WO2011127643A1 - Dérivés de pyridone - Google Patents

Dérivés de pyridone Download PDF

Info

Publication number
WO2011127643A1
WO2011127643A1 PCT/CN2010/071699 CN2010071699W WO2011127643A1 WO 2011127643 A1 WO2011127643 A1 WO 2011127643A1 CN 2010071699 W CN2010071699 W CN 2010071699W WO 2011127643 A1 WO2011127643 A1 WO 2011127643A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
pyridin
oxy
cyclopropyl
halogen
Prior art date
Application number
PCT/CN2010/071699
Other languages
English (en)
Inventor
Linus Lin
Richard Soll
Jingchao Dong
Hao Wu
Takao Suzuki
Bin Hu
Dejun Liu
Jinglai Hao
Ming Xu
Original Assignee
Merck Sharp & Dohme Corp.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Priority to PCT/CN2010/071699 priority Critical patent/WO2011127643A1/fr
Priority to PCT/US2011/031518 priority patent/WO2011130086A1/fr
Priority to US13/578,653 priority patent/US20120316200A1/en
Priority to EP11769326.7A priority patent/EP2558094A4/fr
Publication of WO2011127643A1 publication Critical patent/WO2011127643A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to novel pyridone derivative compounds.
  • the compounds act as melanin concentrating hormone receptor antagonists, and can be useful in preventing, treating or acting as a remedial agent for various circular system diseases, nervous system diseases, metabolic diseases, genital diseases, respiratory diseases and digestive diseases.
  • MCH Melanin concentrating hormone
  • MCH-containing neuron cells are localized in specific areas in the brain such as the hypothalamus lateral field, with nerve fibers projecting over a very wide scope in the brain [see The Journal of Comparative Neurology, Vol. 319, 218 (1992)].
  • the hypothalamus lateral field is known as the feeding center, and recent molecular biological and pharmacological discoveries suggest MCH participates in controlling energetic homeostasis. That is, it has been reported that expression of mRNA, which is an MCH precursor, is accelerated in the brains of ob/ob mice, db/db mice, Ay/a mice, Zucker fatty rats and in the brains of fasting mice [see Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998); Biochemical and Biophysical Research Communications, Vol. 268, 88 (2000); Molecular Brain Research, Vol. 92, 43 (2001)].
  • MCH precursor gene-deficient mice showed ether reduced food ingestion or an increase in oxygen consumption per body weight compared to wild type mice and lower body weight due to a decrease in body fat was observed [see Nature, Vol. 396, 670 (1998)].
  • MCH is an important factor in developing obesity and participates in diseases induced by metabolic disorders or respiratory diseases for which obesity is one risk factor. MCH is known to participate also in anxiety-causing action, epilepsy, memory, learning, diuretic action, sodium/potassium excretory action, oxytocin secreting action, reproduction and reproductive function [see Peptides, Vol. 17, 171 (1996); Peptides, Vol. 18, 1095 (1997); Peptides, Vol. 15, 757 (1994); Journal of
  • MCH causes versatile pharmacological actions through MCH receptors which are present mainly in the central nervous system.
  • MCH- 1R or SLC-1 type 1 MCH receptors
  • MH-2R or SLT type 2 MCH receptors
  • MCH-1R gene-deficient mice chronically administered with MCH do not develop polyphagy or obesity. Furthermore, the deficiency of MCH-1R is known to promote activity in mice [see Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, 3240 (2002)], and MCH-IRs participation in central diseases accompanied by behavioral disorders, for example, attention- deficit hyperactivity disorder, schizophrenia, depression and the like also is strongly suggested [see Molecular Medicine Today, Vol. 6, 43 (2000); Trends in Neuroscience, Vol. 24, 527 (2001)].
  • MCH-1R autoantibody to MCH-1R
  • a human autoantibody to MCH-1R is present in serum of vitiligo vulgaris patients [see The Journal of Clinical Investigation, Vol. 109, 923 (2002)].
  • expression of MCH-1R in certain species of cancer cells was reported, and in vivo expression sites of MCH and MCH-1R also suggest MCH's participation in cancer, sleep, vigil, drug dependence and digestive disorders [see Biochemical and Biophysical Research Communications, Vol. 289, 44 (2001); Neuroendocrinology, Vol. 61, 348 (1995); Endocrinology, Vol. 137, 561 (1996); The Journal of Comparative Neurology, Vol. 435, 26 (2001)].
  • MCH functions of MCH are expressed upon it binding to MCH receptors. Therefore, when the receptor's binding to MCH receptor is inhibited, the expression of MCH action can be inhibited.
  • substances which are antagonists for binding of MCH with its receptor are useful for preventing, treating or acting as remedial agents for those various diseases in which MCH participates, for example, metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver; cardiovascular disorders such as stenocardia, acute or congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases, electrolyte abnormality; central and peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention- deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence, alcoholism; reproductive disorders such as infertility, preterm labor and sexual dysfunction; and other digestive disorders, respiratory disorders,
  • the present invention is directed to pyridone derivative compounds of formula I
  • Such compounds are antagonists of the melanin-concentrating hormone ("MCH") type 1 receptor which are useful in the treatment or prevention of diseases in which the melanin-concentrating hormone is involved, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy and electrolyte abnormality; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence and alcohol dependence; reproductive system diseases such as infertility, premature delivery and sexual dysfunction; and other conditions including digestive diseases, respiratory diseases, cancer, chromatosis.
  • MCH melanin-concentrating hormone
  • the invention also
  • R and R 2 are independently selected from the group consisting of halogen, hydrogen, -OH, Ci-C 6 alkyl, -OCi-C 6 alkyl, -O-halogen- substitutedCi-C 6 alkyl and halogen-substitutedCi-C 6 alkyl; W is -N- or -C- ; Q is -0-, - H-, or - C-; R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, d-C 6 alkyl, -0-halogen-substitutedCi-C 6 alkyl, halogen-substitutedCi-C 6 alkyl, cyano, -S0 2 Ci-C 6 alkyl or taken together with aromatic
  • OCi-C 6 alkyl halogen-substitutedCi-C 6 alkyl, halogen-substitutedC 3 -C 6 alkyl or when R 5 and R 6 are taken together form an oxo group or C 3 -C 6 cycloalkyl, or when R 5 and R 4 taken together form a C 3 -C 6 cycloalkyl; and n is 1-3.
  • R 1 is selected from the group consisting of halogen, hydrogen, -OH, Ci-C 6 alkyl, -OCi-C 6 alkyl, -O-halogen- substitutedCi-C 6 alkyl and halogen-substitutedCi-C 6 alkyl.
  • R 1 is halogen or hydrogen.
  • R 1 is hydrogen.
  • R 1 is a halogen wherein the halogen is selected from fluorine or chlorine.
  • R 2 is selected from the group consisting of halogen, hydrogen, -OH, Ci-C 6 alkyl, -OCi-C 6 alkyl, -O-halogen- substitutedCi-C 6 alkyl and halogen-substitutedCi-C 6 alkyl.
  • R 2 is halogen or hydrogen.
  • R 2 is hydrogen.
  • R 2 is a halogen wherein the halogen is selected from fluorine or chlorine.
  • R and R 2 are both halogen. In other embodiments of the compounds described herein, R 1 and R 2 are both hydrogen.
  • R 1 is a halogen and R 2 is hydrogen.
  • R 1 is hydrogen and R 2 is halogen.
  • R and R 2 are halogen, wherein the halogen is selected from the group consisting of fluorine and chlorine.
  • R 1 is halogen, wherein the halogen is selected from the group consisting of fluorine and chlorine and R 2 is hydrogen.
  • R is halogen, wherein the halogen is selected from the group consisting of fluorine and chlorine and R 1 is hydrogen.
  • W is -N-. In other embodiments of the compounds described herein, W is -C-.
  • Q is selected from the group consisting of-O-, - H-, and -C-.
  • Q is -O- or -C-.
  • Q is -0-.
  • Q is -C-.
  • Q is - H-.
  • Q is -O- or -C- or Q is only - H- when Q, taken together with R 4 , aromatic ring B and R 3 form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, d-C 6 alkyl, -0-halogen-substitutedCi-C 6 alkyl, halogen- sub stitutedCi- C 6 alkyl, cyano, -S0 2 Ci-C 6 alkyl or taken together with aromatic ring B, R 4 and Q form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, Ci- C 6 alkyl. In other embodiments, R 3 is hydrogen or -OCi-C 6 alkyl.
  • R 3 is -OCi-C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is a halogen selected from the group consisting of chlorine or fluorine.
  • R 3 is -0-halogen-substitutedCi-C 6 alkyl or halogen-substitutedCi-C 6 alkyl, wherein the halogen is selected from the group consisting of chlorine or fluorine.
  • R 3 is cyano.
  • R 3 is -S0 2 Ci-C 6 alkyl such as
  • R 4 is hydrogen, oxo, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl or together with aromatic ring B, R 3 and Q form a heteroaryl or taken together with R 5 form a C 3 -C 6 cycloalkyl.
  • R 4 is an oxo group.
  • R 4 is halogen-substitutedCi-C 6 alkyl.
  • R 4 is Ci-C 6 alkyl.
  • R 4 is hydrogen.
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedCi-C 6 alkyl, halogen-substitutedC 3 -C 6 cycloalkyl, Ci-C 6 alkylC 3 -C 6 cycloalkyl, - OH, Ci-C 6 alkyl-OH and -OCi-C 6 alkyl.
  • R 5 , R 6 and R 7 are not all hydrogen at the same time.
  • at least one of R 5 , R 6 and R 7 is not hydrogen.
  • R 5 and R 6 are taken together form an oxo group or C 3 -C 6 cycloalkyl. In other embodiments, R 4 and R 5 are taken together form a C 3 -C 6 cycloalkyl.
  • R 5 , R 6 , R 7 are independently selected from the group consisting of hydrogen, -OH, Ci-C 6 alkyl-OH and cyclopropane. In other embodiments, R 5 , R 6 , R 7 are independently selected from the group consisting of hydrogen, -OH, d-C 6 alkyl-OH and Ci-C 6 alkylC 3 -C 6 cycloalkyl. In other
  • R 5 , R 6 , R 7 are independently selected from the group consisting of halogen- substitutedCi-C 6 alkyl and halogen-substitutedC 3 -C 6 cycloalkyl.
  • R 5 and R 6 together form an oxo group and R 7 is -O Ci- C 6 alkyl.
  • R 5 and R 6 are Ci-C 6 alkyl and R 7 is Ci-C 6 alkyl-OH.
  • R 5 and R 6 together are cyclopropyl and R 7 is -OCi-C 6 alkyl.
  • n is 1-3. In some embodiments of the compounds described herein n is 1. In other embodiments described herein, n is 2. In still other embodiments, n is 3.
  • R 1 is halogen or halogen-substitutedCi-C 6 alkyl
  • W is -N- or -C-
  • Q is -0-, - H- or -C-
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, d- C 6 alkyl, -0-halogen-substitutedCi-C 6 alkyl, halogen-substitutedCi-C 6 alkyl, cyano, -S0 2 Ci-C 6 alkyl or taken together with aromatic ring B, Q and R 4 form a heteroaryl
  • R 4 is hydrogen, oxo, Ci- C 6 alkyl, halogen-substitutedCi-C 6 alkyl or together with aromatic ring B, R 3 and Q form a heteroaryl, or taken together with R 5 form a C 3 -C 6 cycloalkyl
  • R 5 and R 6 are each independently selected from
  • R 1 is selected from the group consisting of halogen and halogen-substitutedCi-C 6 alkyl.
  • R 1 is halogen, wherein the halogen is selected from fluorine or chlorine.
  • R 1 is fluorine.
  • R 1 is halogen-substitutedCi-C 6 alkyl, wherein the halogen-substitutedCi-C 6 alkyl is selected from the group consisting of fluoromethyl, difluoromethyl and trifluoromethyl.
  • W is -N-. In other embodiments of the compounds described herein, W is -C-. In certain embodiments of the compounds described by formula la, Q is selected from the group consisting of-O-, - H-, and -C-. In some embodiments described herein Q is - O- or -C-. For example, in certain embodiments, Q is -0-. In other embodiments, Q is -C-. In yet other embodiments, Q is - H-. In still other embodiments, Q is -O- or -C- or Q is only - H- when Q, taken together with R 4 , aromatic ring B and R 3 form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, d-C 6 alkyl, -0-halogen-substitutedCi-C 6 alkyl, halogen- sub stitutedCi- C 6 alkyl or taken together with aromatic ring B, R 4 and Q form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, Ci-C 6 alkyl.
  • R 3 is hydrogen or -OCi-C 6 alkyl.
  • R 3 is -OCi-C 6 alkyl.
  • R 3 is -0-halogen-substitutedCi-C 6 alkyl or halogen-substitutedCi-C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is a halogen selected from the group consisting of chlorine or fluorine.
  • R 4 is hydrogen, oxo, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl or together with aromatic ring B, R 3 and Q form a heteroaryl or taken together with R 5 form a C3-C 6 cycloalkyl.
  • R 4 is an oxo group.
  • R 4 is hydrogen.
  • R 4 is halogen- substitutedCi-C 6 alkyl or Ci-C 6 alkyl.
  • R 4 , taken together with aromatic ring B, R 3 and Q form a heteroaryl such as the following:
  • R and R 6 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 - C 6 cycloalkyl, halogen-substitutedCi-C 6 alkyl, halogen-substitutedC 3 -C 6 cycloalkyl, Ci-C 6 alkylC 3 - C 6 cycloalkyl, or R 5 and R 6 taken together form a C 3 -C 6 cycloalkyl.
  • R 5 and R 6 are both Ci-C 6 alkyl.
  • R 5 and R 6 are both methyl.
  • R 5 is hydrogen and R 6 is cyclopropyl.
  • R 5 and R 6 together form cyclopropyl or cyclobutyl.
  • R 5 and R 6 are independently selected from the group consisting of halogen-substitutedCi-C 6 alkyl and halogen- sub stitutedC 3 - C 6 cycloalkyl.
  • R 1 is a halogen or halogen- sub stitutedCi- C 6 alkyl; - H-or -C-;
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, d-C 6 alkyl, O-halogen- substitutedCi-C 6 alkyl, halogen-substitutedCi-C 6 alkyl, cyano, S0 2 Ci-C 6 alkyl or taken together with aromatic ring B, Q and R 4 form a heteroaryl;
  • R 4 is hydrogen, oxo, Ci-C 6 alkyl, halogen substitutedCi-C 6 alkyl or together with aromatic ring B, R 3 and Q form a heteroaryl, or taken together with R 5 form a C 3 -C 6 cycloalkyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, halogen-substitutedCi
  • R 1 is selected from the group consisting of halogen and halogen-substitutedCi-C 6 alkyl.
  • R 1 is halogen, wherein the halogen is selected from fluorine or chlorine.
  • R 1 is fluorine.
  • R 1 is halogen-substitutedCi-C 6 alkyl, wherein the halogen-substitutedCi-C 6 alkyl is selected from the group consisting of fluoromethyl, difluoromethyl and trifluoromethyl.
  • Q is selected from the group consisting of-O-, - H-, and -C-.
  • Q is - O- or -C-.
  • Q is -0-.
  • Q is -C-.
  • Q is - H-.
  • Q is -O- or -C- or Q is only - H- when Q, taken together with R 4 , aromatic ring B and R 3 form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, Ci-C 6 alkyl, -0-halogen-substitutedCi-C 6 alkyl, halogen- sub stitutedCi- C 6 alkyl or taken together with aromatic ring B, R 4 and Q form a heteroaryl.
  • R 3 is a halogen, hydrogen, -OCi-C 6 alkyl, Ci-C 6 alkyl.
  • R 3 is hydrogen or -OCi-C 6 alkyl.
  • R 3 is -OCi-C 6 alkyl.
  • R 3 is -0-halogen-substitutedCi-C 6 alkyl or halogen-substitutedCi-C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is a halogen selected from the group consisting of chlorine or fluorine.
  • R 4 is hydrogen, oxo, halogen- substitutedCi-C 6 alkyl, Ci-C 6 alkyl or together with aromatic ring B, R 3 and Q form a heteroaryl or taken together with R 5 form a C 3 -C 6 cycloalkyl.
  • R 4 is an oxo group.
  • R 4 is hydrogen. In other embodiments, R 4 is halogen-substitutedCi-C 6 alkyl or Ci-C 6 alkyl. In still other embodiments R 4 , taken together with aromatic ring B, R 3 and Q form a heteroaryl such as the following:
  • R and R 6 are each independently selected from the group consisting of hydrogen, d-C 6 alkyl, C 3 - C 6 cycloalkyl, halogen-substitutedCi-C 6 alkyl, halogen-substitutedC 3 -C 6 cycloalkyl, Ci-C 6 alkylC 3 - C 6 cycloalkyl, or taken together form a C 3 -C 6 cycloalkyl.
  • R 5 and R 6 are both Ci-C 6 alkyl.
  • R 5 and R 6 are both methyl.
  • R 5 is hydrogen and R 6 is cyclopropyl.
  • R 5 and R 6 together form cyclopropyl or cyclobutyl.
  • R 5 and R 6 are independently selected from the group consisting of halogen-substitutedCi-C 6 alkyl and halogen-substitutedC 3 -C 6 cycloalkyl.
  • Ci-C 6 alkyl, C 3 - C 6 cycloalkyl, -OCi-C 6 alkyl, Ci-C 6 alkylC 3 -C 6 cycloalkyl can further be substituted with one or more halogens.
  • Non-limiting examples of the compounds encompassed by the present invention include the examples shown in Table 1 :
  • the compounds described herein are:
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 3 -C6cycloalkyl encompasses cycloalkyls having 3 to 6 carbons, forming one or more carbocyclic rings that are fused.
  • Cycloalkyl also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • -OCl-C 6 alkyl refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group.
  • Ci-C 6 alkyr encompasses straight alkyl having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1 -dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl,
  • halogen-substitutedCi-C 6 alkyl encompasses Ci-C 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difiuoromethyl, trifiuoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • Ci-C 6 alkyl-OH encompasses Ci-C 6 alkyl with one or more of the hydrogen atoms thereof being substituted with -OH, also known as an alcohol group, examples thereof including methanol, ethanol, propanol and butanol.
  • Heteroaryl unless otherwise specified, means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls also include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic.
  • heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, 2-oxo-(lH)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl
  • Ring and ring systems containing from 3-15 atoms are included, forming 1-3 rings.
  • S0 2 Ci-C6alkyl means a group in which a Ci-C 6 alkyl group is attached to a sulfonyl (-S0 2 -) group. Specific examples thereof include methanesulfonyl, ethanesulfonyl, n- propylsulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl and tert-butanesulfonyl groups and the like.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
  • the compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of these compounds.
  • Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • alcohol compounds can be converted to the esters of phosphate, amino acid, acetic acid, etc, which can be used as pro-drugs to improve
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds described herein.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Also encompassed by the present invention are methods of treating MCH-related deseases.
  • MCH-related diseases such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis,
  • central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis.
  • the compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
  • One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I, formula la or formula lb.
  • Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of treatment may be preventing body weight, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • arteriosclerosis such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
  • Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
  • Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
  • the present invention is also directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating various MCH- related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromato
  • the present invention is directed to the use of a compound of structural formula I, formula la or formula lb in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
  • compositions are directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating obesity.
  • Compounds of the invention may be administered orally or parenterally.
  • the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
  • the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered.
  • pharmaceutically acceptable it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • additives various additives ordinarily used in the field of pharmaceutical preparations are usable.
  • gelatin lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, poly oxy ethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.
  • Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations.
  • the liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use.
  • the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.
  • compositions may contain the compound of the invention in an
  • compositions may further contain any other therapeutically-effective compounds.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect.
  • the dose when orally administered, may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times.
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day.
  • the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of the formulas described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I, la or lb.
  • a compound of formula I, la or lb is used
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I, la or lb is preferred.
  • the combination therapy may also include therapies in which the compound of formula I, la or lb and one or more other drugs are administered on different overlapping schedules.
  • the compounds described herein and the other active ingredients may be used in lower doses than when each is used singly Accordingly, the pharmaceutical compositions described herein include those that contain one or more other active ingredients, in addition to a compound of formula I, la or lb.
  • Examples of other active ingredients that may be administered in combination with a compound of formula I, la or lb, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • (2) insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/ ⁇ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4)
  • insulin or insulin analogs such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
  • amylin and amylin analogs such as pramlintide
  • sulfonylurea and non- sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose, voglibose and might ol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • incretin mimetics such as GLP- 1 , GLP- 1 analogs, derivatives, and mimetics
  • GLP- 1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl Co A: cholesterol acyltransferase inhibitors, such as avasimibe;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof
  • MK-524A which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists
  • antiobesity compounds (13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • Patent No. 6,730,690 WO 03/104207; and WO 04/058741;
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS);
  • GPR-105 antagonists such as those disclosed in WO 2009/000087;
  • inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1 , SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR.
  • Dipeptidyl peptidase-IV (DPP -4) inhibitors that can be used in combination with compounds of formula I, la or lb include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
  • Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, la or lb include, but are not limited to:
  • Antiobesity compounds that can be combined with compounds of formula I, la or lb include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and
  • melanocortin receptor agonists in particular, melanocortin-4 receptor agonists
  • CCK-1 agonists melanin- concentrating hormone (MCH) receptor antagonists
  • neuropeptide Yi or Y5 antagonists such as MK- 0557
  • CB l receptor inverse agonists and antagonists such as rimonabant and taranabant
  • ⁇ 3 adrenergic receptor agonists ghrelin antagonists
  • bombesin receptor agonists such as bombesin receptor subtype-3 agonists
  • 5-hydroxytryptamine-2c (5-HT2c) agonists such as lorcaserin.
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Glucokinase activators that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Selective PPARy modulators that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I, la or lb include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 include, but are not limited to:
  • a pharmaceutical composition which comprises one or more of the following agents: (a) a compound of structural formula I, formula la or formula lb;
  • DPP-4 dipeptidyl peptidase-IV
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ dual agonists such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARyM's selective PPARy modulators
  • PPARy partial agonists include (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and
  • GlucophageXR® (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
  • lovastatin simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • bile acid sequestering agents such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran
  • inhibitors of cholesterol absorption such as ezetimibe
  • acyl CoA cholesterol acyltransferase inhibitors, such as avasimibe
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof; MK-524 A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMP-activated Protein Kinase activators (16) AMP-activated Protein Kinase (AMPK) activators; (17) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-40;
  • neuromedin U receptor agonists including, but not limited to, neuromedin S (NMS);
  • (22) inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Step A 4-(4-Fluorobenzyloxy)pyridin-l -oxide
  • Step B 4-(4-Fl robenzyloxy)pyridin-2(lH)-one
  • Step A 2-Bromo-l-cyclopropyl-ethanone > ⁇ * ⁇
  • Step B 2-(4-Bromophenoxy)-l-cyclopropylethanone
  • Step B l-[4-(2-Cyclopropyl-2-hydroxyethoxy)phenyl]-4-[4-fluorobenzyl)oxy]pyridin-2(lH)-one
  • the title compound was further separated into its two enantiomers by preparative HPLC eluting on a Berger MultiGramTM SFC AD column (250x20mm) eluting with 60% IPA in carbon dioxide.
  • the retention time of enantiomer 1 is 5.49 min, and the retention time of enantiomer 2 is 6.63 min.
  • Step A Methyl (4- ⁇ 4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl ⁇ -2- ethylphenoxy)acetate
  • Step B 4-(4-Fluorobenzyloxy)- 1 - ⁇ 4- [( 1 -hydroxy cyclopropyl)methoxy] -3 -methylphenyl ⁇ pyridin- 2(lH -one
  • yridin-2(lH)-one 29 4-[(4- 412 fluorobenzyl)oxy] - 1 - ⁇ 4-[(l- hydroxycyclopropyl) Vrr- methoxy]-3- methoxyphenyl ⁇
  • a cDNA sequence encoding human MCH-1R [FEBS Letters, Vol. 398, 253 (1996); Biochimica et Biophisica Acta, Vol. 1401, 216 (1998)] was cloned to a plasmid vector pEF/myc/cyto (manufactured by Invitrogen).
  • the obtained expression vector was transfected to a host cell CHO-K1 (American Type Culture Collection) using Lipofectamine Plus reagent (manufactured by Life Technology) to provide MCH-1R expression cells.
  • Membrane samples prepared from the MCH-1R expression cells were incubated with a test compound and 50 pM [ 125 I]MCH (manufactured by EN) in an assay buffer (50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetate, 0.01% bacitracin, and 0.2% bovine serum albumin; pH 7.4) at 25°C for one hour, followed by filtration through a glass filter GF/C (manufactured by Wattman).
  • an assay buffer 50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetate, 0.01% bacitracin, and 0.2% bovine serum albumin; pH 7.4
  • the glass filter was washed with 50 mM Tris buffer (pH 7.4) containing 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetate, and 0.04% Tween-20, and then the radioactivity on the glass filter was determined.
  • Non-specific binding was measured in the presence of 1 ⁇ human MCH, and, with respect to each test compound, 50% inhibition concentration (IC 5 o value) for specific [ 125 I]MCH binding was determined.
  • Examples 1-31 had an IC 5 o value of less that 500 nM. Specific IC 5 o values are shown in Table 3 :

Landscapes

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

Abstract

La présente invention divulgue des composés dérivés de phénylpyridone. Le composé agit comme un antagoniste du récepteur hormonal concentrant la mélanine, et peut être utilisé dans la prévention, le traitement ou l'action comme agent réparateur pour diverses maladies du système circulaire, des maladies du système nerveux, des maladies métaboliques, des maladies génitales, des maladies respiratoires et des maladies digestives.
PCT/CN2010/071699 2010-04-12 2010-04-12 Dérivés de pyridone WO2011127643A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/CN2010/071699 WO2011127643A1 (fr) 2010-04-12 2010-04-12 Dérivés de pyridone
PCT/US2011/031518 WO2011130086A1 (fr) 2010-04-12 2011-04-07 Dérivés de pyridone
US13/578,653 US20120316200A1 (en) 2010-04-12 2011-04-07 Pyridone derivatives
EP11769326.7A EP2558094A4 (fr) 2010-04-12 2011-04-07 Dérivés de pyridone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2010/071699 WO2011127643A1 (fr) 2010-04-12 2010-04-12 Dérivés de pyridone

Publications (1)

Publication Number Publication Date
WO2011127643A1 true WO2011127643A1 (fr) 2011-10-20

Family

ID=44798252

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/071699 WO2011127643A1 (fr) 2010-04-12 2010-04-12 Dérivés de pyridone

Country Status (1)

Country Link
WO (1) WO2011127643A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013105676A1 (fr) 2012-01-12 2013-07-18 Takeda Pharmaceutical Company Limited Dérivés de benzimidazole comme antagonistes du récepteur mch
WO2013168759A1 (fr) 2012-05-10 2013-11-14 武田薬品工業株式会社 Composé cyclique aromatique
WO2013168760A1 (fr) 2012-05-10 2013-11-14 武田薬品工業株式会社 Composé cyclique aromatique
WO2015005489A1 (fr) 2013-07-09 2015-01-15 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole
WO2023242810A1 (fr) 2022-06-17 2023-12-21 Richter Gedeon Nyrt. Antagonistes de mchr1 pour le traitement du syndrome de prader-willi

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085200A1 (fr) * 2004-03-05 2005-09-15 Banyu Pharmaceutical Co., Ltd. Dérivé pyridone
WO2007142217A1 (fr) * 2006-06-07 2007-12-13 Banyu Pharmaceutical Co., Ltd. Dérivé de 1-phénylpyridone
WO2007141200A1 (fr) * 2006-06-02 2007-12-13 Janssen Pharmaceutica N.V. Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085200A1 (fr) * 2004-03-05 2005-09-15 Banyu Pharmaceutical Co., Ltd. Dérivé pyridone
WO2007141200A1 (fr) * 2006-06-02 2007-12-13 Janssen Pharmaceutica N.V. Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1
WO2007142217A1 (fr) * 2006-06-07 2007-12-13 Banyu Pharmaceutical Co., Ltd. Dérivé de 1-phénylpyridone

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013105676A1 (fr) 2012-01-12 2013-07-18 Takeda Pharmaceutical Company Limited Dérivés de benzimidazole comme antagonistes du récepteur mch
US9365540B2 (en) 2012-01-12 2016-06-14 Takeda Pharmaceutical Company Limited Benzimidazole derivatives as MCH receptor antagonists
US9440987B2 (en) 2012-05-10 2016-09-13 Takeda Pharmaceutical Company Limited Aromatic ring compound
WO2013168759A1 (fr) 2012-05-10 2013-11-14 武田薬品工業株式会社 Composé cyclique aromatique
WO2013168760A1 (fr) 2012-05-10 2013-11-14 武田薬品工業株式会社 Composé cyclique aromatique
US9505772B2 (en) 2012-05-10 2016-11-29 Takeda Pharmaceutical Company Limited Aromatic ring compound
WO2015005489A1 (fr) 2013-07-09 2015-01-15 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US9199963B2 (en) 2013-07-09 2015-12-01 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole
CN107466294A (zh) * 2015-04-15 2017-12-12 吉瑞工厂 吲哚衍生物
US10329296B2 (en) 2015-04-15 2019-06-25 Richter Gedeon Nyrt. Indole derivatives
EA034427B1 (ru) * 2015-04-15 2020-02-06 Рихтер Гедеон Нирт. Производные индола
WO2023242810A1 (fr) 2022-06-17 2023-12-21 Richter Gedeon Nyrt. Antagonistes de mchr1 pour le traitement du syndrome de prader-willi

Similar Documents

Publication Publication Date Title
US10662171B2 (en) Antidiabetic bicyclic compounds
AU2011256444B2 (en) Spiro isoxazoline compounds as SSTR5 antagonists
EP3177287B1 (fr) Composés bicycliques antidiabétiques
US8742110B2 (en) Spiroxazolidinone compounds
US20120316200A1 (en) Pyridone derivatives
CN111683951B (zh) 用作饥饿素o-酰基转移酶(goat)抑制剂的三唑并嘧啶衍生物
US9834563B2 (en) Antidiabetic substituted heteroaryl compounds
WO2013096093A1 (fr) Composés en tant qu'inhibiteurs de dgat-1
EP2464228B1 (fr) Composés cyclopropyle substitués, compositions contenant de tels composés et procédés de traitement
AU2009304508A1 (en) Azetidine derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
WO2011127643A1 (fr) Dérivés de pyridone
JP2013531037A (ja) スピロ環式化合物
WO2012024179A1 (fr) Dérivés d'amide substitués en tant qu'inhibiteurs de dgat-1
AU2009299091A1 (en) Heteroaromatic compounds as inhibitors of stearoyl-coenzyme A delta-9 desaturase
US10065945B2 (en) Isoquinoline derivatives as MGAT2 inhibitors
WO2012044567A2 (fr) Dérivés d'imidazole
EP2760855B1 (fr) Composés de cyclopropyle substitués, compositions contenant ces composés ainsi que leur utilisation pour le traitement du diabète de type 2
EP3383388B1 (fr) Utilisation d'arylacylsulfonamides en tant qu'antagonistes de blt1
WO2012015693A1 (fr) Dérivés d'imidazole
WO2012064569A1 (fr) Dérivés d'imidazole
WO2011037771A1 (fr) Dérivé de diarylméthylamide présentant une activité d'antagoniste des récepteurs de l'hormone de mélano-concentration
WO2012096813A1 (fr) Dérivés d'imidazole
WO2012047772A2 (fr) Dérivés d'imidazole
WO2012112364A1 (fr) Dérivés de lactame en tant qu'inhibiteurs de dgat-1
WO2013068328A1 (fr) Composés d'acide bicyclo[2.2.2]octan-1-ylcarboxylique comme inhibiteurs de la dgat-1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10849653

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10849653

Country of ref document: EP

Kind code of ref document: A1