WO2012066077A1 - 1,4 di substituted pyrrolidine - 3 - yl -amine derivatives and their use for the treatment of metabolic disorders - Google Patents
1,4 di substituted pyrrolidine - 3 - yl -amine derivatives and their use for the treatment of metabolic disorders Download PDFInfo
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- WO2012066077A1 WO2012066077A1 PCT/EP2011/070346 EP2011070346W WO2012066077A1 WO 2012066077 A1 WO2012066077 A1 WO 2012066077A1 EP 2011070346 W EP2011070346 W EP 2011070346W WO 2012066077 A1 WO2012066077 A1 WO 2012066077A1
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- 0 *C(CNC1)C1N Chemical compound *C(CNC1)C1N 0.000 description 14
- CEIDPKDDQXCZMO-UHFFFAOYSA-N C=C1CCC(CF)CCC1 Chemical compound C=C1CCC(CF)CCC1 CEIDPKDDQXCZMO-UHFFFAOYSA-N 0.000 description 1
- JYHLMZKMISILOT-UHFFFAOYSA-N CC(C)(C)OC(N(CCOC)C1CCNCC1)=O Chemical compound CC(C)(C)OC(N(CCOC)C1CCNCC1)=O JYHLMZKMISILOT-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N CC(C)(C)OC(N)=O Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- VRWXWAWFVLQHBW-QUCCMNQESA-N CC(C)(C)OC(N[C@@H](CN(Cc1ccccc1)C1)[C@H]1c(cccc1)c1F)=O Chemical compound CC(C)(C)OC(N[C@@H](CN(Cc1ccccc1)C1)[C@H]1c(cccc1)c1F)=O VRWXWAWFVLQHBW-QUCCMNQESA-N 0.000 description 1
- ZFGRSXRVCUWAHJ-UHFFFAOYSA-N CC(C)C(C)OC(NC(CNC1)C1C(C(F)=CC1F)=CC1F)=O Chemical compound CC(C)C(C)OC(NC(CNC1)C1C(C(F)=CC1F)=CC1F)=O ZFGRSXRVCUWAHJ-UHFFFAOYSA-N 0.000 description 1
- XVWXBNYLGOSJRZ-UHFFFAOYSA-N CC(C)N(C(C)OC1C(C)(C)C1)C(CC1)CCN1C#N Chemical compound CC(C)N(C(C)OC1C(C)(C)C1)C(CC1)CCN1C#N XVWXBNYLGOSJRZ-UHFFFAOYSA-N 0.000 description 1
- DUXPFRRFZLRICX-SCSAIBSYSA-N NC([C@H]1COCC1)=O Chemical compound NC([C@H]1COCC1)=O DUXPFRRFZLRICX-SCSAIBSYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Definitions
- the present invention is directed to therapeutic compounds useful for the treatment of metabolic disorders including type II diabetes.
- the present invention is directed to compounds which have activity as agonists of GPR119.
- 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.
- GPR119 (previously referred to as GPR1 16) is a GPCR identified as SNORF25 in WOO /50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: ⁇ 95194 (human), AAN95195 (rat) and A N95196 (mouse)).
- GPRi 19 is expressed in the pancreas, small intestine, colon and adipose tissue.
- the expression profile of the human GPR1 19 receptor indicates its potential utility as a target for the treatment of diabetes.
- GPR 1 19 agonists have been shown to stimulate the release of GLP-1 from the GI tract.
- GPR1 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-l '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-prolinc or 1.-alanine at the penultimate position.
- DPP-IV inhibitors show the principle role of DPP- ⁇ * is in the inactivation GLP-1 . By extending the duration of action of GLP- 1 , insulin secretion is stimulated, glucagon release inhibited, and gastric emptying slowed.
- DPP-IV inhibitors are of use for the treatment of type II diabetes, examples of DPP-IV inhibitors include vildagliptin, sitagliptin, alogliptin and saxagliptin.
- WO 2009/034388, WO 2010/103333, WO 2010/103334 and WO 2010/103333 disclose dual GPR119 agonists and DPP-IV inhibitors.
- the compounds of the invention preferably have dual activity as agonists of GPRl 19 and inhibitors of DPP-IV
- the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:
- A is a para-linked phenyl, pyridinyl, pyrimidinyl, pyrazinyl or triazinyl;
- R* is hydrogen, halo, cyano, Cj ⁇ alkyl, C ⁇ haloalkyl, C j ⁇ alkoxy or C ⁇ .galkoxyalkyl;
- R is selected from the group consisting of:
- R3 is methyl, t ⁇ .gcycloalkyl, 4 to 6 membered saturated heterocyclyl (comprising 1 or 2 ring heteroatoms selected from O and S) or C2_4alkyl wherein the C3_gcycloalkyl and C2-4alkyl are optionally substituted by fluoro, cyano, h dro or C j ⁇ alkyloxy
- p and q are each 0, 1 or 2, provided that 0 ⁇ p+q ⁇ 2;
- Z is selected from the group consisting of:
- heteroaryl ring or fused bicyclic system optionally substituted by one or two groups independently selected from halo, cyano, C 1.4 alkyl, C ⁇ haloalkyl, C ⁇ alkoxy, C. ⁇ alkoxyalkyl, heterocyclyl (a)
- heterocyclyl 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from ⁇ , O and S), heterocyclyl C ⁇ ⁇ alkyl (wherein the heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from ⁇ , O and S) and C3 -0 cycloaIkyl optionally substituted by Cj .4 alkyl, C ⁇ .4 alkoxy or halo;
- R4 is selected from the group consisting of:
- X is selected from C(O) or S(0) 2 with the proviso that when X is S(0) 2 then is methyl, p and q are both 1 and Z is a 5 to 6 membered heteroaryl ring;
- R ⁇ i hydrogen, halo, Cj ⁇ alkyl, Cj ⁇ haloalkyl or C ⁇ alkoxy;
- s 0, 2 or 3
- p and q are independently 0, 1 or 2 provided that p+q does not exceed 2, i.e., forming a 4-, 5- or 6-membcred ring.
- p and q may be the same, i.e., forming a 4- or 6- membered ring.
- p and q are both I .
- A is suitably pyridine, pyrimidine or pyrazine typically pyridine or pyrimidinc, e.g., 2- or 3- pyridyl or 2- or 5-pyrirnidinyi, where the 2-, 3- or 5- refers to the point of attachment of the pyrrolidine ring (X being attached in the para position and R 1 being attached at any suitable position).
- R1 is suitably hydrogen, halogen or cyano.
- R ⁇ is preferably hydrogen.
- R ⁇ may optionally be substituted by 1, 2 or 3 substituents.
- R ⁇ is optionally substituted by 1 or 2 substituents and in further embodiments it is substituted by 2 or 3 substituents.
- R ⁇ is preferably optionally substituted by 1, 2, or 3 substituents independently selected from halo and methyl.
- R ⁇ is preferably optionally substituted by 1 or 2 substituents independently selected from halo and methyl.
- R- is suitably phenyl substituted by 2 or 3 halo groups.
- Halo is suitably fluoro. may be an optionally substituted phenyl or pyridyl, e.g.
- R ⁇ examples include phenyl 2-pyridinyl, 4-fluoro-2- pyridinyl, 5-fluoro-2-pyridinyl, 4-methyl-2-pyridinyl 5-methyl-2-pyridinyl, 2- fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,3-di fluorophenyl, 2,4-difluorophenyl, 2, 5 -di fluorophenyl 2,6- di luorophenyl 2,3 ,4-tri fluorophenyl 2, 3 , 5 -t ri fl uoropheny 1 , 2,3,6-trifluorophenyl, 2,4,5- tri fluorophenyl, 2,4,6-tri fluorophenyl, 2-fluoro-5-methylphenyl and 2 ,4-d ifl uoro -5 -methylpheny 1.
- R ⁇ may suitably be methyl, C3_(-,cycloaIkyl or alkyl wherein the C2.4 alkyl is optionally substituted by fluoro, cyano, hydroxy or Cj ⁇ alkyloxy.
- Suitable examples of include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, CH 2 CH 2 OCH 3 and CH 2 CF 3 .
- p and q are independently 0, 1 or 2 provided that p+q does not exceed 2, i.e., forming a 4-, 5- or 6-membered ring, in some embodiments, p and q may be the same, i.e., forming a 4- or 6- membered ring.
- p and q are both 1. In certain embodiments p is 1 and q is 0. In other embodiments p is 0 and q is 1 .
- Z is -C(0)OR 4 . In further embodiments Z is C(0)R 4 . In still further embodiments it is S(0)2R .
- R 4 may suitably be alkyl, C .galkoxyalkyl, C3_gcyeloalkyl or €3.5 cy d oalky lalky 1 , wherein said C3_gcycloalkyl or C ⁇ .gcycloalkylC ⁇ ⁇ alkyl is optionally substituted by C j .4 alkyl.
- R 4 examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, cyclopropyl and 1 -methylcyclopropyl.
- R 4 is propyl, especially isopropyl.
- Z may be a heteroaryl group optionally substituted by one or two groups selected from halo, Cj_4 alkyl, Cj ⁇ haloalkyl, C j ⁇ alkoxy, C2_4alkoxyalkyl, 4 to 6 membercd saturated heterocyclyl comprising 1 or 2 ring heteroatoms selected from N, O and S, C ⁇ .gheterocyclyl C j ⁇ alkyl (wherein the heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S) and C3_gcycloalkyl wherein the cycloa!kyl is optionally substituted by C ⁇ .
- C j ⁇ haloalkyls are perfluoroalkyls, e.g. CF 3 , CF2Me and CHF ?
- Z is heteroaryl suitable heteroaryl groups include oxadiazole, pyrimidinc, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazole, e.g., oxadiazole and pyrimidine.
- Z may comprise l,2,4-oxadiazoi-3-yi, 1 ,2,4-oxadiazol-5-yl, pyrimidin-2-yi or a 2H- tetrazol-5-yl, which may be substituted by any of the aforementioned substituents.
- Z is a substituted heteroaryl
- suitable substituents include ethyl, i-propyl, t-butyl, cyclopropyl, chloro, 1-methylcyclopropyl, CF 3 , CH 2 F, CF 2 H, CH(OMe)Me, C(Me) 2 OH, C(Me) 2 F, CF 2 Me, CH 2 OMe and 2-tetrahydrofuranyl.
- Z may be -CFFj-phenyl, wherein the phenyl is optionally substituted by one or two groups independently selected from Ci .4 alkyl, Cj_4 haloalkyl and halo.
- Particular embodiments include those wherein Z is - €3 ⁇ 4 -phenyl optionally substituted by one or two halo or methyl groups, e.g. 4-fluorophcnyl
- R7 is preferably hydrogen.
- X is suitably C(O), have the formula:
- the molecular weight of the compounds of the invention is suitably less than about 800, typically less than about 600.
- the invention also includes isotopically labeled compounds, which are similar to those recited in formulae (I), (la) and (lb) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 ⁇ 4, HC, 14 C and ⁇ F.
- Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 ⁇ 4 14Q are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 ⁇ 4 and carbon- 14, i.e., ⁇ C, isotopes are particularly preferred for their ease of preparation and detectability. and % isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
- isotopically labeled compounds of formula (I), (la) and (lb) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- the compounds of formula (I), (la) and (lb) or salts thereof are not isotopically labelled.
- alkyl means carbon chains which may be linear or branched. Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. Such alkyl groups may in some embodiments be substituted with one or more halo groups, particularly fluoro.
- cycloalkyl refers to a 3 to 6 C saturated carbocycle moiety e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- heterocyclyl refers to a 4 to 6 membered saturated heterocyele comprising 1 or 2 ring hetcroatoms selected from N, O and S.
- hetcroeyeles include tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, oxetane and azetidine.
- heteroaryl refers to a 5- or 6-membered hcteroaryl ring optionally containing one or more, e.g. 1. 2 or 3 heteroatoms selected from N, O and S, or a 8 to 10 membered fused bicyclic system optionally containing one or more, e.g.
- heteroaryl rings include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl and benzothiazolyl.
- 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, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, cthanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholinc, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimcthylamine, 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, iscthionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-tolucnesulfonic, trifluoroacetic acid and the like.
- the compounds of the invention are intended for pharmaceutical use they arc preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
- R 5 , R , R , A, X, Z, p, q, r and s are as defined for formula (I).
- PG is a protecting group
- LG is a leaving group
- Hal is halogen
- Het is heteroaryl.
- esters of formula (V) can be prepared by SN Ar displacement of suitable haloaromatic compounds of formula (III) with amines of formula (IV) under standard conditions, for example, DBU and DMSO at 80 - 100°C.
- Acids of formula (VI) can be prepared from esters of formula (V) under standard conditions, for example, LiOH, water and methanol at room temperature.
- Amides of formula (If) can be prepared from acids of formula (VI) with amines of formula (VII) under standard amide coupling conditions, for example, HOBT and EDCI, in a suitable solvent, such as DCM.
- Sulfonamides of formula (IX) can be prepared by reaction of amine of formula (VII) with sulfonyl chloride of formula (VIII) under standard conditions, for example, triethylamine in a suitable solvent, such as DCM.
- Compounds of formula (II) can be prepared by SN Ar displacement of suitable haloaromatic compounds of formula (IX) with amines of formula (IV) under standard conditions, for example, DBU and DMSO at 80 - 100°C.
- Sulfonamides of formula (XVI) can be prepared from amines of formula (X) and sulfonyl chlorides of formula (XV) under standard conditions, for example, triethylamine in a suitable solvent, such as
- Compounds of formula (VII) where Z is heteroaryl can be prepared as outlined in Scheme 7.
- Compounds o formula (XVIII) can be prepared by SN Ar displacement of suitable haloaromatic compounds of formula (XVII) with amines of formula (X) under standard conditions, for example, DBU and DMSO at 80 - 100°C.
- compounds of formula (XVIII) can be prepared by reaction of suitable haloaromatic compounds of formula (XVII) with amines of formula (X) under Buchwald-Hartwig conditions, such as, Pd 2 (dba) 3 and BIN/VP in a suitable solvent, such as toluene at 1 10°C. Removal of the protecting group PG from the amine functionality in compounds of formula (XVIII) can be achieved using standard conditions well known to those skilled in the art.
- Compounds of formula (IV) where R 2 is N-pyridonyl can be prepared as outlined in Scheme 8.
- Compounds of formula (XX) can be prepared from alcohols of formula (XIX) under standard conditions, for example, methanesulfonyl chloride and triethylamine in a suitable solvent, such as, THF at 0°C.
- Diazabicyclo compounds of formula (XXI) can be prepared from compounds of formula (XX) by treatment with sodium hydride in a suitable solvent, such as, THF at 0°C.
- Compounds of formula (XXII) can be prepared from compounds of formula (XXI), pyrid-2-one and potassium tert- butoxide in a suitable solvent, such as, ⁇ in a microwave reactor at 100°C. Removal of the protecting group PG' from the amine functionality in compounds of formula (XXII) can be achieved using standard conditions well known to those skilled in the art.
- 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 (1).
- 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 (1) 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-Interscience, New York, 2 nd edition.
- the compounds of the invention are useful as GPR1 19 agonists, 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 compounds of the invention may also be 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, in combination with a pharmaceutically acceptable carrier.
- the composition is comprised of a pharmaceutically acceptable carrier and a nontoxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
- the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPR1 19 and optionally DPP-IV, resulting in the prophylactic or therapeutic treatment of diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of the invention, or a pharmaceutically acceptable salt thereof.
- 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 carrier according to conventional pharmaceutical compounding techniques.
- a pharmaceutical carrier 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 carrier that constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers 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 carrier employed can be, for example, a solid, liquid, or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- any convenient pharmaceutical media may be employed.
- water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers 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. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers 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 0.05mg to about 5g 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 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about Img to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 2()0mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
- 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 carrier 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. As an example, 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 carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers 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 carrier(s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- other adjuvants ca be included to render the formulation isotonic with the blood of the intended recipient
- 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 ().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 optionally DPP-IV play a role.
- the invention also provides a method for the treatment of a disease or condition in which GPR119 and optionally DPP-TV " 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 dyslipidacmia).
- the compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, 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 o 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, hyperlipidemia, 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 lowerin 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-1 antagonists and CB-1 antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somo statin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, FTP IB inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g.
- sibutraminc CRT antagonists, CRF binding proteins, thyromimctic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 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, coadministration 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 antiobesity agent, and a pharmaceutically acceptable carrier.
- the invention also encompasses the use of such compositions in the methods described above.
- LCMS-method 2 Phenomencx Kinetex CI S column (3.0x30mm, 2.6 ⁇ , flow rate l .OmL/min) eluting with a H 2 0-MeCN solution containing 0.1% HC0 2 H over 2 min with UV detection at 220 nm.
- Gradient information 0.0-0.1 min 2% MeCN 98% I O to 5% MeC 95% H- 2 0; 0.1-1.50 min: Ramp up to 100% MeCN; 1 .5-1.75min: Hold at 100% MeCN; 1.75-1 .Smin: 100% MeCN to 2% MeCN 98% H 2 0 ; 1.8-2.0 min: Hold at 2% MeCN 98% H 2 0.
- the mass spectra were obtained using an electrospray ionisation source in both the positive (ES + ) or negative (ES " ) ion modes.
- LCMS-method 3 data were obtained as follows: Xbridge C18 column (3.0 x 150mm, 5 ⁇ , flow rate l .OmL/min) eluting with an McCN-l OmM NH 4 HCO 3 solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-0.1 min: hold at 5% MeCN 95% NH 4 HCO,; 0.1- 3,0 min: 5% MeCN 95%NH 4 HC ⁇ 3 ⁇ 4 to 5% NH 4 HC(3 ⁇ 4 95% MeCN; 3.0-3.9min: hold at 5% NH 4 HCO 3 95% MeCN.
- the mass spectra were obtained using an electrospray ionisation source in the positive (ES ) mode.
- LCMS -method 4 data were obtained as follows: Xbridge C 1 g column (2.1 x 50mm, 2.5 ⁇ , flow rate 0.8mL/min) eluting with an MeCN-lOmM NH 4 HCO 3 solution over 1.5 min with UV detection at 215 - 350nm. Gradient information: 0-0.8 min: 98% MeCN 2% NH 4 HCO 3 to 98% NH 4 HCO 3 2% MeCN; 0.8-1.2min: hold at 98% NH 4 HCO 3 2% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES " ) mode.
- LCMS-method 5 data were obtained as follows: Xbridge C 18 column (2.1 5.0mm, 2.55 ⁇ , flow rate 0.8mL/min) eluting with an MeCN- 10m VI NH 4 HCO3 solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-4 min: 98% MeCN 2% NH4HCO3 to 98% NH 4 HCO 3 2% MeCN; 4-4.6miri: hold at 98% NH 4 HCO3 2% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES ) mode.
- ES electrospray ionisation source
- Preparative I IPLC purification was carried out using either a standard or basic method.
- Standard method Gemini-NX C 18 column (21.2 x 100mm, 5 ⁇ , flow rate 20mL/min) eluting with a H 2 0-MeCN solution containing 0.1 % HC0 2 H using a 10 minute gradient with UV detection at 220 nm.
- Basic method XBridge Prep Qg column (19 x 100mm, 5 ⁇ , flow rate 20mL/min) cluting with a
- Chiral-HPI.C was performed on a Oaicel chiralpak ⁇ 250 x 20 mm, 5 ⁇ column.
- the title compound was prepared by reacting 2-[(3i?,45)-3-teri-butoxycarbonylamino-4-(2,5- difluoro ⁇ henyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90) with trans- ⁇ l-[3- (1 ,1 -difluoro-ethyl)-[l ,2,4]oxadiazol-5 -yl] -3 -fluoro-piperidin-4-yl ⁇ -mcthyl-amine (Procedure 40) employing a procedure similar to that outlined in Preparation 105 to afford the title compound as a mixture of diastereoisomers.
- Nitromethane (227mL, 4.22mol) was added in one portion to a solution of 2,5- difluorobenzaldehyde (500g, 3.52mol) in MeOI I (5L) in a 10 L jacketed vessel
- the solution was cooled to 4 °C (jacket -10 °C ) and a solution of NaOH (169g, 4.22mol) in water (500mL) was added over 40 min causing a 6 °C exothcrm.
- the solution was stirred for 60 min (jacket 0 °C) after which time a thick white precipitate formed.
- Ice water ( L) was added (jacket 5 °C) followed by NH 4 C1 (sat.
- Acetic anhydride (665mL, 7.05mol) was added in one portion to 1 -(2,5-difluoro-phenyl)-2- nitro-ethanol (Preparation 200, 672g, 3.31mol) at 0 °C under argon.
- DMAP 28.3g, 0.23mol was added and the solution darkened in colour.
- the reaction was warmed to r.t. over 18 h.
- the reaction mixture was cautiously poured into NaHCCh (sat. aq., 3.5L) and stirred to form a yellow solid.
- the slurry was stirred for 30 min at r.t. before filtering.
- the solid was washed with NaHC0 3 (sat. aq., 2L) then water (2L).
- the resulting paler yellow solution was stirred at -10 °C for 1 h before quenching cautiously with NaHCOs (sat. aq., 1 L). The two batches were combined and the layers partitioned. The DCM layer was washed with water (2L) then brine (2L), dried over MgS0 4 and evaporated to give 209g of an orange oil. The material was purified by dry flash chromatography eluting with DCM to afford the title compound.
- Triethylamine (244mL, 1.75mol) was added to a solution of 1 -benzyl -4-(2,5-difluoro- phenyl)-pyrrolidin-3-ylaminc (Preparation 203, 252g, 0.87mol) in THF (3.8L) and the cloudy light brown solution was cooled to 0 °C.
- Di-ieri-butyldicarbonate (229g, l .OSmol) was added in one portion and the suspension warmed to room temperature over 18 h. The THF was removed by evaporation and the off-white slurry taken up into EtOAc (2.5L).
- Nitromethane (274mL, 5.10mol) was added in one portion to a solution of 2,4,5- trifluorobenzaldehyde (680g, 4.25mol) in MeOH (7.2L) in a 10 L jacketed vessel.
- the solution was cooled to 0 °C (jacket -10 °C) and a solution of NaOH (204g, 5.10mol) in water (680mL) was added over 30 min. A 5 °C exothcrm was observed.
- the solution was stirred for 30 min (jacket 0 °C) after which time a white precipitate had formed.
- Half of the material was transferred to a second vessel and both slurries stirred for a further 30 min becoming very thick.
- Acetic anhydride (849mL, 8.99mol) was added to 2-nitro- 1 -(2,4,5-trifluoro-phenyl)-ethanol (Preparation 207, 935g, 4.22mol) at 0 °C under argon. ⁇ (36g, 0.30mol) was added in one portion and the solution darkened in colour. The temperature reached 50 °C over 20 min before cooling back to 0 °C. The solution was allowed to warm to r.t. over 18 h. The reaction mixture was cautiously poured into NaHC0 3 (sat. aq., 6L) and stirred to form a yellow solid. The slurry was stirred for 30 min at r.t. before filtering and washing with NaHCOj (sat.
- Triethylamine (210mL, 1.51 mol) was added to l -bcnzyl-4-(2,4,5-trifluoro-phcnyl)- pyrrolidin-3-ylamine (Preparation 210, 23 I g, 0.75mol) in TI IF (1.8L) and the light brown cloudy solution was cooled to 0 °C.
- Di-ferf-butyldicarbonate (198g, 0.91 mol) was added in one portion and the suspension warmed to room temperature over 18 h. The suspension was concentrated and the off- white slurry dissolved into EtOAc (2.5L).
- the reaction was stirred at 50 °C for 2 h.
- the reaction was cooled to r.t. and the TIIF removed under reduced pressure.
- the residue was dissolved in DCM (50mL) and the organic layer washed with I M HCI solution (2 x 1 OOmL) and saturated sodium bicarbonate solution (lOOmL), The organics were dried (magnesium sulfate) before being concentrated under reduced pressure.
- Preparation 245
- Preparation 256 [(3 ⁇ ,4£)-1- [5-( ⁇ 1- [3-(l ,1-Difluoro-ethyl)- [1,2,4) oxadiazol-5-yl] -piperidin-4-yl ⁇ - methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyI)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester
- Prep aration 25 [(3R,4S)-l- [3-Cyano-5-( ⁇ l-[3-(l, l-difluoro-ethyl)-[l ,2,4] oxadiazol-5-yl] - piperidin-4-yl ⁇ -methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyl)-pyrroiidin-3-yl]- carbamic acid tert-but l ester
- Example 1 2-[(3/?, S -3-Amino-4-(2,4,5-trifluoro-phcnyl)-pyrrolidin-l-yi]-pyrimidine-5- carboxylic acid cyclopropyl- [ 1 -(3-isopropyl- [ 1 ,2,41 oxadiazol-5-yl)-piperidin-4-yl] -amide hydrochloride
- Example 2 2-[(3/?,45)-3-Amino-4-(2,5-difluoro-phcnyl)-pyrrolidin-l- l]-pyrimidine-5- carboxylic acid [ 1 -(3-isopropyI- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4-yl] -methyl-amide
- Example 3 2-
- Example 4 2-[(3if,45 ⁇ -3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid ⁇ l-[3-(l-fluoro-l-methyl-cthyl)-[l,2,4
- Example 88 2- [(3/?,45 ⁇ -3-Amino-4-(2-fluoro-5-methyI-phenyl)-pyrroIidin-l-yl] -pyrimidine-5- carboxylic acid [l-(3-ethyl- l,2,4]oxadiazol-5-yl)-pipcridin-4-yl)-methyl-amide hydrochloride
- Example 89 2- [(3/?,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin- 1 -yl) -pyrimidine-5- carboxylic acid [ l-(3-isopropyl- [1,2,4] oxadiazol-5-yl)-piperidin-4-yl] -methyl-amide hydrochloride
- Example 90 2-[(3 ?,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]-pyrimidinc-5- carboxylic acid ethyl-[l-(3-iso ropyl-[l,2,41oxadiazol-5-yl)-piperidin-4-yl]-amide hydrochloride
- Example 91 2-[(3R,45 -3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid ⁇ 1- [5-(l , 1 -difluoro-cthyl)- f 1 ,2,4]oxadiazol-3-yl] -piperidin-4-yl ⁇ -methyl-amide hydrochloride
- Example 92 2-[(3 f,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yI]-pyrimidine-5- carboxylie acid cyclopropyl- ⁇ 1- [5-(l-methoxy- 1-methyl-ethyl)- [1 ,2,4] oxadiazol-3-yl] -piperidin- 4-yl ⁇ -amide hydrochloride
- Example 93 2-[(3 ?,4A')-3-Ammo-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimicline-5- carboxylic acid cyclopropyl- ⁇ l-[5-(l,l-difluoro-ethyl)-[l,2,4Joxadiazol-3-yI]-piperidin-4-yl ⁇ - amide hydrochloride
- Example 94 2- [(3/?,45 -3-Amino-4-(2,5-difluoro-phenyl)-pyrroiidin-l-yll-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[( ?)-S-(tetrahydro-furan-3-yl)-
- Example 95 2-[(3-?,4.S)-3-Aniino-4-(2,5-difluoro-phenyl)-pyrroIidin-l-yl]-pyriinidine-5- carboxylic acid cyclopropyl- ⁇ 1- ((5)-3-(tetrahydro-furan-3-yl)- [ 1 ,2,4] oxadiazol-5-yl j -pipcridin- 4-yl ⁇ -amide hydrochlori
- Example 96 2-[(3/?,4 )-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-sulfonic acid ⁇ l -f3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-ylJ-piperidin-4-yl ⁇ -methyl-amide hydrochloride
- Example 97 2-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l -yl] -pyrimidine-5 carboxylic acid (l-cycloprop amide hydrochloride
- Example 98 2- [(3/i,45)-3-Amino-4-(2 ,5-difluoro-phenyl)-pyrro!idin- 1 -yl] -pyriniidine-: carboxylic acid cycloprop - [ 1 -(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl] -amide hydrochloride
- Example 100 2-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyI)-pyrrolidin-l-yl)-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ 1 - [3-( 1-methoxy-cyclopropyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4- yl ⁇ -amide hydrochloride
- Example 101 2- f(3S,45 3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin- 1-ylJ -pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[(5)-3-(tetrahydro-furan-2-yl)- [ 1,2,4] oxadiazol-5-yl] -piperidin- 4-yl ⁇ -amide hydrochloride
- Example 102 2-[(3iZ,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- car boxylic acid cyclopropyl- ⁇ 1- [ ⁇ R )-3-(tetrahyd o-f uran-2-yl)- f 1 ,2,4] oxadiazol-5-yl] -piperidin- 4-yI ⁇ -amide hydrochloride
- Example 103 5-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrazinc-2- carboxylic acid ⁇ l-[3-(l,l-difluoro-ethyI)-(l,2,4]oxadiazol-5-yI]-piperidin-4-yl ⁇ -methyl-amide hydrochloride
- Example 104 e-KS ⁇ -S-Amino ⁇ -il ⁇ -dmuoro-phen lJ-p rroHdin-l-yll- ⁇ -il-ia-il,!- difluoro-ethyl)-[ 1,2,4] oxadi ide hydrochloride
- Example 105 6-[(3 i,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5-cyano-A'- ⁇ l-[3- ( 1 ,1 -difluoro-ethyl)- [1 ,2,4] oxa diazol-5- l] -piperidin-4-yl ⁇ -A-methyl-nicotinamide hydrochloride
- the biological activity of the compounds of the invention may be tested in the following assay systems: GPR119 cAMP Assay
- cAMP cyclic AMP
- the cell monolayers were washed with phosphate buffered saline and stimulated at 37°C for 30 min 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.
- 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 380 nm and emission 460 nm.
- Assays were carried out in 96-weIl plates (Black OptiPlate-96F) in a total volume of 100 ⁇ , per well consisting of 50 inM Tris pH 7.6, 100 ⁇ GP-AMC, 10-25 ⁇ ) recombinant human DPP-IV and a range of inhibitor dilutions in a final concentration of 1% DM SO. Plates were read in a fluorimeter after 30 min incubation at 37"C.
- Recombinant human DPP-IV residues Asn29-Pro766 was purchased from BioMol.
- I IIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM sodium selemte. 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). cAMP assay
- HIT-T15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ 0.1 mL well and cultured for 24 h and the medium was then discarded. Cells were incubated for 15 min at room temperature with 1 ⁇ stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7.4). 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 30 min.
- 1 ⁇ stimulation buffer Hors buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7.4
- 75 uL lysis buffer (5mM HEPES, 0.3% Tween-20, 0,1% BSA, pH 7.4) was added per well and the plate was shaken at 900 rpin for 20 min. Particulate matter was removed by centrifugation at 3000rpm for 5 min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly 25 reactions were set up containing 8 ⁇ L ⁇ 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 1 0 min, 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, 1000 n.Vl) 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 EC5 0 of less than 10 ⁇ . Compounds showing an EC5 0 of less than 1 ⁇ in the cAMP assay may be preferred.
- HIT-T15 cells are plated in standard culture medium in 12-well plates at 106 cells/ 1 ml/ well and cultured for 3 days and the medium then discarded. Cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 1 19 raM NaCl, 4.74 mM Cl, 2.54 mM CaCl,, 1 .19 mM MgS0 4 , 1.19 mM ⁇ , ⁇ , 25 mM NaHCOj, 10 mM HEPES at pi I 7.4 and 0.1% bovine serum albumin. Cells are incubated with 1ml KRB at 37°C for 30 min which is then discarded.
- KRB Krebs-Ringer buffer
- Compounds of the invention preferably increase insulin secretion at an EC5 0 of less than 10 ⁇ .
- the effects of compounds of the invention on oral glucose (Glc) tolerance may be evaluated in male Sprague-Dawley rats. Food is withdrawn 16 h before administration of Glc and remains withdrawn throughout the study. Rats have free access to water during the study. A cut is made to the animals' tails, then blood (1 drop) is removed for measurement of basal Glc levels 60 min before administration of the Glc load. Then, the rats are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl /j-cyclodextrin) 45 min before the removal of an additional blood sample and treatment with the Glc load (2 g kg -1 p.o.).
- Blood samples are taken from the cut tip of the tail 5, 15, 30, 60, 120, and 1 0 min after Glc administration. Blood glucose levels are measured just after collection using a commercially available glucose-meter (OneTouch® UltraTM from Lifescan). Compounds of the invention preferably statistically reduce the Glc excursion at doses ⁇ 100 mg kg ' .
- mice The effects of compounds of the invention on oral glucose (Glc) tolerance were evaluated in male C57B1/6 or male oblob mice.
- Food was withdrawn 5 h before administration of Glc and remained withdrawn throughout the study. Mice had free access to water during the study.
- a cut was made to the animals' tails, then blood (20 ⁇ .) was removed for measurement of basal Glc levels 45 min before administration of the Glc load. Then, the mice were weighed and dosed orally with test compound or vehicle (20% aqueous or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood sample (20 ⁇ .) and treatment with the Glc load (2-5 g kg "1 p.o.).
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WO2014037327A1 (en) * | 2012-09-10 | 2014-03-13 | Boehringer Ingelheim International Gmbh | N-cyclopropyl-n-piperidinyl-amides, pharmaceutical compositions containing them, and uses thereof |
CN104860946A (zh) * | 2015-05-14 | 2015-08-26 | 湖北生物医药产业技术研究院有限公司 | Ccr5拮抗剂的制备方法 |
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