WO2012006955A1 - Composés pour le traitement de troubles du métabolisme - Google Patents
Composés pour le traitement de troubles du métabolisme Download PDFInfo
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- WO2012006955A1 WO2012006955A1 PCT/CN2011/077130 CN2011077130W WO2012006955A1 WO 2012006955 A1 WO2012006955 A1 WO 2012006955A1 CN 2011077130 W CN2011077130 W CN 2011077130W WO 2012006955 A1 WO2012006955 A1 WO 2012006955A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the present invention is directed to novel compounds which have dual activity as agonist of
- GPR119 and inhibitor of DPP-IV are GPR119 and inhibitor of DPP-IV.
- novel compounds for the treatment of metabolic disorders including type II diabetes are particularly, novel compounds for the treatment of metabolic disorders including type II diabetes.
- the present invention is directed to novel compounds that have dual activity as agonist of GPR119 and inhibitor of DPP-IV.
- the present invention is directed to novel therapeutic compounds useful for the treatment of metabolic disorders including type II diabetes.
- Drugs aimed at the pathophysiology associated with non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
- metabolic syndrome places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low HDL cholesterol, and high blood pressure.
- central obesity excessive fat tissue in the abdominal region
- glucose intolerance high triglycerides
- low HDL cholesterol high blood pressure
- Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
- Obesity is characterized by an excessive adipose tissue mass relative to body size.
- body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m) 2 ), or waist circumference.
- BMI body mass index
- Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers.
- GPRl 19 is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse)).
- GPRl 19 is expressed in the pancreas, small intestine, colon and adipose tissue.
- the expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of diabetes.
- GPRl 19 agonists have been shown to stimulate the release of GLP-I from the GI tract. In doing so, GPRl 19 agonists (1) enhance glucose-dependent insulin release from the pancreas leading to improvements in oral glucose tolerance; (2) attenuate disease progression by increasing ⁇ -cell cAMP concentrations; and (3) induce weight loss possibly through GLP-I's ability to reduce food intake.
- Dipeptidyl peptidase IV is a ubiquitous, yet highly specific, serine protease that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position.
- DPP-IV inhibitors show the principle role of DPP-IV in the inactivation GLP-I. By extending the duration of action of GLP-I, insulin secretion is stimulated, glucagon release inhibited, and gastric emptying slowed.
- DPP-IV inhibitors include vildagliptin, sitagliptin and saxagliptin.
- the present invention is directed to novel compounds which have dual activity as agonist of GPRl 19 and inhibitor of DPP-IV and are useful for the treatment of metabolic disorders including type II diabetes.
- the present invention is directed to compounds of Formula (I),
- Ri is a member selected from the group consisting of H, Ci_ioalkyl, Ci_ioSubstituted alkyl, Cs-ycycloalkyl, C 2 -i 0 alkenyl, C 2 -i 0 alkynyl, -R4COR5, -R 4 C0 2 R 5 , -R4CONR5R6, -S0 2 R 5 , a 4-7 membered heterocyclo group, aryl and a 5-10 membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1-4 substituents independently selected from halo, Ci_ioalkyl, Ci_ioSubstituted alkyl, C 3 -7cycloalkyl, C 2 _i 0 alkenyl, C 2 _i 0 alkynyl, aryl, heteroaryl, -CN, -NR 5 COR
- R 2 is hydrogen or methyl
- X is a bond, -O- or -(CH 2 ) n -, wherein n is any integer selected from 1-4;
- R 3 is selected from the group consisting of perhaloCi_ioalkyl, amino, Ci_ioalkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, C(0)Ci_ 3 alkyl, C(S)Ci_ 3 alkyl, S(0) m Ci_ 3 alkyl, iminoCi_ 3 alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfmyl group, each substituted or unsubstituted thereof, and a substituted or unsubstituted 3-7 membered ring;
- L is a linker providing 1, 2 or 3 atom separation between Y and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S);
- Y is selected from the group consisting of Ci_ioalkyl, C 3 _i 2 cycloalkyl, heteroC 3 _i 2 cycloalkyl, arylCi_ioalkyl, heteroarylCi_salkyl, C9-i 2 bicycloaryl, heteroC 4 -i 2 bicycloaryl, C(0)Ci_ 3 alkyl, C(S)Ci_ 3 alkyl, S(0) m Ci_ 3 alkyl, iminoCi_ 3 alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfmyl group, and each substituted or unsubstituted;
- R 5 is selected from the group consisting of a bond, C 2 _ 6 alkene, C 2 _ 6 alkyne, -C(O)-, and - C(0)-(CH 2 )i_4-, wherein the aliphatic portions of R 5 are optionally substituted with one to three members selected from halogen, Ci_ 4 alkyl, Ci_ 4 substituted alkyl and Ci_ 4 haloalkyl; and wherein m is 1 or 2;
- Re is selected from the group consisting of a bond, C 2 _ 6 alkene, C 2 _ 6 alkyne, -C(O)-, and - C(0)-(CH 2 )i_4-, wherein the aliphatic portions of Re are optionally substituted with one to three members selected from halogen, Ci_ 4 alkyl, Ci_ 4 substituted alkyl and Ci_ 4 haloalkyl; and wherein m is 1 or 2.
- R 3 is selected from the group consisting of amino, Ci_ioalkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, each substituted or unsubstituted, and a substituted or unsubstituted 3-7 membered ring.
- R 7 and R 8 are each independently selected from the group consisting of hydrogen, perhalo(Ci_io)alkyl, amino, (Ci_io)alkyl, (C 3 _i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, aryl(Ci_ io)alkyl, heteroaryl(Ci_s)alkyl, (C9_i 2 )bicycloaryl, hetero(C4_i 2 )bicycloaryl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl(Ci_ 3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfmyl group, and each substituted or unsubstituted thereof, or R 7 and R 8 are taken together to form a 4-7 membered ring, and each substituted or unsubstitute
- R 3 is a substituted or unsubstituted 3-7 membered ring selected from a group consisting of a substituted or unsubstituted 3-7 membered cycloalkyl, or a substituted or unsubstituted 3-7 membered heterocycloalkyl.
- R 3 is selected from a group consisting of a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.
- R 3 is selected from the group consisting of
- each Rg is independently selected from the group consisting of halo, perhalo(Ci_io)alkyl, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group, sulfmyl group, and each substituted or unsubstituted.
- compounds of Formula (I) in the present invention may comprise compounds wherein R 3 is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, benzothiazole, and each substituted or unsubstituted.
- R 3 is a substituted or unsubstituted hetero
- R 3 may be selected from the group consisting of (C 3 _i2)cycloalkyl, hetero(C 3 _i2)cycloalkyl, aryl(Ci_io)alkyl, heteroaryl (Ci_ 5 )alkyl, (Cc>-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
- R 3 is a substituted or unsubstituted (C 3 _ 7 )cycloalkyl ring, optionally comprising O, N(O), N, S, SO, S0 2 or a carbonyl group in the ring.
- R 3 may also be substituted such that R 3 comprises a substituent selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
- R 3 comprises a basic nitrogen (N) atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
- the basic nitrogen of R 3 is separated from the ring atom to which R 3 is attached by between 1-5 atoms.
- the basic nitrogen atom forms part of a primary, secondary or tertiary amine.
- the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl or a heteroaryl.
- the present invention comprises compounds wherein the 1, 2 or 3 atoms of L providing the separation consist of carbon atoms.
- the 1 , 2 or 3 atoms of L providing the separation are selected from the group of linkers consisting of at least one oxygen or at least one nitrogen atom.
- L separates Y from the ring atom by one atom selected from C, O, N, or S.
- L is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(O)-, -CH 2 C(0)-, -C(0)CH 2 -, -CH 2 -C(0)CH 2 -, -C(0)CH 2 CH 2 -, -CH 2 CH 2 C(0)-, -0-, -OCH 2 -, -CH 2 0-, -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 0-, - N(CH 3 )-, -NHCH 2 -, -CH 2 NH-, -CH 2 NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 CH 2 NH-, -NH-C(O)-, -NCH 3 - C(O)-, -C(0)NH-, -C(0)NCH 3 -, -NHC(0)NH-, -C(0)NCH
- L is selected from the group consisting of -CH 2 -, -C(O)-, -CH 2 C(0)-, -C(0)CH 2 -, -CH 2 -C(0)CH 2 -, -C(0)CH 2 CH 2 -, - CH 2 CH 2 C(0)-, and each substituted or unsubstituted.
- Y is selected from a substituted or unsubstituted (C 3 _7)cycloalkyl, a substituted or unsubstituted (C 3 _7)hetero-cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.
- the invention provides compounds wherein X is a substituted or unsubstituted phenyl.
- Y is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring.
- Y is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring selected from the group consisting of (Ci_i 0 )alkyl, (C 3 _i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, aryl(Ci_i 0 )alkyl, heteroaryl(Ci_5)alkyl, (C9-i 2 )bicycloaryl, hetero(C4_i 2 )bicycloaryl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl(Ci_ 3 )alkyl, S(0) m (Ci_ 3 )alkyl, imino(Ci_ 3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, nitro, halo, imino group,
- Y is selected from the group consisting of a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl. In yet another variation of the above, Y is a substituted or unsubstituted halophenyl or dihalophenyl.
- -L-Y taken together is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano)phenyl, -(CH 2 )-(2-hydroxy)- phenyl, -(CH 2 )-(3 -hydroxy )phenyl, -(CH 2 )-(2-alkenyl)phenyl, -(CH 2 )- (3-alkenyl)-phenyl, - (CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3-alkynyl)phenyl, -(CH 2 )-(2- methoxy)-phenyl, -(CH 2 )-(3- methoxy)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(2-nitro)phenyl,
- the molecular weight of the compounds of the invention is preferably less than 800, more preferably less than 600, especially less than 500.
- alkyl groups examples include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl.
- heteroaryl rings means 5- or 6-membered N-containing heteroaryl rings containing up to 2 additional heteroatoms selected from N, O and S.
- heteroaryl rings are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
- Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
- the present invention includes all stereoisomers of the compounds of the invention and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
- the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise.
- the present invention includes any possible solvates and polymorphic forms.
- a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
- water, ethanol, propanol, acetone or the like can be used.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
- Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
- organic non-toxic bases from which salts can be formed include arginine, betaine, caffeine, choline, ⁇ ', ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
- the compound of the invention When the compound of the invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
- reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
- Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
- Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
- specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
- many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
- hydroxy- protecting group refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
- Suitable hydroxyl-protecting groups include for example, allyl, acetyl (Ac), silyl (like thmethylsily (TMS) or tert-butyldimethylsilyl (TBS)), benzyl (Bn), para- methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para-nitrobenzoyl and the like (benzylidene for protection of 1,3-diols).
- TMS thmethylsily
- TBS tert-butyldimethylsilyl
- benzyl Bn
- para- methoxybenzyl PMB
- Tr para-bromobenzoyl
- para-nitrobenzoyl and the like benzylidene for protection of 1,3-diols.
- the need for such protection is readily determined by one skilled in the art.
- the compounds of the present invention can be produced by one or more of the following general reaction schemes.
- Pyrimidinone (1) is commercial available or been prepared by conventional methods known by those skilled in the art.
- step 1 of Scheme 1 the treatment of 1 with strong base such as sodium hydride in mixture solvent of DMSO and THF and followed by the addition of intermediates (2) gave Compounds of Formula (3).
- the R ls R 2 and X groups has been defined above.
- 3-aminopiperidine groups can be introduced by treating the intermediate 3 from step 1 with the appropriate reagents and procedures.
- the appropriate reagents and procedures For example, potassium carbonate as base and THF as solvent.
- a suitable catalyst is [Rh(norbornadiene) 2 ]BF 4 and (5 , )-I-[(R)-2-(di-ferf-butylphosphino)ferrocenyl]ethylbis(2- methylphenyl)phosphine.
- Compounds of Formula (2) can then be obtained by reduction of the carboxylic acids of Formula (7) under standard conditions, for example borane in a suitable solvent such as THF.
- the compounds of Formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of Formula (I).
- Compound libraries may be prepared by a combinatorial "split and mix” approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.
- labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
- the protecting groups may be removed at any stage in the synthesis of the compounds of Formula (I) or may be present on the final compound of Formula (I).
- a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Inter science, New York, 2 nd edition.
- the compounds of the invention are useful as dual GPR119 agonists/DPP-IV inhibitors, e.g. for the treatment and/or prophylaxis of diabetes.
- the compounds of the invention will generally be administered in the form of a pharmaceutical composition.
- the invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.
- pharmaceutically acceptable excipient refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered..
- composition is comprised of a non-toxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPR119 and DPP-IV, resulting in the prophylactic or therapeutic treatment of diabetes, comprising a non-toxic therapeutically effective amount of compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- compositions may optionally comprise other therapeutic ingredients or adjuvants.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical excipient, according to conventional pharmaceutical compounding techniques.
- a pharmaceutical excipient may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
- compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
- the compound of the invention, or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
- the compositions may be prepared by any of the methods of pharmacy.
- such methods include a step of bringing into association the active ingredient with the excipient that constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid excipients or finely divided solid excipients or both. The product can then be conveniently shaped into the desired presentation.
- the compounds of the invention can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical excipients employed can be, for example, a solid, liquid, or gas.
- solid excipients include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid excipients are sugar syrup, peanut oil, olive oil, and water.
- gaseous excipients include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed.
- oral liquid preparations such as suspensions, elixirs and solutions
- excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical excipients are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free -flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
- a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of excipient material which may vary from about 5 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the excipient can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices.
- These Formulations may be prepared, using a compound of the invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods.
- a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration wherein the excipient is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable excipients include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted excipient(s) followed by chilling and shaping in molds.
- the pharmaceutical Formulations described above may include, as appropriate, one or more additional excipient ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional excipient ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional excipient ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional excipient ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- other adjuvants can be included to render the Formulation iso
- dosage levels on the order of O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above -indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
- obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
- the compounds of the invention may be used in the treatment of diseases or conditions in which GPR1 19 and DPP-IV play a role.
- the invention also provides a method for the treatment of a disease or condition in which GPR119 and DPP-IV play a role comprising a step of administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
- diseases or conditions diabetes, obesity, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia.
- the compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.
- the invention also provides a method for the treatment of type II diabetes, comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
- the invention also provides a method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
- the invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.
- the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.
- treatment includes both therapeutic and prophylactic treatment.
- the compounds of the invention may exhibit advantageous properties compared to known compounds or combination therapies for the treatment of diabetes.
- the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds.
- the other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of the invention or a different disease or condition.
- the therapeutically active compounds may be administered simultaneously, sequentially or separately.
- the compounds of the invention may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, a2 agonists, glitazones, PPAR- ⁇ agonists, mixed PPAR- ⁇ / ⁇ agonists, RXR agonists, fatty acid oxidation inhibitors, a-glucosidase inhibitors, ⁇ -agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g.
- active compounds for the treatment of obesity and/or diabetes for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, a2 agonists, glitazones, PPAR- ⁇ agonists
- pancreatic lipase inhibitors MCH-I antagonists and CB-I antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g.
- sibutramine CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-I inhibitors or sorbitol dehydrogenase inhibitors.
- Combination therapy comprising the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other agent represents a further aspect of the invention.
- the present invention also provides a method for the treatment of diabetes in a mammal, such as a human, which method comprises administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent, to a mammal in need thereof.
- the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent for the treatment of diabetes.
- the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another agent, for the treatment of diabetes.
- the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) may be co-administered or administered sequentially or separately.
- Co-administration includes administration of a Formulation which includes both the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s), or the simultaneous or separate administration of different Formulations of each agent. Where the pharmacological profiles of the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) allow it, co-administration of the two agents may be preferred.
- the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent in the manufacture of a medicament for the treatment of diabetes.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another anti-obesity agent, and a pharmaceutically acceptable excipient.
- the invention also encompasses the use of such compositions in the methods described above.
- Step 1 Synthesis of 3-(6-Chloro-3- ⁇ 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-propyl ⁇ -2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile 3a
- additives may be used, including LiBr, Lil, Nal and the like.
- the alkylation can be performed using methyliodide and K 2 CO 3 in acetone.
- the reaction may be performed at about 15-45 ° C , preferably at about 20-43 ° C , and more preferably at about 35-41 ° C until the reaction is complete.
- the residue was dissolved in CHCI 3 and washed with water and brine, dried (Na 2 S0 4 ), and filtered then concentrated in vacuo.
- the crude product was crystallized from THF-Hexanes to give 7.6g (72%) of the title Compound 3a.
- the benzonitrile may be purified in a variety of organic solvents or solvent mixtures.
- the benzonitrile can be purified by adding a mixture of dichloromethane and heptane.
- the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like.
- the product is purified and washed with ethyl acetate.
- reaction was filtered through Celite, concentrated in vacuo, and then diluted with CHCI 3 , and washed with water.
- the water phase was extracted with CHCI 3 and the combined organic phases were washed with water, dried (Na 2 S0 4 ), and filtered.
- TFA (lmL) was added into the solution which was then concentrated in vacuo.
- the residue was dissolved in a small amount of MeOH, and Et 2 0 was added to force precipitation.
- the mixture was allowed to stand at RT overnight. It will be understood by those skilled in the art that condensation with the amine or amine hydrochloride may be performed in a solvent or mixture of solvents with a base, such as potassium carbonate, sodium bicarbonate and the like, or mixtures thereof.
- the solvent may comprise both protic and aprotic solvents, or mixtures thereof.
- the solvent may comprise a mixture of isopropyl alcohol and water.
- the reaction may be heated to about 30-100 ° C , preferably about 35-55 ° C , and more preferably about 45-50 ° C until the reaction is complete. Solvents were decanted, and the solid was washed with Et 2 0 two times to give 270mg product as off-white powder. It will also be understood that the product may be further purified by washing with an organic solvent or mixture of solvents.
- Non- limiting examples of solvent or solvent mixtures include isopropyl acetate, ethyl acetate, dichloromethane, heptane, and the like.
- the product may optionally be purified by column chromatography.
- the benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to the corresponding acid addition salt, such as the benzoic acid salt.
- the benzonitrile product is treated with benzoic acid to form 3-(6-(3R-3-Amino-piperidin-l-yl)-3- ⁇ 3- [l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-propyl ⁇ -2,4-dioxo-3,4-dihydro-2H- pyrimidin-l-ylmethyl)-benzonitrile (5a) benzoate.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C 3 iH 42 N 8 0 3 (MH+) 575.7170, found 575.9007.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H42N6O4 (M+H) + 551.6923, found 551.6907.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C2 H40N6O4 (M+H) + 537.6657, found 537.6667.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H37N7O2 (M+H) + 528.6605, found 528.6627.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H37N7O2 (M+H) + 528.6605, found 528.6627 .
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H38N8O2 (M+H) + 543.6751, found 543.6747.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C31H40N8O2 (M+H) + 558.7017, found 558.7037.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C32H42N8O2 (M+H) + 571.7283, found 571.7289.
- the desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C 3 oH3 8 N 8 0 3 (MH+) 559.6745, found 559.6759.
- the biological activity of the compounds of the invention may be tested in the following assay systems:
- yeast cell-based reporter assays have previously been described in the literature (e.g. see Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887; Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418; King K. et al, 1990, Science, 250: 121-123); W099/14344; WOOO/12704; and US6,100,042). Briefly, yeast cells have been engineered such that the endogenous yeast G-alpha (GPA1) has been deleted and replaced with G-protein chimeras constructed using multiple techniques.
- GPA1 endogenous yeast G-alpha
- yeast GPCR Ste3 has been deleted to allow for heterologous expression of a mammalian GPCR of choice.
- elements of the pheromone signaling transduction pathway which are conserved in eukaryotic cells (for example, the mitogen-activated protein kinase pathway), drive the expression of Fusl.
- ⁇ -galactosidase LacZ
- Fuslp Fusl promoter
- Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al, (Agatep, R. et al, 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/ss-DNA/PEG) protocol. Technical Tips Online, Trends Journals, Elsevier). Briefly, yeast cells were grown overnight on yeast tryptone plates (YT).
- the yeast expression plasmid containing the receptor/ no receptor control has a LEU marker.
- Yeast cells were inoculated into this mixture and the reaction proceeds at 30 ° C for 60min. The yeast cells were then heat-shocked at 42 ° C for 15min. The cells were then washed and spread on selection plates.
- the selection plates are synthetic defined yeast media minus LEU, URA and TRP (SD-LUT). After incubating at 30 ° C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ assay.
- yeast cells carrying the human or mouse GPR119 receptor were grown overnight in liquid SD-LUT medium to an unsaturated concentration (i.e. the cells were still dividing and had not yet reached stationary phase). They were diluted in fresh medium to an optimal assay concentration and 90 ⁇ of yeast cells added to 96-well black polystyrene plates (Costar). Compounds, dissolved in DMSO and diluted in a 10%DMSO solution to 10X concentration, were added to the plates and the plates placed at 30 ° C for 4h. After 4h, the substrate for the ⁇ -galactosidase was added to each well.
- Fluorescein di ⁇ -D-galactopyranoside
- FDG Fluorescein di
- a substrate for the enzyme that releases fluorescein allowing a fluorimetric read-out.
- 20 ⁇ per well of 500 ⁇ FDG/2.5% Triton XIOO was added (the detergent was necessary to render the cells permeable).
- 20 ⁇ ⁇ per well of IM sodium carbonate was added to terminate the reaction and enhance the fluorescent signal.
- the plates were then read in a fluorimeter at 485/535 nm.
- the compounds of the invention give an increase in fluorescent signal of at least 1.5-fold that of the background signal (i.e. the signal obtained in the presence of 1%DMS0 without compound).
- Compounds of the invention which give an increase of at least 5-fold may be preferred.
- cAMP cyclic AMP
- the cell monolayers were washed with phosphate buffered saline and stimulated at 37 ° C for 30min with various concentrations of compound in stimulation buffer plus 1% DMSO. Cells were then lysed and cAMP content determined using the Perkin Elmer AlphaScreenTM (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. Buffers and assay conditions were as described in the manufacturer's protocol.
- Compounds of the invention produced a concentration-dependent increase in intracellular cAMP level and generally had an EC50 of ⁇ 10 ⁇ . Compounds showing and EC50 of less than 1 ⁇ in the cAMP assay may be preferred.
- DPP-IV activity was measured by monitoring the cleavage of the fluorogenic peptide substrate, H-Gly-Pro-7-amino-4-methylcoumarin (GP-AMC) whereby the product 7-amino-4- methylcoumarin is quantified by fluorescence at excitation 380nm and emission 460nm.
- Assays were carried out in 96-well plates (Black OptiPlate-96F) in a total volume of ⁇ per well consisting of 50mM Tris pH7.6, ⁇ GP-AMC, 10-25 ⁇ recombinant human DPP- IV and a range of inhibitor dilutions in a final concentration of l%DMSO.
- HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30nM sodium selenite. All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan; 38(l):44-8).
- HIT-T 15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ O.lmL/well and cultured for 24h and the medium was then discarded. Cells were incubated for 15min at room temperature with ⁇ stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, pH7.4). This was discarded and replaced with compound dilutions over the range 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 ⁇ in stimulation buffer in the presence of 0.5%DMSO. Cells were incubated at room temperature for 30min.
- ⁇ stimulation buffer Hors buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, pH7.4
- 75uL lysis buffer (5mM HEPES, 0.3%Tween-20, 0.1%BSA, pH7.4) was added per well and the plate was shaken at 900rpm for 20min. Particulate matter was removed by centrifugation at 3000rpm for 5min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly reactions were set up containing 8 ⁇ sample, 5 ⁇ , acceptor bead mix and 12 ⁇ detection mix, such that the concentration of the final reaction components is the same as stated in the kit instructions. Reactions were incubated at room temperature for 150min, and the plate was read using a Packard Fusion instrument.
- Measurements for cAMP were compared to a standard curve of known cAMP amounts (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, ⁇ ) to convert the readings to absolute cAMP amounts. Data was analysed using XLfit 3 software.
- Representative compounds of the invention were found to increase cAMP at an EC50 of less than 10 ⁇ . Compounds showing an EC50 of less than ⁇ in the cAMP assay may be preferred. Insulin secretion assay
- HIT-T 15 cells are plated in standard culture medium in 12-well plates at 106cells/l ml/well and cultured for 3 days and the medium then discarded. Cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119mM NaCl, 4.74mM KC1, 2.54mM CaCl 2 , 1.19mM MgS0 4 , 1.19mM KH 2 P0 4 , 25mM NaHC0 3 , lOmM HEPES at pH7.4 and 0.1%bovine serum albumin. Cells are incubated with 1ml KRB at 37 ° C for 30min which is then discarded.
- KRB Krebs-Ringer buffer
- Compounds of the invention preferably increase insulin secretion at an EC 50 of less than
- Blood samples were then taken from the cut tip of the tail 5, 15, 30, 60, 120, and 180min after Glc administration. Blood glucose levels were measured just after collection using a commercially available glucose-meter (OneTouch ® UltraTM from Lifescan). Representative compounds of the invention statistically reduced the Glc excursion at doses of ⁇ 100mg kg "1 .
- mice The effects of compounds of the invention on oral glucose (Glc) tolerance may also be evaluated in male C57B1/6 or male oblob mice.
- Food is withdrawn 5h before administration of Glc and remained withdrawn throughout the study. Mice have free access to water during the study. A cut was made to the animals' tails, then blood (20 ⁇ ) is removed for measurement of basal Glc levels 45min before administration of the Glc load. Then, the mice are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl- A -cyclodextrin or 25% aqueous Gelucire 44/14) 30min before the removal of an additional blood sample (20 ⁇ ) and treatment with the Glc load (2-5g kg "1 p.o.).
- Blood samples (20 ⁇ ) are then taken 25, 50, 80, 120, and 180min after Glc administration.
- the 20 ⁇ ⁇ blood samples for measurement of Glc levels are taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480 ⁇ of haemolysis reagent.
- Duplicate 20 ⁇ , aliquots of the diluted haemolysed blood are then added to 180 ⁇ of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate.
- Trinders glucose reagent Sigma enzymatic (Trinder) colorimetric method
- the samples are left at room temperature for 30min before being read against GIc standards (Sigma glucose/urea nitrogen combined standard set).
- Compounds of the invention preferably statistically reduce the GIc excursion at doses ⁇ 100mg kg "1 .
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Abstract
L'invention concerne des composés ayant une activité en tant qu'agoniste de GPR119 et qu'inhibiteur de DPP-IV. Ces composés peuvent être utilisés pour le traitement et la prévention de maladies ou d'états dans lesquels GPR119 et DPP-IV sont mis en jeu, choisis parmi le diabète, l'obésité, l'intolérance au glucose, l'insulinorésistance, les complications diabétiques et la dyspepsie fonctionnelle et des maladies du métabolisme provoquées par une sensibilité anormale à des graisses ingérées chez des patients.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2012170867A1 (fr) | 2011-06-09 | 2012-12-13 | Rhizen Pharmaceuticals Sa | Nouveaux composes utilises comme modulateurs de gpr-119 |
WO2014011926A1 (fr) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique |
RU2523558C2 (ru) * | 2012-08-22 | 2014-07-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Воронежская государственная медицинская академия им. Н.Н. Бурденко" Министерства здравоохранения и социального развития Россиской Федерации | Способ лечения и повышения качества жизни больных с синдромом диспепсии в сочетании с ожирением |
CN112805002A (zh) * | 2018-09-12 | 2021-05-14 | 东亚St株式会社 | 用于预防或治疗非酒精性脂肪肝病的含有gpr119配体作为活性成分的药物组合物 |
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WO2010018217A2 (fr) * | 2008-08-15 | 2010-02-18 | Boehringer Ingelheim International Gmbh | Composés organiques pour la cicatrisation de lésion |
WO2010048149A2 (fr) * | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Modulateurs hétérocycliques de gpr119 pour le traitement d'une maladie |
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JPH0597887A (ja) * | 1991-10-02 | 1993-04-20 | Tanabe Seiyaku Co Ltd | 新規2’−デオキシ−5−フルオロウリジン誘導体 |
WO2010018217A2 (fr) * | 2008-08-15 | 2010-02-18 | Boehringer Ingelheim International Gmbh | Composés organiques pour la cicatrisation de lésion |
WO2010048149A2 (fr) * | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Modulateurs hétérocycliques de gpr119 pour le traitement d'une maladie |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012170867A1 (fr) | 2011-06-09 | 2012-12-13 | Rhizen Pharmaceuticals Sa | Nouveaux composes utilises comme modulateurs de gpr-119 |
WO2014011926A1 (fr) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique |
RU2523558C2 (ru) * | 2012-08-22 | 2014-07-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Воронежская государственная медицинская академия им. Н.Н. Бурденко" Министерства здравоохранения и социального развития Россиской Федерации | Способ лечения и повышения качества жизни больных с синдромом диспепсии в сочетании с ожирением |
CN112805002A (zh) * | 2018-09-12 | 2021-05-14 | 东亚St株式会社 | 用于预防或治疗非酒精性脂肪肝病的含有gpr119配体作为活性成分的药物组合物 |
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