WO2008112674A1 - Composés et compositions comme inhibiteurs de l'activité du récepteur cannabinoïde 1 - Google Patents

Composés et compositions comme inhibiteurs de l'activité du récepteur cannabinoïde 1 Download PDF

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WO2008112674A1
WO2008112674A1 PCT/US2008/056484 US2008056484W WO2008112674A1 WO 2008112674 A1 WO2008112674 A1 WO 2008112674A1 US 2008056484 W US2008056484 W US 2008056484W WO 2008112674 A1 WO2008112674 A1 WO 2008112674A1
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phenyl
thiazolidin
trifluoromethyl
phenoxy
chloro
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PCT/US2008/056484
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English (en)
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Ha-Soon Choi
Zhicheng Wang
Xuefeng Zhu
Xiaohui He
Kunyong Yang
Hong Liu
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Irm Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/16—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CBl).
  • CBD Cannabinoid Receptor 1
  • the cannabinoids are psychoactive ingredients of marijuana, principally delta-9-tetrahydrocannabinol.
  • Two cannabinoid receptors have been cloned, CBl and CB2.
  • CBl is predominantly expressed in the central nervous system whereas CB2 is expressed in peripheral tissues, principally in the immune system. Both receptors are members of the G-protein coupled class and their inhibition is linked to adenylate cyclase activity.
  • novel compounds of this invention inhibit the activity of CBl and are, therefore, expected to be useful in the treatment of CBl-associated diseases or disorders such as, but not limited to, psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, substance abuse (such as smoking cessation), stress, epilepsy, Parkinson's disease, schizophrenia, osteoporosis, constipation, chronic intestinal pseudoobstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake.
  • CBl-associated diseases or disorders such as, but not limited to, psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, substance abuse (such as smoking cessation), stress, epilepsy, Parkinson's disease, schizophrenia, osteoporosis, constipation, chronic intestinal pseudoobstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake.
  • the present invention provides a compound of Formula I:
  • Y 1 is selected from N and CR n ;
  • Y 2 is selected from N and CR 8 ;
  • Y 3 is selected from N and CR 6 ; wherein R 6 is selected from hydrogen, halo, nitro, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo-substituted-Ci_ 6 alkyl, halo-substituted-Ci_ 6 alkoxy,
  • R] 6 is selected from Ci_6alkyl, C ⁇ -ioaryl, C 1- l oheteroaryl, C 3 _iocycloalkyl and C 3 _ 8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R] 6 is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_ 6 alkyl;
  • Z 1 is selected from S, S(O), SCH 2 , S(O)CH 2 , CH 2 S(O), CH 2 S and NR 2 ; wherein R 2 is selected from hydrogen, -C(O)X 2 Ri 8 , -C(O)OX 2 Ri 8 , -S(OV 2 X 2 Ri 8 , ; wherein X 2 is selected from a bond and Ci ⁇ alkylene; Ri 8 is independently selected from hydrogen, Ci_ 6 alkyl, Ci_ioheteroaryl and C 3 _ 8 heterocycloalkyl; wherein said heteroaryl or heterocycloalkyl of Ri 8 is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_ 6 alkyl;
  • Z 2 is selected from O, NH, N(OH), N(CN) and S;
  • Ri is selected from hydrogen, C 1-6 alkyl, -XiC(O)NRi 7a Ri 7b , -
  • R 17a and R 17 b are independently selected from hydrogen, Ci_ 6 alkyl, C 3 _i 2 cycloalkyl and C 3 _ sheterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl of R 17a or R 17b can be optionally substituted with 1 to 3 radicals independently selected from halo, C]_ 6 alkyl, C 1- ⁇ alkoxy, halo-substituted-Ci_ 6 alkyl and halo-substituted-Ci_ 6 alkoxy; [0013] R 3 , R 5 , and R 7 are selected from hydrogen, halo, hydroxy, nitro, Ci_ 6 alkyl,
  • R 4 is selected from halo, nitro, cyano, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo- substituted- Ci _6alkyl, halo-substituted-Ci_6alkoxy, -Ri3a, -NRi3 a Ri3b, -OX 4 OC(O)R 133 , - 4 OC(O)R 13a , -C(O)Ri 38 , -C(O)ORi 38 , -OX 4 OR 133 , -OX 4 R 133 , -X 4 NR 133 C(O)R 133 , - X 4 NRi 3a S(0)o-2Ri3 3 , -OR] 33 , ; wherein X 4 is selected from a bond and Ci ⁇ alkylene; R] 33 and R] 3b are independently selected from hydrogen, Ci_ 6 alkyl, C 6-10 aryl, Ci_ioheteroary
  • Rg, R 9 , Rn and R 12 are independently selected from hydrogen, halo, hydroxyl, cyano, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo-substituted-Ci_ 6 alkyl, halo-substituted-Ci_ ⁇ alkoxy, -S(O) 0-2 R 1S , -OR 15 and -R 15 ; wherein R 15 is selected from hydrogen, Ci_ 6 alkyl, halo-substituted-Ci_ 6 alkyl and C 6 -i 0 aryl; wherein said aryl of R 15 is optionally substituted with 1 to 3 radicals independently selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo- substituted- Ci _ 6 alkyl and halo-substituted-Ci_ 6 alkoxy; or Rn and R ]2 together with he carbon atoms to which Rn and R 12 are attached form
  • R] 0 is selected from halo, cyano, hydroxy, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo- substituted- Ci - 6 alkyl, halo-substituted-Ci_ 6 alkoxy, -X 3 ORi 9 , -X 3 S(O) 0 -2Ri 9 , -X 3 NR 20 Ri 9 and -X 3 Ri 9 ; wherein X 3 is selected from a bond and Ci ⁇ alkylene; R 20 is selected from hydrogen and C ⁇ alkyl; and R] 9 is selected from C 6 -i 0 aryl and Ci_i 0 heteroaryl; wherein Rj 9 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, amino, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo-substituted-Ci_ 6 alkyl and halo- substituted- Ci _ 6 alkoxy;
  • Ri 3 is selected from hydrogen and Ci_ 6 alkyl; and the pharmaceutically acceptable salts, hydrates, solvates and isomers thereof.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which modulation of CB 1 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched.
  • Ci_ 6 alkoxy includes, methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl can be phenyl or naphthyl, preferably phenyl.
  • “Arylene” means a divalent radical derived from an aryl group.
  • C]_ioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, lH-pyridin-2-onyl, 6-oxo-l,6-dihydro-pyridin-3-yl, etc.
  • C ⁇ -ioarylCo ⁇ alkyl means an aryl as described above connected via a alkylene grouping.
  • C ⁇ -ioarylCo ⁇ alkyl includes phenethyl, benzyl, etc.
  • Heteroaryl also includes the N-oxide derivatives, for example, pyridine-N-oxide derivatives with the following structure:
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3 _iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3 _ 8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo- pyrrolidin-1-yl, 2-oxo-piperidin-l-yl, etc.
  • Halogen (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the present invention provides compounds, compositions and methods for the treatment of diseases in which inhibition of CB 1 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.
  • Y] is selected from N and CRn; Y 2 is selected from N and CRs; or Rn and R] 2 together with the carbon atoms to which Rn and R] 2 are attached form a phenyl ring optionally substituted with 1 to 3 halo radicals.
  • Y 3 is selected from N and CR 6 ; wherein R 6 is selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro- methoxy, benzyl-oxy, phenyl-sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl- sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo.
  • Z 1 is selected from S, S(O), SCH 2 , S(O)CH 2 ,
  • R 2 is selected from hydrogen, acetyl, methyl-sulfonyl, ethoxy-carbonyl, 4-methyl-piperazinyl, methyl-carbonyl and morpholino-methyl- carbonyl;
  • Z 2 is selected from O and S;
  • R 8 , R n and R ]2 are independently selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.
  • R 9 is selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.
  • Ri is selected from hydrogen, methyl, ethyl, propyl-amino-carbonyl-methyl, butyl-amino-carbonyl-methyl, trifluoroethyl-amino- carbonyl-methyl, cyclopropyl-amino-carbonyl-methyl, 2,6-dimethyl-morpholino- carbonyl-methyl, pyrrolidinyl-carbonyl-methyl and morpholino-ethyl-amino-carbonyl- methyl.
  • R 3 , R 5 and R 7 are selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro-methoxy, benzyl-oxy, phenyl- sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl- sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo.
  • R 4 is selected from amino, methyl-carboxy- ethoxy, methyl-carbonyl-amino, trifluoro-methyl, hydroxy-ethoxy, methyl-sulfonyl- amino, benzyl-oxy, cyclopropyl, morpholino, phenoxy, phenyl, phenyl-carbonyl, phenyl- amino, isoxazolyl-methoxy, oxazolyl-methoxy, methoxy-carbonyl, trifluoro-methoxy, nitro, cyano, ethoxy, acetate, hydroxy, methyl, halo, pyrrolyl and methoxy; or R 4 and R 5 together with the carbon atoms to which R 4 and R 5 are attached form a ring selected from 1,3-dioxolane and pyrrole; wherein said benzyl, phenyl, oxazolyl or isoxazolyl of R
  • Rio is selected from hydroxy, methyl, methyl- sulfanyl, trifluoromethyl-sulfanyl, isopropyl, trifluoromethyl, methoxy, phenyl, phenyl- amino, phenyl-sulfanyl, phenyl-sulfinyl, phenyl-sulfonyl, pyridinyl-oxy, halo, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy; wherein said phenyl, phenyl-sulfonyl, phenyl- amino, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy can be optionally substituted with 1 to 3 radicals independently selected from ethyl, nitro, trifluoromethoxy, methoxy, halo, amino and hydroxyl.
  • compounds of Formula I are selected from: 3-(4-Methoxy-
  • the compounds of Formula (I), pharmaceutically acceptable salts, solvates, N- oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein also includes all suitable isotopic variations of such compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 36 Cl and 123 I.
  • Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • isotopic variations of the compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein are prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • Another embodiment provides for a method of treating a disease mediated by the Cannabinoid- 1 receptor (for example, an eating disorder associated with excessive food intake like obesity, bulimia nervosa, and compulsive eating disorders) comprising administration of to a patient in need of such treatment of a therapeutically effective amount of a compound selected from the Summary of the Invention (supra).
  • a disease mediated by the Cannabinoid- 1 receptor for example, an eating disorder associated with excessive food intake like obesity, bulimia nervosa, and compulsive eating disorders
  • Another embodiment provides for a method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound selected from the Summary of the Invention (supra).
  • Further compounds of the invention are detailed in the Examples and Table
  • Compounds of the invention inhibit the activity of CB 1 and, as such, are useful for treating diseases or disorders in which the activity of CB 1 contributes to the pathology and/or symptomology of the disease.
  • This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which CB 1 activity contributes to the pathology and/or symptomology of the disease.
  • CB 1 mediated diseases or conditions include, but are not limited to, metabolic disorders as well as conditions associated with metabolic disorders including obesity, bulimia nervosa, compulsive eating disorders, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, osteoporosis, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, and hyperlipidemic conditions; or psychiatric disorders such as substance abuse, psychosis, depression, anxiety, stress, epilepsy, mania and schizophrenia; or cognitive disorders such as dementia including Alzheimer's disease, memory deficits, short term memory loss and attention deficit disorders; or neurodegenerative disorders such as Parkinson's Disease, cerebral apoplexy and craniocerebral trauma, hypotension, catabolism in connection with pulmonary dysfunction and ventilator dependency; or cardiac dysfunction including valvular disease, myocardial infarction, cardiac hypertrophy and congestive heart failure); or the
  • T-cell mediated hypersensitivity disease T-cell mediated hypersensitivity disease
  • psoriasis asthma
  • Hashimoto's thyroiditis Guillain-Barre syndrome
  • cancer contact dermatitis
  • allergic rhinitis ischemic or reperfusion injury
  • head trauma and movement disorders The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine including smoking cessation.
  • the compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith, including left ventricular hypertrophy.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, osteopororsis, and cirrhosis of the liver.
  • Marijuana and its derivatives have been used for centuries for medicinal and recreational purposes.
  • a major active ingredient in marijuana and hashish has been determined to be ⁇ 9-Tetrahydrocannabinol ( ⁇ 9-THC).
  • ⁇ 9-THC ⁇ 9-Tetrahydrocannabinol
  • the biological action of ⁇ 9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CBl and CB2.
  • the CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
  • the CB2 receptor is found primarily in lymphoid tissues and cells.
  • mice The genes for the respective cannabinoid receptors have each been disrupted in mice.
  • the CB 1 receptor knockout mice appeared normal and fertile. They were resistant to the effects of ⁇ 9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia.
  • the CB2 receptor knockout mice were also healthy and fertile. They were not resistant to the central nervous system mediated effects of administered ⁇ 9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions.
  • Excessive exposure to ⁇ 9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation.
  • CB 1 receptor modulators such as CB 1 inverse agonists
  • CB 1 inverse agonists presynaptic cannabinoid CBl receptors mediate the inhibition of noradrenalin release.
  • CB 1 receptor modulators Treatment of cirrhosis of the liver with CB 1 receptor modulators is supported by the finding that a CB 1 receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure.
  • the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations can also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • therapeutic agents such as, psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders such as smoking cessation, osteoporosis, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake, obesity, etc. (see “Pharmacology and Utility", supra).
  • a combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3)
  • GI-262570 Diacylglycerol acetyltransferase (DGAT) inhibitors such as those disclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO 2004047755; ypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pravastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat.
  • DGAT Diacylglycerol acetyltransferase
  • phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent such as melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators,
  • a thyroid receptor beta modulator such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or
  • ECE inhibitors e.g. SLV306
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
  • angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
  • renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
  • beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
  • inotropic agents such as digoxin, dobutamine and milrinone
  • calcium channel blockers such as digoxin, dobutamine and milrinone
  • Cholesterol absorption modulator such as ZETIA® and KT6-971
  • h) thrombin inhibitors such as Ximelagatran
  • i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone
  • j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate
  • a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4- methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2- pyrimidine- amine ⁇ ) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)
  • tegaserod hydrogen maleate cisapride, cilansetron
  • an agent for treating tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename ZYB AN®) and nicotine replacement therapies
  • an agent for treating erectile dysfunction e.g., dopaminergic agents, such as apomorphine
  • ADD/ ADHD agents e.g., RITALIN®, STRATTERA®, CONCERTA® and ADDERALL®
  • an agent for treating alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename REVIA®) and nalmefene), disulfiram (also known under the tradename ANTABUSE®), and acamprosate (also known under the tradename CAMPRA1®)).
  • opioid antagonists e.g., naltrexone (also known under the tradename REVIA®) and nalmefene
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NEURONTIN®); q) other agents that are useful including anti-inflammatory agents (e.g., COX-2 inhibitors) ; antidepressants (e.g., fluoxetine hydrochloride (PROZAC®)); cognitive improvement agents (e.g., donepezil hydrochloride (ARICEPT®) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (GEODON®), risperidone (RISPERDAL®), and olanzapine (ZYPREXA®)); or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.
  • anti-inflammatory agents e.g., COX-2 inhibitors
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combinations e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co- administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non- fixed combination means that the active ingredients, e.g.
  • a compound of Formula I and a co-agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable acid e.g., hydrochloric acid, etc.
  • Compounds of the invention in unoxidized form can be prepared from ⁇ - oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., lj-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Hydrates of compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of Formula I can be made by a process, which involves:
  • reaction scheme 1 and 2 (a) that of reaction scheme 1 and 2; and (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;
  • Step A To a solution of N-Boc glycine (175 mg, 1.0 mmol) in anhydrous
  • Step B ⁇ [4-(4-Chloro-phenoxy)-phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester from above is treated with TFA (1.5 ml) in CH 2 Cl 2 (6 mL) at room temperature for 30 min and then concentrated.
  • Step C To a solution of 2-amino-N-[4-(4-chloro-phenoxy)-phenyl]- acetamide (100 mg, 0.36 mmol) in anhydrous EtOH (1 mL) is added 3-trifluoromethyl- benzaldehyde (76 mg, 0.43 mmol). The resultant solution is stirred at room temperature for 14 h and concentrated to provide the crude N-[4-(4-chloro-phenoxy)-phenyl]-2-[(3- trifluoromethyl-benzylidene)-amino]-acetamide.
  • Homogenized membranes are prepared from CHO cell clones stably expressing a human cannabinoid receptor 1 (CBl) or human cannabinoid receptor 2 (CB2). Cells are grown and scrapped from 15cm tissue culture plates, and then subsequently centrifuged down. Cells are washed once with cold PBS, and resuspended in ⁇ 20 ml of Buffer A (20 mM HEPES, pH 7.4, 10 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/25 ml]). The cell suspension is homogenized on ice, using a Polytron homogenizer at 25000 rpm at three intervals of 15 seconds each.
  • CBDl cannabinoid receptor 1
  • CB2 human cannabinoid receptor 2
  • the homogenate is first centrifuged at 2000 rpm on a tabletop low speed centrifuge for 10 minutes.
  • the supernatant after passing through a cell strainer, is then centrifuged at 50,000 x g for 25 minutes at 4 0 C.
  • the pellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4, 0.1 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/10 ml]).
  • Protein concentration of the prep is determined using the BCA Protein Assay kit using BSA as standard.
  • the membranes are aliquoted and kept frozen at - 8O 0 C.
  • [ 3 H]-CP55940 ligand binding assay Solutions of test compounds ranging from 100 ⁇ M to 0.01 nM are prepared in DMSO. The desired amount of membrane prep is diluted with ice-cold assay buffer (5OmM Tris-HCl, 2.5mM EDTA, 5 mM MgCl 2 , 0.05% BSA, pH 7.4) and vortexed well. 2 Dl or less of compound is distributed into each well of a round-bottom 96- well polystyrene assay plate, followed by addition of 100 Dl of diluted membranes (3-10 Dg/well) and the mixture is kept on ice until the addition of hot CP55940 (final concentration of 0.5nM).
  • ice-cold assay buffer 5OmM Tris-HCl, 2.5mM EDTA, 5 mM MgCl 2 , 0.05% BSA, pH 7.4
  • 2 Dl or less of compound is distributed into each well of a round-bottom 96- well polysty
  • [ 3 H]-CP55940 is diluted 1:6300 (v/v) with cold assay buffer and 100 Dl is added into each well. The reaction is carried out at room temperature for 120 minutes before the membranes are harvested onto a PerkinElmer Unifilter GF/B-96 filter plate using a Packard Filtermate Harvester. After nine washes with wash buffer (5OmM Tris-HCl, 2.5mM EDTA, 5 mM MgCl 2 , 0.05% BSA, pH 7), the filter is dried in a 37°C oven for 30 minutes. MicroScint- 20 is added and the plate sealed for scintillation counting on TopCount. EC 50 values are obtained by fitting the data with the sigmoidal dose response curve-fitting tool of GraphPad Prism. Eight or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration).
  • GTPDS binding assay Solutions of test compounds ranging from 100 ⁇ M to 0.01 nM are prepared in DMSO. The desired amount of membrane prep is diluted with ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 0.1% Fatty acid- free BSA, 5 DM GDP) and vortexed well. 2 Dl or less of compound is distributed into each well of a round-bottom 96- well polystyrene assay plate, followed by addition of 100 Dl of diluted membranes (3-10 Dg/well) and the mixture is kept on ice until the addition of hot GTPDS.
  • ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 0.1% Fatty acid- free BSA, 5 DM GDP
  • [ 35 S]-GTPDS (Perkin Elmer NEG030H; 1 DCi/Dl, 1250 Ci/mmol) is diluted 1:1000 (v/v) with cold assay buffer and 100 Dl is added into each well. The reaction is carried out at room temperature for 90 minutes before the membranes are harvested onto PerkinElmer Unifilter GF/B-96 filter plate using a Packard Filtermate Harvester. After several washes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2) , and a rinse with 95% ethanol, the filter is dried in a 37°C oven for 30 minutes. MicroScint-20 is added and the plate sealed for scintillation counting on TopCount. EC 50 values are obtained by fitting the GTP [D- 3 S] binding data with the sigmoidal dose response curve-fitting tool of GraphPad Prism. Six or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration).
  • mice To evaluate the efficacy of compounds of the invention on inhibition of food intake and body weight gain, genetically obese (Lep ob /Lep ob ) mice and diet-induced obese (DIO) mice are used in acute and sub-chronic models, respectively.
  • Male ob/ob mice (age 7-8 weeks old, Jackson Labs, Bar Harbor, Maine) are housed in groups of four and fed commercial standard pellet diet (Lab Diet 5001, PMI Nutrition International, LLC). Diet-induced obese mice are generated using 6-7 weeks old C57BL6 mice (Jackson Labs, Bar Harbor, Maine) placed on high fat diet (D12331, Research Diets) for 12-17 weeks. All mice are maintained on a 12-hour light/dark cycle (lights on at 06:00) in a humidity- and temperature-controlled environment with free access to food and water.
  • mice are singly housed and a habituation to treatment is performed to establish baseline food consumption and body weight. Animals are randomized into treatment groups based on their initial body weight and food consumption.
  • test compound a compound of the invention
  • DIO mice are treated with either vehicle, a known antagonist as a positive control, or with test compound(s) for up to 7-35 days.
  • Test compounds are dosed at ranges between 0.1 up to 100 mg/kg. Animals are treated one hour prior to the start of the dark cycle. Food intake and body weight are recorded manually using an electronic balance prior to treatment, 16 hours post-treatment, followed by daily measurements for up to 7- 35 days after the start of study. Compound efficacy is determined by comparing food intake and body weight data between vehicle treated, standard positive control treated, and test compound treated mice.
  • Compounds of Formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application.
  • Compound of the invention show a K 1 of between 1x10 " and Ix 10 "10 M, preferably less than 50OnM, more preferably less than 10OnM. Additionally, compounds of the invention show a 10 fold, preferably 20, 50 and 100 fold, selectivity for CBl over CB2.

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiques comprenant de tels composés et des procédés d'utilisation de tels composés pour traiter ou prévenir des maladies ou des troubles associés à l'activité du récepteur cannabinoïde 1 (CB1).
PCT/US2008/056484 2007-03-12 2008-03-11 Composés et compositions comme inhibiteurs de l'activité du récepteur cannabinoïde 1 WO2008112674A1 (fr)

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