WO2009120655A1 - Dérivés de l'indole - Google Patents

Dérivés de l'indole Download PDF

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Publication number
WO2009120655A1
WO2009120655A1 PCT/US2009/038022 US2009038022W WO2009120655A1 WO 2009120655 A1 WO2009120655 A1 WO 2009120655A1 US 2009038022 W US2009038022 W US 2009038022W WO 2009120655 A1 WO2009120655 A1 WO 2009120655A1
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Prior art keywords
indol
methyl
azetidin
pyridin
compound
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Ceased
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PCT/US2009/038022
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English (en)
Inventor
Yu Jiang
Sang-Phyo Hong
Bin Chen
Eman Eldemenky
Arifa Husain
Lingyun Wu
Kai Lu
Gil Ma
Marc Labelle
Mohammad Marzabadi
Michael Sabio
Andrew White
Christine Mazza
Mathivanan Packiarajan
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H Lundbeck AS
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H Lundbeck AS
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Publication of WO2009120655A1 publication Critical patent/WO2009120655A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention is directed to indole derivatives which bind to the MCHl receptor.
  • the subject invention relates to uses of said compounds in the preparation of a pharmaceutical composition for the treatment of obesity and CNS related disorders and to methods of treating said disorders comprising administering a therapeutically effective amount of a compound of the invention.
  • MCH Melanin-concentrating hormone
  • MCH exerts several physiological effects through interaction with its receptors. For example, an icv injection of MCH in rats stimulates food intake (Levens, et al. Int. J. Obesity 2002, 26, 1289-1295), and chronic administration leads to increased body weight (Kanatani, et al. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E583-E588).
  • the link between MCHl-R and the effects of MCH on feeding is demonstrated by reports on the phenotype of MCHl-R knockout mice. Independent groups generated knock-out mice with the targeted deletion of MCHl-R.
  • mice The phenotype of these mice was lean, hyperphagic and hypermetabolic, with an increased resistance to diet-induced obesity (Marsh, et al. Proc. Natl. Acad. ScL 2002, 99, 3240-3245). These observations suggest that MCHl-R antagonists could be useful for the treatment of obesity related disorders.
  • MCHl -R binding sites in the CNS such as the amygdala, accumbens nucleus, dorsal raphe and locus cocruleus is suggestive of a role for MCH in the regulation of mood and stress
  • several groups have identified selective, high affinity MCHl-R antagonists and evaluated their effects in in-vivo behavioral paradigms predictive of antidepressant and/or anxiolytic activity.
  • mice or rats spend immobile in the forced-swim test decrease the amount of time mice or rats spend immobile in the forced-swim test (Porsolt, et al. Arch bit Phannacodyn Ther. 1977, 229, 327- 336 and Luki, ct al. Psychopharmacology 2001 , 155, 315-322).
  • Pretreatmenl of rats with a single oral dose of SNAP-7941, a selective MCHl-R antagonist, or fluoxetine decreased the duration of immobility compared with vehicle-treated controls, and increased the time these animals spent swimming (Borowsky, et al. Nature Medicine 2002, 8, 825-830).
  • the profile of SNAP-7941 in the rat forced-swim test is similar to that of clinically used antidepressants, indicating that MCH l-R receptor blockage may be a therapeutic modality for the treatment of mood-disorders such as depression.
  • the rat social interaction test has been used as a model of anxiety (File and Hyde Br. J. Pharmacol. 1987, 62, 19-24).
  • Acute treatment with 3, 10 and 30 mg/kg SNAP-7941 or 5 mg/kg chlordiazepoxide increased social interaction time compared with vehicle- treated controls (Borowsky, et al. Nature Medicine 2002, 8, 825-830) without an overall increase in locomotor activity.
  • the response to the two lower doses of SNAP-7941 was as robust as the response to 5 mg/kg chlordiazepoxide.
  • the profile of this potent MCHl-R antagonist in the rat social interaction test suggests that MCHl-R antagonists may have potential as anxiolytic agents.
  • the compounds of the subject invention can be used to treat obesity, mood and anxiety related disorders as well as the additional indications which are disclosed herein in the detailed description section.
  • the objective of the subject invention is to provide compounds which are ligands at the MCHl receptor. Accordingly, the present invention relates to compounds of Formula Ia and Ib:
  • each B 1 , B 2 and B 3 is independently CH or N;
  • R 1 is -(CHR 7 ) m N(R 8 )(R 9 ) or -(CHR 7 J n R 10 , and where the R 1 containing moiety of formula Ib is connected to one A but not when A is N;
  • R 2 is H or straight chained or branched C 1 -C 7 alkyl optionally substituted with one or more fluorine and where the carbons of the Ci-C 7 alkyl are optionally replaced with one to three N, O or S atoms;
  • R ⁇ is -X(CH 2 ) p YR l ' or X(CHCH)YR 1 ', and where B 1 of the R 3 containing moiety of formula Ia is connected to one A but not when A is N;
  • each X and Y is independently CH 2 , O, S, NH or a bond, provided that an O, S or NH is separated from another O, S or NH by at least two carbon atoms;
  • each R 4 , R ⁇ and R 6 is independently H, halogen or straight chained or branched Ci-C 6 alkyl;
  • each R 7 is independently H, OH, or wherein one R 7 can combine with another R 7 on an adjacent carbon atom to form C 3 -C f1 cycloalkyl and wherein one R 7 can combine with a H on the shared carbon atom to form CrQs cycloalkyl; wherein each R 8 and R 9 is independently H or straight chained or branched Ci-C 7 alkyl;
  • R 10 is a nitrogen containing heterocyclic moiety optionally substituted with one or
  • halogen -COR ", a S or O containing heterocyclic ring, or straight chained or branched CpC 7 alkyl optionally substituted with halogen or -OCH- ? ;
  • R 1 1 is CrC 6 cycloalkyl, straight chained or branched alkoxy-Cs-Q, cycloaikyl, straight chained or branched Ci-C 4 alkyl/alkoxy, phenyl, napthyl, 5 to 6-membered heteroaryl, benzothiophenyl, indolyl or benzoxazolyl, where each of which is optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched C]-C 4 alkyl optionally substituted with F;
  • n is an integer from I to 4 inclusive;
  • n is an integer from 0 to 4 inclusive
  • p is independently an integer from 0 to 3 inclusive, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from one of the exemplified compounds which are disclosed in the Experimental Section.
  • the subject invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a subject suffering from mood disorders, anxiety or obesity comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia or Ib.
  • the present invention further provides uses of a compound of Formula Ia or Ib in the manufacture of a pharmaceutical composition for the treatment of mood disorders, anxiety or obesity.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disorder, stabilized (i.e., not worsening) state of disorder, delay or slowing of disorder progression, amelioration or palliation of the disorder stale, and remission (whether partial or total), whether detectable or undetectable.
  • terapéuticaally effective amount is an amount sufficient to effect beneficial or desired clinical or biochemical results.
  • a “therapeutically effective amount” can be administered one or more times.
  • a therapeutically effective amount” of a compound is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disorder state.
  • the term "antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
  • agonist refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
  • the term "straight chained or branched Ci-C 7 alkyl” refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive.
  • substiluents include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2 -butyl, 2-melhyl-2-propyl, 2-mcthyl-l -propyl and n-heptyl.
  • the term “straight chained or branched C]-C 4 alkyl” refers to a saturated hydrocarbon having from one to four carbon atoms inclusive.
  • C ⁇ -C 6 cycloalkyl refers to the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a nitrogen containing heterocyclic moiety refers Io the following groups:
  • a S or O containing heterocyclic moiety refers to the following groups:
  • R % containing moiety of formula Ia refers to the following moiety:
  • heteroaryl is used to include five and six membered unsaturated rings that contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazoiyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and tria/inyl.
  • halogen refers to F, Cl, Br of I.
  • the compounds of the invention may have an advantage over other compounds in the art in that they possess reduced p-glycoproiein (pGP) activity and accordingly, the compounds may have unexpectedly enhanced brain-blood penetration. Additionally, the present invention further provides certain embodiments which are immediately described below.
  • pGP p-glycoproiein
  • each A is independently CR 6 or N provided that when one A is N, the other A is CR 6 ;
  • each B 1 , B 2 and B 3 is independently CH or N;
  • R 1 is -(CHR 7 ), n N(R 8 )(R 9 ) or -(CHR 7 ) n R 10 , and where the R 1 moiety of formula Ib is connected to one A but not when A is N;
  • R 2 is H or straight chained or branched Ci-C 7 alkyi optionally substituted with one or more fluorines and where the carbons of the C 1 -C 7 alkyl arc optionally replaced with one to three N, O or S atoms;
  • R 1 is -X(CH 2 ) P YR' ' or X(CHCH)YR 1 1 , and where B 1 of the R 1 containing moiety of formula
  • Ia is connected to one A but not when A is N;
  • each X and Y is independently CH 2 , O, S, NH or a bond, provided that an O, S or NH is separated from another O, S or NH by at least two carbon atoms;
  • each R 4 , R 5 and R 6 is independently H, halogen or straight chained or branched CpC 7 alkyl
  • each R 7 is independently H, OH, or wherein one R 7 can combine with another R 7 on an adjacent carbon atom to form C 3 -C U cycloalkyl and wherein one R 7 can combine with a H on the shared carbon atom to form C 3 -C 6 cycloalkyl;
  • each R and R is independently H or straight chained or branched Cj -C 7 alkyl
  • R 1( is a nitrogen containing heterocyclic moiety optionally substituted with one or more halogen or straight chained or branched Cj-C 7 alkyl;
  • R 11 is C 3 -Q, cycloalkyl, phenyl or a 5 to 6-membered heteroaryl, where the phenyl or 5 to 6- membered heteroaryl can be optionally substituted with F, Cl, Br, or straight chained or branched Cj-C 4 alkyl optionally substituted with F;
  • n is an integer from 1 to 4 inclusive
  • n is an integer from 0 to 4 inclusive; and p is independently an integer from 0 to 3 inclusive, or a pharmaceutically acceptable salt thereof.
  • the compound has the following structure:
  • B 1 is N and B 2 and B 3 are CH;
  • R 1 is -(CHR 7 ) m N(R 8 )(R 9 ) or -(CHR 7 ) n R 10 ;
  • R 2 is H or straight chained or branched C 1 -C 7 alkyl optionally substituted with one or more fluorine or -OH and where the carbons of the Ci-C 7 alkyl are optionally replaced with one to three N, O or S atoms;
  • each R and R " is independently H, halogen or straight chained or branched Ci-C 7 alkyl
  • each R 7 is independently H, OH, or wherein one R 7 can combine with another R 7 on an adjacent carbon atom to form CrQ cycloalkyl and wherein one R 7 can combine with a H on the shared carbon atom to form C 3 -C 6 cycloalkyl;
  • each R 8 and R 9 is independently H or straight chained or branched Ci-C 7 alkyl optionally substituted with one or more fluorine; wherein R J is a nitrogen containing heterocyclic moiety optionally substituted with one or more halogen, -COR 12 , a S or O containing heterocyclic ring, or .straight chained or branched Ci -C 7 alkyl optionally substituted with halogen or -OCH- ? ;
  • R 1 1 is C 3 -C 6 cycloalkyl, straight chained or branched alkoxy-CrC ⁇ cycloalkyl, straight chained or branched C 1 -C 4 aikyl/alkoxy, phenyl, napthyl, 5 to 6-membcred heteroaryl, benzothiophenyl, indolyl or benzoxazolyl, where each of which is optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched CpC 4 alkyl optionally substituted with F;
  • R " is straight chained or branched C]-C 7 alkyl or Ci-C 6 cycloalkyl, where each of which is optionally substituted with one or more halogen or methoxy;
  • n is an integer from 0 to 4 inclusive, or a pharmaceutically acceptable salt thereof.
  • R 1 is-(CHR 7 ) m N(R 8 )(R 9 ).
  • R 1 is-(CHR 7 ) n R 10 .
  • each R 4 and R 5 is independently H or straight chained or branched C 1 -C 4 alkyl.
  • R 10 is piperazinyl or morpholinyl, where each of which is optionally substituted with a S or O containing heterocyclic ring or one or more straight chained or branched Ci-C 4 alkyl optionally substituted with halogen.
  • R 10 is piperidinyl optionally substituted with a S or O containing heterocyclic ring or one or more straight chained or branched Ci-C 4 alkyl optionally substituted with halogen.
  • R 10 is pyrrolidinyl optionally substituted with a S or O containing heterocyclic ring or one or more straight chained or branched Ci-C 4 alkyl optionally substituted with halogen. In one embodiment, R 10 is azetidinyl optionally substituted with a S or O containing heterocyclic ring or one or more straight chained or branched Ci-C 4 alkyl optionally substituted with halogen.
  • R 10 is piperazinyl or morpholinyl, where each of which is optionally substituted with straight chained or branched C 1 -C 4 alkyl optionally substituted with halogen.
  • R 10 is piperidinyl optionally straight chained or branched C 1 -C 4 alkyl optionally substituted with fluorine.
  • R K) is pyrrolidinyl optionally straight chained or branched C 1 -C 4 alky] optionally substituted with fluorine,
  • R 10 is azetidinyl optionally straight chained or branched Ci-C 4 alkyl optionally substituted with fluorine.
  • R 7 is H; and R 4 and R 5 is independently H, or straight chained or branched C 1 -C 4 alkyl.
  • n is 0 and R 2 is H, methyl or ethyl.
  • n 1 or 2.
  • R 1 ' is C 3 -C 6 cycloalkyl or alkoxy-C 3 -Cc, cycloalkyl, where each of which is optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched C 1 - C 4 alkyl optionally substituted with F.
  • R 1 ' is phenyl or napthyl, where each of which is optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched C 1 -C 4 alkyl optionally substituted with F.
  • R ⁇ is a 5 to 6-membered heteroaryl optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched CpC 4 alkyl optionally substituted with F.
  • R.” is bcnzothiophcnyl, indolyl or benzoxazolyl, where each of which is optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched C 1 -C 4 alkyl optionally substituted with F.
  • R s ' is phenyl optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched Cj-C 4 alkyl optionally substituted with F.
  • R 1 1 is napthy! optionally substituted with one or more F, Cl, Br, -OH, or straight chained or branched Ci-C 4 alkyl optionally substituted with F.
  • the compound falls under formula Ia.
  • the compound falls under formula Ib.
  • B 1 is CH. In a separate embodiment, B 1 is N.
  • B " is CH. In a separate embodiment, B" is N,
  • B 1 is CH. In a separate embodiment, B 3 is N.
  • B 1 is CH and B 3 is CH. In a separate embodiment, B 1 is CH, B 1 is N and
  • B 3 is CH.
  • each R 4 , R 5 and R 6 is independently H, halogen or straight chained or branched Ci-C 4 alkyl; and wherein each R 8 and R 9 is independently H or straight chained or branched Cj-C 4 alkyl.
  • R 10 is azetidinyl, cyclopropyl, cyclobutyl, cyclopenyl or cyciohcxyl, wherein the azetidinyl, cyclopropyl, cyclobutyl, cyclopenyl or cyclohexyl is optionally substituted with with one or more halogen or straight chained or branched Ci-C 4 alkyl.
  • R 3 is -X(CH 2 ) P YR' '
  • R 3 is -X(CHCH)YR 1 '.
  • R 2 is H or straight chained or branched Ci-C 4 alkyl.
  • X is CH 2 or O; and p is 1 or 2.
  • X is S; and p is 1 or 2.
  • R 1 1 is is C 3 -C 6 cycloalkyl or phenyl, where the phenyl can be optionally substituted with F, Cl, Br, or straight chained or branched Cj-C 4 alkyl optionally substituted with F.
  • R 1 ' is is C 3 -C 6 cycloalkyl
  • R 1 ' is phenyl optionally substituted with F, CI, Br, or straight chained or branched CpC 4 alkyl optionally substituted with F.
  • R l ' is heteroaryl optionally substituted with F, Cl, Br, or straight chained or branched Ci -C 4 alkyl optionally substituted with F.
  • the subject invention is also directed to a compound selected from the group consisting of A-
  • the subject invention is also directed to a compound selected from the group consisting of 4- (4-chIoro-phenyl)- 1 -[3 ⁇ ( 1 -methyl-azetidin-3-yI)- 1 h-indol-6-yl]- lh-pyridin-2-one; 4-(4-chloro- phenyl)- 1 - ⁇ 3-[ 1 -(2-fluoro-ethyl)-azctidin-3-yl]- 1 h-indol-6-yl ⁇ - 1 h-pyridin-2-one; 4 ⁇ (4 ⁇ chlo ⁇ > phenyl)- 1 - ⁇ 3-[ 1 -(2-methoxy-cthyl)-azetidin-3-yl]- 1 h-indol- ⁇ -yl ⁇ - lh-pyridin-2-one; 4-(4- chloro-phenyl)- 1 -[ 1 -methyl-3-(
  • the subject invention is also directed to a compound selected from the group consisting of3- [3-(l -methyl-azetidin-3-yl)- lh-indol-6-yl]-6-(4-trifluoromethyl-phenyl)-3h-pyrimidin-4-one; 1 - ⁇ 3-[ 1 -(2-fluoro-cthyl) ⁇ azetidin-3 ⁇ yI]- 1 -methyl- 1 h ⁇ indol ⁇ 6 ⁇ yl ⁇ -4-(4-fluoro-phenyI)- 1 h- pyridin-2-one; 5-fluoro- 1 '- ⁇ 3-[ 1 -(2-fluoro-ethyl)-azetidin-3-yl]- 1 -methyl- 1 h-indol-6-yI ⁇ - l'h- [2,4'lbipyridinyl-2'-onc; 1'- ⁇ 3-[ 1 -(2-fluoro
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and an acceptable pharmaceutical carrier,
  • the present invention is also directed to a method of treating mood disorders in a subject comprising administering a therapeutically effective amount of a compound of the invention.
  • the present invention is also directed to method of treating anxiety in a subject comprising administering a therapeutically effective amount of a compound of the invention,
  • the present invention is also directed to a method of treating obesity in a subject comprising administering a therapeutically effective amount of a compound of the invention.
  • the present invention is also directed to method of treating urinary disorders in a subject comprising administering a therapeutically effective amount of a compound of the invention,
  • the invention is directed to uses of a compound of the invention for the manufacture of a pharmaceutical composition for treating a disorder selected from the group consisting of mood, anxiety and obesity related disorders.
  • Pharmaceutically Acceptable Salts are provided.
  • the present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, malcic, malic, malonic, mandelic, oxalic, pyruvic, salicylic, succinic, methane sulfonic, elhanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycoiic, p-aminobenzoic, glutamic, bcnzenesulfonic, p- to
  • compositions include the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Pharw, Set,, 1977, 66, 2 and Paulekuhn, el al. J. Med. Chem. 2007 (December online publication), the contents of all which are hereby incorporated by reference.
  • the compounds of this invention may exist in unsolvated as well as in solvatcd forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • Racemic forms may be resolved into the optical antipodes by known methods, for example, by separation of diastcreomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization.
  • the optically active acids suitable for this purpose may include, but are not limited to d- or 1- tartaric, mandelic or camphorsulfonic acids.
  • Another method for resolving racematcs into the optical antipodes is based upon chromatography on an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation and chromatographic separation of diastereomeric derivatives from chiral derivatizing reagents, such as, e.g., chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Any of the above methods may be applied either to resolve the optical antipodes of the compounds of the invention per se or to resolve the optical antipodes of synthetic intermediates, which can then be converted by methods described herein into the optically resolved final products which are the compound of the invention.
  • chiral derivatizing reagents such as, e.g., chiral alkylating or acylating reagents
  • Optically active compounds may also be prepared from optically active starting materials.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 lh Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, ⁇ t will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Suitable administration forms include, but arc not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one Io three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of Formula the invention and a pharmaceutically acceptable carrier,
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of Formula Ia or Ib with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids arc described above.
  • solutions of the compounds of the invention in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of the invention may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium slearatc, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostcarate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the compounds of the invention and a pharmaceutically acceptable carrier arc then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or waier-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the compounds of Formula Ia and Ib bind to the MCHl receptor. Accordingly, the present invention provides a method of treating depression in a subject which comprises administering to the subject a therapeutically effective amount of a compound of this invention. This invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject a therapeutically effective amount of a compound of this invention,
  • This invention also provides a method of treating a subject suffering from obesity which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • the obesity indication includes in particular exogenic obesity, hypei ⁇ nsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity.
  • This range of indications also includes cachexia, anorexia and hyperphagia.
  • the treatment of obesity is expected to weight loss in a subject.
  • This invention also provides a method of treating a subject suffering from urinary disorders which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • Another range of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, hyperactive bladder, urgency, nycturia, enuresis, while the hyperactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.
  • the subject is a human being.
  • TLC Thin-layer chromatography
  • the compounds of Formula Ia may be synthesized according to the procedures described in Scheme 1.
  • the compounds of Formula II and III are commercially available or may be synthesized by those skilled in the art.
  • the compounds of Formula II may be synthesized according to the procedures described in Scheme 14, 15, and 16.
  • the compounds of Formula III may be synthesized according to the procedures described in Scheme 6, 7, 8, 9, 10, 1 1, 12, and 13. Copper-catalyzed coupling reaction of compounds II with compounds III in the presence of copper iodide, potassium carbonate and trans-N,N'-DimethyI- cyclohexane- 1 ,2-di amine in DMF at about 100 0 C affords the compounds of Formula Ia.
  • the compounds of Formula Ia may be prepared according to the procedures described in Scheme 2.
  • the compounds of Formula V may be synthesized via dehydroxylation of alcohols of Formula IV with TFA and lriethyl silane in DCM at about 0 0 C for about 10 min.
  • Pyridinoncs of Formula III arc coupled with compound V in the presence of copper iodide, potassium carbonate and trans-N,N'-dmiethyl-cyclohexane-l,2-diamine in DMF at about 100 0 C for about 18 h, followed by dcprotection of N-Boc in the presence of TFA, to afford the compound VI.
  • the reductive amination of compound VI with aldehydes (or ketones) or the alkylation with alkyl halides affords the compounds of Formula Ia.
  • the compounds of Formula Ia may be prepared according to the procedures described in Scheme 3.
  • Scheme 4
  • the compounds of Formula Ia may be prepared according to the procedures described in Scheme 4.
  • the compounds of Formula VIII are prepared via Suzuki reactions of pyridinones of Formula III and indole VII in the presence of palladium chloride, base and a suitable ligand in DMF at about 80 0 C for about 12 h.
  • the compounds of Formula Ia are prepared via iridium-catalyzed reactions of indoles of Formula VIII and alcohols IX in the presence of [Cp*IrCl 2 ]2 and potassium hydroxide in DCM in sealed tube at about 110 0 C for about 24 h.
  • reaction conditions in connection with the iridium-catalyzed reactions sec R. Grigg et al., Org. Letters 2007, 9 (17), 3299-3302 and references cited therein.
  • the compounds of Formula Ia may be prepared according to the procedures described in Scheme 5. Mitsunobu reaction of compounds of Formula X and phenols of Formula XI in the presence of triphenylphosphine and DBAD in THF affords ethers or thio ethers of Formula XII.
  • Pyridine-N-oxidcs of Formula XIII can be prepared via oxidation of XII with mCPBA in DCM at room temperature.
  • the compounds of Formula XIV are prepared via reaction of pyridine-N-oxidc of Formula XIII with POCl 3 in toluene at about 90 0 C for about 12 h.
  • the pyridinoncs of Formula XV are synthesized from hydrolysis of XIV in acetic acid and water at about 90 0 C for about 24 h.
  • the compounds of Formula Ia are prepared via Suzuki coupling reactions of XV and XVI in the presence of palladium, base and a suitable ligand in DMF at about 80 0 C for about 12 h.
  • the compounds of Formula III may be prepared according to the procedures described in Scheme 6.
  • the compounds of Formula XIX are synthesized via nucleophilic substitution of 4-chloropyridine N-oxide of Formula XVIII with alcohols or thio alcohols of Formula XVII in the presence of tris[2-(2-melhoxycthoxy)- ⁇ thyl]amine (TDA-I), potassium hydroxide and potassium carbonate in toluene under reflux for about 3 h.
  • TDA-I tris[2-(2-melhoxycthoxy)- ⁇ thyl]amine
  • Pyridinones of Formula III are prepared via reaction of compounds XIX in acetic anhydride at about 140 0 C overnight.
  • the compounds of Formula III may be synthesized according to the procedures described in Scheme 7.
  • the compounds of Formula XX which are commercially available or synthesized by those skilled in the art, are treated with alcohols or thio alcohols XI in the presence of triphenylphosphine and DBAD in THF at room temperature for about 2 h to afford ethers or thio ethers of Formula XXI.
  • the compounds of Formula XXI are treated with acetic acid in water at about 120 0 C for about 12 h to afford pyridinones of Formula HI.
  • the compounds of Formula III may be prepared according to the procedures described in Scheme 8.
  • the mesylates of Formula XXII are synthesized from reaction of alcohols of Formula XX and mesyl chloride in the presence of base.
  • the compounds of Formula III are prepared via substitution reaction of mesylates of Formula XXII with alcohols or thio alcohols XI in the presence of base such as cesium carbonate.
  • R 3 aryl, heteroaryl
  • the compounds of Formula III may be prepared according to the procedures described in Scheme 9.
  • the compounds of Formula XXIV arc synthesized via Suzuki reaction of 4-chloropyridinc N-oxide XVIII with aryl boronic acid or aryl boronic ester of Formula XXIII, which is commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPh- ⁇ ) 4 and Na 2 CO 3 in 1 ,2-dimelhoxy ethane/water under reflux for about 16 h.
  • Pyridinones of Formula III are prepared via reaction of compounds XXIV in acetic anhydride at about 140 0 C overnight.
  • the compounds of Formula IH may be prepared according to the procedures described in Scheme 10.
  • the compounds of Formula XXV can be treated with aryl boronic acid or aryl boronic ester XXIII, which are commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPlIs) 4 and Na 2 CO- ? in 1,2-dimethoxy ethane under reflux for about 16 h to afford the compounds of Formula XXVI.
  • the compounds of Formula XXVI can be treated with acetic acid at about 110 0 C for overnight to afford pyridinones of Formula III.
  • the compounds of Formula III may be prepared according to the procedures described in Scheme 11.
  • the compounds of Formula XXVIII which are commercially available or synthesized by those skilled in the art, are treated with pyridinyl boronic acid or pyridinyl boronic ester XXVII, which is commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPh 3 ) 4 and Na 2 CO 3 in 1,2-dimethoxy ethane under reflux for about 16 h to afford Formula XXVI.
  • the compounds of Formula XXVI are treated with acetic acid at about 1 10 0 C for overnight to afford pyridinones of Formula HI.
  • the compounds of Formula III may be prepared according to the procedures described in Scheme 12.
  • the compounds of Formula XXIX which are commercially available or may be synthesized by those skilled in the art, can be treated with aryl boronic acid or aryi boronic ester XXIII, which is commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPhO 4 and Na 2 CO 3 in 1 ,2-dimethoxy ethane under reflux for 16 h to afford pyridinones of Formula III.
  • the compounds of pyridinone XXXII may be prepared according to the procedures described in Scheme 13.
  • the compounds of Formula XXXII are prepared via Wittig reaction of aldehydes XXX and phosphonates XXXI in the presence of potasium f ⁇ r/ ⁇ butoxide in THF at room temperature for about 4 h.
  • Scheme 14
  • the compounds of Formula XXXV may be synthesized according to the procedures described in Scheme 14.
  • the compounds of Formula XXXIII and VII are commercially available or may be synthesized by those skilled in the art.
  • the azetidinone of Formula XXXIV is prepared by reaction of XXXIII with sulphur trioxide pyridine complex in the presence of triethylamine in DMSO and DCM at about 10 0 C for about 30 min and at about 20 0 C for about 1 h.
  • l-(3 ⁇ Indolyl)azetidin-3 ⁇ ol IV is prepared via condensation of azetidone XXXIV with indoles of Formula VII in the presence of potassium hydroxide in methanol at about 45-50 0 C for about 6 h.
  • the compound XXXV is prepared via reduction of l-(3-indolyl)azetidin»3-ol IV with LAH in THF under reflux for about 6 h.
  • the substituted indoles VII may be synthesized according to the procedures described in
  • Boc-azetidin-3-one (68.0 g, 397 mmol) was added in one portion. The resulting solution was stirred at 45-50 0 C for 6 h and concentrated in vacuo. The residue was diluted with EtOAc
  • Example Ib I -[ I -Ethyl-3-((S)- 1 -mcthyl- ⁇ yrroIidin-2-yImethyl)- 1 H-indol-6-yl]-4-(pyridin-3- ylmethoxy)- 1 H-pyridin-2-one
  • the compound was prepared from 4-(4-fluoro-phenoxyniethyl)-i H-pyrid in-2-one and 6- bromo-3-(l-melhyI-azelidin-3-yl)-lH-indolc VI.
  • Example Id 4-(4-Chloro ⁇ benzyloxy)- 1 -[3-( 1 -melhyl-azetidin-3-yl)- 1 H-indol-6-yl j- 1 H- pyridin-2-one
  • the compound was prepared from 4-(4-chloro-benzyloxy)-lH-pyridin-2-onc and bromo-3-(l - methyl-azetidin-3-yl)-lH-indole.
  • ESMS m/e: 420 (M+H) + .
  • the compound was prepared from 4-(4-fluoro-phenylsulfanylmethyl)-lH-pyridin-2-one and 6-bromo-3-( 1 -methyl-azetidin-3-yl)- I H-indole.
  • the compound was prepared from 4-[(E)-2 ⁇ (4»fluoro ⁇ phenyl) ⁇ vinyl] ⁇ l-[3 ⁇ (l-melhyl-azelidin- 3-yl)- lH-indol-6-yl] - 1 H-pyridin-2-one and 6-bromo-3-( 1 -methyl-azetidin-3-yl)- 1 H-indoic.
  • Example Ig 4-( 1 -Cyclopropyl-ethoxy)- 1 -[3-( 1 -melhyl-azclidin-3-yl)- 1 H-indol-6-yll- 1 H- pyridin ⁇ 2-onc
  • the compound was prepared from 4-(l-cyclopropyI-cthoxy)-l H-pyridin-2-one and 6-bromo- 3-( 1 -methyl-azetidin-3-yl)" 1 H ⁇ indole ESMS m/e: 364.0 (M+H) + .
  • Example 2a 4-(4-Chloro-phenyl)-l -[3-(I -methyl-azetidin-3-yl)- lH-indol-6-yl]-lH-pyridin-2-one
  • Example 2b 4-(4-Chloro-phenyl)- l- ⁇ 3-[ l-(2-fluoro-ethyl)-azetidin-3-yl]- lH-indol-6-yl ⁇ - lH- pyi ⁇ din-2-one
  • the compound was prepared from 4-(4-chloro-phenyI)- 1 H-pyridin-2-one and 6-bromo-3-[ 1 - (2-fluoro-cthyl)-azelidin-3-yl]- lH-indole.
  • Example 2c 4-(4-Chloro-phenyl)- 1 - ⁇ 3-[ 1 -(2-mcthoxy-ethyl)-azelidin-3-yI]- 1 H-indol-6-yl ⁇ - 1 H-pyridin-2-one
  • the compound was prepared from 6-bromo-3-[l-(2-mcthoxy-ethyI)-azetidin-3-yl]-lH-indole and 4-(4-chlor ⁇ - ⁇ hcnyI)-l H- ⁇ yridin-2-one.
  • ESMS m/e: 433.9 (M+H) + .
  • Example 2d 4-(4-ChIoro-phenyl)- 1 -[ 1 -methyl-3-( 1 -methyl-azetidin-3-yl)- 1 H-indol-6-yl]- 1 H- pyridin-2-one
  • the compound was prepared from 6-bromo- 1 -methyl-3-( 1 -methyl-azetidin-3-yl)- 1 H-indole and 4-(4-chloro-phenyl)-l H-pyridin-2-one.
  • the compound was prepared from 6-biOmo-3-(l-isopropyl ⁇ azetidin-3-yl)- lH-indole and 5- chloro-rH-[2,4']bipyridinyl-2'-one.
  • ESMS m/e:419.0 (M+H) + .
  • the compound was prepared from 6-bromo-3-[l-(2-fluoiO-ethyl)-azetidin-3-yl]-lH-indolc and 6-trifluoromethyl" rH-[3,4']bipyridinyl ⁇ 2'-one.
  • ESMS m/e: 456.9 (M+H) + .
  • Example 2g 4-(2-FI uoro-4-trifluoiOtnethyl -phenyl)- 1 -[3-( 1 -methyl ⁇ aze ⁇ din ⁇ 3 ⁇ yl) ⁇ 1 H ⁇ indo! ⁇ yll-1 H-pyridin-2-one
  • the compound was prepared from 6-biOmo-3-( l-methyl-azctidin-3-yl)-lH-indolc and 4-(2- fluoro-4-trifluor ⁇ methyl- ⁇ henyl)- 1 H-pyridin-2-one.
  • Example 2h 4-[4-( 1 -Hydroxy- 1 -methyl-ethyl) ⁇ phenyl] ⁇ 1 ⁇ [3-( I -methyl-azetidin ⁇ 3-yl) ⁇ 1 H- indoI-6-yl]-l H-pyridin-2-one
  • the compound was prepared from 6-bromo-3-( l-methyl-azetidin-3-yl)-lH-indole and 6-(4- chloro- ⁇ henyI)-3H-pyrimidin-4-one.
  • the compound was prepared from 6 ⁇ bromo-2-methyl-3-(l-methyI-azetidin-3-y!)-l H-indole and ⁇ -trifluoiOmethyl-l ⁇ -tS ⁇ 'Jbipyridinyl ⁇ '-one.
  • the compound was prepared from 6-bromo-3-(l-mcthyl-azetidin-3-yl)-l H-indole and 4-(5- methyl-bcnzo[b]thiophen-2-yl)-I H-pyridin-2-one.
  • ESMS m/e:425.9 (M+H) + .
  • Example 21 1 -[3-( l-Methyl-azetidin-3-yl)- 1 H-indol-6-yI]-4-( 1 ⁇ methyl- 1 H-indol-5-yl)- 1 H- pyridin-2-one
  • the compound was prepared from 6-bromo-3-(l-mcthyl-azetidin-3-yl)-lH-indole and 4- na ⁇ hthalen-2-yl-l H- ⁇ yridin-2-onc.
  • ESMS m/e: 406.1 (M+H) + .
  • the compound was prepared from 3-(l-methyl-azelidin-3-yl)-l H-indolc and 4-(5-fluoro- benzooxazol-2-yl)-l H-pyridin-2-one ESMS m/e: 415.0 (M+H) + .
  • the compound was prepared from 6-bromo-3-[l-(2-fluoro-ethyl)-azetidin-3-yl]-lH-indole and 4-(5-ethyl-pyrimidin-2-yl)-l H-pyridin-2-one.
  • ESMS m/e: 417.9 (M+H) + .
  • the compound was prepared from 6-bromo-3-[ l-(2-fluoiO-ethyt)-azetidin-3-yl]- l -methyl- IH- indole and S-chloro- l ⁇ - ⁇ 'Jbipyridinyl-a'-one.
  • the compound was prepared from 4-(4-tTrifluoroniethoxy-phenyl)-lH-pyridin-2-one and 6- bromo-3-(l-methyl-azetidin-3-yl)-lH-indole ESMS m/e: 439.9 (M+H) ⁇
  • the compound was prepared from 6-(4-trifluoromethyl-phenyl)-3H-pyrimidin-4-one and 6- bromo-3-(l-methyl-azetidin-3-yl)-lH-indole.
  • ESMS m/e: 424.9 (M+H) + .
  • the compound was prepared from 4-(4-fluoro-phenyl)-l H-pyridin-2-one and 6-bromo-3-[l- (2-fluoro-ethyI)-azetidin-3 -yl]-l -methyl- IH-indole.
  • the compound was prepared from 5-trifluoromethyI-l 'H-[2,4']bipyridinyl-2'-one and 6- bromo-3-[ 1 -(2-fluoro-elhyl)-azetidin-3-yIJ- 1 -methyl- 1 H-indole.
  • the compound was prepared from 5-trifluorornethyi-l ⁇ -[2,4']bipyridinyI ⁇ 2' ⁇ onc and 6- bromo- 1 -methyl-3-( 1 -methyI-aze ⁇ din-3-yl)- 1 H-indole.
  • the compound was prepared from 6-trifluoiOmethyI-rH-[3,4']bipyridinyi-2'-one and 6- bromo-3-[ 1 -(2-fluoro-ethyl)-azetidin-3-yI J-I -methyl- 1 H-indole.
  • ESMS m/e: 470.9 (M+H) + .
  • the compound was prepared from 6-(4-chloro-phenyl)-3H-pyrimidin-4-one and 6-bromo-2- methyl-3-( 1 -methyl-azetidin-3-yl)- 1 H-indole.
  • Example 3a 4-(4-Chloro-phenyl)- 1 - ⁇ 3 ⁇ [ 1 -(tetrahydro-thiophcn-3-yl)-azetidin-3-yl]- 1 H-indol- 6-yl ⁇ - 1 H-pyridin-2-one
  • Example 3b 4-(4-Chloro-phenyl)- 1-[3-Cl -oxetan-3-yl-azetidin-3-yl)- 1 H-indol-6-yl]- 1 H- pyridin-2-one
  • the compound was prepared from l-(3-azetidin-3-yl- l H-indoI-6-yl)-4-(4-chloro-phenyl)- lH- pyridin-2-one and oxclan-3-one.
  • ESMS m/e: 432.0 (M+H) + .
  • the compound was prepared from l-[3-azctidin-3-yl-l-(2-hydroxy-cthy])-l H-indol-6-yi]-4- (4-chloro-phenyI)-l H-pyridin-2-onc and acetaldehyde.
  • ESMS m/e: 447.9 (M+H) + .
  • Example 3d 4-(4-Chloro-phenyl)- 1 - ⁇ 3-f l-(3,3,3 ⁇ trifluoro-piOpionyl)-azctidin-3-yl]-lH-indol-
  • the compound of example 3d were prepared in an analogous manner to the procedure described for example 3e and was prepared from l-(3-azetidin-3-yl-l H-indol-6-yl)-4-(4- chloro-phenyl)- l H-pyridin-2-one and 3,3,3-t ⁇ fluoro-propionyl chloride.
  • Example 3e 4-(4-Chloro-phcnyl)- 1 -[3-( 3 -cyclopropanecarbonyl-azetidin-S-yl)- 1 -methyl- 1 H- indol-6-yl] ⁇ l H-pyridin-2-one
  • Example 3f 4-(4-Chloro-phenyl)-l ⁇ l-mcthyl-3-[ l-(tetrahydro-furan-3 ⁇ yl) ⁇ azetidin-3-yl]- 1 H-indol-6-yl ⁇ - 1 H-pyridin-2-one
  • the compound was prepared from l-(3-azetidin-3-yl- l -methyl- 1 H-indol-6-yl)-4-(4-chloro- phcnyl)- lH-pyridin-2-onc and dihydro-furan-3-one.
  • ESMS m/e: 459.9 (M+H) + .
  • the compound was prepared from l' ⁇ (3-azetidin ⁇ 3-yl-l -methyl- lH-indoI-6-yl)-5-chloro- l 'H-
  • the compound was prepared from l'-(3-azetidin-3-yl-l -methyl- lH ⁇ indol ⁇ 6 ⁇ yl)-5-chloro-l 1 H- [2,4']bipy ⁇ dinylTM2'-onc and acetone.
  • ESMS m/e: 432.9 (M+H) + .
  • Example 3i 1 -[ 1 -Methyl-3-( 1 -methyl-azetidin-3-yl)- 1 H-indoI-6-yl]-4-(4-trifluoromethyl- phenyl)- lH-pyridin-2-one
  • the compound was prepared from l-(3-azetidin-3-yl- l -methyl- lH-indol-6- yl)-4-(4- trifluoiOmethyl-phenyl)- lH-pyridin-2-onc and formaldehyde.
  • ESMS m/e: 437.9 (M+H) + .
  • the compound of example 3j were prepared in an analogous manner to the procedure described for example 3e and was prepared from I -(3-azetidin-3-yl- 1 -methyl- lH-indol-6-yl)- 4-(4-trifluoromethyl-phenyl)-l H-pyridin-2-one and acetyl chloride.
  • the compound was prepared from 3-(3-azetidin-3-yl-lH-indoI-6-yl) ⁇ 6-(4-chloro-phenyl)-3H- pyrimidin-4-one and tetrahydro-furan-3-carbaldehyde.
  • Example 31 4-(4-Fluoro-phenyl)- 1 -[3-( 1 -isopropyl-azetidin-3-yl)- 1 -methyl- 1 H-indol-6-yl] - 1 H-pyridin-2-one
  • the compound was prepared from I -(3-azetidin-3-yl ⁇ l -methyl- l H-indol-6-yl)-4-(4-fluoro- phcnyl)-lH- ⁇ yridin-2-one and acetone.
  • ESMS m/e: 41 ⁇ .0(M+H) + .
  • Example 4b 1 -[ 1 -Methyl-3-( 1 -methyl-azetidin-3-y ⁇ )- 1 H-indol-6-yl]-4-(2,2,2-tri ⁇ uoiO- ethoxy)- 1 H-pyridin-2-one
  • the compound was prepared from l-[3-(l-methyl-azetidin-3-yl)-l H-indof-6-yll-4-(2,2,2- trifluoro-elhoxy)-lH-pyridin-2-onc and iodomethane.
  • ESMS m/e: 392.0 (M+H) + .
  • the compound was prepared from 5-chloro-l '-[3-(l -ethyl-azetidin-3-yl)- l H-indol-6-yl]-l TI- [2,4']bipyridinyl-2'-one and 1 -bromo-2-fluor ⁇ -elhane.
  • Thc compound was prepared 5-Chloro- 1 '-[3-(I -ethyl-azetidin-3-yl)- lH-indol-6-yll- l 1 H- [2,4'JbipyridinyI-2'-one and iodomethane.
  • ESMS m/e: 419.2 (M+H) + .
  • the affinity of the compounds of the invention at the MCHl receptor was determined by measuring the inhibition of binding of a radioactive ligand ant the MCHl receptor.
  • the procedure for determining specific binding of a test compound may be used as described by Audinot, et al. British Journal of Pharmacology, 2001, 133, 371-378.
  • the specific binding of test compounds can be measured at the rat MCHl receptor (GenBank Accession No. NM_031758) using [ 125 I]-S3 ⁇ 057 (NEX396; PcrkinElmcr Life Sciences, Inc.) as the radioligand.
  • the compounds of the invention were tested for their affinity at the MCH IR receptor. All the compounds disclosed herein show Ki values of less than about 5.0 ⁇ M. Nearly all the compounds show Ki values of less than about l .O ⁇ M. Most of the compounds have Ki values of less than about 20OnM with many of compounds having Ki values of less than about 5OnM.
  • Functional activity of the compounds of the invention can be measured by receptor assays which determine the degree of intracellular second messenger response.
  • receptor assays which determine the degree of intracellular second messenger response.
  • Cos-7 ceils are transfected with the MCHl receptor using the DEAE-dcxtran method (Gerald, ct al. J. Biol. Chcm. 1995, 270, 26758-26761).
  • Other cell transfcction methods employing various host cells, are well-known in the art. Certain compounds were tested to determine their functional activity and were determined to be potent antagonists at the MCHl receptor.
  • the in-vivo effects of the compounds of the present invention may be evaluated by using the following in-vivo behavioral animal models.
  • the behavioral models described below are not intended to be the only models used to determine the efficacy of a compound of the invention to treat the corresponding disorder.
  • the marble burying experiment can also be used to screen for compounds for potential as anxiolytics. The skilled artisan would recognize the changes in certain parameters of the experiments to acquire the most exact data.
  • Rat Forced-swim Test Male Long-Evans rats are used and housed individually, maintained on about 12 h reverse light/dark cycle with lights off at about 09:00, and given free access to either a high-fat diet (#D 12451; fat percentage, about 45% kcal; Research Diets, New Brunswick, New Jersey) or a control diet (#D124508, fat percentage, about 10% kcal; Research Diets, New Brunswick, New Jersey) and water. After about 1 1 weeks, rats on the high fat diet began receiving a compound of the invention or vehicle by i.p. injection twice daily, about 1 h before lights off and about 10 h later, for about 4 weeks. Rat Forced-swim Test:
  • Rat Social-interaction Test The procedure is performed for about 15 min as previously described (File and Hyde Br. J, Pharmacol. 1987, 62, 19-24) under low-light conditions using pairs of unfamiliar male Sprague-Dawley rats previously housed singly and exposed to the test arena for about 15 min on the previous day.
  • a compound of the invention, chlordiazepoxide or vehicle is injected i.p. as ⁇ 1.0 ml/kg solution. All test sessions are videotaped and recorded for later scoring.
  • Active social interaction defined as sniffing, grooming, biting, boxing and crawling over and under, as well as locomotor activity (defined as squares crossed), is scored by a single rater, who is blinded to the treatment of each pair.
  • Rat Models of Micturition Compounds useful in the treatment of urinary disorders are assessed in various animal models of the micturition reflex as described in the art. (See, e.g., Maggi, CA, et al. J Pharmacol Exp Ther, 1987, 240, 998-1005; Morikawa, K, et al. Eur. J Pharmacol., 1992 213:409-415; Yoshiyama, M, et al. Eur J Pharmacol 287:73-78; and Yoshiyama, Urology, 1999, 54(5), 929- 33.)

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Abstract

La présente invention porte sur des dérivés de l'indole qui se lient au récepteur MCH1. Sous des aspects séparés, la présente invention porte sur des utilisations desdits composés dans la préparation d'une composition pharmaceutique destiné au traitement de l'obésité et de troubles liés au système nerveux central ainsi que sur des procédés de traitement desdits troubles comprenant l'administration d'une quantité thérapeutiquement efficace d'un composé de l'invention.
PCT/US2009/038022 2008-03-28 2009-03-24 Dérivés de l'indole Ceased WO2009120655A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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CN103214408A (zh) * 2013-05-07 2013-07-24 南京理工大学 一种合成双吲哚甲烷衍生物的方法
EP2558094A4 (fr) * 2010-04-12 2013-09-25 Merck Sharp & Dohme Dérivés de pyridone
JP2015503502A (ja) * 2012-01-12 2015-02-02 武田薬品工業株式会社 Ｍｃｈ受容体拮抗剤としてのベンゾイミダゾール誘導体

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WO2000043393A1 (fr) * 1999-01-20 2000-07-27 Merck & Co., Inc. Inhibiteurs d'angiogenese
US6358992B1 (en) * 1998-11-25 2002-03-19 Cell Pathways, Inc. Method of inhibiting neoplastic cells with indole derivatives
WO2003074047A1 (fr) * 2002-03-04 2003-09-12 4Sc Ag Modulateurs des canaux potassiques a base de derives indole
US20070299068A1 (en) * 2004-07-14 2007-12-27 Karp Gary M Methods for treating hepatitis C

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US6358992B1 (en) * 1998-11-25 2002-03-19 Cell Pathways, Inc. Method of inhibiting neoplastic cells with indole derivatives
WO2000043393A1 (fr) * 1999-01-20 2000-07-27 Merck & Co., Inc. Inhibiteurs d'angiogenese
WO2003074047A1 (fr) * 2002-03-04 2003-09-12 4Sc Ag Modulateurs des canaux potassiques a base de derives indole
US20070299068A1 (en) * 2004-07-14 2007-12-27 Karp Gary M Methods for treating hepatitis C

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2558094A4 (fr) * 2010-04-12 2013-09-25 Merck Sharp & Dohme Dérivés de pyridone
JP2015503502A (ja) * 2012-01-12 2015-02-02 武田薬品工業株式会社 Ｍｃｈ受容体拮抗剤としてのベンゾイミダゾール誘導体
CN103214408A (zh) * 2013-05-07 2013-07-24 南京理工大学 一种合成双吲哚甲烷衍生物的方法
CN103214408B (zh) * 2013-05-07 2015-09-30 南京理工大学 一种合成双吲哚甲烷衍生物的方法

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