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WO2013102929A1 - Nouveaux composés pour le traitement du diabète, de l'obésité ou de troubles associés - Google Patents

Nouveaux composés pour le traitement du diabète, de l'obésité ou de troubles associés Download PDF

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Publication number
WO2013102929A1
WO2013102929A1 PCT/IN2012/000821 IN2012000821W WO2013102929A1 WO 2013102929 A1 WO2013102929 A1 WO 2013102929A1 IN 2012000821 W IN2012000821 W IN 2012000821W WO 2013102929 A1 WO2013102929 A1 WO 2013102929A1
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Prior art keywords
imidazol
thio
propan
fluorophenyl
dimethoxyphenyl
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PCT/IN2012/000821
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English (en)
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WO2013102929A4 (fr
Inventor
Sameer Agarwal
Ranjit C. Desai
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Cadila Healthcare Limited
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Publication of WO2013102929A1 publication Critical patent/WO2013102929A1/fr
Publication of WO2013102929A4 publication Critical patent/WO2013102929A4/fr

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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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of the general Formula I their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, polymorphs, use of these compounds in medicine and the intermediates involved in their preparation.
  • the compounds of the invention are suitable for the treatment of diabetes and associated disorders. Additionally, these compounds may also be useful in the management of obesity.
  • Diabetes is a major worldwide health problem. In 2000, 171 million people were living with diabetes, and this number is projected to rise to 366 million in 2030. [Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047- 53.]
  • Type II diabetes also known as diabetes mellitus, is now internationally recognized as one of the major threats to human health in the 21st century. According to the International Diabetes Federation (IDF), diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined. Those that suffer from type II diabetes have too little insulin or cannot use insulin effectively. As a result, glucose levels build up in the blood and urine and, if left untreated, can cause life-threatening complications, including blindness, kidney failure, and heart disease. The huge human and economic costs of diabetes and associated complications prompted the research for appropriate and efficient treatments.
  • IDF International Diabetes Federation
  • BAs bile acids
  • GPCR G-protein-coupled receptor
  • TGR5 also known as BG37, M-BAR, or hGPCR19
  • BG37 a bile acid G protein-coupled receptor primarily expressed in monocytes and macrophages, lung, spleen, and the intestinal tract.
  • Bile acids are known to be key regulators of lipid, glucose and overall energy metabolism.
  • TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. [Thomas et al.
  • Bile acid activation of the G protein-coupled receptor TGR5 has been shown to induce energy expenditure in muscle and brown fat, thereby conferring resistance to weight gain.
  • An article published in Cell Metabolism (Vol. 10, Issue 3, Sept. 2, 2009) elaborates on a separate TGR5 -regulated mechanism in the gut that drives secretion of the hormone glucagon-like peptide (GLP-1) and resulting insulin sensitization. Binding of TGR5 agonist increases cAMP stimulates the secretion of GLP-1 from intestinal endocrine cells. [Katsuma, et al, Biochem. Biophys. Res. Commun.
  • GLP-1 has an insulinotropic effect in the pancreas and reduces the appetite.
  • the combined effects of FXR and TGR5 in metabolically-active tissues leads to a reduction of hyperglycaemia and insulin resistance.
  • TGR5 activation is followed by release of the Gas subunit and activates the transcription of target genes by binding to cAMP response elements (CREs) contained in their promoter.
  • CREs cAMP response elements
  • BAT brown adipose tissue
  • TGR5 activation of TGR5 leads to the activation of type 2 iodothyronine deiodinase 2 (D2) which converts thyroxine (T4) to triiodothyronine (T3) and up-regulates (PPARa), uncoupling protein (UCP-1, UCP2) and PPAR-coactivator (PGCla) activity inducing beta-oxidation, oxidative phosphorylation and energy uncoupling.
  • D2 type 2 iodothyronine deiodinase 2
  • T4 thyroxine
  • T3 triiodothyronine
  • PPARa up-regulates
  • UCP-1, UCP2 un
  • FXR in the liver stimulates beta-oxidation, down regulates FA synthesis. FXR also stimulates adipocyte differentiation, augmenting the production of leptin and adiponectin. These two hormones enhance energy uncoupling, b-oxidation, oxidative phosphorylation and reduce appetite.
  • TGR.5 modulators have been the subject of a several patent applications listed below: WO/2008/097976 - Heterocyclic Modulators of TGR5 for Treatment of Disease WO/2008/091540 - Substituted Bile Acids as TGR5 Modulators and Methods of Use WO/2008/067219 - Quinazolinone Modulators of TGR5
  • the present invention relates to new heterocyclic compounds which are effective modulators of TGR5 agonists of structural Formula I,
  • the invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof.
  • the invention also comprises use of the compounds and compositions for treating diseases or disorders in which TGR5 is a mediator or is implicated.
  • the invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases and disorders in which TGR5 is a mediator or it's implicated.
  • the present invention also provides compositions and combinations thereof and methods for using such compounds, compositions and combinations to treat these and related disorders.
  • All of the compounds of Formula I disclosed herein may have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds may preferably be in the presence of a pharmaceutically acceptable counter ion.
  • the pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can be any pharmaceutically acceptable counter ion.
  • the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
  • Y S, -S(0)-, -S(0) 2 -;
  • T -(CO)NH-, -NH(CO)-, -NR 7 -;
  • R 1 is selected from aryl, heteroaryl, heterocyclyl or aryl(Ci-C6)alkyl, wherein said aryl, heteroaryl, heterocyclyl or aryl(Ci-C 6 )alkyl can optionally be substituted with one, two, or three R la groups, wherein R la at each occurrence independently represents halogen, Ci-C 4 alkyl, Cj-C 4 haloalkyl, C3-C 8 cycloalkyl, heteroaryl, heterocyclyl, the group representing -R lb , -C, -C 4 alkyl-R lb , or -OC r C 4 alkyl-R lb wherein R lb at each occurrence independently represents cyano, nitro, -N(R lc ) 2 , -OR lc , -SR
  • R 2 is selected from -Z - R z , wherein
  • R Z is -C(R Y ) 2 -, -C(H)(OH)-, -N(R Y )-, -0-, -C(R Y ) 2 0-, -S-, -S(O)-, -S(0) 2 -, -C(O)- wherein R Y at each occurrence independently represents hydrogen, Ci-C 4 haloalkyl, Q- C 4 alkyl, or hydroxy(Ci- C 4 )alkyl groups; and R z is aryl or heteroaryl, heterocyclyl wherein said aryl or heteroaryl or heterocyclyl groups can optionally substituted with one, two, or three R Z1 groups,
  • R Z1 at each occurrence is cyano, halogen, nitro, -R zib ' -N(R zlb ) 2 , -O R zlb , -S R zib , -C(O) R zlb , -C(0)0 R z, , -C(0)N(R zlb ) 2 , -S(0)N(R zlb ) 2 , -S(0) 2 N(R zlb ) 2 , or - S(0) 2 R zlb , -OC(O) R zlb , -OC(0)0 R zlb , -OC(0)N(R ZIb ) 2 , -N(R lc )C(0) R zib , - N(R zlb )C(0)0 R zlb , -N(R z,b )C(0)N(R zlb ) 2 , or -N(R
  • R 3 is (i) aryl, heteroaryl, or aryl(Ci-C 2 )alkyl, wherein said aryl, heteroaryl, or aryl(Ci-C 2 )alkyl can optionally be substituted with one, two, or three R 3a groups, wherein R 3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, acyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing ⁇ R 3b , -Ci-C alkyl-R 3b , or -OCi-C 4 alkyl; wherein the substituted group on C3-C 8 cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C 4
  • R 4 is selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C 4 alkyl, C C 4 haloalkyl, aryl, or heteroaryl heterocyclyl, or -N(R 4a ) 2 groups; wherein R 4a at each occurrence is independently selected from hydrogen, acyl, Q-C 4 alkyl or -S(0) 2 R b ; wherein R 4b at each occurrence is selected from amino, acyl or Ci-C 4 alkyl groups;
  • R 5 and R 6 each independently represents hydrogen, C r C 4 alkyl or alternatively, R 5 and R 6 together with carbon atom to which they are attached form a 3 ⁇ 7 membered ring, optionally comprising 1 or 2 hetroatom selected from O, N and S.
  • R 7 is independently absent or represents hydrogen, Ci-C 4 alkyl or Ci-C 4 haloalkyl.
  • R 1 is selected from aryl wherein aryl is substituted with one, two, or three R la group, wherein R la group is independently selected from halogen or CrC alkyl.
  • R 2 is selected from -Z-R z , wherein Z is - C(R Y ) 2 -, wherein R Y at each occurrence independently represents hydrogen, Q- C 4 alkyl; and R z is aryl wherein said aryl can optionally substituted with one, two, or three R ZI groups selected from cyano, halogen, -O R zib , wherein R zlb is independently selected from hydrogen or Cj-C 4 alkyl.
  • R 3 is aryl, heteroaryl, or aryl(Ci-C 2 )alkyl, wherein said aryl, heteroaryl, or aryl(C 1 -C 2 )alkyl can optionally be substituted with one, two, or three R 3a groups, wherein R 3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C 4 alkyl, C1-C4 haloalkyl, acyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R 3b , -C - C 4 alkyl-R , or -OC1-C4 alkyl; wherein the substituted group on C3-C 8 cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl,
  • R 3 is selected from Q-C 4 alkyl, -Ci- C 4 alkyl-OR 3d , wherein R 3D at each occurrence is independently selected from hydrogen, Ci-C 4 alkyl, or Ci-C 4 haloalkyl groups.
  • the various groups as defined above may be selected from:
  • alkyl as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. -butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C 3- i 0 , the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures.
  • the alkyl group may be optionally substituted with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups;
  • Amino or "amine” refers to a -N(R) 2 radical group, where each R is independently hydrogen, alkyl, aryl, acyl, heterocyclyl, or heteroaryl group.
  • an amino group may be optionally substituted by one or more substituents which independently are with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Cycloalkyl is , the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-10 carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.
  • cycloalkyl group may be optionally substituted with nitro, halogen, Ci-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems.
  • the aryl group may be selected from but not limited to phenyl and naphthyl.
  • aryl group may be optionally substituted with nitro, cyano, halogen, Ci-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • acyl used herein, refers to group R-C(O)-, wherein R is independently selected from hydrogen or alkyl, cycloalkyl, aryl as defined elsewhere in the specification.
  • R is independently selected from hydrogen or alkyl, cycloalkyl, aryl as defined elsewhere in the specification.
  • the acyl group represents formyl, acetyl and the like.
  • acyl group may be optionally substituted with nitro, cyano, halogen, Q- C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Heterocycle and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further including the oxidized forms of sulfur and nitrogen, namely SO, S0 2 , NO, N0 2 .
  • the heterocyclyl group may be selected from but not limited to tetrahydrofuran (THF), dihydrofuran, lj4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, pyridine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3- dithiane, oxathiane, thiomorpholine,
  • the heterocycle group may be optionally substituted with nitro, cyano, halogen, Cj-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N.
  • heteroaryl group includes heteroaryl fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
  • the heteroaryl group may be selected from but not limited to pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthal
  • heteroaryl group may be optionally substituted with nitro, cyano, halogen, Ci-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • halogen refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • the pharmaceutically acceptable salts include the conventional quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination, in treating the conditions or disorders described herein.
  • terapéuticaally effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • 'optional' or 'optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
  • 'optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'.
  • an optionally substituted group includes the unsubstituted group also.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 13 C- or l4 C- enriched carbon are within the scope of this invention.
  • Particularly preferred compounds may be selected from:
  • the compounds of present invention may be prepared by different synthetic schemes as describeed herein below wherein the groups R ZI , R 1 , R 3 , X, & Y are as defined earlier. Synthesis of the compounds of Formulae (I) disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other modifications/alterations that can be used to synthesize the compounds of Formula (I) disclosed herein, in combination with the processes described herein. In the descriptions below, one of ordinary skilled in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure.
  • Step (I): An aldehyde of formula (3) may be prepared by reaction of nitrile (2) with diisobutylaluminum hydride in a suitable solvent, such as THF(tetrahydrofuran) or toluene.
  • Step (II): Formation of carbinol (4) may be achieved by treatment of corresponding aldehyde (3) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
  • Step (III): Conversion of carbinol (4) to corresponding ketone (5) may occur under standard conditions, such as the Swern oxidation— known to one skilled in the art of synthetic organic chemistry.
  • Step (IV): Bromoketone (6) may be prepared by bromination of ketone (5) under typical conditions, such as with tetrabutylammonium tribromide in a solvent mixture of MeOH(methanol)/DCM(dichloromethane).
  • a suitable solvent such as DCM or toluene
  • a base such as triethylamine
  • Multiplicities are recorded as a s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), or m (multiplet). Coupling constants (J) are expressed in hertz.
  • Mass spectra are recorded on Perkin-Elmer Sciex API 3000. HPLC analysis were carried out at max 220 nm using column ODS C-18, 150 mm x 4.6 mm x 4 ⁇ on AGILENT 1100 series. Elemental analyses were performed on a Thermo Quest EA 1110 CHNS. All reactions involving air or moisture sensitive compounds were performed under nitrogen atmosphere. Thin layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel 60 F254, and spots were visualized with UV light. Flash chromatography (FC) was performed using silica gel 230-400 mesh.
  • IR (cm-') (CDC1 3 ): 2967, 2928, 2853, 1641, 1510, 1262,1221, 1152 , 1026, 845.
  • IR (cm -1 ) (CDC1 3 ): 2967, 2928, 2855, 1647, 1510, 1258, 1223, 1153, 1030, 843.
  • IR (cm '1 ) (CDC1 3 ): 3021, 2967, 2897, 1738, 1672, 1512, 1385, 1212, 1 153, 1045, 1030, 845.
  • IR icm “1 ) (CDCI 3 ): 3620, 2974, 2874, 1740, 1603, 1439, 1385, 1153, 1030, 669.
  • Example 42 The following compounds were prepared by following a similar process as described in Example 41 along with suitable modifications as are well known to those skilled in the art.
  • Example 42 The following compounds were prepared by following a similar process as described in Example 41 along with suitable modifications as are well known to those skilled in the art.
  • Example 42
  • IR (cm ) (CDC1 3 ): 629, 669, 770, 843, 928, 1028, 1215, 1256, 1410, 1512, 1603, 2839, 2974, 3021.
  • IR cm “1 ) (CDCI3): 2967, 2932, 2870, 2853, 1601, 1510, 1258, 1221, 1152, 1132, 1026, 843.
  • IR icm “1 ) (CDC1 3 ): 3441, 31 13, 3090, 2965, 2932, 2851, 1638, 1495, 1369, 1265, 1150,
  • Chinese Hamster Ovarian (CHO) Kl cells were plated in 24 well tissue culture plate at a density of 4 X 10 4 cells/well in a Nutrient Mixture F-12 HAM containing 10% Fetal Bovine Serum, cultured for 24 hrs at 37°C/5% C0 2 , and then transfected with 50 ng of human (h) TGR5 expression plasmid (pCMV SPORT6 - hTGR5), 300 ng of cAMP-responsive element (CRE)-driven luciferase reporter plasmid (pCRE-Luc) and 100 ng of ?-galactosidase reporter vector in each well using Polyfect Transfection Reagent (QIAGEN, Cat.
  • luciferase assays 20 //L of cell lysate was mixed with 100 ⁇ , of Luciferase Assay Substrate (Promega, Cat. No.: E1501) & Luminescence was measured in HIDEX Multitechnology Plate Reader.
  • 30 //L of cell lysate was mixed with 30 piL of 2X ONPG Buffer [20 mM sodium phosphate buffer - pH 7.3, 2 mM MgCl 2 , 100 mM ⁇ -mercaptoethanol, and 1.33 mg/mL o-nitrophenyl-/?-D- galactopyranoside (ONPG)] and incubated at 37°C for 2-10 mins. The optical density at 415 nm was determined in SpectraMax 190.
  • Normalized luciferase values were determined by dividing the luciferase activity by the galactosidase activity and expressed as fold induction with respect to (w.r.t.) DMSO control.
  • mice of 8-12 week age Male C57 mice of 8-12 week age, bred in Zydus research Centre Animal house will be used for this experiment. Animal will be issued and subjected for 3-7 days acclimatization. On first day animal will be grouped based on non-fasting serum glucose levels and kept on fasting for overnight. On second day of the experiment, formulation of test compounds will be prepared and fasting body weight of animals will be recorded. Each animal will receive a single dose of vehicle/test compounds administered per orally as per specified group and dose levels. Exactly 15 min post dosing glucose load (3gm/kg/10ml) will be administered orally to all the groups. Then exactly after 10 min of glucose load animal will bled from retro orbital plexus.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of Formula (I) of pharmaceutical compositions containing them are useful as antidiabetic and antiobesity compounds suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration. :
  • the compounds described herein may be administered at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent.
  • a combination therapy Several reasons can be attributed for using a combination therapy depending on the need of the patient.
  • one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent.
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the use of combination therapy may be envisaged for all such situations.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide- 1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR- 1 19 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta. agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents.
  • an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glu
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG- CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin and like), cholesterol-lowering drugs (for example, fibrates which include: fenofibrate,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de la formule générale (I), leurs sels pharmaceutiquement acceptables, leurs solvates pharmaceutiquement acceptables, des énantiomères, des diastéréomères, des promédicaments, leur N-oxyde, des métabolites, des polymorphes, l'utilisation de ces composés en médecine et les produits intermédiaires employés dans leur préparation.
PCT/IN2012/000821 2011-12-26 2012-12-17 Nouveaux composés pour le traitement du diabète, de l'obésité ou de troubles associés WO2013102929A1 (fr)

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WO2016144647A1 (fr) * 2015-03-06 2016-09-15 Stc.Unm Procédé de traitement d'obésité, de diabète, de maladies cardiovasculaires et rénales par régulation d'activité de gpr30/gper
US10251870B2 (en) 2015-03-06 2019-04-09 Stc.Unm Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER activity
US10471047B2 (en) 2015-03-06 2019-11-12 Stc.Unm Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER activity
US10682341B2 (en) 2015-03-06 2020-06-16 Stc.Unm Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER activity
US10980785B2 (en) 2015-03-06 2021-04-20 Unm Rainforest Innovations Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER activity
US11963949B2 (en) 2015-03-06 2024-04-23 Unm Rainforest Innovations Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER activity

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