WO2006117743A1 - Composes aromatiques substitues, agents anti-diabetiques - Google Patents

Composes aromatiques substitues, agents anti-diabetiques Download PDF

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Publication number
WO2006117743A1
WO2006117743A1 PCT/IB2006/051346 IB2006051346W WO2006117743A1 WO 2006117743 A1 WO2006117743 A1 WO 2006117743A1 IB 2006051346 W IB2006051346 W IB 2006051346W WO 2006117743 A1 WO2006117743 A1 WO 2006117743A1
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ethoxy
benzyl
carbonyl
methyl
ethyl
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PCT/IB2006/051346
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English (en)
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Jitendra A. Sattigeri
Mrinalkanti Kundu
Lalima Sharma
Priya Gupta
Sachin Ramesh Kandalkar
Srinivasan Thangathirupathy
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Ranbaxy Laboratories Limited
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Publication of WO2006117743A1 publication Critical patent/WO2006117743A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to substituted aromatic compounds, which have
  • PPAR modulating activity and hence can be used as anti-diabetic agents.
  • PPAR peroxisome proliferation activated receptor
  • Such compounds can also be used as therapeutic agents for treating diseases and conditions mediated through any of the isoforms of PPAR, diabetes and diabetes-associated complications, diseases or conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity.
  • Processes for the preparation of the described compounds, pharmaceutical compositions containing such compounds, and methods for treating diabetes mellitus and diseases and conditions mediated through insulin resistance are also provided.
  • Type II insulin-resistant diabetes mellitus also known as non insulin-dependent diabetes mellitus afflicts an estimated 6 % of the adult population in western society and is expected to grow at a rate of 6 % per annum worldwide.
  • Type II diabetes is a complex metabolic disorder and is characterized by hyperglycemia, which results from impaired insulin secretion from the pancreas and insulin resistance mainly in muscle and liver. Insulin-resistant individuals also exhibit a variety of closely related clinical indications, which include obesity, hypertension, dyslipidaemia, and premature atherosclerosis. 80 % of diabetic mortality arises from atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late-stage complications, such as nephropathy, neuropathy and retinopathy.
  • ASCVD atherosclerotic cardiovascular disease
  • Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise.
  • several pharmacological agents are also available as hypoglycemic agents including insulin secretogogues e.g., sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide), which increase insulin secretion from pancreatic cells; biguanides (metformin), which lower hepatic glucose production; and ⁇ -glucosidase inhibitors (acarbose), which delay intestinal absorption of carbohydrates.
  • insulin secretogogues e.g., sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide), which increase insulin secretion from pancreatic cells; biguanides (metformin), which lower hepatic glucose production; and ⁇ -glucosidase inhibitors (acarb
  • PPAR Peroxisome-Proliferator- Activated Receptor
  • PPAR ⁇ is abundantly expressed in adipose tissues. Direct activation of PPAR ⁇ leads to induction of adipocyte genes, such as for fatty acid transporter 1, which in turn contributes to lowering of triglycerides and free fatty acid (FFA) levels.
  • FFA free fatty acid
  • Glitazones for example, rosiglitazone and pioglitazone
  • rosiglitazone and pioglitazone belong to this class of drug and are now proven insulin sensitizers (Moller, D.E.; Nature, (2001), 414, 6865, 821-827).
  • PCT Publication No. WO 01/21602 and U.S. Patent No. 6,414,002 disclose oxa and thiazole derivatives, which have been described to be useful as antidiabetic and antiobesity agents.
  • PCT Publication No. WO 02/040481 discloses adenine-based inhibitors of adenylyl cyclase, pharmaceutical compositions and a method of use thereof.
  • PCT Publication No. WO 04/004655 discloses substituted heterocyclic derivatives that have been said to be useful as antidiabetic and antiobesity agents.
  • PCT Publication No. WO 03/082841 discloses 5-substituted 1 , 1 -dioxo- 1 ,2,5 thiazolidine-3-one derivatives that have been said to be useful as PTPASE inhibitors.
  • the present invention relates to substituted aromatic compounds, which have PPAR modulating activity, and accordingly can be used as anti-diabetic agents.
  • the present invention also relates to processes for synthesizing such compounds.
  • compositions containing one or more compound(s) provided herein, optionally together with one or more pharmaceutically acceptable carriers or diluents.
  • Such pharmaceutical compositions can be used for treating diseases and conditions mediated through any of the isoforms ( ⁇ , ⁇ or ⁇ ) of PPAR, diabetes mellitus or diseases or conditions mediated through insulin resistance.
  • X 12 and X 13 can each independently be CR' or N, wherein R' can be hydrogen or alkyl;
  • X] 5 can be CH or N;
  • X 16 and V can each independently be O, NR', or S, wherein R' can be the same as defined earlier;
  • D and E can be substituted or unsubstituted alkyl, aryl or a bond
  • R 1 -Rs and R 1O -Rn can each independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino
  • A can be N(CH 3 ), O, C(O), NH, S or a bond
  • Y can be COOR 28 (wherein R 28 can be hydrogen or substituted or unsubstituted alkyl) or
  • a 1 , A 2 or A 3 can be substituted or unsubstituted C 1-4 alkylene.
  • the compounds can include one or more of the following embodiments.
  • the compound can be:
  • Formula ⁇ Q _ Formula in pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein: Het, A 1 -A 3 , Z, Y, R 18 and R ⁇ can be the same as defined above.
  • compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • provided herein are methods of treating a mammal suffering from a disease or condition mediated through ⁇ , ⁇ or ⁇ isoforms comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
  • provided herein are methods of treating a mammal suffering from diabetes or associated diabetes complications comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
  • Formula IV with a compound of Formula Het-A]-OH or HeI-A 1 -L 1 (wherein L 1 can be a leaving group selected from Cl, Br, I, acetate, 4-methylbenzenesulfonate, 4- bromobenzenesulfonate, 4-nitrobenzenesulfonate, methanesulfonate, or trifluoromethanesulfonate) to form a compound of Formula V,
  • Het is selected from: wherein:
  • X 12 and X 13 are each independently CR' or N, wherein R' is hydrogen or alkyl;
  • X 15 is CH or N;
  • X 16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier;
  • D and E are substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A is N(CH 3 ), O, C(O), NH, S or a bond;
  • R 28 is substituted or unsubstituted alkyl or aryl;
  • Z is O, S, NH, N-Me or a bond;
  • a 1 is substituted or unsubstituted C 1-4 alkylene.
  • X 12 and X 13 are each independently CR' or N, wherein R' is hydrogen or alkyl;
  • X 15 is CH or N;
  • X 16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier;
  • D and E are substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A is N(CH 3 ), O, C(O), NH, S or a bond;
  • R 28 is substituted or unsubstituted alkyl or aryl
  • Z is O, S, NH, N-Me or a bond
  • a 1 is substituted or unsubstituted C 1-4 alkylene.
  • X 12 and X 13 each can independently be CR' or N, wherein R' can be hydrogen or alkyl;
  • X] 5 can be CH or N; X 16 and V each can independently be O, NR' or S;
  • D and E each can independently be substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn each can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A can be N(CH 3 ), O, C(O), NH, S, or a bond;
  • Formula II pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof wherein Het, A 1 -A 3 , Z, Y, R 18 and R ⁇ are the same as defined for Formula I above.
  • kits for treating patients e.g., mammals
  • methods for treating patients comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • provided herein are methods for treating patients (e.g., mammals) suffering from diseases or conditions in which insulin resistance is the central pathophysiological mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • patients e.g., mammals
  • diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, psoriasis or obesity, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, p
  • the compounds described herein can also be used in combination with another type(s) of anti-diabetic agent(s) and/or hypolipidemic agent(s) and/or anti-hypertensive agent(s) and/or platelet aggregation inhibitor(s) and/or anti-osteoporosis agent(s) for the treatment of patients (e.g., mammals) suffering from diseases and conditions described herein.
  • patients e.g., mammals
  • PPAR agonists e.g., biguanides, protein tyrosine phosphate- IB inhibitors, dipeptidyl peptidase inhibitors), insulin or insulin mimetics, sulphonylureas, ⁇ -glucosidase inhibitors, cholesterol lowering agents (HMG-CoA reductase inhibitors, sequesterants, nicotinyl alcohol, nicotinic acid or salt thereof, PPAR ⁇ agonists, PPAR ⁇ / ⁇ agonists, inhibitors of cholesterol absorption, Acyl CoA: cholesterol acyl tranferase inhibitors, antioxidants), PPAR ⁇ agonists, antiobesity compounds, an ideal bile acid transporter inhibitor, agents intended to be used in inflammatory for the treatment of mammal suffering from diseases and conditions described herein.
  • PPAR agonists e.g., biguanides, protein tyrosine phosphate- IB inhibitors, dipeptidyl
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR 8 -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl.
  • This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkylene refers to the divalent radical of the above defined alkyl. It may optionally be substituted with the substituents as defined for alkyl.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and - NR a -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR 8 -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF 3 , -NR p R q , -C(O)NR p R,, -NHC(O)NR p R q , -C(O)NR p R, (wherein R p and R q are the same as defined earlier), cyano, or S(O) D1 R 66 (wherein m is an integer from 0-2 and R 66 is same as defined earlier).
  • cycloalkyl refers to saturated or unsaturated cyclic alkyl of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Groups such cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropylene, cyclobutylene, and the like exemplify single ring structures.
  • Groups such as adamantanyl, bicyclo [2.2.1]heptane, and the like exemplify fused ring structures.
  • Cycloalkyl can also be fused with an aryl, for example indane, and the like.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • optionally substituted amino herein refers to NR g R h , wherein R g and R h can be hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -S(O) a R b or COR d (wherein a and R d are the same as defined earlier).
  • aryl herein refers to aromatic system having 2 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like.
  • the aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • a cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phen
  • heterocyclyl refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, haloalkyl, cyano, nitro, COR S , COOR s (wherein R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), oxo, carboxy, heterocyclyl, heteroaryl
  • Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl.
  • the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring.
  • the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl and the like.
  • solvates refers to solvates with water (i.e., hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
  • the present invention also includes, within its scope, prodrugs of the compounds described herein.
  • prodrugs can be functional derivatives of these compounds, which can be readily convertible in vivo to the required compound, and they may be carrier-linked or bioprecursors.
  • Carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired.
  • W is a group that can be easily removed under physiological conditions during or after administration to a patient (e.g., mammal) to form a compound having Formula I, or the carboxylate anion thereof, or a pharmaceutically acceptable salt, wherein W is selected from -OR 25 , -OCH 2 OR 25 , -OCH(CH 3 )OR 25 , -OCH 2 OC(O)R 25 , -OCH(CH 3 )OC(O)R 25 , -OCH 2 OC(O)OR 25 , -OCH(CH 3 )OC(O)OR 25 and -N(R 26 ) 2 (wherein R 25 can be independently selected from C 1-6 alkyl optionally substituted with one or two groups selected from -CO 2 H, -CONH 2 , -NH 2 , -OH, -OAc, -NHAc or phenyl;
  • the described compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention.
  • polymorphs includes all crystalline forms, as well as amorphous forms, of the compounds described herein and are encompassed within the scope of the present invention.
  • phrases "pharmaceutically acceptable carriers” is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • salts refers to salts prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metals or organic bases.
  • monovalent, divalent or trivalent metals include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc or aluminum and the like.
  • organic bases include, but are not limited to, amino acids, ammonia, mono-alkyl ammoniums, dialkyl ammoniums, trialkyl ammoniums or N-methyl glucamine and the like.
  • free acid forms of compounds of the present invention may be prepared from salt forms, for example, by contacting the salt with dilute aqueous solution of an acid, such as hydrochloric acid.
  • Base addition salts may differ from the free acid forms of the compounds described herein in physical characteristics, for example, solubility or melting point.
  • the salt forms differ from the compound described herein in certain physical properties such as solubility or melting point, but the salts are otherwise equivalent for purposes of this invention.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space.
  • Stereoisomers include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers as defined by the IUPAC 1974 Recommendations for Section E. AU such stereoisomers are encompassed within the scope of this invention.
  • modulate refers to the ability of a modulator for a member of the nuclear hormone receptor superfamily to either directly (e.g., by binding to the receptor as a ligand) or indirectly (e.g., as precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • pharmaceutically acceptable refers to being approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • Reactions of compounds of Formula IV with compounds of Formula Het- Ai -OH to form a compound of Formula V can be carried out in one or more solvents, for example, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, diethylether, dioxane, ethylacetate, acetonitrile, benzene or mixtures thereof.
  • Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in one or more solvents, for example, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in the presence of one or more organic bases (e.g., triethylamine, diethylamine, tributylamine, diisopropylamine, 4-dimethylaminopyridine, 1 ,8-diazabicyclo[5,4,0]-undec-7-ene, l,4-diazabicyclo[2,2,2]octane, N-methylmorpholine, diisopropylethylamine, pyridine, sodium hydride or mixtures thereof); one or more inorganic bases (e.g., potassium carbonate, cesium carbonate or mixtures thereof) or mixtures thereof.
  • organic bases e.g., triethylamine, diethylamine, tributylamine, diisopropylamine, 4-dimethylaminopyridine, 1 ,8-diazabicyclo[5,4,
  • Reactions of compounds of Formula IV to form compounds of Formula V can be carried out in the presence of one or more redox couple agents, which can be one or more of those known to one of ordinary skill in the art.
  • the oxidizing part of the redox couple can be selected from diisopropylazodicarboxylate (DIAD), diethylazo-dicarboxylate (DEAD), N,N,N',N'-tetramethylazodicarboxamide (TMAD), 1,1 '- (azodicarbonyl)dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP), 4,7- dimethyl-3,5,7-hexahydro-l ,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N'N'-tetraisopropyl- azodicarboxamide (TIPA) or mixtures thereof.
  • DIAD diisopropylazodicarboxylate
  • DEAD diethy
  • the reduction part of the redox couple can be one or more phosphines selected from trialkylphosphines (e.g., tributylphosphine), triarylphosphines (e.g., triphenylphosphine), tricycloalkylphosphines (e.g., tricyclohexylphosphine), triheteroarylphosphine, 4-(diphenylphosphino)-N,N'-dimethyl- aniline or mixtures thereof.
  • Phosphine reagents having a combination of aryl, alkyl or heteroaryl substituents may also be used (e.g., diphenylpyridylphosphine).
  • HC1 to form compounds of Formula VI can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, toluene, diethylether, dioxane, ethylacetate, acetonitrile or mixtures thereof.
  • Reactions of compounds of Formula V to form compounds of Formula VI can be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, 4-dimethylaminopyridine or mixtures thereof.
  • These reactions can also be carried out in the presence of one or more reducing agents, for example, sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, or mixtures thereof, or any methods known to in the art.
  • Hydrolyzing compounds of Formula VII to form compounds of Formula VIII can be carried out in the presence of one or more inorganic bases (e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof) and one or more solvents (e.g., tetrahydrofuran, methanol, water, dimethylformamide, diethylether, or mixtures thereof).
  • inorganic bases e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof
  • solvents e.g., tetrahydrofuran, methanol, water, dimethylformamide, diethylether, or mixtures thereof.
  • reaction temperatures and duration may be adjusted according to the desired needs and are well within the capabilities of one of ordinary skill in the art without undue experimentation.
  • the present invention encompasses pharmaceutical compositions comprising, as an active ingredient, one or more compounds described herein and/or one or more pharmaceutically acceptable salts together with one or more pharmaceutically acceptable carriers or diluents.
  • Compounds described herein may be administered to a patient, i.e., human or animal, for treatment by any route, which effectively transports the active compound(s) to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal) routes of administration.
  • a preferred administration route is oral administration.
  • compositions of the present invention comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers includes non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type.
  • Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, sachets or suppositories.
  • Active compounds for solid form preparations can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate or mixtures thereof; binders, for example, carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption acceptors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol monostearate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof; or mixtures thereof.
  • dosage forms may also comprise one or more buffering agents.
  • granules can be prepared with coating and shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
  • Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solution, suspensions, syrups or elixirs.
  • active compounds can be mixed with water or one or more other solvents, solubilizing agents, emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, or fatty acid esters of sorbitan or mixtures thereof.
  • Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • Injectable preparations for example, sterile injections or aqueous solutions may be formulated by methods known by one of ordinary skill in the art using one or more suitable dispersing or wetting suspending agents.
  • Acceptable vehicles and solvents include, for example, water, Ringer's solutions, isotonic sodium chloride or mixtures thereof.
  • Formulation described herein may be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients in need thereof by employing procedures well known to one of ordinary skill in the art.
  • Example 1 Preparation of compounds of Formula V An aldehyde, triphenyl phosphine and a heterocycle (in a ratio of 1.0: 1.4: 1.2 respectively) were added to a dry two-necked round bottom flask containing dry tetrahydrofuran and fitted with a septum and nitrogen balloon. The solution was cooled to -5 0 C to 0 0 C and diisopropylazodicarboxylate was added (1.3 equiv. with respect to aldehyde) dropwise with stirring. After complete addition, the resultant mixture was allowed to come to room temperature and stirred overnight. Volatiles were removed under reduced pressure and a residue was purified over a silica column using a mixture of ethyl acetate and hexane as a mobile phase, yielding a compound of Formula V.
  • a compound of Formula V and the hydrochloride salt of a compound of Formula RCH(NH 2 )COOEt were placed under vacuum for about 20 minutes, then dissolved in dry dichloromethane followed by the addition of dry triethylamine (2.5 equiv.). After stirring the resultant mixture for about 1-2 hours at room temperature, sodium triacetoxyborohydride (3.0 equiv.) was added and mixture was stirred was overnight at room temperature under inert atmosphere. The mixture was then poured into water and the organic layer was extracted with dichloromethane. The organic (dichloromethane) layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • a compound of Formula R 1 C 1 -Cl (either neat or in dry dichloromethane) and triethylamine in dichloromethane was added dropwise to a cold stirred solution (at 0 0 C to -5 0 C) of a compound of Formula VI and the resulting mixture was stirred overnight while being allowed to come to room temperature.
  • Dichloromethane was removed by rotary evaporation and the residue was purified over silica gel column using ethyl acetate :hexane as mobile phase to yield the desired carbamate ester.
  • a compound of Formula VII and lithium hydroxide (1 :2.1) in a mixture of tetrahydrofuran, methanol & water (3:1 :1 v/v) were stirred overnight at room temperature. After removing volatiles under reduced pressure the residue was dissolved in water. ⁇ on- polar impurities were washed with hexane successively, followed by the acidification of the aqueous layer to p ⁇ 4.0-5.0 using IN hydrochloric acid, and the product was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was washed with hexane to yield an acid of Formula VIII.
  • the acid of Formula VIII is chromatographically homogenous and spectroscopically pure.
  • HEK-293 cells purchased from ATCC (USA) cell bank, maintained in Minimum essential medium (Eagle) withlO % charcoal dextran treated serum, were inoculated in 6- well plates (Ix 10 6 cells/well) and cultured approximately 18 hours in Minimum essential medium (Eagle) with 2 mM L- glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, and 1.0 mM sodium pyruvate in 5% CO 2 at 37 0 C.
  • Cells were transfected with each PPAR expression plasmid, pCMV Script- (PPAR ⁇ l/PPAR ⁇ /PPAR ⁇ ) full length (2 ⁇ g in 2 mL/well), pTAL-PPRE-Luc (4 ⁇ g), pAdvantage and pRL-CMV by Lipofection using Lipofectamine-2000 (Invitrogen, Carlsbad, USA) in abovementioned media but without antibiotics. Transfection mixture was replaced by fresh media (without antibiotics) after 5 hours duration.
  • the cells were harvested and seeded into 96-well plate (LumiNuncTM Plates, NUNC, Roskilde, Denmark) at a density of 3 x 10 4 cells/well in 100 ⁇ L of medium with Phenol-red free MEM with 10 % charcoal dextran-treated serum and other components. After the cells adhered, 100 ⁇ L of Phenol-red free MEM with 10 % charcoal dextran treated serum containing compound/standards were added. No drug controls cells were added with DMSO concentration of 0.3 % as final.
  • the firefly luciferase activity was divided by the sea pansy luciferase activity to adjust for the transfection efficiency, and the value was defined as the normalized luciferase activity.
  • Fold activation is calculated as the ratio of PPAR-mediated transcriptional activity in the cells treated with each drug to that in DMSO-treated control cells.
  • Compound EC 50 was calculated with GraphPad Prism 4.0 software. % Maximum standard was calculated as the ratio of maximum firefly (standard) reading and firefly test reading multiplied by 100. Rosiglitazone (BRL-49653) and Ragaglitazar (DRF-2725) were used as standards for PPAR ⁇ l and PP ARa, respectively.
  • the compounds described herein exhibited EC 50 values at PPAR ⁇ from about 0.15 nM to about 30 nM, from about 0.15 nM to about 15.5 M, and even from about 0.15 nM to about 4.75 nM.
  • the compounds described herein exhibited EC 50 at PPAR n from about 0.5 nM to about 30 nM, from about 0.5 nM to about 15.5 nM, and even from about 0.15 nM to about 4.2 nM.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

L'invention porte sur des composés aromatiques substitués à activité modulatrice du PPAR (récepteur activé par le proliférateur du péroxysome) pouvant de ce fait servir d'agents anti-diabétiques, de par de leur caractère de modulateurs du PPAR. De tels composés peuvent servir à traiter des maladies et états médiés par les isoformes du PPAR, dont le diabète et les complications associées au diabète, et les maladies ou états dont la résistance à l'insuline constitue le mécanisme pathophysiologique central, et des maladies ou états tels que: le diabète de type II, la dyslipidémie, l'hypertension, les maladies coronariennes, les maladies cardio-vasculaires, l'athérosclérose, la néphrosclérose, le syndrome polykystique ovarien, les troubles de l'alimentation, les néphropathies diabétiques, les néphrites glomérulaires, la sclérose glomérulaire, le syndrome néphrotique, le psoriasis ou l'obésité. L'invention porte également sur les procédés de préparation des composés décrits, sur des préparations pharmaceutiques les contenant, et sur des méthodes de traitement du diabète sucré et des maladies et états médiés par la résistance à l'insuline.
PCT/IB2006/051346 2005-05-03 2006-04-28 Composes aromatiques substitues, agents anti-diabetiques WO2006117743A1 (fr)

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JP2014527027A (ja) * 2011-05-31 2014-10-09 レセプトス インコーポレイテッド 新規ｇｌｐ−１受容体安定剤および調節剤
US9598430B2 (en) 2013-06-11 2017-03-21 Celgene International Ii Sàrl GLP-1 receptor modulators
US9795613B2 (en) 2014-12-10 2017-10-24 Celgene International Ii Sàrl GLP-1 receptor modulators
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

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US6414002B1 (en) * 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2004004655A2 (fr) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Derives heterocycliques substitues utiles comme agents antidiabetique et anti-obesite et procede correspondant
WO2004048338A1 (fr) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Composes 1,3-dicarbonyle non cycliques utilises comme doubles agonistes de ppar presentant une activite antihyperglycemique et antihyperlipidemique
WO2005049589A2 (fr) * 2003-10-14 2005-06-02 Cadila Healthcare Limited Nouveaux composes heterocycliques

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WO2001021602A1 (fr) * 1999-09-22 2001-03-29 Bristol-Myers Squibb Company Derives d'oxathiazole et de thiazole utiles comme antidiabetiques et agents contre l'obesite
US6414002B1 (en) * 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2004004655A2 (fr) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Derives heterocycliques substitues utiles comme agents antidiabetique et anti-obesite et procede correspondant
WO2004048338A1 (fr) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Composes 1,3-dicarbonyle non cycliques utilises comme doubles agonistes de ppar presentant une activite antihyperglycemique et antihyperlipidemique
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014527027A (ja) * 2011-05-31 2014-10-09 レセプトス インコーポレイテッド 新規ｇｌｐ−１受容体安定剤および調節剤
US9278910B2 (en) 2011-05-31 2016-03-08 Receptos, Inc. GLP-1 receptor stabilizers and modulators
US9700543B2 (en) 2011-05-31 2017-07-11 Celgene International Ii Sàrl GLP-1 receptor stabilizers and modulators
US9598430B2 (en) 2013-06-11 2017-03-21 Celgene International Ii Sàrl GLP-1 receptor modulators
US10259823B2 (en) 2013-06-11 2019-04-16 Celgene International Ii Sàrl GLP-1 receptor modulators
US9795613B2 (en) 2014-12-10 2017-10-24 Celgene International Ii Sàrl GLP-1 receptor modulators
US10034886B2 (en) 2014-12-10 2018-07-31 Celgene International Ii Sàrl GLP-1 receptor modulators
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

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