EP2276748A1 - Composés hétérocycliques bicycliques contenant de l azote pour une utilisation en tant qu inhibiteurs de la stéaroyl-coa désaturase - Google Patents

Composés hétérocycliques bicycliques contenant de l azote pour une utilisation en tant qu inhibiteurs de la stéaroyl-coa désaturase

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Publication number
EP2276748A1
EP2276748A1 EP08742724A EP08742724A EP2276748A1 EP 2276748 A1 EP2276748 A1 EP 2276748A1 EP 08742724 A EP08742724 A EP 08742724A EP 08742724 A EP08742724 A EP 08742724A EP 2276748 A1 EP2276748 A1 EP 2276748A1
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European Patent Office
Prior art keywords
methyl
oxo
ethyl
amino
acetamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP08742724A
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German (de)
English (en)
Inventor
Dmitry Koltun
Jeff Zablocki
Eric Parkhill
Andrei Glushkov
Natalya Vasilevich
Timur Zilbershtein
Alexey Ivanov
Jeffrey Chisholm
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Gilead Sciences Inc
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Gilead Sciences Inc
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Publication of EP2276748A1 publication Critical patent/EP2276748A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring

Definitions

  • the present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as py ⁇ dine[2,3-b]pyrazone de ⁇ vatives, py ⁇ do[4,3-b]pyrazm-2(lH)-one derivatives, and qumoxalm-2(lH)-one de ⁇ vatives, and uses for such compounds in treating and/or preventing va ⁇ ous human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to elevated lipid levels, cardiovascular disease, cancer, diabetes, obesity, metabolic syndrome, oily skm conditions, and the like
  • SCD stearoyl-CoA desaturase
  • SCD's Stearoyl CoA desaturases
  • the mammalian enzymes are localized to the endoplasmic reticulum and require molecular O 2 and NADH to desaturate saturated fatty acids at the ⁇ 9 position and generate monounsaturated fatty acids and water in the process.
  • the primary substrates for these enzymes are the acyl-CoA derivatives of stea ⁇ c (C 18) and palmitic acids (C 16) with the major reaction being the conversion of stea ⁇ c acid to oleic acid (C 18:1).
  • 2-4 isoforms of SCD exist.
  • SCDl The best characte ⁇ zed SCD isozyme is SCDl which is p ⁇ ma ⁇ ly found in liver, adipose and skeletal muscle. Deletion, mutation or inhibition of SCDl in mice and rats results in decreased hepatic triglyceride secretion, decreased hepatic triglycerides and steatosis, resistance to weight gain and improvements m insulin sensitivity and glucose uptake (reviewed in Ntambi et al (2004) Prog Lipid Res 43, 91-104, (2005), Prostaglandins Leukot Essent Fatty Acids 73, 35-41; and (2005) Obes. Rev. 6, 169-174).
  • the present invention presents compounds that are useful in inhibiting SCD activity and thus regulating tissue and plasma lipid levels and fatty acid composition. These compounds are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, including, but not limited to diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases, and the like.
  • SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, including, but not limited to diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases, and the like.
  • R is a) optionally substituted 4 to 6 membered nitrogen containing monocyclic heterocycle, b) -X-NR 4 R 5 , c) -X-C(O)NR 4 R 5 , d) -X-C(O)OR 7 , e) -X-OR 7 , or f) -X-NR 8 -C(O)NR 4 R 5 wherein
  • R 4 is hydrogen or lower alkyl
  • R 6 is hydrogen, optionally substituted Ci -4 alkyl, optionally substituted Ci -4 alkenyl, Cj -4 alkoxy, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl, or
  • R 4 and R 5 along with the nitrogen to which they are attached join to form a 5 or 6 membered monocyclic heteroaryl or heterocyclyl ring;
  • R 7 is hydrogen, optionally substituted C )-4 alkyl, optionally substituted alkenyl, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl;
  • R 8 is hydrogen or Ci -4 lower alkyl
  • X is optionally substituted Ci -4 linear or branched alkylene
  • R 2 is optionally substituted mono or bicyclic heterocyclyl, mono or bicyclic aryl, or mono or bicyclic heteroaryl; wherein the aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR
  • R 3 is hydrogen, optionally substituted C 1-4 alkyl, 5 or 6 membered optionally substituted monocyclic cycloalkyl, optionally substituted monocyclic aryl, 5 or 6 membered optionally substituted monocyclic heterocycle, or 5 or 6 membered optionally substituted monocyclic heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON
  • R 20 and R 22 are independently selected from the group consisting of hydrogen, C 1 . 15 alkyl, C 2-I5 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci_ 6 alkyl, CF 3 , aryl, and heteroaryl;
  • Q is C M alkylene which may optionally contain one or more -NH-, -O-, -S-, or carbonyl linking moieties;
  • W 1 is N or CH, or W 1 is C wherein said C is attached to the R 2 -Q-NH- moiety; and W 2 is N or CH with the proviso that W 1 and W 2 cannot both be N; wherein the R 2 -Q-NH- moiety is attached to the 'a' or 'b' position indicated in Formula I, provided that W 1 is C when the R 2 -Q-NH- moiety is attached to the 'a' position; or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.
  • R 2 -Q-NH- moiety is attached to the 'a' position indicated in Formula I, and the compound has the structure of Formula Ia:
  • R 2 -Q-NH- moiety is attached to the 'b' position indicated in Formula I, and the compound has the structure of Formula Ib:
  • compositions comprising a therapeutically effective amount of an SCD inhibitory compound of Formula I, and at least one pharmaceutically acceptable carrier.
  • the formulation is for oral administration, but in some embodiments the formulation may be provided for administration via other routes.
  • a third embodiment of the invention methods of using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be treated with an SCD inhibitory compound are provided.
  • the method comprises administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I.
  • Such diseases include, but are not limited to, cardiovascular diseases (including, but not limited to, coronary artery disease, atherosclerosis, heart disease, hypertension , and peripheral vascular disease), cancer, cerebrovascular diseases (including, but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy), dyslipidemia, fatty liver diseases, obesity, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, and other diabetic complications.
  • cardiovascular diseases including, but not limited to, coronary artery disease, atherosclerosis, heart disease, hypertension , and peripheral vascular disease
  • cerebrovascular diseases including, but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy
  • dyslipidemia including, but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy
  • dyslipidemia including, but not limited to, stroke,
  • the preferred compounds for use in the invention include, but are not limited to:
  • Additional compounds for use in the invention include, but are not limited to:
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • substituted alkyl refers to: 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
  • alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR 3 -, where R 3 is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
  • lower alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
  • substituted lower alkyl refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and-CH(CH 3 )CH 2 -) and the like.
  • lower alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
  • lower alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
  • substituted alkylene refers to:
  • an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO 2 -alkyl, SO 2 -aryl and
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
  • an alkylene group as defined above that is interrupted by 1 -20atoms independently chosen from oxygen, sulfur and NR a -, where R a is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
  • alkylene group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above.
  • substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH 2 )CH 2 -), methylaminoethylene (-CH(NHMe)CH 2 -), 2-carboxypropylene isomers(- CH 2 CH(CO 2 H)CH 2 -), ethoxyethyl (-CH 2 CH 2 O-CH 2 CH 2 -), ethylmethylaminoethyl (- CH 2 CH 2 N(CH 3 )CH 2 CH 2 -), 1 -ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH 2 CH 2 O-CH 2 CH 2 - OCH 2 CH 2 -OCH 2 CH 2 -), and the like.
  • aralkyl refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
  • Optionally substituted aralkyl refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group.
  • Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
  • alkoxy refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
  • Preferred alkoxy groups are optionally substituted alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.
  • alkylthio refers to the group R-S-, where R is as defined for alkoxy.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1 -6, preferably 1 , double bond (vinyl).
  • lower alkenyl refers to alkenyl as defined above having from 2 to 6 carbon atoms.
  • substituted alkenyl refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 -6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (or prop-l-yn-3-yl, -CH 2 C ⁇ CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
  • substituted alkynyl refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, ammosulfonyl, ammocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , ammo, substituted ammo, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • aminocarbonyl refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morphohno). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , ammo, substituted ammo, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • acylammo refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , ammo, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • acyloxy refers to the groups -O(O)C-alkyl, -O(O)C-cycloalkyl, -O(O)C- aryl, -O(O)C-heteroaryl, and -O(O)C-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • aryl refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) ⁇ ngs (e.g., naphthyl or anthryl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • arylene refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1 ,4-phenylene, 1,3-phenylene, 1 ,2-phenylene, l,4'-biphenylene, and the like.
  • aryl or arylene groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylammo, acyloxy, ammo, aminocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxyamino, nitro, -
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted ammo, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
  • arylthio refers to the group R-S-, where R is as defined for aryl.
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , ammo, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • Carboxyalkyl refers to the groups -C(O)O-alkyl or -C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • cycloalkyl 1 ' refers to carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ⁇ ng or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ⁇ ng structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ⁇ ng structures such as adamantanyl, bicyclo[2.2.1]heptane, 1,3,3- tnmethylbicyclo[2.2.1]hept-2-yl, (2,3,3-t ⁇ methylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example mdane, and the like
  • substituted cycloalkyl refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • halogen refers to fluoro, bromo, chloro, and iodo.
  • acyl denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • heteroaryl refers to a radical derived from an aromatic cyclic group (i.e., fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl).
  • heteroaryls include, but are not limited to, [l,2,4]oxadiazole, [l,3,4]oxadiazole, [l,2,4]thiadiazole, [l,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-oxid
  • heteroarylene refers to a diradical of a heteroaryl group as defined above. This term is exemplified by groups such as 2,5-imidazolene, 3,5-[l,2,4]oxadiazolene, 2,4- oxazolene, 1,4-pyrazolene, and the like.
  • 1 ,4-pyrazolene is:
  • heteroaryl or heteroarylene groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, ammocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxya
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, ammocarbonyl, hydroxy, alkoxy, halogen, CF 3 , ammo, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • heteroarylkyl refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.
  • Optionally substituted heteroaralkyl refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group.
  • Such heteroaralkyl groups are exemplified by 3-py ⁇ dylmethyl, quinohn-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • heterocyclyl refers to a monoradical saturated or partially unsaturated group having a single nng or multiple condensed ⁇ ngs, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the nng.
  • Heterocyclic groups can have a single nng or multiple condensed nngs, and include tetrahydrofuranyl, morpholmo, pipendinyl, piperazmo, dihydropyndmo, and the like.
  • heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylammo, acyloxy, amino, ammocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxyammo, mtro, -SO-alkyl
  • thiol refers to the group -SH.
  • substituted alkylthio refers to the group -S-substituted alkyl.
  • heteroarylthiol refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
  • sulfoxide refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl.
  • substituted sulfoxide refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • sulfone refers to a group -S(O) 2 R, in which R is alkyl, aryl, or heteroaryl.
  • substituted sulfone refers to a group -S(O) 2 R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • keto refers to a group -C(O)-.
  • thiocarbonyl refers to a group -C(S)-.
  • carboxy refers to a group -C(O)-OH.
  • compound of Formula I is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2" stereoisomers possible where n is the number of asymmetric centers).
  • the individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means.
  • the individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
  • Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-supe ⁇ mposable mirror images of each other.
  • a 1 :1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where approp ⁇ ate.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of pola ⁇ zed light at the wavelength of the sodium D line.
  • Parental administration is the systemic delivery of the therapeutic agent via injection to the patient.
  • therapeutically effective amount refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the specific activity of the therapeutic agent being used, and the age, physical condition, existence of other disease states, and nutritional status of the patient. Additionally, other medication the patient may be receiving will effect the determination of the therapeutically effective amount of the therapeutic agent to administer.
  • treatment means any treatment of a disease m a mammal, including:
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of Formula I and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts de ⁇ ved from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, t ⁇ alkyl amines, substituted alkyl amines, di(substituted alkyl) amines, t ⁇ (substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, t ⁇ (cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, t ⁇ substituted cycloalkyl amines, cycloalkenyl
  • Suitable amines include, by way of example only, isopropylamme, t ⁇ methyl amine, diethyl amine, t ⁇ (iso-propyl) amine, t ⁇ (n-propyl) amine, ethanolamine, 2-dimethylammoethanol, tromethamine, lysine, argmine, histidme, caffeine, procaine, hydrabamme, choline, betaine, ethylenediamine, glucosamine, N-alkylglucammes, theobromine, purines, piperazme, p ⁇ e ⁇ dme, morpholme, N-ethylpipe ⁇ dme, and the like.
  • Salts de ⁇ ved from inorganic acids include hydrochlo ⁇ c acid, hydrobromic acid, sulfu ⁇ c acid, nit ⁇ c acid, phospho ⁇ c acid, and the like.
  • Salts denved from organic acids include acetic acid, propionic acid, glycohc acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citnc acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfomc acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, solubilizers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • solvents dispersion media, solubilizers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions.
  • This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, earners, including inert solid diluents and fillers, diluents, including sterile aqueous solution and va ⁇ ous organic solvents, solubihzers and adjuvants.
  • the compounds of Formula I may be administered alone or in combination with other therapeutic agents.
  • compositions are prepared in a manner well known m the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co , Philadelphia, PA 17 lh Ed (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3 rd Ed. (G.S. Banker & CT Rhodes, Eds.). Synthetic Reaction Parameters
  • solvent inert organic solvent
  • inert solvent mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • chloroform chloroform
  • methylene chloride or dichloromethane
  • pyridine a solvent inert gas
  • q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • the compound of formula (2) is made by replacing the halogen group adjacent to the nitro moiety on the commercially available formula (1) compound (i.e., 2,6-dichloro-3- nitropyridine, 2,4-dichloro-5-nitropyridine, 2,4-difluoro-nitrobenzene, or the like) with a compound of formula R 1 NH 2 in the presence of a base.
  • the reaction is earned out in a dipolar aprotic solvent such as tetrahydrofuran (THF), acetone, or ethylacetate, and the like, at a temperature of around -6O 0 C to around -90 0 C, for about 30 minutes to an hour.
  • THF tetrahydrofuran
  • reaction mixture is then allowed to warm to room temperature with continued stirring, approximately 2 to 5 hours.
  • product of formula (2) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel. Alternatively, the compound of formula (2) is used m the next step without purification.
  • the compound of formula (3) is made by replacing the remaining chloro group on the compound of formula (2) with a compound of formula R 2 NH 2 in the presence of a base.
  • a similar procedure is used as desc ⁇ bed with respect to step 2, however, the reaction is conducted at a temperature of approximately 50 0 C to approximately 80 0 C for 12 to 24 hours.
  • the product of formula (3) may by isolated conventional means but is typically used in the next step without purification.
  • the formula (3) nitro compound is then reduced to the corresponding amine analog, compound (4), via conventional reduction techniques.
  • Suitable methods include, but are not limited to, reaction with Na 2 S 2 O 4 and Na 2 CO 3 at a temperature ranging from 20 0 C to 80 0 C for 10 minutes to 12 hours. After the reaction is allowed to cool to room temperature the product may be extracted by dilution with EtOAc followed by washing with saturated. NaHCO 4 solution and bnne. The combined organic phase can then be dried over MgSO 4 and concentrated to provide the compound of formula (4) in crude form which can be used in the next step without further purification.
  • the nitro group can be reduced by reaction with hydrazine and a Raney- Nickel catalyst.
  • the nitro compound is placed in a methanol solution to which the hydrazine is added.
  • the reaction mixture is heated to approximately 50 0 C to 80 0 C and the Raney -Nickel catalyst gently added to insure even and steady evolution of the nitrogen gas
  • the reaction proceeds for approximately 1 hour whereupon the reaction mixture is allowed to cool to room temperature, the catalyst filtered off, and the filter cake washed with methanol.
  • the resulting solution may be concentrated and purified using conventional methods, i.e., chromatography using a methanol/dichloromethane gradient to provide the desired amine.
  • the final step in the synthesis involves the formation of the py ⁇ midme ⁇ ng and the addition of the R 3 substituent. This is achieved by reacting the amino compound of formula (4) with an ethyl oxoacetate derivative having the desired R 3 moiety, i.e., a compound of formula (5).
  • the compound of formula (4) is dissolved in 2% v/v AcOH in EtOH and then the compound of formula (5) is added.
  • the reaction is stirred at 60 0 C to 90 0 C for 12 to 24 hours.
  • the resulting suspension is cooled to room temperature and the final product extracted by the addition of a polar solvent such as methanol followed by filtration and washing with additional polar solvent.
  • the compound of Formula I can then be d ⁇ ed under vacuum to remove any remaining solvent.
  • the py ⁇ midine ⁇ ng can be formed by first dissolving the ammo compound of formula (4) into acetonit ⁇ le followed by the addition of a catalytic drop of acid, such as glacial acetic acid. The oxoacetate de ⁇ vative is then added and the mixture heated for approximately 20 to 40 minutes in a microwave at 120 0 C. The reaction mixture may them be filtered, concentrated, and purified using column chromatography eluting with MeOH/dichloromethane gradient to provide the compound of Formula I.
  • a catalytic drop of acid such as glacial acetic acid
  • R 1 is a nitrogen-containing heterocycle
  • a suitable protecting group such as an N-terf-butoxycarbonyl group.
  • the protecting group may be removed after Step 4 using conventional techniques, i.e , heating at 60 0 C to 80 0 C in a mixture of acetonitnle and hydrochlo ⁇ c acid.
  • the acidic mixture is neutralized after cooling with an aqueous base such as KOH and the product extracted using dichloromethane Alternative Preparation - Secondary Modification of R 1
  • R 1 moiety after the compound of Formula I has been made. As was discussed in the R 1 heterocycles, this type of modification generally will involve the use of a protected terminal R 1 amino group. Once the protecting group is removed, the terminal R 1 amino group may be modified by reaction with any number of reactants allowing for the addition of a desired R 5 or R 7 substituent.
  • the deprotected compound of Formula I is dissolved m the approp ⁇ ate non-protic solvent, i.e., acetomt ⁇ le or the like, and then an acidic version of the desired R 5 substituent, R 6 -C(O)-OH, is added to the reaction mixture followed by 2-(lH-benzot ⁇ azol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) and diisopropylethyleneamme. After briefly heating to approximately 50° to 70 0 C, the reaction mixture is cooled to room temperature and the precipitated end product filtered off and washed with additional solvent to provide the final product of Formula I.
  • TBTU 2-(lH-benzot ⁇ azol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate
  • the deprotected compound of Formula I is dissolved m acetonit ⁇ le and dichloromethane.
  • a base such as diisopropylethyleneamme is then added along with ⁇ lH]-pyrazole-l-hydroxamidme hydrochloride.
  • the reaction is heated at 30 0 C to 50 0 C for 15 to 30 minutes. Cooling and filtration will provide a compound of Formula I wherein R 4 is -C(NH)NH 2 .
  • the present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by SCD.
  • the methods and pharmaceutical compositions are particularly suitable for use in the treatment of diseases related to dyshpidemia and disorders of lipid metabolism, especially diseases related to elevated plasma and tissue lipid levels, such as cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases and the like.
  • the compounds of the invention find utility in the treatment of a patient for, or protecting a patient from developing, a disease related to dyshpidemia and/or a disorder of lipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i e , abnormal lipid level, such as elevated plasma or tissue lipid levels or hepatic or peripheral tissue lipid accumulation), especially levels higher than normal, preferably where said lipid is a fatty acid, such as a free or complexed fatty acid, triglycerides, phospholipids, wax esters, cholesterol or cholesteryl ester, such as where VLDL, hepatic or peripheral tissue triglycerides are elevated, or any combination of these, where said hpid-related condition or disease is an SCD-mediated disease or condition, such as metabolic syndrome, diabetes, nonalcoholic fatty liver disease, obesity, cancer, oily skin and related diseases, comprising administering to an animal, such as a mammal, especially a human patient
  • the general value of the compounds of the invention m inhibiting the activity of SCD can be determined using the assay desc ⁇ bed below m Example 20. Additionally, the general value of the compounds m treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating obesity, diabetes, metabolic syndrome, or abnormal triglyceride or cholesterol levels or for improving glucose tolerance
  • the compounds of the instant invention are inhibitors of SCD and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant SCD biological activity or which may be ameliorated by inhibition of SCD biological activity.
  • an SCD-mediated disease or condition includes but is not limited to a disease or condition which is, or is related to, cardiovascular disease, dyshpidemias, fatty liver diseases, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including, but not limited, to stroke, ischemic stroke and transient ischemic attack (TIA), pe ⁇ pheral vascular disease, ischemic retinopathy, cancer and skin conditions), cancers and oily skin
  • Dyshpidemia includes, but is not limited to, disorders related to the serum and tissue levels of triglycerides, i.e., hypertriglyceridemia, fatty liver diseases LDL, VLDL, and/or HDL, cholesterol, and total cholesterol
  • Dyshpidemia also includes disorders related to the ⁇ 9 fatty acid Desaturation Indexes (e g the ratio of SCD product fatty acids/SCD substrate fatty acids)
  • PUFA polyunsaturated fatty acid metabolism
  • cholesterol disorders such as familial combined hyperhpidemia and those disorders involving defective reverse cholesterol transport
  • SCD-mediated diseases or conditions relating to hypertriglyceridemia include, but are not limited to, hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apohpoprotem deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology
  • Metabolic syndrome, Syndrome X and Pre-Diabetes are also within the scope of the term "SCD-mediated disease” including all of the va ⁇ ous component conditions that make up the syndromes such as, but not limited to, dyshpidemia, obesity, insulin resistance, hype ⁇ nsulenemia, decreased glucose tolerance, hypertension, microalbuminemia, hyperu ⁇ caemia, and hypercoagulability, diabetes, non-insulm-dependent diabetes melhtus, Type I diabetes, Type II diabetes, diabetic complications, body weight disorders such as overweight, cachexia and anorexia, and body mass index and leptin related diseases
  • metabolic syndrome is a recognized clinical term used to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insulin resistance, hype ⁇ nsulmemia, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperu ⁇ caemia, hypercoagulability and/or microalbuminemia
  • An SCD-mediated disease or condition also includes va ⁇ ous hepatic conditions such as hepatitis, hepatic steatosis, hepatic fibrosis, hepatic cirrhosis, non-alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, fatty liver, non-alcoholic fatty liver disease (NAFLD), acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyna, iron overload disorders, hereditary hemochromatosis, hepatoma and conditions related thereto
  • Va ⁇ ous skin and mucosal tissue disorders fall within the scope of an SCD-mediated disease or condition including, but not limited to, eczema, acne, pso ⁇ asis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like Inflammation, sinusitis, asthma, pancreatitis, osteoarth ⁇ tis, rheumatoid arth ⁇ tis, cystic fibrosis, and pre-menstrual syndrome may also be considered SCD-mediated diseases or conditions as may diseases or conditions which is, or is related to cancer, neoplasm, malignancy, metastases, tumors (benign or malignant), carcinogenesis, hepatomas and the like SCD-mediated diseases or conditions also include diseases or conditions which are, or are related to, neurological diseases, psychiatric disorders, multiple sclerosis, eye diseases, and immune disorders An SCD-mediated disease or condition also include, or
  • An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building.
  • Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included herein.
  • CPT I or CPT II carnitine palmitoyltransferase deficiency
  • testing of the compounds may be accomplished in vivo.
  • testing of the compounds is accomplished by administering the compound to an animal afflicted with a plasma or tissue, fatty acid or triglyceride (TG) related disorder or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma or tissue fatty acid composition or triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a plasma or tissue, fatty acid or triglyceride (TG) related disorder or very low density lipoprotein (VLDL)-related disorder.
  • the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder.
  • said change in SCD activity in said animal is a decrease in activity, preferably wherein said SCD modulating agent does not substantially directly inhibit the biological activity of a ⁇ 5 desaturase, ⁇ 6 desaturase, fatty acid synthetase, or other lipogenic enzymes.
  • the model systems useful for compound evaluation may include, but not limited to, the use of liver microsomes, such as from mice or rats that have been maintained on a high carbohydrate or high-fat diet, or from human donors, including persons suffering from obesity.
  • Immortalized cell lines such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used.
  • Primary cell lines such as mouse primary hepatocytes, are also useful in testing the compounds of the invention.
  • mice or rats used as a source of primary hepatocyte cells may also be used wherein the mice or rats have been maintained on a high carbohydrate or other SCD inducing diet to increase SCD activity m microsomes and/or to elevate plasma and/or tissue triglyceride levels or ⁇ 9 fatty acid desaturation indexes or ⁇ 9 fatty acid desaturation indexes (e.g., the 18:1/18:0 ratio); alternatively mice on a normal diet or mice with normal triglyceride levels may be used.
  • Mouse models having hypertriglyceridemia due to genetic or naturally occurring mutations are also available as is the mouse phenome database. Rabbits, hamsters and monkeys are also useful as animal models, especially those with diabetic and obesity phenotypes.
  • Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring changes in fatty acid composition. These include absolute or relative reductions in SCD product fatty acids such as 16:1 n-7, 18:1 n-7 or 18:1 n-9. As well fatty acid composition data may also be used to determine a subject's ⁇ 9 Desaturation Index after administration of the compound. "Desaturation Index(s)" as employed in this specification means the ratio of the product over the substrate for the SCD enzyme as measured from a given tissue or plasma sample.
  • Desaturation Index(s) may be measured in plasma or tissues as well as specific lipid classes containing fatty acids such as triglycerides and phospholipids.
  • the compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as desc ⁇ bed in those patents and patent applications incorporated by reference, including buccal, intranasal, intra-arte ⁇ al injection, intravenously, mtraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant
  • Oral administration is the preferred route for administration of the compounds of Formula I. Administration may be via capsule or enteric coated tablets, or the like.
  • the active ingredient is usually diluted by an excipient and/or enclosed withm such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid mate ⁇ al (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or m a liquid medium), ointments containing, for example, up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and ste ⁇ le packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, manmtol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, cyclodextrms, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known m the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.
  • the compounds of the invention are incorporated into a pharmaceutical formulation containing a pharmaceutically acceptable earner that is generally suited to topical drug administration and comp ⁇ sing any such mate ⁇ al known in the art.
  • a pharmaceutically acceptable earner that is generally suited to topical drug administration and comp ⁇ sing any such mate ⁇ al known in the art.
  • Suitable earners are well known to those of skill m the art and the selection of the earner will depend upon the form of the intended pharmaceutical formulation, e.g., as an ointment, lotion, cream, foam, microemulsion, gel, oil, solution, spray, salve, or the like, and may be comprised of either naturally occurnng or synthetic matenals. It is understood that the selected earner should not adversely affect the compound of Formula I other components of the pharmaceutical formulation.
  • Suitable earners for these types of formulations include, but are not limited to, vehicles including Shephard's Cream, Aquaphor TM , and Cetaphil lotion.
  • Other preferred earners include ointment bases, e.g , polyethylene glycol-1000 (PEG-1000), conventional creams such as HEB cream, gels, as well as petroleum jelly and the like.
  • suitable carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanohn, fatty acids, vegetable oils, parabens, waxes, and the like.
  • Particularly preferred formulations herein are colorless, odorless ointments, lotions, creams, microemulsions and gels.
  • Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
  • an ointment base should be inert, stable, nonirntatmg and nonsensitizing. As explained in Remington 's Pharmaceutical Sciences, 20 th Ed.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystea ⁇ n sulfate, anhydrous lanolin, and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-m-oil (W/O) emulsions or oil-m-water (OAV) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stea ⁇ c acid.
  • Preferred water-soluble ointment bases are prepared from polyethylene glycols (PEGs) of varying molecular weight; again, reference may be had to Remington's, supra, for further information.
  • Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations m which solid particles, including the active agent, are present in a water or alcohol base
  • Lotions are usually suspensions of solids, and preferably, for the present purpose, comp ⁇ se a liquid oily emulsion of the oil-m-water type.
  • Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like.
  • a particularly preferred lotion formulation for use in conjunction with the present invention contains propylene glycol mixed with a hydrophilic petrolatum such as that which may be obtained under the trademark Aquaphor TM from Beiersdorf, Inc. (Norwalk, Conn.).
  • Creams containing the active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-m-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation as explained in Remington's, supra, is generally a nonionic, anionic, cationic, or amphoteric surfactant.
  • Microemulsions are thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).
  • a surfactant emulsifier
  • co-surfactant co-emulsifier
  • an oil phase e.g., a water phase
  • Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams.
  • the co-surfactant is generally selected from the group of polyglycerol derivatives, glycerol derivatives, and fatty alcohols.
  • Preferred emulsifier/co-emulsifier combinations are generally although not necessa ⁇ ly selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and cap ⁇ lic and cap ⁇ c triglycerides and oleoyl macrogolglyce ⁇ des.
  • the water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally comp ⁇ se, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glyce ⁇ des), etc.
  • buffers glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like
  • the oil phase will generally comp ⁇ se, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e
  • Gel formulations are semisolid systems consisting of either small inorganic particle suspensions (two-phase systems) or large organic molecules distributed substantially uniformly throughout a carrier liquid (single phase gels).
  • Single phase gels can be made, for example, by combining the active agent, a earner liquid and a suitable gelling agent such as tragacanth (at 2 to 5%), sodium alginate (at 2-10%), gelatin (at 2-15%), methylcellulose (at 3-5%), sodium carboxymethylcellulose (at 2-5%), carbomer (at 0.3-5%) or polyvinyl alcohol (at 10-20%) together and mixing until a characteristic semisolid product is produced.
  • suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxypropylene, hydroxyethylcellulose and gelatin.
  • additives may be included in the topical formulations of the invention.
  • additives include, but are not limited to, solubihzers, skm permeation enhancers, opacifiers, preservatives (e.g., anti-oxidants), gelling agents, buffe ⁇ ng agents, surfactants (particularly nonionic and amphoteric surfactants), emulsifiers, emollients, thickening agents, stabilizers, humectants, colorants, fragrance, and the like
  • solubilizers and/or skm permeation enhancers is particularly preferred, along with emulsifiers, emollients, and preservatives.
  • solubilizers include, but are not limited to, the following: hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol TM ) and diethylene glycol monoethyl ether oleate (available commercially as Softcutol TM ); polyethylene castor oil de ⁇ vatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, etc.; polyethylene glycol, particularly lower molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol de ⁇ vatives such as PEG-8 caprylic/cap ⁇ c glyce ⁇ des (available commercially as Labrasol ); alkyl methyl sulfoxides such as DMSO; pyrrohdones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers A single solubihzer may
  • Suitable emulsifiers and co-emulsifiers include, without limitation, those emulsifiers and co-emulsif ⁇ ers desc ⁇ bed with respect to microemulsion formulations.
  • Emollients include, for example, propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) my ⁇ styl ether propionate, and the like.
  • Other active agents may also be included in the formulation, e.g., anti-inflammatory agents, analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunblock agents commonly found m sunscreen formulations including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor denvatives, cmnamates (e g , octyl methoxycmnamate), dibenzoyl methanes (e.g., butyl methoxydibenzoyl methane), p-aminobenzoic acid (PABA) and de ⁇ vatives thereof, and salicylates (e.g , octyl salicylate).
  • anti-inflammatory agents e.g., analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunblock agents commonly found m sunscreen formulations including, but not limited to, anthranilates, benzophenones (
  • the active agent is present in an amount in the range of approximately 0.25 wt. % to 75 wt % of the formulation, preferably in the range of approximately 0.25 wt. % to 30 wt. % of the formulation, more preferably in the range of approximately 0.5 wt. % to 15 wt. % of the formulation, and most preferably in the range of approximately 1.0 wt. % to 10 wt. % of the formulation
  • the pharmaceutical formulation may be ste ⁇ hzed or mixed with auxiliary agents, e g , preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure and the like.
  • auxiliary agents e g , preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of Formula I or Formula II m the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered ste ⁇ hzation.
  • dispersions are prepared by incorporating the various ste ⁇ hzed active ingredients into a ste ⁇ le vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known m the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • SCD inhibitors such as the compounds of Formula I are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount Typically, for oral administration, each dosage unit contains from 1 mg to 2 g of an SCD inhibitor, more commonly from 1 to 700 mg, and for parenteral administration, from 1 to 700 mg of a stearoyl- CoA desaturase inhibitor, more commonly about 2 to 200 mg. It will be understood, however, that the amount of the SCD inhibitor actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the p ⁇ ncipal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a pharmaceutical excipient such as a pharmaceutical excipient.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polyme ⁇ c acids with such materials as shellac, cetyl alcohol, and cellulose acetate
  • compositions for inhalation or insufflation include solutions and suspensions m pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as desc ⁇ bed supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, e.g. orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • N-(2-(6-(3,4-dichlorobenzylamino)-3-nitropyridin-2-ylamino)ethyl)acetamide was dissolved m 70 mL of 1 :1 mixture of dioxane and water and 1.7 g OfNa 2 S 2 O 4 (85% tech. grade, 2.9 mmol) and 1.1 g OfNa 2 CO 3 (8.5 mmol) were added. The mixture was stirred at room temperature for 10 min under the blanket of nitrogen, diluted with 50 mL of water, and extracted 3 times with 20 mL portions of EtOAc. Combined organic layers were washed with 20 mL of brine and concentrated.
  • R 1 includes a urea moiety
  • R 1 includes a urea moiety
  • One preferred way includes the use of the reagent phenyl carbamate (Young, RJ. et al, Bioorg. Med Chem Lett 2006, 16, 5953-7).
  • Compounds of Formula I in which R 1 includes an amide moiety may be made using well known coupling agents, such as N,N'-dicyclohexylcarbodnmide (DCC), l-ethyl-3-(3- dimethylammopropyl) carbodiimide hydrochlo ⁇ de (EDC), O-(7-Azabenzot ⁇ azol-l-yl)- N,N,N',N'-tetramethyluromum hexafluorophosphate (HATU), O-Benzot ⁇ azole-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU), or O-Benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU).
  • DCC N,N'-dicyclohexylcarbodnmide
  • EDC l-ethyl-3-(
  • the compound of formula (8) is obtained by reacting amine with the compound of formula (7) in approp ⁇ ate organic solvent (THF, acetonit ⁇ le, DMF, or other). Heating may lead to faster completion of the reaction.
  • the resulting nitro compound of formula (8) undergoes reaction with a reducing agent (hydrazine is preferred) in the presence of metal or metal salt. Raney Nickel is the preferred catalyst.
  • the resulting aniline (9) may not need to be purified and may be used directly for cychzation with ⁇ -ketoester in organic solvent (ethanol is preferred) in the presence of acid catalyst (AcOH is the preferred catalyst) to produce compounds of Formula (10).
  • compounds of Formula (10) can be coupled with an amine (R 2 -Q-NH 2 ) using metal catalyst such as copper or palladium or other (palladium is preferred) in the presence of hgand (organic alcohol, or amine, or phenol, preferred hgand is BEST AP) in organic solvent (THF is preferred) to produce compounds of Formula I.
  • metal catalyst such as copper or palladium or other (palladium is preferred) in the presence of hgand (organic alcohol, or amine, or phenol, preferred hgand is BEST AP) in organic solvent (THF is preferred) to produce compounds of Formula I.
  • N-(2-(5-bromo-2-nitrophenylamino)ethyl)acetamide (1.0 g) was dissolved in MeOH (20 mL) by heating to 80 0 C. Hydrazine was added (1.6 mL) followed by Raney Nickel (50% slurry in water, 6 drops) and the reaction mixture was heated to reflux for 1 h. Filtered through Celite® and concentrated to amber oil containing mostly product by LC/MS. Used for next step without further purification.
  • reaction mixture was concentrated and dissolved in 0.6 mL DMSO without any intermediate workup. Purification was performed using GilsonTM preparatory HPLC system using Phenomenex reverse phase C(18) column and water/acetonitrile as mobile phase with no buffer. After high-vacuum drying product was obtained as tan powder.
  • N-(2-(7-(4-chloro-3- (trifiuoromethyl)benzylamino)-3 -(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)- yl)ethyl)acetamide is a compound of formula I in which R 1 is -CH 2 CH 2 NHAc, R 2 is 4-chloro- 3-(trifluoromethyl)benzyl, R 3 is 4-methoxyphenyl.
  • N-(2-(7-bromo-2-(4-methoxyphenyl)-3-oxopyrido[3,2-b]pyrazin-4(3H)- yl)ethyl)acetamide 100 mg
  • proline 6 mg
  • copper iodide 5 mg
  • potassium carbonate 69 mg
  • 3,4-dichlorobenzylamine 62 mg
  • Compounds of Formula (14) are obtained from 4-chloro-3-nitroanihne (13) by reaction with electrophilic reagents, for example acyl chlo ⁇ des, one of them being benzyl chloroformate (CbzCl).
  • electrophilic reagents for example acyl chlo ⁇ des, one of them being benzyl chloroformate (CbzCl).
  • An appropriate organic solvent and base such as t ⁇ ethylamine, d ⁇ sopropylethylamme, or pyridine are needed. Conversion of compounds (14) into compounds
  • benzyl l-(2-acetamidoethyl)-3-(4- methoxyphenyl)-2-oxo-l,2-dihydroqumoxalin-6-ylcarbamate is a compound of formula I in which R 1 is -CH 2 CH 2 NHAc, R 2 is benzyloxycarbonyl, R 3 is 4-methoxyphenyl.
  • the rats were anesthetized with Isoflurane inhalation anesthetic, the liver perfused with cold phosphate buffered saline (PBS), weighed, and chilled in cold homogenization buffer (250 mM sucrose, 10 mM T ⁇ s, 1 mM EDTA, pH 7.6.
  • PBS cold phosphate buffered saline
  • the livers were finely minced and placed in homogenization tube. 40 mL of homogenization buffer was added to the homogenization tube and the liver homogenized and centrifuged in a pre-chilled SLA-600 TC at 800G rotor for 10 mm at 4°C.
  • the protein concentration of the microsomal preparation was determined by BCA assay (Pierce) and the microsomes were ahquoted and stored at -80 0 C.
  • Biobeads were ground to a smaller size in a mortar and pestle and filtered through 300 ⁇ M mesh and then resuspended in 3.6% TCA.
  • SCD was determined in the desaturase assay buffer.
  • This assay buffer contained 0.1 M T ⁇ s buffer, pH 7.2, 2 mM NADH, 4.8 mM ATP, 0.5 mM CoA, 4.8 mM MgCl 2 , and 0.1% BSA.
  • reaction was initiated by the addition of 50 ⁇ l of substrate solution (20 ⁇ M Stearoyl CoA, [3H]Stearoyl CoA, 74nCi) to the premcubated microsomes/compound suspensions in MiIhQ (Millrpore) H 2 O. The reaction mixtures were then incubated for 45 minutes on the orbital shaker at 50-75 rpm at room temperature.
  • substrate solution (20 ⁇ M Stearoyl CoA, [3H]Stearoyl CoA, 74nCi
  • reaction was terminated by the addition of 10 ⁇ l of 21% trichloroacetic acid (TCA) to the reaction mixture followed incubation on the orbital shaker for 30 minutes at 50-75 rpm at room temperature followed by cent ⁇ fugation for 5 minutes at 3700 rpm.
  • TCA trichloroacetic acid
  • Example 7 The procedures of Example 7 were followed to in order to determine the activity and IC 50 values for example compounds of Formula I.
  • Table 1 presents the IC 50 data for a number of compounds of the invention for which the IC 50 as determined in the above assay was less than 30 ⁇ M

Abstract

La présente invention concerne des composés hétérocycliques bicycliques contenant de l’azote pour une utilisation en tant qu’inhibiteurs de la stéaroyl-CoA désaturase. Les composés sont utiles pour le traitement et/ou la prévention de diverses maladies humaines, médiées par les enzymes stéaroyl-CoA désaturase (SCD), notamment de maladies associées à des niveaux lipidiques anormaux, de maladies cardiovasculaires, du diabète, de l’obésité, de la peau grasse, du syndrome métabolique et analogues.
EP08742724A 2008-04-10 2008-04-10 Composés hétérocycliques bicycliques contenant de l azote pour une utilisation en tant qu inhibiteurs de la stéaroyl-coa désaturase Withdrawn EP2276748A1 (fr)

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