WO2004002480A1 - Nouveaux antagonistes/agonistes inverses du glucagon - Google Patents

Nouveaux antagonistes/agonistes inverses du glucagon Download PDF

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Publication number
WO2004002480A1
WO2004002480A1 PCT/DK2003/000350 DK0300350W WO2004002480A1 WO 2004002480 A1 WO2004002480 A1 WO 2004002480A1 DK 0300350 W DK0300350 W DK 0300350W WO 2004002480 A1 WO2004002480 A1 WO 2004002480A1
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Prior art keywords
general procedure
alkyl
compound according
amino
methyl
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PCT/DK2003/000350
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English (en)
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Jesper Lau
Inge Thøger Christensen
Peter Madsen
Paw Bloch
Carsten Behrens
János Kodra KODRA
Poul Enrico Nielsen
Anker Steen JØRGENSEN
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Novo Nordisk A/S
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Priority to EP03727245A priority Critical patent/EP1519723A1/fr
Priority to AU2003233780A priority patent/AU2003233780A1/en
Priority to JP2004516507A priority patent/JP2006500325A/ja
Publication of WO2004002480A1 publication Critical patent/WO2004002480A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
  • Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.
  • Diabetes mellitus is a common disorder of glucose metabolism.
  • the disease is characterized by hyperglycemia and may be classified as type 1 diabetes, the insulin- dependent form, or type 2 diabetes, which is non-insulin-dependent in character.
  • Subjects with type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
  • absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state.
  • glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients.
  • the action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent glucagon-induced responses.
  • the antagonist can be peptidic or non-peptidic in nature.
  • Native glucagon is a 29 amino acid peptide having the sequence: His-Ser-GIu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH
  • Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family.
  • the receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
  • Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred.
  • non-peptide glucagon antagonists a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7- dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)).
  • WO 1 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
  • US 4,359,474 discloses the glucagon inhibiting properties of 1 -phenyl pyrazole derivatives.
  • US 4,374,130 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- substituted aryl pyrroles as glucagon antagonists. WO 98/24780, WO 98/24782, WO
  • Halogen designates an atom selected from the group consisting of F, CI, Br and I.
  • C 1-6 -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, n- pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.
  • C- M o-alkyl denotes a saturated, branched or straight hydrocarbon group having from 1 to 10 carbon atoms.
  • C 2-6 -alkenyl 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-methyM-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- ⁇ 0 -alkenyl denotes a saturated, branched or straight hydrocarbon group having from 2 to 10 carbon atoms.
  • C 1-6 -alkoxy refers to the radical -O-C ⁇ -alkyl, wherein d- 6 -alkyl is as defined above.
  • Representative examples are methoxy, ethoxy, n-propoxy, iso- propoxy, butoxy, sec-butoxy, fe/f-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 1-6 -alkylthio refers to the radical -S-C 1-6 -alkyl, wherein C 1-6 -alkyl is as defined above.
  • Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert- butylthio, n-pentylthio, isopentylthio, neopentylthio, terf-pentylthio, n-hexylthio, isohexylthio and the like.
  • C 3- ⁇ 0 -cycloalkyl represents a saturated, carbocyclic group having from 3 to 10 carbon atoms. Representative examples are cyclopropyl, cyclobutyli cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • C 7-10 -bicycloalkyl represents a bicyclic, saturated, carbocyclic group having from 7 to 10 carbon atoms. Representative examples are bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl and the like.
  • C 3-10 -cycloalkenyl represents a non-aromatic, carbocyclic group having from 3 to 10 carbon atoms containing one or two double bonds.
  • aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems.
  • Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, indanyl and the like.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • arylthio as used herein denotes a group -S-aryl, wherein aryl is as defined
  • heteroaryl as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen,' oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • furyl thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxa- diazolyl, 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, indo
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3- dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • Aryl-d-s-alkyl means C 1-6 -alkyl or C 2-6 -alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof ' are included within the scope of the invention.
  • diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, butyl-, tetramethylammonium salts and the like.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
  • the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. 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 of disorders and diseases in which such an antagonism is beneficial.
  • the compounds according to the invention preferably have an IC 50 value of no greater than 5 ⁇ M as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the compounds according to the invention have an IC 50 value of less than 1 ⁇ M, preferably of less than 500 nM and even more preferred of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
  • the compounds according to the invention preferably have a higher binding affinity to the glucagon receptor than to the GIP receptor. Accordingly, the present compounds may be applicable for the treatment of hyperglycemia, hyper insulinemia, beta-cell rest, improved beta-cell function by restoring first phase response, prandial hyperglycemia, preventing apoptosis, IFG, metabolic syndrome, hypoglycemia, hyper-/hypokalemia, normalising glucagon levels, improved LDL/HDL ratio, reducing snacking, eating disorders, weight loss, PCOS, obesity as a consequence of diabetes, LADA, insulitis, islet transplantation, pediatric diabetes, gestational diabetes, diabetic late complications, micro-/macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic foot ulcers, reduced intestinal motility due to glucagon administration, short bowel syndrome, antidiarrheic, increasing gastric secretion, decreased blood flow, erectile dysfunction (male & female), glaucoma
  • 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.
  • They may also be useful as tool or reference molecules in labelled form in binding assays to identify new glucagon antagonists.
  • the invention relates to a compound according to the invention for use as a medicament.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and > especially preferred from about 0.5 mg to about 200 mg of the compound according to the invention.
  • the invention relates to the use of a compound of the general formula (I) as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial.
  • the invention also relates to a method for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment of any glucagon-mediated conditions and diseases.
  • the present compounds are used for the preparation of a medicament for the treatment of hyperglycemia.
  • the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
  • the present compounds are effective in lowering the blood glucose, both in the fasting and the postprandial stage.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is normally accompanied by insulin therapy.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of obesity.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of disorders of the lipid metabolism.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment 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.
  • Such further active substances may eg be selected from antidiabetics, antiobesity agents, antihypertensive 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 administered in combination with one or more antidiabetics.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214826 and EP 705275 (Novo Nordisk A/S), eg Asp 828 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro 629 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 refererice, as well as orally active hypoglycemic agents.
  • the orally active hypoglycemic agents preferably comprise imidazolines, sulpho- nylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, insulin secretagogues, such as glimepiride, ⁇ -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 agonists such
  • 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 628 human insulin, Lys B28 Pro B29 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 628 human insulin, Lys B28 Pro B29 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea such as glibenclamide, glipizide, tolbautamide, chloropamidem, tolazamide, glimepride, glicazide and glyburide.
  • the present compounds are administered in combination 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.
  • 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.
  • 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
  • the present compounds may be , administered in combination with an insulin sensitizer eg such as GI 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 such as ragaglitazar (NN 622 or (-)DRF 2725) (Dr.
  • an insulin sensitizer eg such as GI 262570, YM-440, MCC- 555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516
  • 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, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • 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 or antihyperiipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate or atorvastin.
  • an antilipidemic agent or antihyperiipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate or atorvastin.
  • the present compounds are administered in combination with compounds lowering food intake.
  • 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 glyburide; a sulphonylurea and acarbose; nateglinide and metformin; repaglinide 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.
  • the present compounds 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
  • MC3 melanocortin 3
  • TNF tumor necrosis factor
  • CRF corticotropin releasing factor
  • CRF BP corticotropin releasing factor binding protein
  • urocortin agonists ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140
  • MSH melanocyte-stimulating hormone
  • MCH melanocyte-concentrating hormone
  • CCK cholesterolecystokinin
  • serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,
  • the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is leptin.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine. In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam. Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents examples include ⁇ -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.
  • ACE angiotensin converting enzyme
  • the compounds of the present invention may be administered in combination with FAS inhibitors.
  • the compounds of the present invention may also be administered in combination with chemical uncouplers, hormone sensitive lipase inhibitore, imidazolines, 11- ⁇ - hydroxysteroid dehydrogenase inhibitors, lipoprotein lipase activatore, AMPK activators, immunosuppresive drugs, nicotinamide, ASIS, anti-androgens or carboxypeptidase inhibitors. 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.
  • 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 pharmaceutical 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, intracistemal, 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 powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • 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
  • typical doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is a base addition salt of a compound having the utility of a free acid.
  • a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically 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.
  • 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 Lactosum Ph. Eur. 67.8 mg
  • the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • reaction may not be applicable as described to each compound included within the disclosed scope of the invention.
  • the compounds for which this occurs will be readily recognised by those skilled in the art.
  • the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions.
  • other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the ⁇ corresponding compounds of the invention.
  • all starting materials are known or may easily be prepared from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when referring to solvents and eluents.
  • DIPEA V, ⁇ /-diisopropylethylamine
  • the Sciex Sample control software running on a Macintosh Power G3 computer was used for the instrument control and data acquisition.
  • the HPLC pump was connected to two eluent reservoirs containing: A: Acetonitrile containing 0.05% TFA
  • the requirements for the samples are that they contain approximately 500 ⁇ g/ml of the compound to be analysed in an acceptable solvent such as methanol, ethanol, 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 0.05% TFA
  • the eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 ⁇ l/min through approx. 1 m 75 ⁇ fused silica capillary to the API interface of AP1 150 spectrometer.
  • the remaining 1.48 ml/min was passed through the UV detector and to the ELS detector.
  • the detection data were acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.
  • the instrument was controlled by HP Chemstation software.
  • the HPLC pump was connected to two eluent reservoirs containing:
  • the analysis was performed at 40 °C by injecting an appropriate volume of the sample (preferably 1 ⁇ L) onto the column, which was eluted with a gradient of acetonitrile.
  • an appropriate volume of the sample preferably 1 ⁇ L
  • the HPLC conditions, detector settings and mass spectrometer settings used are given in the following table.
  • the reaction generally is known (P.C. Kearney et al., J. Org Chem., 1998, 63, 196- 200 and J. Stadlwieser et al., Angew. Chem. Int. Ed. Engl., 1998, 37, 1402-4) and is performed by reacting a resin-bound thiourea with a ⁇ -haloketone under basic or acidic conditions.
  • the reaction is normally performed at ambient temperature or at elevated temperature, up to the temperature of the boiling point of the solvent(s).
  • the solvent can be one (or a mixture of two or more) of the following: dioxane, THF, DCM, 1 ,2-dichloropropane, acetonitrile, DMF, / -methylpyrrolidone, DMSO, toluene and ethyl acetate.
  • This step is analogous to the corresponding transformations described in WO 00/69810 and WO 02/00612.
  • Fmoc- ⁇ -Ala-Wang resin (0.57 mmol/g, 50 ⁇ mol) was treated with piperidine (20% in NMP, 1000 ⁇ L) for 10 min and the resin was drained. This was repeated once. The resin was washed with NMP (6 x 1000 ⁇ L). 4-Carboxybenzaldehyde (0.5 M in NMP, 500 ⁇ L), HOBt (0.5 M in NMP, 500 ⁇ L) and DIC (0.5 M in toluene, 500 ⁇ L) were added and the resulting mixture was shaken for 15 hours at room temperature. The resin was drained and washed with DMF (3 x 1000 ⁇ L).
  • the resulting resin-bound aldehyde was added the appropriate amine, in this case 4-(cyclohex-1-enyl)aniline, prepared as described in WO 00/69810 (1.0 M in NMP, 600 ⁇ L), NaCNBHs (1.0 M in NMP:methanol (7:3), 600 ⁇ L) and acetic acid (140 ⁇ L).
  • the resulting mixture was shaken for 9 hours at room temperature, drained and washed with MeOH (1000 ⁇ L) for 1 hour, followed by washing with with 5% DIPEA in methanol (1 x) and NMP (2 x) (1000 ⁇ l each).
  • the resulting resin-bound amine was treated with Fmoc-isothiocyanate (0.55 M in DCP, 1000 ⁇ L) and the mixture was shaken for 10 hours at room temperature and washed with NMP (2 x 1000 ⁇ L) and DCM (1000 ⁇ L).
  • the resin was treated with piperidine (20% in NMP, 1000 ⁇ L) for 10 min and the resin was drained. This was repeated once.
  • the resin was washed with NMP (6 x 1000 ⁇ L).
  • the compounds of the invention may be further purified by methods known to those skilled in the art, eg by flash chromatography or HPLC.
  • the compounds in the following examples 2 - 249 were similarly prepared and all found to be hits when screening at 1.4 ⁇ M (a "hit” is defined as a compound at the given concentration that is able to displace >40% of labelled glucagon from the human glucagon receptor).

Abstract

L'invention concerne de nouveaux composés de formule (I), dans laquelle A représente (1), (2) ou (3) ; X désigne une liaison de valence, -CR1R2- ou -NR1- ; Y représente >CR3- ou >N- ; B représente (4), (5), (6), (7) ou (8) ; X' représente -N= ou -CR8= ; Y' représente -S-, -O- ou -NR9- et D désigne aryle ou hétéroaryle, lesdits composés possédant un effet antagoniste sur l'action de l'hormone peptidique glucagon sur le récepteur du glucagon. Cette invention concerne, plus particulièrement, des antagonistes ou agonistes inverses du glucagon.
PCT/DK2003/000350 2002-06-27 2003-05-27 Nouveaux antagonistes/agonistes inverses du glucagon WO2004002480A1 (fr)

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EP03727245A EP1519723A1 (fr) 2002-06-27 2003-05-27 Nouveaux antagonistes/agonistes inverses du glucagon
AU2003233780A AU2003233780A1 (en) 2002-06-27 2003-05-27 Novel glucagon antagonists/inverse agonists
JP2004516507A JP2006500325A (ja) 2002-06-27 2003-05-27 新規なグルカゴンアンタゴニスト

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