WO2006082010A1 - Inhibitors of diacylglycerol acyltransferase (dgat) - Google Patents
Inhibitors of diacylglycerol acyltransferase (dgat) Download PDFInfo
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- WO2006082010A1 WO2006082010A1 PCT/EP2006/000786 EP2006000786W WO2006082010A1 WO 2006082010 A1 WO2006082010 A1 WO 2006082010A1 EP 2006000786 W EP2006000786 W EP 2006000786W WO 2006082010 A1 WO2006082010 A1 WO 2006082010A1
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- hydrazide
- isopropyl
- acetyl
- biphenyl
- yloxy
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- 0 CC(C)*(*C(c1ccccc1)=O)C(COc(c(*)cc(N)c1)c1N)=O Chemical compound CC(C)*(*C(c1ccccc1)=O)C(COc(c(*)cc(N)c1)c1N)=O 0.000 description 2
- LYFIAPKQSWGERY-UHFFFAOYSA-N C=[Br]c(cccc1)c1SCC(O)=O Chemical compound C=[Br]c(cccc1)c1SCC(O)=O LYFIAPKQSWGERY-UHFFFAOYSA-N 0.000 description 1
- RLXIKTHDCDJPEF-UHFFFAOYSA-N CC(C(C=C1F)F)C(Br)=C1OCC(O)=O Chemical compound CC(C(C=C1F)F)C(Br)=C1OCC(O)=O RLXIKTHDCDJPEF-UHFFFAOYSA-N 0.000 description 1
- SBCFCSNQVXAKBC-UHFFFAOYSA-N CC(C)N(C(COc(ccc(F)c1)c1-c(cc1)ccc1OC)=O)NC(c1ccccc1)=O Chemical compound CC(C)N(C(COc(ccc(F)c1)c1-c(cc1)ccc1OC)=O)NC(c1ccccc1)=O SBCFCSNQVXAKBC-UHFFFAOYSA-N 0.000 description 1
- UPGIOHFFUBTYLX-UHFFFAOYSA-N CC(C)N(C(COc(ccc(F)c1)c1-c(ccc(F)c1)c1F)=O)NC(c1ccccc1)=O Chemical compound CC(C)N(C(COc(ccc(F)c1)c1-c(ccc(F)c1)c1F)=O)NC(c1ccccc1)=O UPGIOHFFUBTYLX-UHFFFAOYSA-N 0.000 description 1
- RXJLAIARPLEXER-UHFFFAOYSA-N CC(C)N(C(COc(ccc(F)c1)c1-c(cccc1)c1S(C)(=O)=O)=O)NC(c1ccccc1)=O Chemical compound CC(C)N(C(COc(ccc(F)c1)c1-c(cccc1)c1S(C)(=O)=O)=O)NC(c1ccccc1)=O RXJLAIARPLEXER-UHFFFAOYSA-N 0.000 description 1
- DXSCNXNWADBGRF-UHFFFAOYSA-N CC(C)N(C(COc(ccc(F)c1)c1-c1ccccc1)=O)NC(c1ccccc1)=O Chemical compound CC(C)N(C(COc(ccc(F)c1)c1-c1ccccc1)=O)NC(c1ccccc1)=O DXSCNXNWADBGRF-UHFFFAOYSA-N 0.000 description 1
- MVNXHHDXZKYBHU-UHFFFAOYSA-N CCc(cccc1)c1-c(cc(cc1F)F)c1OCC(N(C(C)C)NC(c1ccccc1)=O)=O Chemical compound CCc(cccc1)c1-c(cc(cc1F)F)c1OCC(N(C(C)C)NC(c1ccccc1)=O)=O MVNXHHDXZKYBHU-UHFFFAOYSA-N 0.000 description 1
- YDRZYJATKMBSJX-UHFFFAOYSA-N Oc(c(F)cc(F)c1)c1Br Chemical compound Oc(c(F)cc(F)c1)c1Br YDRZYJATKMBSJX-UHFFFAOYSA-N 0.000 description 1
- YUQUNWNSQDULTI-UHFFFAOYSA-N Sc(cccc1)c1Br Chemical compound Sc(cccc1)c1Br YUQUNWNSQDULTI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic 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
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the invention relates to inhibitors of diacylglycerol acyltransferase.
- the inhibitors include, for example, phenoxy- and thiophenoxyacetamide derivatives and are useful for the treatment of diseases such as obesity, type II diabetes mellitus and metabolic syndrome. All documents cited or relied upon below are expressly incorporated herein by reference.
- the invention relates to inhibitors of diacylglycerol acyltransferase of formula (I)
- X is O or S
- R 1 is hydrogen, halogen, (d-C 6 )alkyl or cyano
- R 2 , R 2 ' are independently of each other H or halogen
- R 3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, NH(CH 2 ) n CH(CH 3 ) 2 , or -O(CH 2 ) n OCH 3 , unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (Ci-C 6 ) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring;
- R 4 is branched or unbranched (C 2 -C 6 ) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, -O(CH)(CH 3 ) 2 , -CF 3 , -O(CH 2 ) n CH 3 , -OCF 3 , -SCH 3 , -SO 2 CH 3 , -NO 2 , -(CH 2 )-Aryl and
- R 5 is (C 1 -C 6 ) alkyl or -CH(CH 3 ) 2 ; n is O, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
- Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids, and storage in fat tissue (see Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270).
- Diacylglycerol O-acyltransferase also known as diglyceride acyltransferase or DGAT
- DGAT is a key enzyme in triglyceride synthesis.
- DGAT catalyzes the final and rate-limiting step in triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates.
- DAG 1,2-diacylglycerol
- DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, 395-400).
- DGAT has a specificity for sn-1,2 diacylglycerols and will accept a wide variety of fatty acyl chain lengths (see Farese et al, Current Opinions in Lipidology (2000) 11, 229-234). DGAT activity levels increase in fat cells as they differentiate in vitro and recent evidence suggests that DGAT may be regulated in adipose tissue post-transcriptionally (see Coleman et al, Journal of Molecular Biology (1978) 253, 7256-7261 and Yu et al, Journal of
- DGAT activity is primarily expressed in the endoplasmic reticulum (see Colman, Methods in Enzymology (1992) 209, 98-104). In hepatocytes, DGAT activity has been shown to be expressed on both the cytosolic and luminal surfaces of the endoplasmic reticular membrane (see Owen et al, Biochemical Journal (1997) 323 (pt 1), 17-21 and Waterman et al, Journal of Lipid Research (2002) 43, 1555-156).
- DGATl and DGAT2 Two forms of DGAT were cloned and designated DGATl and DGAT2 (see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, 13018-13023,
- mice Although unable to express a functional DGAT enzyme (Dgat-/- mice), are viable and continue to synthesize triglycerides (see Smith et al, Nature Genetics (2000) 25, 87-90). This would suggest that multiple catalytic mechanisms contribute to triglyceride synthesis, such as DGAT2.
- An alternative pathway has also been shown to form triglycerides from two diacylglycerols by the action of diacylglycerol transacylase (see Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210).
- Dgat-/- mice are resistant to diet-induced obesity and remain lean. When fed a high fat diet, Dgat-/- mice maintain weights comparable to mice fed a diet with regular fat content. Dgat- /- mice also have lower tissue triglyceride levels. The resistance to weight gain seen in the knockout mice, which have a slightly higher food intake, is due to an increased energy expenditure and increased sensitivity to insulin and leptin (see Smith et al, Nature Genetics (2000) 25, 87-90, Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-
- Dgat-/- mice have reduced rates of triglyceride absorption, improved triglyceride metabolism, and improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in comparison to wild-type mice (see Buhman et al, Journal of Biological Chemistry (2002) 277, 25474-25479 and Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192). neighbourhood .
- Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack, et al, EP1219716 and Burrows et al, 26 th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, 1340-1346), substituted benzyl- phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, 1433-1437, Goto, et al, Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Uceda, et al, Thirteenth International Symposium on Athersclerosis (2003), abstract 2P-0401, and Miyata, et al, JP 2004067635) and substituted ary
- Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) 1125, 203-9), 2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, 942-7), isochromophilone, prenylflavonoids (see Chung et al, Planta Medica (2004) 70, 258-260), polyacetylenes (see Lee et al, Planta Medica (2004) 70, 197-200), cochlioquinones (see Lee et al, Journal of Antibiotics (2003) 56, 967- 969), tanshinones (
- alkyl means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted.
- the alkyl group is preferably C 3 to C 12 , more preferably C 5 to C 10 , more preferably C 5 to C 7 .
- the alkyl group is preferably C 1 to C 10 , more preferably C 1 to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl.
- alkyl as used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl.
- (C 1 -C 6 ) alkyl preferably is branched or unbranched, unsubstituted and not cyclic.
- lower alkyl means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical wherein said cyclic lower alkyl group is C 5 , C 6 or C 7 , and wherein said acyclic lower alkyl group is C 1 , C 2 , C 3 or C 4 , and is preferably selected from methyl, ethyl, propyl (n-propyl or r
- lower alkyl as used herein includes lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower alkynyl (branched or unbranched), cycloloweralkyl, cycloloweralkenyl and cycloloweralkynyl. Branched or unbranced, unsubstituted and acyclic lower alkyl are preferred.
- aryl means, for example, a substituted or unsubstituted carbocyclic aromatic group, such as phenyl or naphthyl, or a substituted or unsubstituted heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, imidazolyl, triazolyl, pyrimidinyl pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolyl, quinazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl. Substituted or unsubstituted carbocyclic aromatic group
- alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substituents present, preferably 1 substituent.
- Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g.
- aminocarbonyl mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono-or di-alkylaminocarbonylalkyl, arylaminocarbonyl
- carbamates e.g. alkoxycarbonylamino, arloxycarbonylamino, aminocarbonyloxy, mono-or di- alkylaminocarbonyloxy, arylminocarbonloxy
- ureas e.g. mono- or di- alkylaminocarbonylamino or arylaminocarbonylamino
- nitrogen-containing groups such as amines (e.g.
- the lower alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substitutents present, preferably 1 substituent.
- alkoxy means, for example, alkyl-O- and "alkoyl” means, for example, alkyl-CO-.
- Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups.
- halogen means, for example, a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical.
- salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
- acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
- Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids.
- Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
- X is O or S
- R 1 is hydrogen, halogen, (C 1 -C 6 )alkyl or cyano;
- R 2 , R 2' are independently of each other H or halogen;
- R 3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, NH(CH 2 ) n CH(CH 3 ) 2 , or -O(CH 2 ) n OCH 3 , unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with
- R 4 is branched or unbranched (C 2 -C 6 ) alkyl, unsubstituted phenyl, substituted phenyl which is phenyl mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -O(CH)(CH 3 ) 2 ,
- R 5 is (C 1 -C 6 ) alkyl or -CH(CH 3 ) 2 ; n is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
- Compounds of formula (I) are individually preferred and physiologically acceptable salts thereof are individually preferred, with the compounds of formula (I) being particularly preferred.
- the compounds of formula (I) can have one or more asymmetric C atoms and can therefore exist as an enantiomeric mixture, mixture of stereoisomers or as optically pure compounds.
- Preferred compounds of formula (I) are those, wherein X is O or S; R 1 is hydrogen, halogen, (Ci-C 6 )alkyl or cyano; R 2 , R 2' are independently of each other H or halogen;
- R 3 is unsubstituted phenyl, substituted phenyl with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, NH(CH 2 ) n CH(CH 3 ) 2 , or -O(CH 2 ) n OCH 3 , unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6- membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C 1 -C 6 ) alkyl, or substituted or unsubstituted 5-10-membered carboxylic ring;
- R 4 is branched or unbranched (C 2 -C 6 ) alkyl, unsubstituted phenyl, substituted phenyl which is pheny
- R 3 is:
- Y is O or S.
- X is O.
- Other preferred compounds are those, wherein X is S.
- a preferred embodiment of the present invention is related to compounds as defined above, wherein R 4 is substituted phenyl which is phenyl mono.-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -O(CH)(CH 3 ) 2 , -CF 3 , -O(CH 2 ) n CH 3 , -OCF 3 , -SCH 3 , -SO 2 CH 3 , and -NO 2 .
- R 4 is substituted phenyl which is phenyl mono.-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -O(CH)(CH 3 ) 2 , -CF 3 , -O(CH 2 ) n CH
- R 1 is halogen. More preferably, R 1 is fluorine. It is also preferred that R 2 and R 2' are hydrogen.
- R 3 is phenyl
- R 4 is (C 1 -C 6 ) alkyl, cyclopentyl, benzyl, unsubstituted phenyl or phenyl which is mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -O(CH)(CH 3 ) 2 , -CF 3 , -OCF 3 , - SCH 3 , -SO 2 CH 3 , -NO 2 and -C(O)-O-CH 3 .
- R 4 is unsubstituted phenyl or phenyl which is mono- or di-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (Ci-C 6 ) alkoxy, -O(CH)(CH 3 ) 2 , -OCF 3 , -SCH 3 , -NO 2 and -C(O)-O-CH 3 .
- R 4 is phenyl, 4-methoxy-phenyl, 4-chloro-phenyl, 3- methoxy-phenyl, 3-fluoro-phenyl, 3-chloro-phenyl, 3-isopropyl-phenyl, 2-methylsylfanyl- phenyl, 2-nitro-phenyl, 2-isopropoxy-phenyl, 2-ethyl-phenyl, 2-propoxy-phenyl, 2- methoxycarbonyl-phenyl, 2,3-dimethyl-phenyl, 2-trifluoromethoxy-phenyl or 2-efhoxy- phenyl.
- R 5 is -CH(CH 3 ) 2 -
- Other preferred compounds are those wherein n is 0, 1 or 2.
- Preferred compounds of formula (J) as defined above are those selected from the group consisting of
- Particularly preferred compounds of formula (I) as defined above are those selected from the group consisting of Benzoic acid N'-[2-(5-fluoro-4'-methoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl- hydrazide,
- a preferred embodiment of the present invention refers to the compound benzoic acid N'- [2-(5-fluoro-2' -methoxy-biphenyl-2-yloxy)-acetyl]-N' -isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5,2'-difluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-nitro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-isopropoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-ethyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-propoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-methoxycarbonyl-5-fluoro-biphenyl-2-yloxy)-acetyl]-N'- isopropyl- hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(2'-ethoxy-5-fluoro-bi ⁇ henyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-fluoro-2'-isopropyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N' - [2-(2' -ethyl-3 ,5-difluoro-biphenyl-2-yloxy)-acetyl] -N' -isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(5-methyl-2'-trifluoro-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(4,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
- Another preferred embodiment of the present invention refers to the compound benzoic acid N'-[2-(3,5-difluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'-isopropyl hydrazide.
- Another preferred embodiment of the present invention refers to the compound cyclohexanecarboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)- acetyl]-N'-isopropyl-hydrazide.
- Another preferred embodiment of the present invention refers to the compound thiophene- 2-carboxylic acid N'-[2-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yloxy)-acetyl]-N'- isopropyl hydrazide.
- the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
- Another embodiment of the present invention refers to a process for the manufacture of compounds of formula (I) as defined above, which process comprises reacting a compound of formula (H)
- R 1 , R 2 , R 2' , R 3 , R 4 , Rs and X are as defined above.
- the present invention also relates to compounds of formula (I) as defined above, when prepared by a process as described above.
- novel compounds of the present invention have been found to inhibit liver diacylglycerol acyltransferase activity.
- the compounds of the present invention can therefore be used in the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type It diabetes mellitus and metabolic syndrome.
- the invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
- the invention likewise embraces compounds as described above for use as therapeutic active substances, especially as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome.
- the invention relates to a method for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome, which method comprises administering a therapeutically effective amount of a compound as defined above to a human being or animal.
- a method as defined above wherein said therapeutically effective amount of said compound is in an amount of from about 10 mg to about 1000 mg per day.
- the invention also embraces the use of compounds as defined above for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type II diabetes mellitus and metabolic syndrome.
- the invention also relates to the use of compounds as described above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are modulated by diacylglycerol acyltransferase inhibitors, particularly for the therapeutic and/or prophylactic treatment of obesity, type ⁇ diabetes mellitus and metabolic syndrome.
- medicaments comprise a compound as described above.
- hydroxy-substituted be ⁇ zoate esters i can be alkylated with 2-bromoethyl methyl ether by heating in the presence of potassium carbonate to give the alkoxy-ether substituted benzoate esters ii, where R 1 ' is lower alkyl.
- tetrahydro-2H-thiopyran-4-one ⁇ i can be treated with tosylmethylisocyanide and potassium t-butoxide in t-butyl alcohol (6.61 g, 33.8 mmol) in an appropriate solvent to yield the nitrile iv.
- Nitrile iv can be treated with hydrogen chloride gas in a lower alkyl alcohol solution to yield ester v, where R 1 ' is lower alkyl.
- esters vi where Ri' is lower alkyl and R 2 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl can be treated with hydrazine monohydrate in an appropriate solvent with heating to yield hydrazide vii.
- Hydrazide vii can be dissolved in acetone, heated and then concentrated to dryness. The residue can be dissolved in and treated with triethylsilane, with warming, to yield alkyl hydrazide viii, where R 2 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl.
- a substituted bromo-benzene ix where X is O or S and R 3 ' is H, halogen, cyano or lower alkyl, in an appropriate solvent can be treated with triethylamine and t-butyl bromoacetate.
- the intermediate can then be treated with a solution of hydrochloric acid in an appropriate to yield to yield x, where R 3 ' is H, halogen, cyano or lower alkyl.
- a substituted phenol xi where R 3 ' is H, halogen, cyano or lower alkyl and R 4 ' is H, lower alkyl, cycloalkyl, arylalkyl, can be alkylated with t-butyl bromoacetate and potassium carbonate in an appropriate solvent.
- the resultant material can be treated with hydrochloric acid in an appropriate solvent to yield the aryloxy acetic acid xii.
- a substituted-bromo-phenol xiii where R 3 ' is H, halogen, cyano or lower alkyl, can be alkylated with t-butyl bromoacetate and potassium carbonate in an appropriate solvent with heating to yield t-butyl ester xiv.
- xiv can be heated with a commercially available substituted arylboronic acid in the presence of a base, typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene, with a catalytic amount of palladium, typically Pd[PPh 3 ] 4 , to yield xv, where R 5 ' is H, halogen, lower alkyl, nitro, alkoxy, thioalkoxy, haloalkoxy, lower alkyl carboxylate, or alkyl sulfonyl.
- a base typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene
- Pd[PPh 3 ] 4 a catalytic amount of palladium
- a substituted acetic acid x where X is O or S and R 3 ' is H, halogen, cyano or lower alkyl from Scheme 4 can be used to acylate a hydrazide viii from Scheme 3, where R 2 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl.
- R 2 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl.
- Various standard amide bond forming conditions as practiced by those skilled in the art, may be used.
- x and viii in an appropriate solvent, may be treated with a base, such as triethyl amine, and PyBroP or ECDI and HOBT to yield acyl hydrazide xvi.
- the arylbromide xvi can be heated with a commercially available substituted arylboronic acid in the presence of a base, typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene, with a catalytic amount of palladium, typically Pd[PPh 3 ] 4 , to yield xvii, where R 5 ' is H, halogen, lower alkyl, nitro, alkoxy, thioalkoxy, haloalkoxy, lower alkyl carboxylate, or alkyl sulfonyl.
- a base typically an aqueous solution of sodium carbonate in an appropriate solvent, typically, DME, DMF or toluene
- Pd[PPh 3 ] 4 a catalytic amount of palladium
- a substituted phenoxy-acetic acid xii from Scheme 5, where R 3 ' is H, halogen, cyano or lower alkyl and R 4 ' is H, lower alkyl, cycloalkyl, arylalkyl, can be used to acylate a hydrazide viii from Scheme 3, where R 2 ' is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or cycloheteroalkyl.
- Various standard amide bond forming conditions as practiced by those skilled in the art, may be used.
- x and viii in an appropriate solvent, may be treated with a base, such as triethyl amine, and PyBroP or ECDI and HOBT to yield acyl hydrazide xviii.
- an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
- the compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous dosages, including tablets and suspensions.
- buccal cavity e.g., buccal cavity
- parenterally e.g., intramuscularly, intravenously, or subcutaneously
- rectally e.g., by suppositories or washings
- transdermally e.g., skin electroporation
- the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
- the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
- Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
- the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
- formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile.
- Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
- the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
- Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
- the dose of a compound of the present invention depends on a number of factors, such as, for example, the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
- Such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein, and in the claims, as an "effective amount".
- the dose of a compound of the present invention is typically in the range of about 10 to about 1000 mg per day.
- Silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh silica gel for flash chromatography; columns were run under a 0-5 psi head of nitrogen to assist flow.
- Thin layer chromatograms were run on glass thin layer plates coated with silica gel as supplied by E. Merck (E. Merck # 1.05719) and were visualized by viewing under 254 nm UV light in a view box, by exposure to 12 vapor, or by spraying with either phosphomolybdic acid (PMA) in aqueous ethanol, or after exposure to Cl 2 , with a 4,4'- tetramethyldiaminodiphenylmethane reagent prepared according to E. Von Arx, M. Faupel and M Brugger, J. Chromatography, 1976, 220, 224-228.
- PMA phosphomolybdic acid
- Reversed phase high pressure liquid chromatography was carried out using a Rainin HPLC employing a 41.4 x 300 mm, 8 uM, DynamaxTM C-18 column at a flow of 49 mIVmin employing a gradient of acetonitrile:water (each containing 0.75% TFA) typically from 5 to 95% acetonitrile over 35-40 min.
- HPLC conditions are typically described in the format (5-95-35-214); this refers to a linear gradient of from 5% to 95% acetonitrile in water over 35 min while monitoring the effluent with a UV detector at a wavelength of 214 nM.
- Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fisher or Baker reagent grade and were used without additional purification except as noted, acetonitrile was Fisher or Baker HPLC grade and was used as is.
- DGAT is diacylglycerol:acyl CoA 0-acyltransferase
- THF is tetrahydrofuran
- DMF is N,N-dimemylformamide
- DMA is N,N-dimethylacetamide
- DMSO dimethylsulfoxide
- DCM dichloromethane
- DME dimethoxyethane
- NaOH sodium hydroxide
- TFA 1,1,1-trifluoroacetatic acid
- HOBT 1-hydroxybenzotriazole
- PyBroP is bromotripyrrolidinophosphonium hexafluorophosphate
- EDCI is l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
- DIPEA diisopropylethylamme
- brine is saturated aqueous sodium chloride solution
- DAG is 1,2-dioleoyl-sn-glycerol
- APCI-MS is atmospheric pressure chemical ionization mass spectrometry
- ES-MS electrospray mass spectrometry
- RT room or ambient temperature.
- Silica gel chromatography on Biotage columns refers to use of a flash chromatography system supplied by the Biotage Division of the Dyax Corporation employing prepacked 4Og (40s columns), 9Og (40m columns) or 80Og (75m columns). Elution is carried out with hexane-ethyl acetate mixtures under 10-15 psi nitrogen pressure.
- reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was saturated with brine and extracted with DCM. The combined organics were dried over sodium sulfate and concentrated under vacuum to afford the product as a white solid (198 mg, 53%).
- nitrile 1 as colorless oil (1.98 g, 50.7%).
- a solution of nitrile 1 (1.0 g, 7.9 mmoles) in ethanol (15 ml) was cooled in an ice bath. Hydrogen chloride gas was bubbled into the solution until saturation.
- the reaction mixture was then stirred at room temperature for 2 hours. Water (5 ml) was added and stirring was continued at room temperature for 2.5 hours, at 60° C for 4 hours, and finely at room temperature for 12 hours.
- the reaction mixture was concentrated and partitioned between water and ethyl acetate.
- ester 2 (539 mg, 40%).
- a solution of ester 2 (539 mg, 3.1 mmoles) and hydrazine monohydrate (3 ml, 61.9 mmoles) in MeOH (1 ml) was heated in a microwave oven at 160° C for 10 min. Concentration of the reaction mixture under reduced pressure afforded hydrazide 3 (481 mg, 97%).
- a solution of 3 (481 mg, 3 mmoles) in acetone (2 ml) was heated in a microwave oven at 120° C for 20 min..
- the reaction mixture was diluted with 250 ml of IN HCl and extracted with hexanes (2 x 100 ml). The aqueous layer was cooled in an ice bath and the pH was adjusted to 12.5 by the addition of NaOH pellets. This mixture was extracted with ethyl acetate (3 x 250 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 5% ethyl acetate/hexanes and poured through a silica gel plug. The silica gel was eluted with 35% ethyl acetate/hexanes and the filtrates were evaporated to afford the product as a white solid (3 g, 100%).
- the crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid.
- This material was treated with 4 N HCl in dioxane (10 ml) at room temperature for 72 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.26 g, 93%).
- the crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid.
- This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.46 g, 100%).
- the crude was absorbed on silica and purified on a silica gel column with a 10-20% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid.
- This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 72 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.63 g, 85%).
- the crude was absorbed on silica and purified on a silica gel column with a 5-10% ethyl acetate/hexanes gradient to afford the t- butyl ester as a white solid ' .
- This material was treated with 4 N HCl in dioxane (25 ml) at room temperature for 12 hours. The reaction mixture was concentrated, and the solid residue was triturated with hexane, and then collected by filtration (1.15 g, 97%).
- PL-FlashPlate Phospholipid FlashPlates from PerkinElmer, catalog number SMP108; DAG (1,2-Dioleoyl-sn-glycerol) 10 mM suspended in water containing 0.1% Triton X-100; 14 C-PaI-CoA (palmitoyl coenzyme A, [palmitoyl-l- 14 C]) from PerkinElmer, catalog number NEC-555 with a specific activity of 55 mCi/mmol; and DGAT pellet (in house preparation), with a protein concentration of 9.85 mg/ml.
- Aqueous buffers were prepared or purchased as follows:
- the coating buffer (CB) was purchased from PerkinElmer, catalog number SMP900A;
- the reaction buffer (RB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.01 % BSA in water;
- the washing buffer (WB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.05 % deoxycholic acid sodium salt in water;
- the dilution buffer (DB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM EDTA, 0.2 % Triton X-100 in water.
- 1,2-Dioleoyl-sn-glycerol (DAG, 10 mmoles) was diluted to 500 ⁇ M with coating buffer (CB). The diluted DAG solution was then added to 384-well PL-FlashPlates at 60 ⁇ l per well, and incubated at room temperature for 2 days. The coated plates were then washed twice with washing buffer (WB) before use. Test compounds were serial diluted to 2000, 666.7, 222.2, 74.1, 24.7, 8:2, 2.7 and 0.9 ⁇ M in 100 % DMSO. Diluted compound were further diluted 10 fold with reaction buffer (PvB). 14 C-PaI-CoA was diluted to 8.3 ⁇ M with RB.
- the DGAT pellet was diluted to 0.13 mg protein/ml with dilution buffer (DB) immediately before it was added to the PL-FlashPlates to start the reaction.
- 20 ⁇ of the RB-diluted compounds (or 10% DMSO in RB for Total and Blank), 15 ⁇ of RB diluted 14C-PaI-CoA and 15 ⁇ l of DB diluted DGAT pellet (DB without DGAT for Blanks) were transferred to each well of the PL-FlashPlates.
- the reaction mixtures were incubated at 37 0 C for 1 hour. The reactions were stopped by washing 3 times with WB. Plates were sealed with Top-seal and read on a Topcount instrument.
- ICgn The IC 50 values for each compound were generated using an Excel template. The Topcount rpm readings of Total and Blank were used as 0 % and 100 % inhibition. The percent inhibition values of reactions in the presence of compounds were calculated, and plotted against compound concentrations. AU data were fitted into a Dose Response One Site model (4 parameter logistic model) as the following:
- the compounds of the present invention preferably have IC50 values in the range of 1 nM to 10 ⁇ M.
- Table 1 The results are summarized in Table 1 :
- CHOK1/DGAT cell culture medium was prepared with DMEM/F12 (Gibco # 11330- 032),10% FBS, 1% L-Glutamine, and 20ul G418/ml media.
- l,2-dioleoyl ⁇ 3- ⁇ almitoyl- glycerol was prepared by dissolving lOmg into ImI chloroform and stored at -20° C in lOO ⁇ l aliquots.
- Test compounds were prepared as 10 mM stock solutions in DMSO and store at -20° C before use.
- Test dilutions were prepared by five fold serial dilutions over final concentrations.
- CHOKl cells transfected with DGATl were diluted in 6 well plates at 2.5 x 10 5 cells per well and cultured overnight. Cells were then washed twice with PBS. Test compound solutions (lO ⁇ l/ 2ml media aliquots) in DMEM High Glucose with 0.01% BSA (fatty acid free) were added to cell culture plates at 800 ⁇ l per well. 14 C Palmitic acid (0.5 ⁇ ,Ci, 5/xl) was added to each well. The plates were incubated for 1 hour at 37° C. After the incubation period, the plates were placed on ice, cells were scraped into media and transferred to microfuge tubes. 400 ⁇ l chloroform: methanol (2:1) was added to each tube. Each tube was briefly vortexed by hand, then mechanically vortexed for 10 minutes. Each tube was then centrifuged at 14,000 RPM for 10 minutes at 4° C and the bottom layer removed and transferred to a new microfuge tube.
- TLC plates Extracted samples were spotted onto TLC plates at 20 ⁇ l per lane.
- the TLC plates were eluted with a solvent mixture of petroleum ether, diethyl ether and acetic acid (80:20:1) and air dried.
- Trigylceride (TG) spots were visualized by placing in an iodine chamber for several minutes, l ⁇ l of 14 C palmitic acid (diluted 1:10 in 100% EtOH) was spotted on the TG standard lane (at TG level) as a reference.
- the TLC plates were wrapped in plastic wrap and placed in a phosphorimager cassette for scanning.
- the compunds of the present invention preferably have EC50 values in the range of 0.1 to 40 ⁇ M.
- the EC 50 values for those compounds tested in this Example were generated using an Excel template, the results of which are shown in Table II:
- Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
- the active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water.
- the granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively.
- the kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
- Capsules containing the following ingredients can be manufactured in a conventional manner:
- the components are sieved and mixed and filled into capsules of size 2.
- Injection solutions can have the following composition:
- the active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part).
- the pH is adjusted to 5.0 by Acetic Acid.
- the volume is adjusted to 1.0 ml by addition of the residual amount of water.
- the solution is filtered, filled into vials using an appropriate overage and sterilized.
- Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
- the active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
- the filled soft gelatin capsules are treated according to the usual procedures.
- Sachets containing the following ingredients can be manufactured in a conventional manner:
- Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
- Flavoring additives 1.0 mg
- the active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water.
- the granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.
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Abstract
Description
Claims
Priority Applications (7)
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JP2007553522A JP2008529983A (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferase (DGAT) |
EP06706491A EP1848687A1 (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferase (dgat) |
BRPI0607861-3A BRPI0607861A2 (en) | 2005-02-07 | 2006-01-30 | compounds, process for their manufacture, pharmaceutical compositions containing them, method for the therapeutic and / or prophylactic treatment of diseases and use of the compounds |
KR1020077018042A KR100883694B1 (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferasedgat |
MX2007009210A MX2007009210A (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferase (dgat). |
CA002596639A CA2596639A1 (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferase (dgat) |
AU2006210056A AU2006210056A1 (en) | 2005-02-07 | 2006-01-30 | Inhibitors of diacylglycerol acyltransferase (DGAT) |
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US (1) | US7317125B2 (en) |
EP (1) | EP1848687A1 (en) |
JP (1) | JP2008529983A (en) |
KR (1) | KR100883694B1 (en) |
CN (1) | CN101115711A (en) |
AU (1) | AU2006210056A1 (en) |
BR (1) | BRPI0607861A2 (en) |
CA (1) | CA2596639A1 (en) |
MX (1) | MX2007009210A (en) |
WO (1) | WO2006082010A1 (en) |
Cited By (12)
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WO2007126957A2 (en) | 2006-03-31 | 2007-11-08 | Novartis Ag | New compounds |
US7749997B2 (en) | 2005-12-22 | 2010-07-06 | Astrazeneca Ab | Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors |
US7795283B2 (en) | 2004-12-14 | 2010-09-14 | Astrazeneca Ab | Oxadiazole derivative as DGAT inhibitors |
WO2010111665A1 (en) | 2009-03-27 | 2010-09-30 | Bristol-Myers Squibb Company | Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors |
US7994179B2 (en) | 2007-12-20 | 2011-08-09 | Astrazeneca Ab | Carbamoyl compounds as DGAT1 inhibitors 190 |
US8003676B2 (en) | 2006-05-30 | 2011-08-23 | Astrazeneca Ab | 1,3,4-oxadiazole derivatives as DGAT1 inhibitors |
US8084478B2 (en) | 2006-05-30 | 2011-12-27 | Asstrazeneca Ab | Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase |
US8188092B2 (en) | 2009-06-19 | 2012-05-29 | Astrazeneca Ab | Substituted pyrazines as DGAT-1 inhibitors |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014039412A1 (en) | 2012-09-05 | 2014-03-13 | Bristol-Myers Squibb Company | Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US9586900B2 (en) | 2012-09-05 | 2017-03-07 | Bristol-Myers Squibb Company | Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists |
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US7632540B2 (en) * | 2003-07-01 | 2009-12-15 | Transitions Optical, Inc. | Alignment facilities for optical dyes |
US20060216767A1 (en) * | 2005-03-22 | 2006-09-28 | Saladax Biomedical Inc. | Docetaxel immunoassay |
ES2331535T3 (en) * | 2005-05-10 | 2010-01-07 | Via Pharmaceuticals, Inc. | DIACILGLICEROL ACILTRANSFERASA INHIBITORS. |
US8115506B2 (en) * | 2007-05-14 | 2012-02-14 | Applied Materials, Inc. | Localization of driver failures within liquid crystal displays |
US8115011B2 (en) * | 2007-05-22 | 2012-02-14 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
US8153644B2 (en) * | 2007-05-22 | 2012-04-10 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
US8058299B2 (en) * | 2007-05-22 | 2011-11-15 | Via Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
US8211884B2 (en) * | 2008-08-06 | 2012-07-03 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
EP3025727A1 (en) | 2008-10-02 | 2016-06-01 | The J. David Gladstone Institutes | Methods of treating liver disease |
US8324385B2 (en) * | 2008-10-30 | 2012-12-04 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
WO2010077861A1 (en) * | 2008-12-17 | 2010-07-08 | Via Pharmaceuticals, Inc | Inhibitors of diacylglycerol aclytransferase |
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- 2006-01-30 CA CA002596639A patent/CA2596639A1/en not_active Abandoned
- 2006-01-30 MX MX2007009210A patent/MX2007009210A/en not_active Application Discontinuation
- 2006-01-30 KR KR1020077018042A patent/KR100883694B1/en not_active IP Right Cessation
- 2006-01-30 JP JP2007553522A patent/JP2008529983A/en not_active Withdrawn
- 2006-01-30 CN CNA2006800041541A patent/CN101115711A/en active Pending
- 2006-01-30 BR BRPI0607861-3A patent/BRPI0607861A2/en not_active IP Right Cessation
- 2006-01-30 AU AU2006210056A patent/AU2006210056A1/en not_active Abandoned
- 2006-01-30 WO PCT/EP2006/000786 patent/WO2006082010A1/en active Application Filing
- 2006-01-31 US US11/343,567 patent/US7317125B2/en not_active Expired - Fee Related
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Cited By (21)
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US7795283B2 (en) | 2004-12-14 | 2010-09-14 | Astrazeneca Ab | Oxadiazole derivative as DGAT inhibitors |
US8017603B2 (en) | 2005-12-22 | 2011-09-13 | Astrazeneca Ab | Pyrimido [4,5-B]-oxazines for use as DGAT inhibitors |
US7749997B2 (en) | 2005-12-22 | 2010-07-06 | Astrazeneca Ab | Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors |
EP2402319A1 (en) | 2006-03-31 | 2012-01-04 | Novartis AG | DGAT Inhibitors |
EP2301923A1 (en) | 2006-03-31 | 2011-03-30 | Novartis AG | New compounds |
WO2007126957A2 (en) | 2006-03-31 | 2007-11-08 | Novartis Ag | New compounds |
EP2418202A1 (en) | 2006-03-31 | 2012-02-15 | Novartis AG | New compounds |
EP2404905A1 (en) | 2006-03-31 | 2012-01-11 | Novartis AG | New compounds |
EP2402317A1 (en) | 2006-03-31 | 2012-01-04 | Novartis AG | DGAT inhibitor |
EP2402318A1 (en) | 2006-03-31 | 2012-01-04 | Novartis AG | DGAT inhibitors |
EP2402320A1 (en) | 2006-03-31 | 2012-01-04 | Novartis AG | Anorectic agents |
US8003676B2 (en) | 2006-05-30 | 2011-08-23 | Astrazeneca Ab | 1,3,4-oxadiazole derivatives as DGAT1 inhibitors |
US8084478B2 (en) | 2006-05-30 | 2011-12-27 | Asstrazeneca Ab | Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase |
US7994179B2 (en) | 2007-12-20 | 2011-08-09 | Astrazeneca Ab | Carbamoyl compounds as DGAT1 inhibitors 190 |
WO2010111665A1 (en) | 2009-03-27 | 2010-09-30 | Bristol-Myers Squibb Company | Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors |
US8188092B2 (en) | 2009-06-19 | 2012-05-29 | Astrazeneca Ab | Substituted pyrazines as DGAT-1 inhibitors |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014039412A1 (en) | 2012-09-05 | 2014-03-13 | Bristol-Myers Squibb Company | Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists |
US9499482B2 (en) | 2012-09-05 | 2016-11-22 | Bristol-Myers Squibb Company | Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists |
US9586900B2 (en) | 2012-09-05 | 2017-03-07 | Bristol-Myers Squibb Company | Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
Also Published As
Publication number | Publication date |
---|---|
JP2008529983A (en) | 2008-08-07 |
KR20070093448A (en) | 2007-09-18 |
CA2596639A1 (en) | 2006-08-10 |
AU2006210056A1 (en) | 2006-08-10 |
CN101115711A (en) | 2008-01-30 |
MX2007009210A (en) | 2007-08-17 |
US7317125B2 (en) | 2008-01-08 |
BRPI0607861A2 (en) | 2009-10-20 |
US20060178532A1 (en) | 2006-08-10 |
KR100883694B1 (en) | 2009-02-12 |
EP1848687A1 (en) | 2007-10-31 |
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