[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2005049615A1 - Derives de pyrazolo[1,5-a][1,3,5]triazin-4-one en tant qu'antagonistes des recepteurs cb1 - Google Patents

Derives de pyrazolo[1,5-a][1,3,5]triazin-4-one en tant qu'antagonistes des recepteurs cb1 Download PDF

Info

Publication number
WO2005049615A1
WO2005049615A1 PCT/IB2004/003673 IB2004003673W WO2005049615A1 WO 2005049615 A1 WO2005049615 A1 WO 2005049615A1 IB 2004003673 W IB2004003673 W IB 2004003673W WO 2005049615 A1 WO2005049615 A1 WO 2005049615A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
chlorophenyl
substituents
methyl
Prior art date
Application number
PCT/IB2004/003673
Other languages
English (en)
Inventor
David Andrew Griffith
Original Assignee
Pfizer Products Inc.
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 Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2005049615A1 publication Critical patent/WO2005049615A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one compounds.
  • the invention also relates to the use of such compounds as cannabinoid receptor ligands, in particular CB1 receptor antagonists, and uses thereof for treating diseases, conditions and/or disorders modulated by cannabinoid receptor antagonists.
  • 10 BACKGROUND Obesity is a major public health concern because of its increasing prevalence and associated health risks. Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms 15 divided by height in meters squared (kg/m 2 ).
  • Overweight is typically defined as a BMI of 25-29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 .
  • the increase in obesity is of concern because of the excessive health risks associated with obesity, including coronary heart disease, strokes, hypertension, type 2 diabetes mellitus, dyslipidemia, sleep apnea, osteoarthritis, gall bladder disease, depression, and certain forms of cancer 25 (e.g., endometrial, breast, prostate, and colon).
  • the negative health consequences of obesity make it the second leading cause of preventable death in the United States and impart a significant economic and psychosocial effect on society. See, McGinnis M, Foege WH., "Actual Causes of Death in the United States," JAMA, 270, 2207-12 (1993).
  • 30 Obesity is now recognized as a chronic disease that requires treatment to reduce its associated health risks.
  • weight loss is an important treatment outcome
  • one of the main goals of obesity manag'ement is to improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality. It has been shown that 5-10% loss of body weight can substantially improve metabolic values, such as blood glucose, blood pressure, and lipid concentrations. Hence, it is believed that a 5-10% intentional reduction in body weight may reduce morbidity and mortality.
  • Currently available prescription drugs for managing obesity generally reduce weight by inducing satiety or decreasing dietary fat absorption. Satiety is achieved by increasing synaptic levels of norepinephrine, serotonin, or both.
  • stimulation of serotonin receptor subtypes 1 B, 1 D, and 2C and 1 - and 2-adrenergic receptors decreases food intake by regulating satiety. See, Bray GA, "The New Era of Drug Treatment. Pharmacologic Treatment of Obesity: Symposium Overview," Obes Res., 3(suppl 4), 415s-7s (1995).
  • Adrenergic agents e.g., diethylpropion, benzphetamine, phendimetrazine, mazindol, and phentermine
  • Older adrenergic weight-loss drugs e.g., amphetamine, methamphetamine, and phenmetrazine
  • Fenfluramine and dexfenfluramine both serotonergic agents used to regulate appetite, are no longer available for use.
  • CB1 cannabinoid receptor antagonists/inverse agonists have been suggested as potential appetite suppressants.
  • R 1 is an aryl optionally substituted with one or more substituents, or a heteroaryl optionally substituted with one or more substituents
  • R 3 is hydrogen or a chemical moiety selected from the group consisting of (CrC 4 )alkyl, and (C ⁇ -C )alkoxy, where said chemical moiety is optionally substituted with one or more substituents, or R 3 taken together with R 4 forms a nitrogen containing 5- to 6- membered partially or fully saturated heterocyclic ring optionally substituted with one or more substituent
  • R 1 and R 2 are each independently a chemical moiety selected from phenyl, thiophenyl, pyridyl or pyrimidinyl, where each chemical moiety is substituted with one or more substituents. More preferably, R 1 is a phenyl substituted with one to three substituents independently selected from the group consisting of halo (preferably, chloro or fluoro), (CrC )alkoxy, (Ci- C 4 )alkyl, halo-substituted (CrC )alkyl (preferably fluoro-substituted alkyl, more preferably, trifluoromethyl) and cyano; and R 2 is a phenyl, pyridyl, thiophenyl, or pyrimidinyl, where the phenyl, the pyridyl, the thiophenyl, and the pyrimidinyl are each substituted with one to three substituents independently selected from the group consisting of
  • R 1 is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro- 4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-methylphenyl or 2,4-difluorophenyl; and R 2 is 4-chlorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-ethyl phenyl, 4- isopropylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4- trifluoromethylphenyl, 4-fluorophenyl, 4-bromophenyl, 6-methylpyridin-3-yI, 6- methoxypyridin-3-yl, 5-chloropyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5- methylpyridin-2-yl, 5-chlorothiophen-2-yl, or 2,4-dimethoxypyrimi
  • R 3 is hydrogen or (C ⁇ -C 4 )alkyl, where the (d-C 4 )alkyl is optionally substituted with one or more substituents, or R 3 taken together with R 4 forms a nitrogen containing 5- to 6-membered partially or fully saturated heterocyclic ring optionally substituted with one or more substituents.
  • R 3 is hydrogen, fluoro-substituted (CrC 4 )alkyl, or (C ⁇ -C 4 )alkyl, wherein the (CrC 4 )alkyl is optionally substituted with (C-i- C 3 )alkylamino, di((C ⁇ -C 3 )alkyI)amino, azetidine, pyrrolidine, piperidine, or morpholine, where the (CrC 3 ) alkyl is optionally substituted with one to three fluorines.
  • R 3 is H, methyl, ethyl or trifluoromethyl.
  • R 4 is a chemical moiety selected from the group consisting of (C ⁇ -C 8 )alkyl, aryl(C- ⁇ -C )alkyl, and 3- to 8-membered partially or fully saturated carbocyclic ring(s), where said chemical moiety is optionally substituted with one or more substituent. More preferably, R 4 is (C- ⁇ -C 4 )alkyl, halo-substituted (C ⁇ -C 4 )alkyl (preferably, fluoro-substituted (C ⁇ -C )alkyl), cyclopentyl or cyclohexyl.
  • Preferred embodiments include any combination of the preferred substituents for R 1 , R 2 , R 3 and/or R 4 with each other or with any or all of the original definitions for R 1 , R 2 , R 3 and/or R 4 .
  • R 1a , R 1b , R 2b , and R 2c are each independently halo, (d-C 4 )alkoxy, (C ⁇ -
  • R 1a is chloro, fluoro, or methyl
  • R 1b is chloro, fluoro or hydrogen (i.e., m is 0)
  • R 2b is chloro, fluoro, (CrC 4 )alkyl, trifluoromethyl, (C- ⁇ -C 4 )alkoxy, or cyano
  • R 2c is hydrogen (i.e., n is 0)
  • n and m are each independently 0, 1 or 2
  • R 3 and R 4 are as defined above (including any combination of the preferred substituents); a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.
  • R 1a is chloro, fluoro, or methyl
  • R 1b is chloro, fluoro, or methyl
  • R 2b is chloro, fluoro, (CrC 4 )alkyl, trifluoromethyl, (C ⁇ -C )alkoxy, or cyano
  • m is 0 or 1
  • n is 0.
  • More preferred embodiments also include any combination of the preferred substituents for R 3 and R 4 discussed above.
  • Preferred compounds of the present invention include: 7-(2-chlorophenyl)-2-methyl-8-styryl-3-(2,2,2-trifluoroethyl)-3H- pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one; 7-(2-chlorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-3-(2,2,2- trifluoroethyl)-3H-pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one; 7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methyl-3-(2,2,2-trifluoroethyl)- 3H-pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one; 7-(2-chlorophenyl)-8-(4-chlorophenyl)-3-(2,2-difluoro
  • Another embodiment of the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising (1 ) a compound of the present invention and (2) a pharmaceutically acceptable excipient, diluent, or carrier.
  • the composition comprises a therapeutically effective amount of a compound of the present invention.
  • the composition may also contain at least one additional pharmaceutical agent (described herein).
  • Preferred agents include nicotine receptor partial agonists, opioid antagonists (e.g., naltrexone and nalmefene), dopaminergic agents (e.g., apomorphine), attention deficit disorder (ADD including attentin deficit hyperactivity disorder (ADHD)) agents (e.g., RitalinTM, StratteraTM, ConcertaTM and AdderallTM), and anti-obesity agents (described herein below).
  • opioid antagonists e.g., naltrexone and nalmefene
  • dopaminergic agents e.g., apomorphine
  • ADHD attention deficit disorder
  • agents e.g., RitalinTM, StratteraTM, ConcertaTM and AdderallTM
  • anti-obesity agents described herein below.
  • Diseases, conditions, and/or disorders modulated by cannabinoid receptor antagonists include eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake), tobacco abuse (e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking), dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), sexual dysfunction in males (e.g.,
  • the method is used in the treatment of obesity, attention deficit hyperactivity disorder, dementia, alcoholism, and/or tobacco abuse.
  • Compounds of the present invention may be administered in combination with other pharmaceutical agents.
  • Preferred pharmaceutical agents include nicotine receptor partial agonists, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene), dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidate hydrochloride (e.g., RitalinTM and ConcertaTM), atomoxetine (e.g., StratteraTM), and amphetamines (e.g., AdderallTM)) and anti-obesity agents, such as apo-B/MTP inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1 ) inhibitors, peptide YY 3-36 ⁇ r analogs thereof, MCR-4
  • the combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
  • kits for use by a consumer to treat diseases, conditions or disorders modulated by cannabinoid receptor antagonists in an animal.
  • the kit comprises a) a suitable dosage form comprising a compound of the present invention; and b) instructions describing a method of using the dosage form to treat diseases, conditions or disorders that are modulated by cannabinoid receptor (in particular, the CB1 receptor) antagonists.
  • Another embodiment includes a pharmaceutical kit comprising: a) a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) a second dosage form comprising (i) an additional pharmaceutical agent described herein, and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and c) a container.
  • a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent
  • b) a second dosage form comprising (i) an additional pharmaceutical agent described herein, and (ii) a pharmaceutically acceptable carrier, excipient or diluent
  • a container comprising: a) a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) a second dosage form comprising (i) an additional pharmaceutical agent
  • (C ⁇ -C6)alkyl refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, ⁇ -propyl, /-propyl, n-butyl, /-butyl, s-butyl, f-butyl, ⁇ -pentyl, 1 -methylbutyl, 2- methylbutyl, 3-methyl butyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2- methylpentyl, and the like).
  • 1 to 6 carbon atoms e.g., methyl, ethyl, ⁇ -propyl, /-propyl, n-butyl, /-butyl, s-butyl, f-butyl, ⁇ -pentyl, 1 -methylbutyl, 2- methylbutyl, 3-methyl butyl,
  • alkyl portion i.e., alkyl moiety
  • acyl e.g., alkanoyl
  • alkylamino dialkylamino
  • alkylthio group alkyl portion of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group
  • alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls) independently selected from the group of substituents listed below in the definition for "substituted.”
  • Halo-substituted alkyl refers to an alkyl group substituted with one or more halogen atoms (e.g., "fluoro- substituted alkyl” refers to fluoromethyl, difluoromethyl, trifluoromethyl, 1- fluoroethyl, 2-fluoroethyl, 1 ,1-difluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl, 1 ,1 ,1-trifluoroethyl, 2,2,2-trifluoroethy
  • Preferred halo-substituted alkyls are the chloro- and fluoro-substituted alkyls, more preferably, fluoro-substituted alkyls.
  • the alkane radicals or alkyl moieties are preferably substituted with 1 to 3 fluoro substituents, or 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 3 )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, cyano, hydroxy, (C ⁇ -C 3 )alkoxy, aryloxy, amino, (d-
  • partially or fully saturated carbocyclic ring refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8-membered ring.
  • partially or fully saturated carbocyclic rings include groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl, bicyclo[2.2.2]octyl, and the like.
  • the partially saturated or fully saturated cycloalkyl group may be unsubstituted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • a substituted carbocyclic ring also includes groups wherein the carbocyclic ring is fused to a phenyl ring (e.g., indanyl).
  • the carbocyclic group may be attached to the chemical entity or moiety by any one of the carbon atoms within the carbocyclic ring system.
  • the carbocyclic group is preferably substituted with 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl, (C 2 -C 3 )alkenyl, (CrC 6 )alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (C ⁇ -C 3 )alkoxy, aryloxy, amino, (C ⁇ -Ce)alkyl amino, di-(C ⁇ -C )alkyl amino, aminocarboxylate (i.e., (C ⁇ -C 3 )alkyl-O-C(O)-NH-), hydroxy(C 2 - C 3 )alkylamino, or keto (oxo), and more preferably 1 or 2 from substituents independently selected from (C ⁇ -C 2 )alkyl, 3- to 6-membered heterocycle, fluoro, (C ⁇ -C 3 )alkoxy, (C ⁇ -C 4
  • any cycloalkyl portion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definition as above.
  • the term "partially saturated or fully saturated heterocyclic ring” (also referred to as “partially saturated or fully saturated heterocycle”) refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring.
  • the heterocyclic ring is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N- methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, and the like.
  • the partially saturated or fully saturated heterocycle group may be unsubstiuted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • a substituted heterocyclic ring includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3- dihydrobenzofuranyl, 2,3-dihydroindolyl, 2,3-dihydrobenzothiophenyl, 2,3- dihydrobenzothiazolyl, etc.).
  • the heterocycle group is preferably substituted with 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C )alkenyl, aryl, heteroaryl, 3- to 6- membered heterocycle, chloro, fluoro, cyano, hydroxy, (CrC 3 )alkoxy, aryloxy, amino, (C ⁇ -Ce)alkyl amino, di-(C ⁇ -C 3 )alkyl amino, aminocarboxylate (i.e., (C ⁇ -C 3 )alkyl-O-C(O)-NH-), or keto (oxo), and more preferably with 1 or 2 substituents independently selected from (CrC 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 )aryl, 6-membered-heteroaryl, 3- to 6-membered heterocycle, or fluoro.
  • substituents independently
  • heterocyclic group may be attached to the chemical entity or moiety by any one of the ring atoms within the heterocyclic ring system.
  • any heterocycle portion of a group e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.
  • aryl or "aromatic carbocyclic ring” refers to aromatic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • a typical aryl group is a 6- to 10-membered aromatic carbocyclic ring(s).
  • the aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • substituents preferably no more than three substituents
  • Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.).
  • the aromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (d-d ⁇ lkyl, (C 2 -C 3 )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C ⁇ -C 4 )alkoxy, aryloxy, amino, (d-C 6 )alkyl amino, di-(d-C 3 )alkyl amino, or aminocarboxylate (i.e., (C ⁇ -C 3 )alkyl-O-C(O)-NH-), and more preferably, 1 or 2 substituents independently selected from (C ⁇ -C )alkyl, chloro, fluoro, cyano, hydroxy, or (C ⁇ -C 4 )alkoxy.
  • 1 or 2 substituents independently selected from (d-d ⁇ lkyl, (C 2 -C 3 )alkenyl, aryl, hetero
  • the aryl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the aromatic ring system.
  • the aryl portion (i.e., aromatic moiety) of an aroyl or aroyloxy (i.e., (aryl)-C(O)-O-) has the same definition as above.
  • heteroaryl or “heteroaromatic ring” refers to aromati ⁇ moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.).
  • a 5- to 10-membered aromatic ring system e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazo
  • the heteroaromatic moiety may consist of a single or fused ring system.
  • a typical single heteroaryl ring is a 5- to 6-membered ring containing one to three heteroatoms independently selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10- membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen.
  • the heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • the heteroaromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (C -C 4 )alkyl, (C 2 -C 3 )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (d- C 4 )alkoxy, aryloxy, amino, (C ⁇ -C 6 )alkyl amino, di-(d-C 3 )alkyl amino, or aminocarboxylate (i.e., (d-C 3 )alkyl-O-C(O)-NH-), and more preferably, 1 or 2 substituents independently selected from (d-C
  • the heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl).
  • the heteroaryl portion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaryoloxy i.e., (heteroaryl)- C(O)-O-
  • acyl refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups.
  • acyl includes groups such as (C ⁇ -Ce)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, f-butylacetyl, etc.), (C 3 -C 6 )cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.
  • alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions above.
  • the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.
  • substituted specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament.
  • Suitable substituents for any of the groups defined above include (d- C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, (C C 6 )alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (d-C 6 )alkoxy, aryloxy, sulfhydryl (mercapto), (C ⁇ -C 6 )alkylthio, arylthio, amino, mono- or di-(C 1 -C 6 )alkyl amino, quaternary ammonium salts, amino(C ⁇ -C 6 )alkoxy, aminocarboxylate (i.e., (d-C 6 )alkyl- O-C(O)-NH-), hydroxy(C 2 -C 6 )alkyla
  • substituted combinations such as "substituted aryl(C ⁇ -C 6 )alkyl"
  • either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl groups may be substituted with one or more substituents (typically, one to three substituents except in the case of perhalo substitutions).
  • An aryl or heteroaryl substituted carbocyclic or heterocyclic group may be a fused ring (e.g., indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.).
  • solvate refers to a molecular complex of a compound represented by Formula (I) or (II) (including prodrugs and pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • protecting group or “Pg” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound.
  • an “amino- protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p- toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)- ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • animal refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • “Edible animals” refers to food-source animals such as cows, pigs, sheep and poultry.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated, therewith.
  • the terms “treating”, “treat”, or “treatment” embrace both preventative, i.e., prophylactic, and palliative treatment.
  • the terms “modulated by a cannabinoid receptor” or “modulation of a cannabinoid receptor” refers to the activation or deactivation of a cannabinoid receptor.
  • a ligand may act as an agonist, partial agonist, inverse agonist, antagonist, or partial antagonist.
  • antagonist includes both full antagonists and partial antagonists, as well as inverse agonists.
  • CB-1 receptor refers to the G-protein coupled type 1 cannabinoid receptor.
  • compounds of the present invention refer to compounds of Formulae (I) and (II), prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by cannabinoid receptor antagonists.
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.
  • the 3-aminopyrazole (1a) may be purchased or prepared using procedures analogous to those described in Pakamigawa, A., Yakugaku Zasski, 84, 1113 (1964).
  • Suitable alkylimidates include ethyl acetimidate, methyl acetimidate, and ethyl formimidate.
  • Suitable acids include alkanoic acids (e.g., acetic acid, trifluoroacetic acid), sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid) and hydrochloric acid. Isolation of amidine (lb) as its acetic acid salt is preferred.
  • Pyrazolotriazinone (1c) may then be formed by treating amidine (l b) with a dialkyl carbonate (e.g., diethyl carbonate or dimethylcarbonate) or dialkyl dithiocarbonate in the presence of base (e.g., sodium methoxide or sodium ethoxide) in a suitable solvent (e.g., methanol or ethanol) at reaction temperatures from about 30 °C to about 150 °C.
  • a dialkyl carbonate e.g., diethyl carbonate or dimethylcarbonate
  • dialkyl dithiocarbonate e.g., sodium methoxide or sodium ethoxide
  • base e.g., sodium methoxide or sodium ethoxide
  • suitable solvent e.g., methanol or ethanol
  • pyrazolotriazinone (1 c) may be formed by treating amidine (l b) with reagents such as phosgene, triphosgene, or carbonyl diimidazole in the presence or absensce of a base (e.g., triethylamine, diisopropylethyl amine, pyridine, or imidazole) in a reaction inert solvent (e.g., methylene chloride, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether or acetonitrile) at reaction temperatures from about -40 °C to about 100 °C.
  • a base e.g., triethylamine, diisopropylethyl amine, pyridine, or imidazole
  • a reaction inert solvent e.g., methylene chloride, tetrahydrofuran, diethyl
  • a bromine or iodine may be introduced at the 3-position of pyrazolotriazinone (1 c) using procedures analogous to those described in Senga, K., et al., J. Med. Chem.. 25, 243-249 (1982).
  • position 3 may be iodinated by treating the pyrazolotriazinone (1 c) with a reagent such as N-iodosuccinimide (NIS), iodine, or iodonium bis-symcollidine perchlorate (preferably NIS) in an aprotic solvent (e.g., carbon tetrachloride, methylene chloride, or chloroform).
  • aprotic solvent e.g., carbon tetrachloride, methylene chloride, or chloroform.
  • Suitable reaction temperatures range from about -78 °C to about 30 °C (preferably, about 0 °C).
  • Intermediate (le) may be prepared using procedures analogous to those described for Scheme 17 of U.S. Patent No. 6,372,743 and incorporated herein by reference.
  • the second aryl or heteroaryl group (R 2 ) is introduced via metal-mediated cross-coupling reactions such as the Suzuki reaction (See: A. Suzuki in Metal-Catalyzed Cross-Coupling Reactions; F. Diederich and P.J. Stang, Eds.; Wiley-VCH Verlag, Weinheim, Germany, Chapter 2 (1998) and N. Miyaura and A. Suzuki Chem. Rev., 95, 2457-2483 (1995)) and the Stille reaction (T.N. Mitchell in Metal-Catalyzed Cross-Coupling Reactions; F. Diederich and P.J. Stang, Eds.; Wiley-VCH Verlag, Weinheim, Germany, Chapter 4 (1998)).
  • Suzuki reaction See: A. Suzuki in Metal-Catalyzed Cross-Coupling Reactions; F. Diederich and P.J. Stang, Eds.; Wiley-VCH Verlag, Weinheim, Germany, Chapter 2 (1998) and N. Miyaura and A. Suzuki Chem. Rev.
  • the compound of the Formula (le) may be produced by Suzuki reaction of intermediate (Id) with a compound of Formula R 1 -B(OH) 2 in the presence of a complex or salt of palladium (e.g., Pd(PPh 3 )4, Pd(OAc) 2 , PdCI 2 (dppf)), a base (e.g., cesium carbonate, sodium carbonate, cesium fluoride, potassium phosphate), and a suitable solvent (e.g., toluene, water, dioxane, N,N-dimethylformamide) in the presence or absence of added ligand (e.g., dppf, dppb).
  • a complex or salt of palladium e.g., Pd(PPh 3 )4, Pd(OAc) 2 , PdCI 2 (dppf)
  • a base e.g., cesium carbonate, sodium carbonate, cesium fluoride, potassium phosphate
  • a suitable solvent e
  • reaction temperatures range from about 0 °C to about 120 °C (more preferably, from about 80 °C to about 110 °C).
  • N-Alkylation of intermediate (le) can then be accomplished using an alkylating agent, such as an alkyl iodide, alkyl triflate, or a substituted benzyl bromide, and a base, preferably cesium carbonate or potassium carbonate, in a polar non-protic solvent such as DMF or THF, at temperatures ranging from about 37 °C to about 150 °C (preferably, from about 20 °C to 40 °C) to provide compounds of Formula (I) or (II).
  • an alternative preparation of compounds of Formula (I) and (II) is outlined in Scheme II below.
  • N-alkylation of intermediate (Id) may be accomplished using procedures analogous to the alkylation of (1e) described above.
  • the second aryl or heteroarly group (R 2 ) may then be introduced by metal-mediated cross-coupling as described above in the preparation of (1 e) to provide (I) or (II).
  • the Suzuki and Stille reactions are particularly preferred.
  • intermediate (2a) may be converted to a metal reagent such as stannane (2b) using standard condtions (see V.P. Palle et al. in Bioorg. & Med. Chem. Lett., 12, 2935-2939 (2002) and references within).
  • the compounds of the present invention may be isolated and used perse or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate.
  • salts refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound, N-oxide, or prodrug with a suitable organic or inorganic acid or base and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, iactobionate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C ⁇ -Cs)alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Cr C 6 )alkanoyloxymethyl, 1 -((C ⁇ -C 6 )alkanoyIoxy)ethyl, 1 -methyl-1 -((d- C 6 )alkanoyloxy)ethyl, (CrC 6 )alkoxycarbonyloxymethyl, N-(d- C 6 )alkoxycarbonylaminomethyl, succinoyl, (d-C 6 )alkanoyl, ⁇ -amino(C ⁇ - C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , P(O)
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C 3 - C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl-natural ⁇ -aminoacyl, -C(OH)C(O)OY' wherein Y' is H, (C ⁇ -C ⁇ )alkyl or benzyl, -C(OY 0 )Y ⁇ wherein Y 0 is (d-C 4 ) alkyl and Y is (d-C 6 )alkyl, carboxy(C ⁇ -C 6 )alkyl, amino(CrC 4 )alkyl or mono-N- or di-N
  • the compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. It is also possible that the compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all of the tautomeric forms of the aromatic and heteroaromatic moieties are included in the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, such as H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 123 l, and 36 CI, respectively.
  • Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by cannabinoid receptor antagonists; therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients described above.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the present invention further provides a method of treating diseases, conditions and/or disorders modulated by cannabinoid receptor antagonists in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the method is particularly useful for treating diseases, conditions and/or disorders modulated by cannabinoid receptor (in particular, CB1 receptor) antagonists.
  • eating disorders e.g., binge eating disorder, anorexia, and bulimia
  • weight loss or control e.g., reduction in calorie or food intake, and/or appetite suppression
  • obesity depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference)
  • substance abuse e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake
  • tobacco abuse e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking
  • dementia including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder
  • sexual dysfunction in
  • the compounds of the present invention described herein are useful in treating diseases, conditions, or disorders that are modulated by cannabinoid receptor antagonists. Consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein.
  • disorders associated with impulsive behaviours such as, disruptive behaviour disorders (e.g., anxiety/depression, executive function improvement, tic disorders, conduct disorder and/or oppositional defiant disorder), adult personality disorders (e.g., borderline personality disorder and antisocial personality disorder), diseases associated with impulsive behaviours (e.g., substance abuse, paraphilias and self-mutilation), and impulse control disorders (e.g., intermittene explosive disorder, kleptomania, pyromania, pathological gambling, and trichotillomania)), obsessive compulsive disorder, chronic fatigue syndrome, sexual dysfunction in males (e.g., premature ejaculation), sexual dysfunction in females, disorders of sleep
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of from about 0.7 mg to about 7,000 mg per day.
  • dosage levels in the range of from about 0.7 mg to about 7,000 mg per day.
  • a dosage in the range of from about 0.01 mg to about 100 mg per kilogram body weight is typically sufficient.
  • some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like.
  • the determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
  • the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
  • Suitable pharmaceutical agents include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 1 ⁇ -HSD type 1 ) inhibitors, peptide YY 3 - 36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5
  • anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 1 ⁇ -HS
  • anorectic agents such as a bombesin agonist
  • Neuropeptide-Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analog thereof such as glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like.
  • AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • anti-obesity agents including the preferred agents set forth hereinbelow, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • anti-obesity agents selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY 3-3 6 ⁇ r an analog thereof, and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; and PYY 3-3 6 (including analogs) can be prepared as described in US Publication No. 2002/0141985 and WO 03/027637. All of the above recited references are incorporated herein by reference.
  • tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename ZybanTM) and nicotine replacement therapies
  • agents to treat erectile dysfunction e.
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).
  • AA Alcohol Anonymous
  • anti- inflammatory agents e.g., COX-2 inhibitors
  • antidepressants e.g., fluoxetine hydrochloride (ProzacTM)
  • cognitive improvement agents e.g., donepezil hydrochloride (AirceptTM) and other acetylcholinesterase inhibitors
  • neuroprotective agents e.g., memantine
  • antipsychotic medications e.g., ziprasidone (GeodonTM), risperidone (RisperdalTM), and olanzapine (ZyprexaTM)
  • insulin and insulin analogs e.g., LysPro insulin
  • GLP-1 (7-37) insulinotropin
  • GLP-1 (7-36)-NH 2 sulfonylureas and analogs thereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepir
  • the compounds of the present invention may also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels.
  • a naturally occurring compound that acts to lower plasma cholesterol levels.
  • Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts, and niacin.
  • the dosage of the additional pharmaceutical agent will also be generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • the dosage range of an anti-obesity agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day.
  • a compound of the present invention or a combination of a compound of the present invention and at least one additional pharmaceutical agent is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
  • the compound of the present invention and at least one other pharmaceutical agent may be administered either separately or in the pharmaceutical composition ( comprising both. It is generally preferred that such administration be oral.
  • parenteral or transdermal administration may be appropriate.
  • a combination of a compound of the present invention and at least one other pharmaceutical agent are administered together, such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred.
  • a compound of the present invention and the additional pharmaceutical agent can be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
  • the administration of each can be by the same or by different methods.
  • a compound of the present invention or a combination of a compound of the present invention and at least one additional pharmaceutical agent is preferably administered in the form of a pharmaceutical, composition.
  • a compound of the present invention or a combination can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral, (for example, intravenous, intramuscular, or subcutaneous) intracistemal, intravaginal, intraperitoneal, intravesical, local (for example, powder, ointment or drop), or buccal, or nasal, dosage form.
  • compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • a compound of the present invention or a combination is admixed with at least one inert customary pharmaceutical excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders e.g., starches, lactose, sucrose, mannitol, silicic acid and the like
  • binders e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like
  • humectants e.g., glycerol and the like
  • disintegrating agents e.g., agar-agar, calcium carbonate, potato or tapioca starch, alg
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the present invention and/or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes.
  • the drug can also be in micro- encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, eth
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the compound of the present invention or the combination, may further comprise suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the present invention or a combination with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • Dosage forms for topical administration of the compounds of the present invention and combinations of the compounds of the present invention with anti-obesity agents may comprise ointments, powders, sprays and inhalants.
  • the drugs are admixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also intended to be included within the scope of the present invention. The following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals.
  • the administration of the compounds of the present invention and combinations of the compounds of the present invention with anti-obesity agents can be effected orally or non-orally (e.g., by injection). An amount of a compound of the present invention or combination of a compound of the present invention with an anti-obesity agent is administered such that an effective dose is received.
  • a daily dose that is administered orally to an animal is between about 0.01 and about 1 ,000 mg/kg of body weight, preferably between about 0.01 and about 300 mg/kg of body weight.
  • a compound of the present invention (or combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply.
  • the compound can be directly metered into drinking water, preferably in the form of a liquid, water- soluble concentrate (such as an aqueous solution of a water-soluble salt).
  • a compound of the present invention (or combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate.
  • a premix or concentrate of the compound in a carrier is more commonly employed for the inclusion of the agent in the feed.
  • Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly ' employed in poultry feeds.
  • a particularly effective carrier is the respective animal feed itself; that is, a small portion of such feed.
  • the carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended.
  • the compound is thoroughly blended into the premix and, subsequently, the feed.
  • the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier.
  • a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like
  • the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.
  • High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet.
  • such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the present invention.
  • the mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity. If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.
  • Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the present invention with a sufficient amount of animal feed to provide from about 10 "3 to about 500 ppm of the compound in the feed or water.
  • the preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of a compound of the present invention (or combination) per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed.
  • the preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of a compound of the present invention (or combination) per ton of feed.
  • the compounds of the present invention (or combination) may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean meat to fat ratio is sought.
  • parenteral administration involves injection of a sufficient amount of a compound of the present invention (or combination) to provide the animal with about 0.01 to about 20 mg/kg/day of body weight of the drug.
  • the preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from about 0.05 to about 10 mg/kg/day of body weight of drug.
  • Paste formulations can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
  • Pellets containing an effective amount of a compound of the present invention, pharmaceutical composition, or combination can be prepared by admixing a compound of the present invention or combination with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
  • a diluent such as carbowax, carnuba wax, and the like
  • a lubricant such as magnesium or calcium stearate
  • implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
  • the present invention has several advantageous veterinary features.
  • the instant invention provides the means by which this may be accomplished.
  • utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.
  • Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. EXAMPLES Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc.
  • Atmospheric pressure chemical ionization mass spectra were obtained on a FisonsTM Platform II Spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK).
  • Chemical ionization mass spectra were obtained on a Hewlett-PackardTM 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, CA).
  • Electrospray ionization mass spectra were obtained on a WatersTM ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35 CI/ 37 CI-containing ions and 1 :1 for 79 Br/ 81 Br-containing ions) and the intensity of only the lower mass ion is given.
  • l-1A-1 d To a suspension of 7-(2-chlorophenyl)-3H-pyrazolo[1 ,5-a][1 ,3,5]- triazin-4-one (l-1A-1c: 2.59 g, 10.5 mmol) in chloroform (115 ml) cooled in an ice bath was added ⁇ /-iodosuccinimide (2.36 g, 10.5 mmol), portionwise, over 15 minutes. After stirring for 3 hours, the reaction was added to stirring water and methylene chloride. A solution of saturated aqueous Na 2 S 2 O 4 was added until the color remained light yellow.
  • the biphasic mixture was filtered through Celite ® to remove the brown solids that formed on quench.
  • the organic layer was separated and washed with saturated aqueous NaHCO 3 (200 ml) and then brine (200 ml).
  • the organic solution was concentrated, in vacuo, to A volume and then filtered through a cotton plug. The solution was further concentrated to % volume, at which point, a yellow solid began to precipitate. Hexane (300 ml) was then added and stirred for 1 hour.
  • 3A-3 7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2-methyl-3-(2-oxobutyl)-3H- pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one (3A-3) was prepared from 7-(2-chloro- phenyl)-8-(4-chlorophenyl)-2-methyl-3H-pyrazolo[1 ,5-a][1 ,3,5]triazin-4-one (l-1A-3e) using procedures analogous to those described above for the synthesis of Compound 3A-1 : +ESI MS (M+1 ) 441.4.
  • the reaction was heated at 85 °C for 4 hours, cooled, and then diluted with ethyl acetate and filtered through Celite ® .
  • the organic solution was washed with water, saturated aqueous sodium bicarbonate, 0.02 M aqueous HCI, and then brine.
  • SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25 ⁇ l were added to the plate.
  • a BCA protein assay was used to determine the appropriate tissue concentration and then 200 ⁇ l of rat brain tissue at the appropriate concentration was added to the plate.
  • the plates were covered and placed in an incubator at 20 °C for 60 minutes. At the end of the incubation period 250 ⁇ l of stop buffer (5% BSA plus TME) was added to the reaction plate.
  • the plates were then harvested by Skatron onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filter was washed twice.
  • the supernatant was recovered and centrifuged at 25.000X G for 20 minutes at 4 °C.
  • the pellet was then re-suspended in 10 ml of homogenization buffer and re-spun at 25.000X G for 20 minutes at 4 °C.
  • a protein assay was performed and 200 ⁇ l of tissue totaling 20 ⁇ g was added to the assay.
  • the test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO and TME) and then 25 ⁇ l were added to a deep well polypropylene plate.
  • [ 3 H] SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25 ⁇ l were added to the plate. The plates were covered and placed in an incubator at 30 °C for 60 minutes. At the end of the incubation period 250 ⁇ l of stop buffer (5% BSA plus TME) was added to the reaction plate. The plates were then harvested by Skatron onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filter was washed twice. The filters were dried overnight. In the morning the filters were counted on a Wallac BetaplateTM counter (available from PerkinElmer Life SciencesTM, Boston, MA).
  • a protein assay was performed and 200 ⁇ l of tissue totaling 10 ⁇ g was added to the assay.
  • the test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO, and 80.5% TME) and then 25 ⁇ l were added to the deep well polypropylene plate.
  • [ 3 H] 5-(1 ,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy- propyl)-cyclohexyl]-phenol was diluted a ligand buffer (0.5% BSA and 99.5% TME) and then 25 ⁇ l were added to each well at a concentration of 1 nM.
  • a BCA protein assay was used to determine the appropriate tissue concentration and 200 ⁇ l of the tissue at the appropriate concentration was added to the plate.
  • the plates were covered and placed in an incubator at 30 °C for 60 minutes. At the end of the incubation period 250 ⁇ l of stop buffer (5% BSA plus TME) was added to the reaction plate.
  • CB-1 GTP ⁇ r 35 Sl Binding Assay Membranes were prepared from CHO-K1 cells stably transfected with the human CB-1 receptor cDNA. Membranes were prepared from cells as described by Bass et al, in "Identification and characterization of novel somatostatin antagonists," Molecular Pharmacology, 50, 709-715 (1996).
  • GTP ⁇ [ 35 S] binding assays were performed in a 96 well FlashPlate TM format in duplicate using 100 pM GTP ⁇ [ 35 S] and 10 ⁇ g membrane per well in assay buffer composed of 50 mM Tris HCI, pH 7.4, 3 mM MgCI 2 , pH 7.4, 10 mM MgCI 2 , 20 mM EGTA, 100 mM NaCI, 30 ⁇ M GDP, 0.1% bovine serum albumin and the following protease inhibitors: 100 ⁇ g/ml bacitracin, 100 ⁇ g/ml benzamidine, 5 ⁇ g/ml aprotinin, 5 ⁇ g/ml leupeptin.
  • test compound (1 :10 stock solution (25 mM compound in DMSO) into 50% DMSO/PBS) diluted 10X in PBS with 0.1 % BSA.
  • test compound 1 :10 stock solution (25 mM compound in DMSO) into 50% DMSO/PBS) diluted 10X in PBS with 0.1 % BSA.
  • test compound 1 :10 stock solution (25 mM compound in DMSO) into 50% DMSO/PBS) diluted 10X in PBS with 0.1 % BSA.
  • 2 ⁇ M of Forskolin was added and then incubated for an additional 20 minutes at 37 °C.
  • the media was removed, 100 ⁇ l of 0.01 N HCI was added and then incubated for 20 minutes at room temperature.
  • test compound sc, po, ip, or icv
  • mice Ninety minutes post injection, the mice were placed on a 6.5 cm steel ring attached to a ring stand at a height of about 12 inches. The ring was mounted in a horizontal orientation and the mouse was suspended in the gap of the ring with fore- and hind-paws gripping the perimeter. The duration that the mouse remained completely motionless (except for respiratory movements) was recorded over a 3-minute period. The data were presented as a percent immobility rating. The rating was calculated by dividing the number of seconds the mouse remains motionless by the total time of the observation period and multiplying the result by 100. A percent reversal from the agonist was then calculated.
  • Latency to kick, lick or flick hindpaw or jump from the platform was recorded to the nearest tenth of a second.
  • the timer was experimenter activated and each test had a 40 second cut off. Data were presented as a percent reversal of the agonist induced analgesia.
  • Food Intake The following screen was used to evaluate the efficacy of test compounds for inhibiting food intake in Sprague-Dawley rats after an overnight fast.
  • Male Sprague-Dawley rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA). The rats were individually housed and fed powdered chow. They were maintained on a 12-hour light/dark cycle and received food and water ad libitum.
  • the animals were acclimated to the vivarium for a period of one week before testing was conducted. Testing was completed during the light portion of the cycle. To conduct the food intake efficacy screen, rats were transferred to individual test cages without food the afternoon prior to testing, and the rats were fasted overnight. After the overnight fast, rats were dosed the following morning with vehicle or test compounds.
  • a known antagonist was dosed (3 mg/kg) as a positive control, and a control group received vehicle alone (no compound).
  • the test compounds were dosed at ranges between 0.1 and 100 mg/kg depending upon the compound.
  • the standard vehicle was 0.5% (w/v) methylcellulose in water and the standard route of administration was oral. However, different vehicles and routes of administration were used to accommodate various compounds when required.
  • Test compounds were generally mixed into a vehicle of 30% (w/v) ⁇ -cyclodextrin in distilled water at a volume of 1-2 ml/kg. Vehicle injections were given to all groups for the first two days of the experiment. This was followed by 2 days of drug injections (to the appropriate groups) and a final day of vehicle injections. On the drug injection days, drugs were given sc 30 minutes prior to a 2-hour alcohol access period.
  • mice were individually housed and given unlimited access to powdered rat chow, water and a 10% (w/v) alcohol solution. After 2-3 weeks of unlimited access, water was restricted for 20 hours and alcohol was restricted to only 2 hours access daily. This was done in a manner that the access period was the last 2 hours of the dark part of the light cycle. Once drinking behavior stabilized, testing commenced. Mice were considered stable when the average alcohol consumption for 3 days was + 20% of the average for all 3 days. Day 1 of test consisted of all mice receiving vehicle injection (sc or ip). Thirty to 120 minutes post injection access was given to alcohol and water.
  • mice were injected with vehicle or drug and the same protocol as the previous day was followed. Day 4 was wash out and no injections were given. Data was analyzed using repeated measures ANOVA. Change in water or alcohol consumption was compared back to vehicle for each day of the test. Positive results would be interpreted as a compound that was able to significantly reduce alcohol consumption while having no effect on water Oxygen Consumption Methods: Whole body oxygen consumption is measured using an indirect calorimeter (Oxymax from Columbus Instruments, Columbus, OH) in male Sprague Dawley rats (if another rat strain or female rats are used, it will be specified).
  • Oxygen Consumption Methods Whole body oxygen consumption is measured using an indirect calorimeter (Oxymax from Columbus Instruments, Columbus, OH) in male Sprague Dawley rats (if another rat strain or female rats are used, it will be specified).
  • Rats (300-380 g body weight) are placed in the calorimeter chambers and the chambers are placed in activity monitors. These studies are done during the light cycle. Prior to the measurement of oxygen consumption, the rats are fed standard chow ad libitum. During the measurement of oxygen consumption, food is not available. Basal pre-dose oxygen consumption and ambulatory activity are measured every 10 minutes for 2.5 to 3 hours. At the end of the basal pre-dosing period, the chambers are opened and the animals are administered a single dose of compound (the usual dose range is 0.001 to 10 mg/kg) by oral gavage (or other route of administration as specified, i.e., sc, ip, iv).
  • Drugs are prepared in methylcellulose, water or other specified vehicle (examples include PEG400, 30% beta-cyclo dextran and propylene glycol). Oxygen consumption and ambulatory activity are measured every 10 minutes for an additional 1-6 hours post-dosing. The Oxymax calorimeter software calculates the oxygen consumption
  • the activity monitors have 15 infrared light beams spaced one inch apart on each axis, ambulatory activity is recorded when two consecutive beams are broken and the results are recorded as counts.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (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

L'invention concerne des composés de formule (I). Ces composés se sont révélés actifs en tant que ligands des récepteurs cannabinoïdes et sont donc utiles dans le traitement des maladies liées à la médiation des récepteurs cannabinoïdes chez les animaux.
PCT/IB2004/003673 2003-11-21 2004-11-08 Derives de pyrazolo[1,5-a][1,3,5]triazin-4-one en tant qu'antagonistes des recepteurs cb1 WO2005049615A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52393703P 2003-11-21 2003-11-21
US60/523,937 2003-11-21

Publications (1)

Publication Number Publication Date
WO2005049615A1 true WO2005049615A1 (fr) 2005-06-02

Family

ID=34619621

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/003673 WO2005049615A1 (fr) 2003-11-21 2004-11-08 Derives de pyrazolo[1,5-a][1,3,5]triazin-4-one en tant qu'antagonistes des recepteurs cb1

Country Status (1)

Country Link
WO (1) WO2005049615A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006131807A1 (fr) * 2005-06-06 2006-12-14 Pfizer Products Inc. Preparation de derives de pyrazole 3-amino-4,5-disubstitues
WO2006138734A1 (fr) * 2005-06-17 2006-12-28 Bristol-Myers Squibb Company Antagonistes du recepteur 1 de cannabinoides de triazolopyrimidine
WO2007120454A1 (fr) * 2006-03-30 2007-10-25 Irm Llc Azolopyrimidines inhibitrices de l'activité du récepteur cannabinoïde 1
US7317012B2 (en) 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
US7728141B2 (en) 2003-11-04 2010-06-01 Merck Sharp & Dohme Corp. Substituted naphthyridinone derivatives
US9238027B2 (en) 2009-01-12 2016-01-19 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191131B1 (en) * 1997-07-23 2001-02-20 Dupont Pharmaceuticals Company Azolo triazines and pyrimidines
FR2814678A1 (fr) * 2000-10-04 2002-04-05 Aventis Pharma Sa Association d'un antagoniste du recepteur cb1 et de sibutramine, les compositions pharmaceutiques les contenant et leur utilisation pour la traitement de l'obesite
WO2002076949A1 (fr) * 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. Derives de 4,5-dihydro-1h-pyrazole ayant une activite d'antagoniste de cb¿1?
WO2004069837A1 (fr) * 2003-02-06 2004-08-19 Pfizer Products Inc. Derives de pyrazolo[1,5-a][1,3,5]triazine en tant que ligands de recepteur cannabinoide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191131B1 (en) * 1997-07-23 2001-02-20 Dupont Pharmaceuticals Company Azolo triazines and pyrimidines
FR2814678A1 (fr) * 2000-10-04 2002-04-05 Aventis Pharma Sa Association d'un antagoniste du recepteur cb1 et de sibutramine, les compositions pharmaceutiques les contenant et leur utilisation pour la traitement de l'obesite
WO2002076949A1 (fr) * 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. Derives de 4,5-dihydro-1h-pyrazole ayant une activite d'antagoniste de cb¿1?
WO2004069837A1 (fr) * 2003-02-06 2004-08-19 Pfizer Products Inc. Derives de pyrazolo[1,5-a][1,3,5]triazine en tant que ligands de recepteur cannabinoide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KADDACHI ET AL.: "Reaction of N-acyl and N-ethoxycarbonyl imidates with 2-aminobenzimidazoles, 3-amino-4-methyl-5-phenylpyrazoles and 3-amino-1,2,4-trazoles", JOURNAL DE LA SOCIETE CHIMIQUE DE TUNISIE, vol. 2, no. 7, 1988, pages 17 - 21, XP001205664 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728141B2 (en) 2003-11-04 2010-06-01 Merck Sharp & Dohme Corp. Substituted naphthyridinone derivatives
WO2006131807A1 (fr) * 2005-06-06 2006-12-14 Pfizer Products Inc. Preparation de derives de pyrazole 3-amino-4,5-disubstitues
WO2006138734A1 (fr) * 2005-06-17 2006-12-28 Bristol-Myers Squibb Company Antagonistes du recepteur 1 de cannabinoides de triazolopyrimidine
US7317012B2 (en) 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
US7452892B2 (en) 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
WO2007120454A1 (fr) * 2006-03-30 2007-10-25 Irm Llc Azolopyrimidines inhibitrices de l'activité du récepteur cannabinoïde 1
JP2009532360A (ja) * 2006-03-30 2009-09-10 アイアールエム・リミテッド・ライアビリティ・カンパニー カンナビノイド受容体１活性の阻害剤としてのアゾロピリミジン類
KR100997601B1 (ko) 2006-03-30 2010-11-30 아이알엠 엘엘씨 카나비노이드 1 활성의 억제제로서의 아졸로피리미딘
AU2007239033B2 (en) * 2006-03-30 2011-12-15 Irm Llc Azolopyrimidines as inhibitors of Cannabinoid 1 activity
US8722691B2 (en) 2006-03-30 2014-05-13 Irm Llc Azolopyrimidines as inhibitors of cannabinoid 1 activity
US9238027B2 (en) 2009-01-12 2016-01-19 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability
US9592237B2 (en) 2009-01-12 2017-03-14 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability

Similar Documents

Publication Publication Date Title
CA2515596C (fr) Ligands du recepteur cannabinoide et leurs utilisations
US7354929B2 (en) Cannabinoid receptor ligands and uses thereof
US7329658B2 (en) Cannabinoid receptor ligands and uses thereof
EP1622903B1 (fr) Ligands de recepteurs cannabinoides et leurs applications
US7151097B2 (en) Bicyclic pyrazolyl and imidazolyl compounds and uses thereof
US7232823B2 (en) Cannabinoid receptor ligands and uses thereof
US7247628B2 (en) Cannabinoid receptor ligands and uses thereof
WO2004096801A1 (fr) Ligands du recepteur cannabinoide et leurs utilisations
WO2005061507A1 (fr) Composes bicycliques de pyrazol-4-one en tant que ligands des recepteurs cannabinoides et leurs utilisations
WO2005103052A1 (fr) Composes de pyrazolo[1,5-a] pyrimidin-7-one et leurs utilisations
WO2005049615A1 (fr) Derives de pyrazolo[1,5-a][1,3,5]triazin-4-one en tant qu'antagonistes des recepteurs cb1
WO2005061505A1 (fr) Composes bicycliques d'imidazolyle pyrimidin-4-one en tant que ligands des recepteurs cannabinoides et leurs utilisations
WO2005061506A1 (fr) Composes bicycliques de pyrazolyle et d'imidazolyle en tant que ligands des recepteurs cannabinoides et leurs utilisations
WO2005061504A1 (fr) Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase