WO2002040444A1 - Antagonistes/agonistes inverses de glucagon - Google Patents
Antagonistes/agonistes inverses de glucagon Download PDFInfo
- Publication number
- WO2002040444A1 WO2002040444A1 PCT/DK2001/000759 DK0100759W WO0240444A1 WO 2002040444 A1 WO2002040444 A1 WO 2002040444A1 DK 0100759 W DK0100759 W DK 0100759W WO 0240444 A1 WO0240444 A1 WO 0240444A1
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- WIPO (PCT)
- Prior art keywords
- propionic acid
- ureidomethyl
- benzoylamino
- cyclohexylphenyl
- cyclohex
- Prior art date
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- VROLEVNZGUMOPL-UHFFFAOYSA-N C=C(c(cc1)ccc1Cl)NC(N(Cc(cc1)ccc1C(NCCC(O)=O)=O)C(CC1)CCC1C1CCCCC1)=O Chemical compound C=C(c(cc1)ccc1Cl)NC(N(Cc(cc1)ccc1C(NCCC(O)=O)=O)C(CC1)CCC1C1CCCCC1)=O VROLEVNZGUMOPL-UHFFFAOYSA-N 0.000 description 1
- PPZMTDOTNGJTHF-UHFFFAOYSA-N CC(C)c1n[o]c(-c2cc(NC(N(Cc(cc3)ccc3C(NCCC(O)=O)=O)C(CC3)CCC3C3CCCCC3)=O)ccc2)n1 Chemical compound CC(C)c1n[o]c(-c2cc(NC(N(Cc(cc3)ccc3C(NCCC(O)=O)=O)C(CC3)CCC3C3CCCCC3)=O)ccc2)n1 PPZMTDOTNGJTHF-UHFFFAOYSA-N 0.000 description 1
- KMSUSFXZQYCQLB-UHFFFAOYSA-N CC(c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c(cc2)ccc2C2=CCCCC2)=O)ccc1)=O Chemical compound CC(c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c(cc2)ccc2C2=CCCCC2)=O)ccc1)=O KMSUSFXZQYCQLB-UHFFFAOYSA-N 0.000 description 1
- ZIDXISBAJADYIX-UHFFFAOYSA-N CC(c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c2ccc(C3CCCCC3)cc2)=O)ccc1)=O Chemical compound CC(c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c2ccc(C3CCCCC3)cc2)=O)ccc1)=O ZIDXISBAJADYIX-UHFFFAOYSA-N 0.000 description 1
- GVAVSOHTQIMWFU-UHFFFAOYSA-O CCc(ccc(NC(N(Cc(cc1)ccc1C(NCCC(O)=O)=O)c(cc1)ccc1C1=CCCCC1)=O)c1)c1[N+](O)=O Chemical compound CCc(ccc(NC(N(Cc(cc1)ccc1C(NCCC(O)=O)=O)c(cc1)ccc1C1=CCCCC1)=O)c1)c1[N+](O)=O GVAVSOHTQIMWFU-UHFFFAOYSA-O 0.000 description 1
- MBTVHPQXEULWOT-UHFFFAOYSA-O CO[N+](c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c(cc2)ccc2C2=CCCCC2)=O)ccc1)=O Chemical compound CO[N+](c1cc(NC(N(Cc(cc2)ccc2C(NCCC(O)=O)=O)c(cc2)ccc2C2=CCCCC2)=O)ccc1)=O MBTVHPQXEULWOT-UHFFFAOYSA-O 0.000 description 1
- 0 OC(CCNC(c1ccc(CN(C(NC(*c2ccc3Cl)=Sc2c3Cl)=O)c2ccc(C3CCCCC3)cc2)cc1)=O)=O Chemical compound OC(CCNC(c1ccc(CN(C(NC(*c2ccc3Cl)=Sc2c3Cl)=O)c2ccc(C3CCCCC3)cc2)cc1)=O)=O 0.000 description 1
- AXTQUBQPPROPKF-UHFFFAOYSA-N OC(CCNC(c1ccc(CN(C(Nc2cc(C(F)(F)F)cc(F)c2)=O)c2ccc(C3CCCCC3)cc2)cc1)=O)=O Chemical compound OC(CCNC(c1ccc(CN(C(Nc2cc(C(F)(F)F)cc(F)c2)=O)c2ccc(C3CCCCC3)cc2)cc1)=O)=O AXTQUBQPPROPKF-UHFFFAOYSA-N 0.000 description 1
- NDLRRZJEYCZAMF-UHFFFAOYSA-N OC(CCNC(c1ccc(CN(C(Nc2nc(ccc(Cl)c3Cl)c3[s]2)=O)c(cc2)ccc2C2=CCCCC2)cc1)=O)=O Chemical compound OC(CCNC(c1ccc(CN(C(Nc2nc(ccc(Cl)c3Cl)c3[s]2)=O)c(cc2)ccc2C2=CCCCC2)cc1)=O)=O NDLRRZJEYCZAMF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- C07C275/26—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 rings other than six-membered aromatic rings
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- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—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
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- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/47—Y being a hetero atom
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/42—Y being a hetero atom
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
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- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
- Glucagon is a key hormonal agent that, in co-operation with insulin, mediates ho- meostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
- Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.
- Diabetes mellitus is a common disorder of glucose metabolism.
- the disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin- dependent form, or Type 2 diabetes, which is non-insulin-dependent in character.
- Subjects with Type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
- absolute or relative elevated glucagon levels have been shown to contrib- ute to the hyperglycemic state.
- glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent glucagon-induced responses.
- the antagonist can be peptidic or non-peptidic in nature.
- Native glucagon is a 29 amino acid peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH.
- Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al., Science 259, 1614, (1993)).
- the receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
- Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred.
- non-peptide glucagon antagonists a quinoxa- line derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6J-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)).
- WO 94/14426 (The Wellcome Foundation Limited) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthra- cenedione groups, and its synthetic analogues, as glucagon antagonists.
- US 4,359,474 (Sandoz) discloses the glucagon inhibiting properties of 1 -phenyl pyrazole derivatives.
- US 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibiting agents.
- WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists.
- US 5,776,954 discloses substituted pyridyl pyrroles as glucagon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and US 5,880,139 (Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. Furthermore, WO 97/16442 and US 5,837,719 (Merck & Co., Inc.) disclose 2,5-substi- tuted aryl pyrroles as glucagon antagonists.
- WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity.
- Madsen et al. J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2- (benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists.
- WO 99/01423 and WO 00/39088 disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists. These known glucagon antagonists differ structurally from the present compounds.
- the present invention is based on the unexpected observation that compounds belonging to the series of the compounds disclosed below have a high binding affinity for the glucagon receptor and act to antagonize the action of glucagon.
- the present invention relates to a compound selected from:
- geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
- the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
- Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedi- sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glu- tamic, benzenesulfonic, p-toluenesulfonic acids and the like.
- compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by refer- ence.
- metal salts include lithium, sodium, potassium, magnesium salts and the like.
- ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, butyl-, tetramethylammonium salts and the like.
- Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
- the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
- the acid addition salts may be obtained as the direct products of compound synthesis.
- the free base may be dissolved in a suitable solvent containing the ap-litiste acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
- the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
- the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharma- cologically active substances. In general, such prodrugs will be functional derivatives of present compounds, which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- the invention also encompasses active metabolites of the present compounds.
- the compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment 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 pre-vention of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, Type 1 diabetes, Type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, gluca- gonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc. Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secretions and to reverse intestinal hypomobility due to glucagon administration.
- the invention relates to a compound according to the invention for use as a medicament.
- the invention also relates to pharmaceutical compositions comprising, as an active 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 inven- tion for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disorder or disease, wherein a glucagon antagonistic action is beneficial.
- the invention also relates to a method for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
- the present compounds are used for the preparation of a medicament for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
- the present compounds are used for the preparation of a medicament for the treatment and/or prevention of hyperglycemia.
- the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
- the present compounds are effective in lowering the blood glucose, both in the fasting and the postprandial stage.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment 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.
- 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. 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.
- 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.
- treatment of a patient with the present compounds is combined with diet and/or exercise.
- the present compounds are administered in combination with one or more further active substances in any suitable ratios.
- further active substances may eg be selected from antiobesity agents, antidiabetics, antihyperten- sive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.
- the present compounds may be adminis- tered in combination with one or more antiobesity agents or appetite regulating agents.
- Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releas- ing 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,
- the antiobesity agent is leptin.
- the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
- the antiobesity agent is sibutramine.
- the antiobesity agent is orlistat.
- the antiobesity agent is mazindol or phentermine.
- the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
- Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg Asp B28 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro B29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 and GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.
- the orally active hypoglycaemic agents preferably comprise imidazolines, sulpho- nylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitiz- ers, insulin secretagogues, such as glimepride, ⁇ -glucosidase inhibitors, 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 mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1
- the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 629 human insulin, Lantus, or a mix-preparation comprising one or more of these.
- insulin an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 629 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, glibencla- mide, glipizide, glimepir.de, glicazide or glyburide.
- a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibencla- mide, glipizide, glimepir.de, glicazide or glyburide.
- the present compounds are administered in combination with a biguanide eg metformin.
- the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
- the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 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), which are incorporated herein by reference.
- the present compounds may be administered in combination with an insulin sensitizer eg such as Gl 262570, YM-440, MCC- 555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr.
- an insulin sensitizer eg 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
- the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
- an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
- the present compounds may be administered in combination with nateglinide.
- the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
- an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
- the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with met- formin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
- a sulphonylurea such as glyburide
- a sulphonylurea and acarbose such as glyburide
- a sulphonylurea and acarbose such as glyburide
- 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.
- ⁇ -blockers such as alprenolol, atenolol, timolol, pin
- 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 sublingual), 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.
- 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 powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
- De- pot 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 dosages such as 1 to 3 dosages.
- the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
- a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
- parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
- typically doses are in the order of about half the dose employed for oral administration.
- the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
- One example is an acid addition salt of a compound having the utility of a free base.
- a compound according to the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound in question with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.
- Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
- solutions of the novel compounds according to the invention in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
- aqueous solutions should be suitably buffered if necessary and the liquid dilu- ent first rendered isotonic with sufficient saline or glucose.
- the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
- the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
- Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
- liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- the pharmaceutical compositions formed by combining the present compounds and the pharmaceutically acceptable carri- ers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
- the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
- the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
- the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
- the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
- a typical tablet that may be prepared by conventional tabletting techniques may contain:
- Active compound (as free compound or salt thereof) 5.0 mg
- composition of the invention may comprise a compound according to the invention in combination with further pharmacologically active substances such as those described in the foregoing.
- the HPLC pump was connected to two eluent reservoirs containing: A 0.01 % TFA in water
- the analysis was performed at 40 °C by injecting an appropriate volume of the sample (preferably 1 ⁇ L) onto the column, which was eluted with a gradient of acetonitrile.
- HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
- Sedex 55 evaporative light scattering detector • A Valco column switch with a Valco actuator controlled by timed events from the pump.
- the Sciex Sample control software running on a Macintosh PowerPC 7200 computer was used for the instrument control and data acquisition.
- the HPLC pump was connected to four eluent reservoirs containing:
- the requirements for the samples are that they contain approximately 500 ⁇ g/ml of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)
- the analysis was performed at room temperature by injecting 20 ⁇ l of the sample solution on the column, which was eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions were used.
- the eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 ⁇ l/min through approx. 1 m 75 ⁇ fused silica capillary to the API interface of API 100 spectrometer.
- the remaining 1.48 ml/min was passed through the UV detector and to the ELS detector.
- the detection data were acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.
- E is 4-cyclohexylphenyl, 4-cyclohex1-enylphenyl or 4-cyclohexylcyclohexyl
- D is as defined for the present compounds and R is C ⁇ -alky!.
- C ⁇ -alky 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, fe/f-butyl, n-pentyl, isopentyl, neopentyl, terf-pentyl, n-hexyl, isohexyl and the like.
- This compound can also be prepared as described in Justus Liebigs Ann. Chem., 472, 1-89, 1929.
- 4-Cvclohexylaniline is commercially available (e.g. from Lancaster or Avocado)
- 4-Cvclohexylcyclohexylamine is described in the literature: H. Booth et al., J. Chem.
- Step B The above 4-[(4-cyclohex-1-enylphenylamino)methyl]benzoic acid methyl ester (5 g,
- Step D To a solution of (A3) (0.81 mmol) in DMF (4 ml) were added 3-[(dimethyliminium)-
- the compounds of the invention may also be prepared according to the following general procedure (B):
- E is 4-cyclohexylphenyl, 4-cyclohex1-enylphenyl or 4-cyclohexylcyclohexyl
- D is as defined for the present compounds and R is C ⁇ - 6 -alkyI.
- the compounds of the invention may also be prepared on solid support according to the following general procedure (C):
- E is 4-cyclohexylphenyl, 4-cyclohex-1-enylphenyl or 4-cyclohexylcyclohexyl
- D is as defined for the present compounds and Resin denotes a polystyrene resin with a linker such as the Wang linker:
- PS denotes polystyrene
- the reaction is known (Wang S. J., J. Am. Chem. Soc. 95, 1328, 1973) and is generally performed by stirring polystyrene resin loaded with a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopro- pylcarbod ⁇ mide or dicyclohexylcarbodiimide in the presence of a catalyst such as ⁇ /,A/-4-di- methylaminopyridine.
- a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopro- pylcarbod ⁇ mide or dicyclohexylcarbodiimide
- a catalyst such as ⁇ /,A/-4-di- methylaminopyridine.
- the esterification is carried out in a solvent such as THF, dioxane, toluene, dichloromethane, DMF, ⁇ /-methylpyrrolidinone or a mixture of two or more of these.
- a solvent such as THF, dioxane, toluene, dichloromethane, DMF, ⁇ /-methylpyrrolidinone or a mixture of two or more of these.
- the reactions are performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
- excess of reagents is removed by filtration.
- the resin is successively washed with the solvent used in the reaction, followed by washings with methanol.
- the resin bound product can be further dried and analyzed.
- the Fmoc protecting group is removed using a solution of 20% piperidine in DMF which is added to the resin and vortexed for 0.5 hours. After draining the resin is washed with DMF containing HOBt (50 mg/ml) and DMF.
- acylation (The combinatorial index, Ed. Bunin, B. A. 1998, Academic Press, p. 78) is performed by adding an excess of acid (111) in a solvent such as DMF, ⁇ /-methylpyrroli- dinone, THF, dichloromethane, 1 ,2-dichloroethane, acetonitrile, DMSO or a mixture of two or more of these, optionally in the presence of a base such as A/-methylmorpholine, triethyl- amine, diisopropylethylamine, dicyclohexylmethylamine or another tertiary amine, followed by a coupling reagent such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 ,1 '-car- bonyldiimidazole, 2-(1/-/-9-azabenzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hex
- the reaction is generally known (The combinatorial index, Ed. Bunin, B. A. 1998, Academic Press, p. 133) and is generally performed by stirring resin bound aldehyde or ketone with an excess of amine at low pH (by addition of an acid, such as acetic acid or formic acid) in a solvent such as THF, DMF, ⁇ /-methylpyrrolidinone, methanol, ethanol, DMSO, di- chloromethane, 1 ,2-dichloroethane, trimethyl orthoformate, triethyl orthoformate, or a mixture of two or more of these.
- reducing agent sodium cyanoborohydride may be used.
- the reaction is performed between 20 °C and 120 °C, preferably at 25 °C.
- the reaction is generally known (Organic synthesis on solid phase. D ⁇ rwald, F.Z. 2000, Wiley VCH, p. 331) and is generally performed by stirring resin bound amine with an excess of isocyanate in a solvent such as THF, DMF, ⁇ /-methylpyrrolidinone, dichloromethane, 1 ,2-dichloroethane, toluene or a mixture of two or more of these.
- the reaction is performed between 20 °C and 80 °C, preferably at 25 °C.
- Step E The reaction is known (The combinatorial index, Ed. Bunin B. A., 1998, Academic press, p. 21) and is generally performed by stirring resin bound intermediate obtained in step D with a 50-95% solution of TFA.
- the final cleavage is carried out in a solvent such as THF, dichloromethane, 1 ,2-dichloroethane, 1 ,3-dichloropropane, toluene or a mixture of two or more of these.
- the reaction is performed between 0 °C and 80 °C, preferably between 20 °C and 40 °C.
- the product is removed by filtration.
- the resin is successively washed with dichloromethane.
- the product and washings are collected.
- the solvent is removed and the product is dried in vacuo.
- the resin can be a 2-chlorotrityl resin.
- step A is a nucleo- philic reaction of Fmoc-protected beta alanine with 2-chlorotritylchloride resin in the presence of a base, such as triethylamine or ⁇ /,A/-diisopropyl-A/-ethylamine. All other steps are identical to those described above with the exception of step E, cleavage from the resin. This can be done with only 5% TFA in dichloromethane.
- preparation of the compounds of the invention according to the general procedure (C) may be prepared as follows: Step A: Resin bound Fmoc ⁇ -alanine (CD
- Fmoc ⁇ -alanine (C1) was added 1000 ⁇ l of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 ml DMF containing HOBt (50 mg/ml) and DMF (2 x 1 ml). Then 200 ⁇ mol 4-formylbenzoic acid (30 mg) and diisopropylethylamine (70 ⁇ l) were dissolved in DMF (430 ⁇ l) and added to the resin followed by 200 ⁇ mol PyBrOP dissolved in DMF (500 ⁇ l). The mixture was shaken for 4 hours at 25 °C followed by filtration and washing of the resin with DMF (3 x 1 ml) and tri- methylorthoformate (1 x 1 ml).
- Step C (C3) The above resin bound 3-(4-formylbenzoylamino)propionic acid (C2) (50 mg) was treated with a solution of E-NH 2 (500 ⁇ mol) in a mixture of DMF (500 ⁇ l) and trimethylortho- formate (500 ⁇ l). Glacial acetic acid (100 ⁇ l) was added and the mixture was shaked for 1 hour at 25 °C.
- Step E .
- Substituted benzothiazol-2-ylamines may be prepared from substituted anilines using the general procedure described in Stuckwisch C. G. J. Am. Chem. Soc. 1949 71 , 3417.
- To a suspension of substituted aniline (9 mmol) and sodium thiocyanate (3.5 g, 43 mmol) in acetic acid (16 ml) was added dropwise, with stirring, bromine (1.4 g, 9 mmol) dissolved in acetic acid (7 ml) while the temperature was kept below 35 °C. After all the bromine had been added the mixture was stirred for 16 hours and then filtered and the residue washed with water.
- the combined filtrate and the washings were neutralized with concen- trated aqueous ammonia.
- the substituted benzothiazol-2-ylamines can be collected on a filter, dried and recrystallized from toluene/hexane. Alternatively, the substituted benzothiazol- 2-ylamines may be isolated by extraction.
- Step A 3- ⁇ 4-r(4-cyclohex-1-enylphenylamino,methyl1benzoylamino)propionic acid methyl ester 3-(4-Formylbenzoylamino)propionic acid methyl ester (10 g, 42.5 mmol) was dissolved in methanol (100 ml). With mechanical stirring a solution of 4-cyclohex-1-enylaniline (7.4 g, 42.5 mmol) in methanol (15 ml) was added and the resulting suspension was stirred at room temperature for 2.5 hours. Sodium cyano borohydride (4.01 g, 63.8 mmol) was added in portions and the resulting mixture was stirred at room temperature for 4 days.
- 3-Bromoaniline (2.63 g, 15.3 mmol) was dissolved in ethyl acetate (100 ml) and 1 N dry hydrogen chloride in diethyl ether (15.3 ml) was added and the solvents were removed in vacuo. The residue was stripped twice with toluene and the residue was suspended in toluene (30 ml). Diphosgene (6.1 ml) was added and the mixture was refluxed for 1.5 hour. After cooling, the solution was concentrated in vacuo to afford 2.63 g (87%) 3-bromophenyliso- cyanate.
- Step C 3- ⁇ 4-f3-(3-Bromophenyl)-1 -(4-cvclohex-1 -enylphenyOureidomethv ⁇ benzoylamino)- propionic acid
- Step B Di-fert-butyltricarbonate method: Di-te/f-butyltricarbonate (0.26 g, 1 mmol) was dissolved in dichloromethane (1 ml) and a solution of 3-trifluoromethoxyaniline (0.18 g, 1 mmol) in dichloromethane (0.5 ml) was added. The mixture was stirred at room temperature for 15 minutes and 3- ⁇ 4-[(4-cyclohex-1- enylphenylamino)methyl]benzoylamino ⁇ propionic acid methyl ester (0.39 g, 1 mmol) was added and the resulting mixture was stirred at room temperature for 4 days.
- Step C Hydrolysis as decscribed above afforded 0.19 g (47%) 3- ⁇ 4-[3-(3-trifluoromethoxy- phenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino ⁇ propionic acid.
- Step A 3- ⁇ 4-r(4-cvclohexylphenylamino.methv ⁇ benzoylamino)propionic acid methyl ester 3-(4-Formylbenzoylamino)propionic acid methyl ester (10 g, 42.5 mmol) was dissolved in methanol (100 ml). With mechanical stirring 4-cyclohexylaniline (7.4 g, 42.5 mmol) was added in portions. Methanol (100 ml) was added and the resulting suspension was stirred under nitrogen at room temperature for 3 hours. Sodium cyano borohydride (4.01 g, 63.8 mmol) was added in portions and the resulting solution was stirred at room temperature for 4 days.
- Step B was performed using the di-tetf-butyltricarbonate method as described above.
- Binding of compounds to the glucagon receptor may be determined in a competition binding assay using the cloned human glucagon receptor.
- Antagonism may be determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.
- Glucagon Binding Assay Receptor binding is assayed using cloned human receptor (Lok et al., Gene 140, 203-
- the receptor is inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al.) is expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones are selected in the presence of 0.5 g/ml G-418 and are shown to be stable for more than 40 passages. The K d is shown to be 0.1 nM.
- Plasma membranes are prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI, pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l ba- citracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk A/S)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 x g for 75 min. The white band located between the two layers is diluted in buffer and centrifuged at 40.000 x g for 45 min. The precipitate containing the plasma membranes is suspended in buffer and stored at -80 °C until use.
- cold buffer 10 mM tris/HC
- Glucagon is iodinated according to the chloramine T method (Hunter and Greenwood, Nature 194, 495 (1962)) and purified using anion exchange chromatography (J ⁇ rgensen et al., Hormone and Metab. Res. 4, 223-224 (1972). The specific activity is 460 ⁇ Ci/ ⁇ g on the day of iodination. Tracer is stored at -18 °C in aliquots and are used immediately after thawing. Binding assays are carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
- the buffer used in this assay is 50 mM HEPES, 5 mM EGTA, 5 mM MgCI 2 , 0.005% tween 20, pH 7.4.
- Glucagon is dissolved in 0.05 M HCl, added an equal amount (w/w) of human serum albumin and freeze-dried. On the day of use, it is dissolved in water and diluted in buffer to the desired concentrations. Test compounds are dissolved and diluted in DMSO. 140 ⁇ l buffer, 25 ⁇ l glucagon or buffer, and 10 ⁇ l DMSO or test compound are added to each well. Tracer (50.000 cpm) is diluted in buffer and 25 ⁇ l are added to each well.
- the functional assay is carried out in 96 well microtiter plates (tissue culture plates, Nunc).
- the resulting buffer concentrations in the assay are 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 ⁇ M GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% human serum albumin. pH is 7.4.
- Glucagon and proposed antagonist are added in aliquots of 35 ⁇ l diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO 4 , 0.0222% tween-20 and 0.111% human serum albumin, pH 7.4.
- MgSO 4 human serum albumin buffer (the actual concentrations are dependent upon the concentration of protein in the stored plasma membranes).
- the total assay volume is 140 ⁇ l.
- the plates are incubated for 2 hours at 37 °C with continuous shaking. Reaction is terminated by addition of 25 ⁇ l 0.5 N HCl.
- cAMP is measured by the use of a scintillation proximity kit (Amersham).
- BHK (baby hamster kidney cell line) cells are fransfected with the human glucagon receptor and a membrane preparation of the cells is prepared.
- Wheat Germ Agglutinin derivatized SPA beads containing a scintillant (WGA beads) (Amersham) bound the membranes.
- WGA beads a scintillant
- 125 l-glucagon bound to human glucagon receptor in the membranes and excited the scintillant in the WGA beads to light emission.
- Glucagon or samples binding to the receptor competed with 125 l-glucagon.
- the pellet is resuspended in homogenisation buffer, homogenised 2 x 10 sec (Polytron) and additional homogenisation buffer is added.
- the protein concentration is normally around 1.75 mg/ml.
- glucagon binding assay is carried out in opti plates (Polystyrene Microplates, Packard).
- BHK (baby hamster kidney cell line) cells are fransfected with the human GIP receptor and a membrane preparation of the cells is prepared.
- Wheat Germ Agglutinin derivatized SPA beads containing a scintillant (WGA beads) (Amersham) bound the membranes.
- 125 I-GIP bound to human GIP receptor in the membranes and excited the scintillant in the WGA beads to light emission. GIP or samples binding to the receptor competed with 125 I-GIP.
- the pellet is resuspended in homogenisation buffer, homogenised 2 x 10 sec (Polytron) and additional homogenisation buffer is added.
- the protein concentration is normally around 1.75 mg/ml.
- the membrane preparation is stored at -80 °C.
- the GIP binding assay is carried out in opti plates (Polystyrene Microplates, Packard).
- 5 ⁇ l GIP or test compound in DMSO
- 50 ⁇ l tracer 125 l-porcine GIP, 50.000 cpm
- 50 ⁇ l mem- branes (20 ⁇ g) containing the human GIP receptor are then added to the wells.
- 50 ⁇ l WGA beads containing 1 mg beads are transferred to the well.
- the opti plates are incubated for 3.5 hours on a shaker and then settled for 8-48 hours.
- the opti plates are counted in a Topcounter. Non-specific binding is determined with 500 nM of GIP.
- the compounds according to the examples show a higher affinity for the glucagon receptor compared to the GIP receptor.
Abstract
Priority Applications (1)
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AU2002223501A AU2002223501A1 (en) | 2000-11-17 | 2001-11-15 | Glucagon antagonists/inverse agonists |
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DKPA200001731 | 2000-11-17 | ||
DKPA200001731 | 2000-11-17 |
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WO2002040444A1 true WO2002040444A1 (fr) | 2002-05-23 |
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PCT/DK2001/000759 WO2002040444A1 (fr) | 2000-11-17 | 2001-11-15 | Antagonistes/agonistes inverses de glucagon |
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WO (1) | WO2002040444A1 (fr) |
Cited By (25)
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WO2004002480A1 (fr) * | 2002-06-27 | 2004-01-08 | Novo Nordisk A/S | Nouveaux antagonistes/agonistes inverses du glucagon |
WO2004056763A2 (fr) * | 2002-12-20 | 2004-07-08 | Novo Nordisk A/S | Nouveaux antagonistes du glucagon |
US6762318B2 (en) | 2001-12-03 | 2004-07-13 | Novo Nordisk A/S | Glucagon antagonists |
WO2004063147A1 (fr) * | 2003-01-10 | 2004-07-29 | Novo Nordisk A/S | Sels et solvates d'antagonistes de glucagon |
US6881746B2 (en) | 2001-12-03 | 2005-04-19 | Novo Nordick A/S | Glucagon antagonists/inverse agonists |
WO2005058845A2 (fr) * | 2003-12-19 | 2005-06-30 | Novo Nordisk A/S | Nouveaux antagonistes/agonistes inverses du glucagon |
JP2006528157A (ja) * | 2003-07-21 | 2006-12-14 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | アリールジカルボキシアミド |
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US7598285B2 (en) | 2004-06-04 | 2009-10-06 | Merck & Co., Inc | Pyrazole derivatives, compositions containing such compounds and methods of use |
WO2009140342A1 (fr) * | 2008-05-16 | 2009-11-19 | Schering Corporation | Antagonistes du récepteur de glucagon, compostions et procédé d'utilisation de ces composés |
US7625938B2 (en) | 2004-07-22 | 2009-12-01 | Merck & Co., Inc. | Substituted pyrazoles, compositions containing such compounds and methods of use |
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US7803951B2 (en) | 2005-03-30 | 2010-09-28 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
US7935713B2 (en) | 2006-05-16 | 2011-05-03 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
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EP2471533A1 (fr) * | 2002-06-27 | 2012-07-04 | Novo Nordisk A/S | Dérivés d'aryle carbonyle en tant qu'agents thérapeutiques |
US8318760B2 (en) | 2005-03-21 | 2012-11-27 | Merck Sharp & Dohme Corp. | Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use |
US8710236B2 (en) | 2007-02-09 | 2014-04-29 | Metabasis Therapeutics, Inc. | Antagonists of the glucagon receptor |
EP2799428A2 (fr) | 2008-08-13 | 2014-11-05 | Metabasis Therapeutics, Inc. | Antagonistes de glucagon |
US10076504B2 (en) | 2014-06-12 | 2018-09-18 | Ligand Pharmaceuticals, Inc. | Glucagon antagonists |
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WO1999001423A1 (fr) * | 1997-07-01 | 1999-01-14 | Novo Nordisk A/S | Antagonistes/agonistes inverses du glucagon |
WO2000039088A1 (fr) * | 1998-12-23 | 2000-07-06 | Novo Nordisk A/S | Antagonistes de glucagon/agonistes inverses |
WO2000069810A1 (fr) * | 1999-05-17 | 2000-11-23 | Novo Nordisk A/S | Antagonistes/agonistes inverses de glucagon |
-
2001
- 2001-11-15 AU AU2002223501A patent/AU2002223501A1/en not_active Abandoned
- 2001-11-15 WO PCT/DK2001/000759 patent/WO2002040444A1/fr not_active Application Discontinuation
Patent Citations (3)
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WO1999001423A1 (fr) * | 1997-07-01 | 1999-01-14 | Novo Nordisk A/S | Antagonistes/agonistes inverses du glucagon |
WO2000039088A1 (fr) * | 1998-12-23 | 2000-07-06 | Novo Nordisk A/S | Antagonistes de glucagon/agonistes inverses |
WO2000069810A1 (fr) * | 1999-05-17 | 2000-11-23 | Novo Nordisk A/S | Antagonistes/agonistes inverses de glucagon |
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