or -CHF-,
wherein R6 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 R7 and R8 selected from halogen, -CN, -CF3) -OCFs, -NO2, -OR9, -NR9R10 and Ci-e-alkyl,
wherein R9 and R10 independently are hydrogen or Cι_6-alkyl,
X is
O
-(CH2)-(CR12R13)r-(CH2)s— -(CR12R13)-(CH2)S-
Figure imgf000136_0001
(CR12R13)-(CH2)S-
Figure imgf000136_0002
Figure imgf000136_0003
or -(CH2)q— (CR12R13)— 0-(CH2)-
Figure imgf000136_0004
wherein
r is 0 or 1 ,
q and s independently are 0, 1 , 2 or 3,
R , R , R and R independently are hydrogen, Ci-e-alkyl or Cs-e-cycloalkyl,
D is
Figure imgf000137_0001
Figure imgf000137_0002
wherein
R15, R16, R17 and R18 independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3> -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH OJNR^R22, -OCH2C(O)NR21R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
• Ci-e-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and Ci-e-alkyl, • C3-s-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-Cι.6-alkyl, C3-β-cyclo- alkyl-Ci-e-alkoxy, Cs-β-cycloalkyloxy, Cs-β-cycloalkyl-d-e-alkylthio, C3_β-cycloalkylthio, C3_8-cycloalkyl-C2-e-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, d-e-cycloalkenyl-d-e-alkyl, C-μ8-cycloalkenyl-C2-e-alkenyl, C -8-cycloalkenyl-C2-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-d-e-alkyl, aryl-C2-e-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-Cι_e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2-β-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen, -C(O)OR21, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C^-alkyl,
wherein R21 and R22 independently are hydrogen, Ci-β-alkyl, aryl-Ci-e-alkyl or aryl,
or R21 and R22 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,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R , R , R25 and R independently are hydrogen, Ci-e-alkyl or fluorine, R19 and R20 independently are hydrogen, Ci-e-alkyl, Cs-β-cycloalkyl or Cs-β-cyclo-
Figure imgf000139_0001
E is
Figure imgf000139_0002
Figure imgf000139_0003
wherein
R and R independently are
hydrogen, halogen, -CN, -CF3, -OR32, -NR32R33, Ci-e-alkyl, C^-cycloalkyl, C^-cycloalkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -NO2, -OR32, -NR32R33 and Ci-e-alkyl,
wherein R and R independently are hydrogen or d-e-alkyl, or R32 and R33 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,
R29, R30 and R31 independently are
■ hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR34, -NR^R35, -SR34, -SfOR34, -S(O)2R34, -C^JNR^R35, -OC(O)NR34R35,
-NR34C(O)R35, -OCH2C(O)NR34R35, -CζOJR34 or -C(O)OR34,
■ Cι_6-alkyl, C2-e-alkenyl or C2-β-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, CN, -CF3, -OCFs, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
■ C3_β-cycloalkyl, C4.8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-Cι-β-alkyl, Oj-β-cyclo- alkyl-C2_6-alkenyl, C3.β-cycloalkyl-C2.6-alkynyl, C4.e-cycloalkenyl-d-6-alkyl, C^-cyclo- alkenyl-C2_e-alkenyl, C4.8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Ci.6-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aroyl, aryl-d-e-alkoxy, aryl- Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2.6-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, hetero- aryl-C2-e-alkenyl or heteroaryl-C2_e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
wherein R and R independently are hydrogen, Ci-e-alkyl or aryl, or R34 and R35 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,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)rO-, -(CH2)t-CR36R37-(CH2)r or -S-(CH2)t-CR36R37-(CH2)rS-,
wherein
t and I independently are 0, 1 , 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or Ci-e-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
35. A compound according to claim 34, wherein R1, R2, R3, R4 and R5 are hydrogen.
36. A compound according to claim 34 or 35, wherein A is -CHF-.
37. A compound according to claim 34 or 35, wherein A is -CH(OR6)-, wherein R6 is as defined in claim 34.
38. A compound according to claim 37, wherein A is -CH(OH)-.
39. A compound according to any of the claims 34-38, wherein Z is
Figure imgf000142_0001
wherein R and R are as defined in claim 34.
40. A compound according to claim 39, wherein Z is
Figure imgf000142_0002
41. A compound according to claims 34-40, wherein X is -C(O)NH-, -C(O)NHCH2-, -C(O)NHCH(CH3)-, -C(O)CH2- or -C(O)-.
42. A compound according to claim 41 , wherein X is -C(O)NH-
43. A compound according to claims 34-42, wherein D is
Figure imgf000142_0003
wherein R15, R16 and R17 independently are hydrogen, halogen, -CN, -CF3, -OCF3 or Ci-e- alkoxy.
44. A compound according to claims 34-43, wherein E is
Figure imgf000143_0001
wherein R and R are both hydrogen, and R is cyclohexenyl,
■ which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
■ wherein R34 and R35 independently are hydrogen, d-β-alkyl or aryl,
■ or R34 and R35 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.
45. A compound according to claim 44, wherein R29, R30 and R31 independently are hydrogen, Ci-e-alkyl, phenyl, C3-β-cycloalkyl or C-μe-cycloalkenyl.
46. A compound according to claim 45, wherein R29 and R31 are both hydrogen and R30 is Ci-e-alkyl, Cs-β-cycloalkyl or d-e-cycloalkenyl
47. A compound according to any one of the claims 34-46 wherein the compound is selected from the following:
(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
(R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Cyano-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Cyano-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (R)-3-{4-[3-(3-Bromophenyl)-1 -(4-cyclohex-1 -enylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(S)-rrans-3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-te_f-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-Trans-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-tetf-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
Trans-(R)-3-{4-[3-(3-methyl-5-trifluoromethylphenyl)-1-(4-terf-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (RS)-3-{4-[1-(4-ten*-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(RS)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- 2-hydroxypropionic acid
(S)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[3-(3-Chlorophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-phenylureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(R)-3-{4-[3-Benzyl-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(RS)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl )3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- fluoropropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexen-1-ylphenyl)-3-(3-methanesulfonyl-4-trifluoromethoxyphenyl)- ureidomethyl]benzoylamino}-2-hydroxypropionic acid Trans-(R)-3-{4-[-3-(3,5-bis(methyl)phenyl)-1 -(4-tetf-butylcyclohexyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-(3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfanylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(2,2,4,4-tetrafluoro-4 -/-benzo[1 ,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid 3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2(R)- methoxypropionic acid:
3-(4-{3-(3,5-Dichlorophenyl)-1-[4-(2-methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoyl- amino)-2-(R)-hydroxypropionic acid and (R,S)-3-(4-{3-(3,5-dichlorophenyl)-1-[4-(6- methylcyclohex-1-enyl)phenyl]ureidomethyl}benzoylamino)-2-(R)-hydroxypropionic acid 3-{4-[1 -[4-(4-ten*-Butylcyclohex-1 -enyl)phenyl]-3-(3,5-dichlorophenyl)ureidomethyl]benzoyl- amino}-2-(R)-hydroxypropionic acid (R,S)-3-(4-(3-(3,5-dichlorophenyl)-1 -(4-(3-methylcyclohex-1 - enyl)phenyl)ureidomethyl)benzoylamino)-2-hydroxypropionic acid
3-{4-[3-[1(S)-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)- hydroxypropionic acid 3-{4-[3-Biphenyl-2-ylmethyl-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)- hydroxypropionic acid
(R)-3-{4-[3-(4-Cyano-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[3-(3-ten*-Butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-hydroxymethyl-4-trifluoromethoxyphenyl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-ten*-Butylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1 -(4-terf-Butylcyclohexyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-te/f-Butylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-te/f-Butylcyclohexyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)ureido- methyl]benzoylamino}-2-hydroxypropionic acid (R)-3-{4-[1-(4-terf-Butylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-fluoro-3-nitrophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-isopropylphenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid
(R)-3-{4-[3-(4-Acetylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxy- propionic acid
3-{4-[3-[1(RS)-(4-Bromophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}- 2(R)-hydroxypropionic acid
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-difluorophenyl)ureidomethyl]benzoylamino}-2- hydroxypropionic acid (R)-3-[4-({(4-te_f-Butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid
(R)-3-[4-({(4-tetf-Butylcyclohexyl)-[2-(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid
(R)-3-[4-({(2,2-Diphenylethyl)-[2-(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid
(R)-3-(4-{[(5-Chlorobenzo[ό]thiophene-3-carbonyl)-(2,2-diphenylethyl)amino]methyl}benzoyl- amino)-2-hydroxypropionic acid
(R)-3-[4-({(2,2-Diphenylethyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid (R)-3-(4-{[(4-ten*-Butylcyclohexyl)-(5-chlorobenzo[D]thiophene-3-carbonyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-(4-{[(2,2-Diphenylethyl)-(5-trifluoromethoxy-1H-indole-2-carbonyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(4-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid (R)-3-[4-({(4-Cyclohexylphenyl)-[(3-trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl- amino]-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3-fluoro-5-trifluoromethylphenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid (R)-3-(4-{([(3,5-Bis(trifluoromethyl)phenyl)acetyl]-(4-cyclohexylphenyl)amino)methyl}benzoyl- amino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3-trifluoromethylphenyl)acetyl]amino}methyl)benzoylamino]- 2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[(3,4-dichlorophenyl)acetyl]amino}methyl)benzoylamino]-2- hydroxypropionic acid
(R)-3-(4-{[[(3-Bromophenyl)acetyl]-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2- hydroxypropionic acid
(R)-3-(4-{[(Biphenyl-4-ylacetyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxy- propionic acid (R)-3-(4-{[(4-Cyclohexylphenyl)-(2-naphthylacetyl)amino]methyl}benzoylamino)-2-hydroxy- propionic acid
(R)-3-(4-{[(3-(3,5-Bis(trifluoromethyl)phenyl)propionyl)-(4-cyclohexylphenyl)amino]methyl}- benzoylamino)-2-hydroxypropionic acid
(R)-3-[4-({(4-Cyclohexylphenyl)-[3-(3-nitrophenyl)propionyl]amino}methyl)benzoylamino]-2- hydroxypropionic acid
(2R)-N-[4-({4-cyclohexyl[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-y-?- alanine (2R)-N-[4-({[1 , 1 '-biphenyl]-4-yl[(3,5-dichloroanilino)carbonyl]amino}methyl)benzoyl]-2- hydroxy- .-alanine.
48. The composition according to any one of the claims 1-2 and 34-47, comprising (R)-[3-{4-[1 -(4-Cyclohex-1 -enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- 2R-hydroxypropionic acid as a tert-butylamine salt.
49. The composition according to any one of the claims 1-2 and 34-47, comprising
(R)-[3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}- 2R-hydroxypropionic acid as an L-arginine salt.
50. The composition according to any one of the claims 1-2 and 34-47, comprising (R)-[3-{4- [1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2R- hydroxypropionic acid as a salt with N.N'-dibenzylethylenediamine.
51. The composition according to claim 50 comprising (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.
52. The composition according to any one of the claims 1-2 and 34-47 comprising (2R)-N-[4- ({[1,1'-biphenyl]-4-yl[(3,5-dichloroanilino)carbonyl]amino}methyl)benzoyl]-2-hydroxy-i-?-alanine and benzathine.
53. The composition according to claim 52 comprising (2R)-N-[4-({[1,1'-biphenyl]-4-yl[(3,5- dichloroanilino)carbonyl]amino}methyl)benzoyl]-2-hydroxy-i-?-alanine and benzathine as a 2:1 ratio between compound and N.N'-dibenzylethylenediamine.
54. The composition according to any one of the claims 1-2 and 34-47 comprising ((2R)-N- [4-({4-cyclohexyl[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-y-?-alanine as a salt with N.N'-dibenzylethylenediamine.
55. The composition according to claim 54 comprising ((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.
56. A composition according to claims 1-2 comprising a compound represented by the general formula (I):
Figure imgf000149_0001
wherein
R2 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 R7 and R8 selected from halogen, -CN, -CF3, -OCFs, -NO2, -OR9, -NR9R10 and Ci-e-alkyl,
wherein R9 and R10 independently are hydrogen or Ci-e-alkyl,
X is
O
-(CH2)-(CR12R13)r-(CH2)s— -(CR1 R13)-(CH2)-
-(CH2)-C=C-(CR12R13)r-(CH2)s- -(CH2)q— N- -(CR12R13)r- (CH2)S-
H H >t VV1 '2's '2'q
,11
Figure imgf000150_0001
(CHa)_(CRi2Ria)_0_(CHa) _
Figure imgf000150_0002
wherein
r is O or l ,
q and s independently are 0, 1 , 2 or 3, R11, R12, R13 and R14 independently are hydrogen or Ci-e-alkyl,
D is
Figure imgf000151_0002
wherein
R15, R1 , R1' and R1β independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR 1R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CHzC JNR2^22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -C(O)R21 or -C(O)OR21,
Ci-e-alkyl, C2-e-alkenyl or C2-e-alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, -CF3, -OCF3, -NO2, -OR21, -NR^R22 and Ci-e-alkyl,
• Cs-e-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, Oj-β-cycloalkyl-d-β-alkyl, C^-cyclo-
Figure imgf000152_0001
C3-8-cycloalkyl-C2-6-alkenyl, C3-β-cycloalkyl-C2_e-alkynyl, d-e-cycloalkenyl-d-β-alkyl, C-wrcycloalkenyl-d-e-alkenyl, d-β-cycloalkenyl-d-e-alkynyl, heterocyclyl-Cι_β-alkyl, heterocyclyl-C2-e-alkenyl, heterocyclyl-C2-β-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-d-e-alkyl, aryl-C2-6-alkenyl, aryl-C2__e-alkynyl, heteroaryl, heteroaryl-d-6-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2-e-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and d-e-alkyl,
wherein R and R independently are hydrogen, Ci-e-alkyl or aryl,
or R21 and R22 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,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R28)c-O-,
wherein
a is O, 1 or 2,
c is 1 or 2, R , R24, R25 and R independently are hydrogen, Ci-e-alkyl or fluorine,
R19 and R20 independently are hydrogen, Ci-e-alkyl, Cs-e-cycloalkyl or C3-a-cyclo- alkyl-Cι-6-alkyl,
E is
Figure imgf000153_0001
wherein
R and R independently are
hydrogen, halogen, -CN, -CF3, -OCF3, -OR32, -NR32R33, C^-alkyl, C3^-cycloalkyl, C^-cyclo- alkenyl or aryl,
wherein the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR32, -NR32R33 and Ci-e-alkyl,
wherein
R and R independently are hydrogen or Ci-e-alkyl, or R32 and R33 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 , Rdϋ and RJ1 independently are
■ hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR34, -NR^R35, -SR34, -SfOJR34, -SfOfeR34. -C(O)NR34R35, -OCfOJNR^R35,
-NR34C(O)R35, -OCH2C(O)NR34R35, -CfOJR34 or -CfOJOR34,
■ Ci-β-alkyl, C2-e-alkenyl or C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, CN, -CFs, -OCFs, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
■ C3-β-cycloalkyl, C-m-cycloalkenyl, heterocyclyl, d-β-cycloalkyl-d-e-alkyl, C3_β-cyclo- alkyl-C2_6-alkenyl, CM-cycloalkyl-C2-β-alkynyl, d-β-cycloalkenyl-d-e-alkyl, C4-e-cyclo- alkenyl-d-e-alkenyl, C4.8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Ci-β-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2^-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, hetero- aryl-C2__e-alkenyl or heteroaryl-C2^-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR^R35 and Ci-e-alkyl,
wherein R and R independently are hydrogen, Ci-e-alkyl or aryl, or R34 and R35 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,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)ι-O-, -(CH2)rCR36R37-(CH2)|- or -S-(CH2)t-CR38R37-(CH2)|-S-,
wherein
t and I independently are 0, 1 , 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or Cι_6-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
57. A compound according to claim 56, wherein R2 is hydrogen.
58. A compound according to any of the claims 56 or 57, wherein Z is
Figure imgf000155_0001
wherein R7 and R8 are as defined in claim 56.
59. A compound according to claim 58, wherein Z is XX
60. A compound according to claims 56-59, wherein X is
1 "(CH, 2)'s
Figure imgf000156_0001
"(CH2)q- -N- -(CH2 2>s -(CH2)q— N- (CH2)— O— H
— (CH2 2)'.s -(CH2)α— N -0-(CHA- -N- (CH2 2V's
H H
>12,
CR H— O— (CH2)— -O-(CH2 2)';s or
-N-(CR12R13)— π
wherein q is 0 or 1 , r is 0 or 1 , s is 0, 1 or 2, and R12 and R13 independently are hydrogen or Ci-e-alkyl.
61. A composition according to claims 1-2 comprising a compound represented by the gen-
eral formula (I):
Figure imgf000156_0002
wherein
A is
Figure imgf000157_0001
m is 0 or 1 ,
n isO, 1,2 or 3,
with the proviso that m and n must not both be 0,
R1 is hydrogen, fluoro or -(CH2)0-OR2
oisOorl,
R2 is hydrogen, Ci-e-alkyl, Ci-β-alkanoyl, aryl or aryl-d-6-alkyl,
Xis-N=or-CH=,
Bis
Figure imgf000157_0002
V and W independently are -CH= or -N=,
Y is -O-, -S- or-NH-,
R3, R4 and R5 independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR6, -NR6R7, -SR6, -NR6S(O)2R7, -S(O)2NR6R7, -S(O)NR8R7, -S(O)R6, -S(O)2R6, -C(O)NR6R7, -OC(O)NR6R7, -NR6C(O)R7,
-CH2C(O)NR6R7, -OCH2C(O)NR6R7, -OCH2C(O)OR6, -OC(O)R6, -C(O)R6 or -C(O)OR6,
• Ci-e-alkyl, C2-6-alkenyl or C2.6-alkynyl,
which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CFs, -OCF3, -OR6 and -NR6R7,
• Oj-e-cycloalkyl, C-μβ-cycloalkenyl, heterocyclyl, C3_β-cycloalkyl-Cι_6-alkyl, C^-cyclo- alkyl-Ci-β-alkoxy, C^-cycloalkyloxy, Cs-β-cycloalkyl-d-e-alkylthio, C3-8-cycloalkylthio,
C3-e-cycloalkyl-C2-β-alkenyl, C3^-cycloalkyl-C2-e-alkynyl, C^-cycloalkenyl-Ci-e-alkyl, C4-β-cycloalkenyl-C2-6-alkenyl, d-β-cycloalkenyl-C^-alkynyl, heterocyclyl-Cι-β-alkyl, heterocyclyl-C2_6-alkenyl, heterocyclyl-C2_e-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from fluoro, -C(O)OR6, -CN, -CF3, -OCF3, -OR7, -NR6R7 and d-β-alkyl,
• aryl, arylthio, aryl-d-e-alkylthio, aryloxy, aryloxycarbonyl, aroyl, aryl-d-e-alkoxy, aryl- Cι__β-alkyl, aryl-C2_e-alkenyI, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, het- eroaryl-C2-e-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR6, -CN, -CF3, -OCF3, -NO2, -OR7, -NR6R7 and d-e-alkyl,
R6 and R7 independently are hydrogen or d-β-alkyl,
or R6 and R7 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,
or two of the groups R3 to R5 when placed in adjacent positions together may form a bridge -(CR8R9)s-O-(CR10R11)rO-,
s is 0, 1 or 2,
t is 1 or 2,
R , R , R and R independently are hydrogen, Ci-e-alkyl or fluoro,
D is -(CH2)P-,
Figure imgf000159_0001
or -(CH2)p-O-
p is O, 1 , 2, 3 or 4,
E is
Figure imgf000160_0001
X1, Z1 and W1 independently are -CH= or -N=,
Y1 is -O-, -S- or -NH-,
Q1 is -CH2- or -NH-,
q is 2, 3, 4, 5 or 6,
r is 1, 2, 3, 4 or 5,
R >12 , D R113J a „n„,dj D R14* independently are
• hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2,
-S(O)2CF3, -SCF3, -NO2, -OR17, -NR17R18, -SR17, -NR17S(O)2R18, -S(O)2NR17R18, -S(O)NR17R18, -S(O)R17, -S(O)2R17, -C(O)NR17R18, -OC(O)NR17R18, -NR17C(O)R18, -CH2C(O)NR17R18, -OCH2C(O)NR17R18, -OC(O)R17, -C(O)R17 or -C(O)OR17,
Ci-e-alkyl, C2_e-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CFs, -OCF3, -OR17 and -NR17R18,
C3-β-cycloalkyl, d-β-cycloalkenyl, heterocyclyl, Cs-e-cycloalkyl-d-e-alkyl, d^-cyclo- alkyl-d-e-alkoxy, C3_e-cycloalkyloxy, C3_e-cycloalkyl-C _6-alkylthio, Cs-β-cycloalkylthio, C3-s-cycloalkyl-C2-e-alkenyl, C3_8-cycloalkyl-C2_β-alkynyl, d-e-cycloalkenyl-Ci-e-alkyl, d-β-cycloalkenyl-d-β-alkenyl, C_w-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-β-alkenyl, heterocyclyl-C2-β-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents se- lected from fluoro, -C(O)OR17, -CN, -CF3, -OCF3, -OR17 and -NR17R18,
aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C^-alkoxy, aryl-Ci-e-alkyl, aryl-C2_e-alkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl- C2-e-alkynyl,
of which the cyclic moieties may optionally be substituted with one or more substituents selected from halogen, -C(O)OR17, -CN, -CF3, -OCF3, -NO2, -OR17, -NR17R18 and Ci-e-alkyl,
R17 and R18 independently are hydrogen or Cι_β-alkyl,
or R17 and R18 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,
or two of the groups R12 to R14 when placed in adjacent positions together may form a bridge -(CR19R20)x-O-(CR21R22)y-O-,
x is O, 1 or 2,
y is 1 or 2,
R19, R20, R21 and R22 independently are hydrogen, Ci-e-alkyl or fluoro, R15 and R16 independently are hydrogen, halogen, -CN, -CF3, -OR23, -NR23R24, Ci-e-alkyl, Cs-e-cycloalkyl, C-^-cycloalkenyl, aryl or aryl-Ci-e-alkyl,
wherein the cyclic moieties may optionally be substituted with one or more substituents se- lected from halogen, -CN, -CF3, -NO2, -OR23, -NR23R24 and Ci-e-alkyl,
R23 and R24 independently are hydrogen or Cι_β-alkyl, or
R23 and R24 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,
or E is
Cι_6-alkyl, C2-β-alkenyl or C2^-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, - CN, -CFs, -OCF3, -NO2, -OR25,-SR25, -NR25R26 and Ci-e-alkyl,
R25 and R26 independently are hydrogen or Ci-e-alkyl, or
R25 and R26 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,
Z is -(CR27R28)V-(O)W-(CR29R30)Z-, v and z independently are 0, 1 or 2,
w is O oM,
R , R , RΛ and R* independently are hydrogen or Ci-β-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
62. A compound according to claim 61, wherein A is o
JL..
HO (CH 2 )„ ^ vvherein n is as defined in claim 61.
63. A compound according to claim 61, wherein A is o
HO"^\ .
64. A compound according to claim 61, wherein A is
Figure imgf000163_0001
65. A compound according to any of the claims 61-64, wherein B is
Figure imgf000164_0001
wherein R3 to R5 are as defined in claim 61.
66. A composition according to claims 1-2 comprising a compound represented by the general formula (I):
Figure imgf000164_0002
wherein
A is
Figure imgf000164_0003
m is 0 or 1 ,
n is 0, 1, 2 or 3,
with the proviso that m and n must not both be 0, R4 is hydrogen, halogen or -(CH2)0-OR5,
o is 0 or 1 ,
R5 is hydrogen, Ci-e-alkyl, Ci-e-alkanoyl, aryl or aryl-d-e-alkyl,
R1 and R2 independently are hydrogen, halogen or Ci-e-alkyl, or R1 and R2 are combined to form a double bond,
R3 is hydrogen, Ci-e-alkyl or halogen, or R3 and R2 are combined to form a double bond to oxygen,
X is arylene or heteroarylene, which may optionally be substituted with one or two groups R6 and R7 selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR8, -NR8R9 and Ci-e-alkyl,
R8 and R9 independently are hydrogen or Ci-e-alkyl,
Y is -C(O)-, -O-, -NR10-, -S-, -S(O)-, -S(O)2- or -CR11R12-,
R10 is hydrogen or Ci-e-alkyl,
R11 and R12 independently are hydrogen, Ci-e-alkyl or hydroxy, or R11 is combined with R1 to form a double bond, and R12 is hydrogen, d-e-alkyl or hydroxy,
Z is -C(O)-(CR13R1V -O-(CR13R1 )p-, -S-(CR13R14)P-, -S(O)-(CR13R14)p-, -S(O)2-(CR13R14)p-, -NR15-(CR13R14)p- or -(CR 3R14)P-, p is 0, 1 or 2,
R13 and R14 independently are selected from hydrogen, -CF3, -OCF3, -OCHF2 and Ci-e-alkyl,
R15 is hydrogen or C1_6-alkyl,
D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R , R17, R18, R19, R20 and R21, wherein
R16, R17, R18 and R19 independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR^R23, -SR22, -NR22S(O)2R23, -S(O)2NR22R23, -S(O)NR22R23, -S(O)R22, -S(O)2R22, -C(O)NR22R23, -OC(O)NR22R23, -NR22C(O)R23, -CH2C(O)NR22R23, -OCH^OJNR^R23, -CH2OR22, -CH2NR22R23,
-OC(O)R22, -dOJR or -Cf jOR22,
Ci-e-alkyl, C2_6-alkenyl or C2-β-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, CN, -CF3, -OCHF2, -OCF3, -NO2, -OR22, -NR^R23 and Ci-e-alkyl,
• C3-β-cycloalkyl, d-β-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-d-e-alkyl, C^-cyclo- alkyl-Cι_e-alkoxy, Cs-β-cycloalkyloxy, Qj-e-cycloalkyl-Ci-β-alkylthio, C3_e-cycloalkylthio, C3.8-cycloalkyl-C2^-alkenyl, Qj-β-cycloalkyl-d-β-alkynyl, C4-β-cycloalkenyl-Cι_e-alkyl,
C4.8-cycloalkenyl-C2-e-alkenyl, C4.8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Ci-e-alkyl, heterocyclyl-C2-β-alkenyl, heterocyclyl-C2_e-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2^-alkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-d-e-alkyl, heteroaryl-C2_e-alkenyl or heteroaryl-C2^-alkynyl, of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -dOJOR22, -CN, -CF3, -OCF3, -OCHF2, -NO2, - OR22, -NR R23 and Ci-e-alkyl,
R22 and R23 independently are hydrogen, Ci-e-alkyl, aryl-Ci-e-alkyl or aryl, or R22 and R23 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR24R25)a-O-(CR26R27)c-O-,
a is 0, 1 or 2,
c is 1 or 2,
R24, R25, R26 and R27 independently are hydrogen, Ci-e-alkyl or fluoro,
R20 and R2 independently are hydrogen, Ci-e-alkyl, Cs-e-cycloalkyl or C^-cyclo- alkyl-Cι-6-alkyl,
E is
Qj-β-cycloalkyl or C-μe-cycloalkenyl, which may optionally be substituted with one or two sub- stituents R28 and R29, which are independently selected from
• hydrogen, halogen, -CN, -CF3, -OCF3, -OCHF2, -OR33, -NR R34, Ci-e-alkyl, C∞- cycloalkyl, C-^-cycloalkenyl, heteroaryl and aryl, wherein the heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR33, -NR∞R34 and d-β-alkyl,
R33 and R34 independently are hydrogen or Ci-e-alkyl,
or R33 and R34 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-C2-6-alkenyl or aryl-C2.6-alkynyl, of which the aryl and heteroaryl moieties may optionally be substituted with one or more substitutents R28, R29, R30, R31 and R32,
wherein R28 and R29 are as defined above, and R30, R31 and R32 are independently selected from
• hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR35, -NR∞R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, -NR35C(O)R36, -OCH2C(O)NR35R36, -C(O)R35 and -C^JOR35,
C2-β-alkenyl and C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CFs, -OCFs, -OCHF2, -NO2, -OR35, -NR35R36 and d-e-alkyl,
• C3-β-cycloalkyl, d-β-cycloalkenyl, heterocyclyl, d-β-cycloalkyl-d-e-alkyl, C^-cyclo- alkyl-C2^-alkenyl, C3-β-cycloalkyl-C2_β-alkynyl, C^-cycloalkenyl-d-e-alkyl, d-β-cyclo- alkenyl-C2_e-alkenyl, d-β-cycloalkenyl-d-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2-e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- d-β-alkyl, aryl-C2-e-alkenyl, aryl-C2_e-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, hetero- aryl-C2_β-alkenyl and heteroaryl-C2-β-alkynyl,
of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -OCHF2, -NO2, -OR35, - NR∞R36 and d-e-alkyl,
wherein R35 and R36 independently are hydrogen, Ci-β-alkyl or aryl,
or R35 and R36 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,
or two of the substituents R30, R31 and R32 when attached to the same ring carbon atom or adjacent ring carbon atoms together may form a bridge -O-(CH2)t-CR37R38-(CH2)rO-, -(CH2)t-CR37R38-(CH2)ι- or -S-(CH2)t-CR37R38-(CH2)i-S-,
t and I independently are 0, 1 , 2, 3, 4 or 5,
R37 and R38 independently are hydrogen or Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
67. A compound according to claim 66, wherein A is
Figure imgf000169_0001
wherein m, n and R4 are as defined in claim 66.
68. A compound according to claim 66, wherein A is
Figure imgf000170_0001
69. A compound according to claim 66, wherein A is
Figure imgf000170_0002
70. A compound according to claim 66, wherein A is
Figure imgf000170_0003
71. A compound according to any of the claims 66-70, wherein X is monocyclic arylene or heteroarylene, which may optionally be substituted as defined in claim 66.
72. A compound according to any of the claim 71 , wherein X is Rθ
-<&
wherein R6 and R7 are as defined in claim 66.
73. A compound according to claim 72, wherein X is
Figure imgf000171_0001
wherein R6 and R7 are as defined in claim 66.
74. A compound according to claims 66-73 wherein E is
Figure imgf000171_0002
wherein R30, R31 and R32 are as defined in claim 66.
75. A compound according to claim 74, wherein R30, R31 and R32 independently are
• hydrogen,
• halogen, -OCF3, -OCHF2 or -SCF3,
• Ci-e-alkyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35 and -NR R36,
cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35, -NR35R36 and Ci-e-alkyl,
• phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 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, -CF3, -OCF3, -NO2, -OR35, _NR 35 R36 and d-e-alkyl,
R35 and R36 independently are hydrogen or Ci-e-alkyl.
76. A compound according to claim 75, wherein E is
Figure imgf000172_0001
Figure imgf000172_0002
77. A compound according to claims 66-76, wherein R and R are both hydrogen
78. A compound according to claims 66-76, wherein R1 and R2 are combined to form a double bond.
79. A compound according to claims 66-78, wherein R3 is hydrogen.
80. A compound according to claim 66-79, wherein Z is NH or -C(O)-
81. A compound according to claim 66-80, wherein D is
Figure imgf000172_0003
wherein R16, R17 and R18 are as defined in claim 66.
82. A compound according to claim 81 , wherein R , R and R independently are
hydrogen, halogen, -CF3, -OCF3, -SCF3, Ci-e-alkyl,
Figure imgf000173_0001
phenyl, cyclopentyl, cyclohexyl or phenoxy,
or two of the groups R to R18 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF2-O- or -O-CH2-O-.
83. A compound according to any one of the claims 66-82 wherein the compound is one of the following:
(Z)-3-{4-[4-Biphenyl-4-yl-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoylamino}propionic acid
(Z)-3-{4-[2-Biphenyl-4-yl-4-(4-chlorophenyl)-4-oxobut-2-enoyl]benzoylamino}propionic acid
(Z)-3-{4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)but-2-enoyl]benzoylamino}- propionic acid
3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo-butyryl]benzoylamino}- propionic acid
((R)3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo- butyryl]benzoylamino}-propionic acid (S)3-{4-[4-(3,5-Bis-trifluoromethylphenyl)-2-(4-cyclohexylphenyl)-4-oxo- butyryl]benzoylamino}-propionic acid
84. A composition according to claims 1-2 comprising a compound represented by the general formula (I):
Figure imgf000173_0002
wherein A is
Figure imgf000174_0001
m is 0 or 1 ,
n is 0, 1 , 2 or 3,
with the proviso that m and n must not both be 0,
R1 is hydrogen, fluoro or -(CH2)0-OR2,
o is 0 or 1 ,
R2 is hydrogen, Ci-β-alkyl, Cι_6-alkanoyl , aryl or aryl-d_β-alkyl,
X is N, CH or C with a double bond to one substituent,
Z is -CR3R4-, -(C=O)-(NR5)-(Cι.e-alkyl)κ-, -(C=O)-O-(C^-alkyl)K-, -(C=O)-(C^-alkyl)K-,
Figure imgf000174_0002
-(C=O)-O-(C2^-alkenyl)K-, -(C=O)-(C2^-alkenyl)K-,
-(Cι_e-alkenyl)κ(C=O)-O-
wherein k is 0 or 1 , R3, R4 and R5are independently selected from hydrogen, d-e-alkyl or aryl,
Y is -(Cι^-alkyl)s-(C=O)-(C1-β-alkyl),-, -(C^-alkenyl)s-(C=O)-(Cι^-alkyl)r, -Ci-e-alkyl-, -C2-e- alkenyl-, or -CR6R7-
wherein s and t independently are 0 or 1 ;
wherein R6 , R7and R8 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 R16, R17, R18, R19, R20 and R21, wherein
R16, R17, R18 and R19 independently are
• hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3,
-OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR^R23, -SR22, -NR22S(O)2R23, -S(O)2NR22R23, -SfOJNR^R23, -SfOJR22, -S^JzR22, -dOJNR^R23, -OC(O)NR22R23, -NR22C(O)R23, -CH2C(O)NR22R23, -OCH2C(O)NR22R23, -CH2OR22, -CHzNR R23, -OdOJR22, -C(O)R22or -C(O)OR22,
Cι.β-alkyl, C2_e-alkenyl or C2^-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, CN, -CFs, -OCF3, -NO2, -OR22, -NR^R23 and d-e-alkyl,
C3-β-cycloalkyl,
Figure imgf000175_0001
C3_β-cyclo-
Figure imgf000175_0002
Cs-β-cycloalkyloxy, C3_β-cycloalkyl-Cι_β-alkylthio, C3-β-cycloalkylthio, C3.8-cycloalkyl-C2^-alkenyl, C3_β-cycloalkyl-C2-e-alkynyl, d-e-cycloalkenyl-d-e-alkyl,
Figure imgf000175_0003
heterocyclyl-Cι^-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2.6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-Ci-e-alkoxy, aryl-Ci-e-alkyl, aryl-C2-β-alkenyl, aryl-C2^-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, heteroaryl-C2-e-alkenyl or heteroaryl-C2_β-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, -C(O)OR22, -CN, -CF3, -OCF3, -NO2, -OR22, -NR22R23 and Ci-e-alkyl,
R22 and R23 independently are hydrogen, Ci-e-alkyl, aryl-Ci-e-alkyl or aryl, or R22 and R23 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,
or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge -(CR24R25)a-O-(CR26R27)c-O-,
a is O, 1 or 2,
c is 1 or 2,
R24, R25, R28 and R27 independently are hydrogen, Ci-e-alkyl or fluoro,
R20 and R21 independently are hydrogen, d-β-alkyl, Cs-e-cycloalkyl or d^-cyclo- alkyl-Cι_β-alkyl,
E is
ds-β-cycloalkyl or d-β-cycloalkenyl, which may optionally be substituted with one or two substituents R28and R29, which are independently selected from • hydrogen, halogen, -CN, -CF3, -OR33, -NR∞R34, Ci-e-alkyl, C^-cycloalkyl, C^-cyclo- alkenyl, heteroaryl and aryl,
wherein the heteroaryl and aryl groups optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -NO2, -OR33, -NR^R34 and Ci-e-alkyl,
R33 and R34 independently are hydrogen or Ci-e-alkyl,
or R33 and R34 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-C2^-alkenyl or aryl-C2^-alkynyl, of which the cyclic moieties may option- ally be substituted with one to three substitutents R30, R31 and R32, which are independently selected from
• hydrogen, halogen, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR35, -NR35R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, -NR35C(O)R3β, -OCH2C(O)NR35R36, -C(O)R35 and -C(O)OR35,
• Ci-e-alkyl, C2_e-alkenyl and C2-e-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCFs, -SCFs, -NO2, -OR35, -NR∞R36 and Ci-e-alkyl,
• C3_β-cycloalkyl, d-e-cycloalkenyl, heterocyclyl, Cs-β-cycloalkyl-Cι_6-alkyl, C^-cycIo- alkyl-C2-e-alkenyl, Cs_β-cycloalkyl-C2.6-alkynyl, d-e-cycloalkenyl-d-e-alkyl, d-β-cyclo- alkenyl-C2-e-alkenyl, d-β-cycloalkenyl-d-e-alkynyl, heterocyclyl-Ci-e-alkyl, heterocy- clyl-C2-e-alkenyl, heterocyclyl-C2_e-alkynyl, aryl, aryloxy, aroyl, aryl-Ci-e-alkoxy, aryl- Ci-e-alkyl, aryl-C2-e-alkenyl, aryl-C2__β-alkynyl, heteroaryl, heteroaryl-Ci-e-alkyl, hetero- aryl-C2-β-alkenyl and heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen, -CN, -CF3, -OCF3, -SCF3, -NO2, -OR35, -NR∞R36 and d-e-alkyl,
wherein R35 and R36 independently are hydrogen, Cι_β-alkyl or aryl,
or R35 and R36 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,
or two of the substituents R30, R31 and R32 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)rCR37R38-(CH2)rO-, -(CH2)»-CR37R38-(CH2)r or -S-(CH2)t-CR37R38-(CH2),-S-,
t and I independently are 0, 1 , 2, 3, 4 or 5,
R37 and R38 independently are hydrogen or Ci-e-alkyl,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
85. A compound according to claim 84, wherein A is
Figure imgf000178_0001
wherein m, n and R4 are as defined in claim 84.
86. A compound according to claim 84, wherein A is
Figure imgf000179_0001
87. A compound according to claim 84, wherein A is
Figure imgf000179_0002
88. A compound according to any one of the preceding claims 84-87, wherein D is
Figure imgf000179_0003
wherein R , R and R independently are
• hydrogen, halogen, CN, -CF3, -OCF3, -SCF3, -S(O) Ci-e-alkyl-, -C(O) d-e-alkyl-, d-e- alkyl, Ci-e-alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy,
• or two of the groups R16 to R18 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF2-O- or -O-CH2-O-.
89. A compound according to any one of the preceding claims 84-88, wherein E is
Figure imgf000180_0001
wherein R , R , Rr, Rdl and Rr are independently selected from
hydrogen,
• halogen, -OCF3, -OCHFz, -SCFs, or -CF3,
Cι_e-alkyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35 and -NR R36,
• cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35, -NR∞R36 and Ci-e-alkyl,
phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 and Cι.β-alkyl,
• phenoxy or benzyloxy, of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR 35 ,
NRd0RJB and Ci-e-alkyl, • thiadiazolyl,
R35 and R3β independently are hydrogen or Cι_β-alkyl.
90. A compound according to claims 84-89, wherein Y is -C=O-, -CH2-.
91. A compound according to claims 84-90, wherein Z is -CH2-, -(C=O)-(NH), -(C=O)-O - or - (C=O)-CH2-.
92. The compound according to any one of the preceding claims 84-91 , wherein the compound is 3-{4-[(4-Cyclohexylbenzyl)-(4-trifluoromethoxybenzyl)amino]benzoylamino}- propionic acid.
93. The composition according to any one of the preceding claims, wherein the basic counter ion is N.N'-dibenzylethylenediamine (benzathine).
94. The composition according to claim 93, wherein the ratio of compound to counter ion is 2:1 ;
95. A composition comprising a glucagon antagonist according to any one of the claims 3-94 as a solvate.
96. A composition according to claim 95 wherein the solvate is selected from ethanol, 2- propanol, 2-methyl-1 -propanol, n-butanol, 2-butanol, 3-methyl-1 -butanol, diethyl ether, tert- butyl-methylether, tetrahydrofuran, anisol, acetone, 2-butanon, methylacetate, ethylacetate, n-propylacetate and toluene.
97. A composition according to any of the claims 95-96 comprising 3-{4-[1-(4-Cyclohex-1- enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2f?-hydroxypropionic acid in a solvate form.
98. A composition according to claim 97 comprising 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, tert-butyl-methylether, tetrahydrofuran, anisol, acetone, 2- butanon, methylacetate, ethylacetate, n-propylacetate and toluene.
99. A composition according to any of the claim 98 comprising 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.
100. A composition according to any of the claims 95-96 comprising Λ/-[4-({4-(1-cyclohexen- 1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-yff-alanine as a solvate
101. A composition according to any of the claim 100 comprising Λ/-[4-({4-(1 -cyclohexen-1 - yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]- _ -alanine as a solvate with acetone, butanol, ethanol 2-propanol or 1 -propanol.
102. A pharmaceutical composition comprising, as an active ingredient a compound accord- ing to any of the claims 1-101 together with pharmaceutically acceptable carriers and/or diluents.
103. A pharmaceutical composition according claim 102 in a unit dosage form comprising from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg compound.
104. The use of a composition according to any of the claims 1-101 for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by glucagon receptors.
105. The invention provides the use of a composition according to claim 104 for the preparation of a medicament useful in the treatment and/or prevention of diabetes and/or obesity.
106. 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 effective amount of a composition according to claims 1-101. 107. 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 composition according to claim 1-101.
108. Use of a composition according to any of the claims 1 -101 , for the preparation of a medicament. 109. 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 :
a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution d) isolating the precipitate e) optionally drying the obtained solvate.
110. The process of claim 109, wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
182
106. 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 effective amount of a composition according to claims 1-101.
107. 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 composition according to claim 1-101.
108. Use of a composition according to any of the claims 1-101 , for the preparation of a medicament.
109. 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 :
a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution d) isolating the precipitate e) optionally drying the obtained solvate.
110. The process of claim 109, wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
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