[go: up one dir, main page]

WO2005061504A1 - Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations - Google Patents

Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations Download PDF

Info

Publication number
WO2005061504A1
WO2005061504A1 PCT/IB2004/004017 IB2004004017W WO2005061504A1 WO 2005061504 A1 WO2005061504 A1 WO 2005061504A1 IB 2004004017 W IB2004004017 W IB 2004004017W WO 2005061504 A1 WO2005061504 A1 WO 2005061504A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
phenyl
chloro
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2004/004017
Other languages
English (en)
Inventor
Philip Albert Carpino
Subas Man Sakya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
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 WO2005061504A1 publication Critical patent/WO2005061504A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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 2,6-dihydro-pyrazolo[3,4-d]pyridazin-7- one and 1 ,5-dihydro-imidazo[4,5-d]pyridazin-4-one compounds.
  • the pyridazinone compounds are useful as cannabinoid receptor ligands, in particular as CB-1 receptor antagonists.
  • the present invention also relates to the use of the pyridazinone compounds in treating diseases, conditions and disorders modulated by cannabinoid receptor ligands including pharmaceutical compositions for such use.
  • BACKGROUND Obesity is a major public health concern because of its increasing prevalence and associated health risks.
  • BMI body mass index
  • 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 (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).
  • 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 management 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. For example, stimulation of serotonin receptor subtypes 1 B, 1 D, and 2C and 1- and 2-adrenergic receptors decreases food intake by regulating satiety.
  • Adrenergic agents e.g., diethylpropion, benzphetamine, phendimetrazine, mazindol, and phentermine
  • Adrenergic agents act by modulating central norepinephrine and dopamine receptors through the promotion of catecholamine release.
  • Older adrenergic weight-loss drugs e.g., amphetamine, methamphetamine, and phenmetrazine
  • CB1 cannabinoid receptor antagonists/inverse agonists have been suggested as potential appetite suppressants. See, e.g., Arnone, M., et al., "Selective Inhibition of Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors," Psvchopharmacol, 132, 104-106 (1997); Colombo, G., et al., "Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR141716.” Life ScL, 63, PL113- PL117 (1998); Simiand, J., et al., "SR141716, a CB1 Cannabinoid Receptor Antagonist, Selectively Reduces Sweet Food Intake in Marmose," Behav.
  • the endogenous CB1 receptor antagonist SR-141716A has been shown to block voluntary ethanol intake in rats and mice. See, Arnone, M., et al., "Selective Inhibition of Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors," Psvchopharmacol, 132, 104-106 (1997). For a review, see Hungund, B.L and B.S. Basavarajappa, "Are Anandamide and Cannabinoid Receptors involved in Ethanol Tolerance? A Review of the Evidence," Alcohol & Alcoholism, 35(2) 126-133, 2000. Current treatments for alcohol abuse or dependence generally suffer from non-compliance or potential hepatotoxicity; therefore, there is a high unmet need for more effective treatment of alcohol abuse/dependence. SUMMARY The present invention provides compounds of Formula (I) or (II).
  • R 1 is an optionally substituted aryl or an optionally substituted heteroaryl (preferably, R 1 is a substituted phenyl, more preferably a phenyl substituted with one to three substituents independently selected from the group consisting of halo (preferably, chloro or fluoro), (C ⁇ -C 4 )alkoxy, (C-i- C 4 )alkyl, halo-substituted (C ⁇ -C 4 )alkyl (preferably fluoro-substituted alkyl), and cyano, more preferably, R 1 is 2-chlorophenyl, 2-fluorophenyl, 2,4- dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4- difluorophenyl); R 2 is an optionally substituted aryl or an optionally substituted heteroaryl (preferably, R 2 is a substituted phenyl, more preferably a phenyl
  • R 2 is 4-chlorophenyl, 4-cyanophenyl, or 4- fluorophenyl
  • R 3 is hydrogen, (C ⁇ -C 4 )alkyl optionally substituted with one or more substituents, or (C 1 -C 4 )alkoxy
  • R 4 is a chemical moiety selected from the group consisting of (C-i- Cg)alkyl, aryl, heteroaryl, aryl(C ⁇ -C 5 )alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), 5-6 membered lactone, 5- to 6-membered lactam, and a 3- to 6-membered partially or fully saturated heterocyde, where said chemical moiety is optionally substituted with one or more substituents; a pharmaceutically acceptable salt thereof,
  • R 1a , R 1b , R 2a , and R 2b are each independently halo, (C ⁇ -C 4 )alkoxy, (C-i- C 4 )alkyl, halo-substituted (C ⁇ -C 4 )alkyl, or cyano; m and n are each independently 0, 1 or 2 (preferably, m and n are each independently 0 or 1 , more preferably, n is 0 and m is 1 ); R 3 and R 4 are as defined above for the compounds of Formulae (I) and (II); a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt.
  • R 3 is hydrogen, (C- ⁇ -C 4 )alkyl, halo-substituted (CrC- 4 )alkyl, or (C-i- C )alkoxy (preferably, R 2 is hydrogen, (C ⁇ -C 4 )alkyl, or halo-substituted (C-i- C 4 )alkyl, more preferably, R 3 is hydrogen or methyl); and R 4 is a chemical moiety selected from (C ⁇ .
  • R 4 is a (d- C 5 )alkyl optionally substituted with phenyl, fluoro-substituted (C ⁇ -C 5 )alkyl, phenyl, cyclopentyl, cyclohexyl, pyranyl, furanyl, pyrrolidinyl, or piperidiny)!; a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt.
  • Preferred compounds of Formula (I) or (III) include: 6-benzyl-3-(4- chloro-phenyl)-2-(2,4-dichloro-phenyl)-2,6-dihydro-pyrazolo[3,4-d]pyridazin-7- one; 6-benzyl-3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-2,6-dihydro- pyrazolo[3,4-d]pyridazin-7-one; and 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)- 6-(2,2,2-trifluoro-ethyl)-2,6-dihydro-pyrazolo[3,4-d]pyridazin-7-one; or a pharmaceutically acceptable solvate or hydrate of the compound.
  • Preferred compounds of Formula (II) or (IV) include: 1-(4-chloro- phenyl)-2-(2,4-dichloro-phenyI)-5-ethyl-1 ,5-dihydro-imidazo[4,5-d]pyridazin-4- one; 2-(4-chloro-phenyl)-1 -(2,4-dichIoro-phenyl)-5-ethyl-1 ,5-dihydro- imidazo[4,5-d]pyridazin-4-one; 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5- cydohexyl-1 ,5-dihydro-imidazo[4,5-d]pyridazin-4-one; and 5-benzyl-2-(4- chloro-phenyl)-1 -(2-chloro-phenyl)-1 ,5-dihydro-imidazo[4,5-d]pyridazin-4
  • compositions that comprises (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.
  • 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 attention deficit hyperactivity disorder (ADHD)) agents (e.g., RitalinTM, StratteraTM, ConcertaTM and AdderallTM), and antiobesity agents (described herein below).
  • a method for treating a disease, condition or disorder modulated by a cannabinoid receptor (preferably, a CB1 receptor) antagonists in animals that includes the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof).
  • a cannabinoid receptor preferably, a CB1 receptor
  • 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 weight loss, obesity, bulimia, ADD/ADHD, 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 or
  • 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. Definitions As used herein, the term "alkyl” refers to a hydrocarbon radical of the general formula C n H 2n+ ⁇ .
  • the alkane radical may be straight or branched.
  • (Ci-C ⁇ jalkyl” 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, /7-pentyl, 1-methylbutyl, 2-methyl butyl, 3-methyl butyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
  • 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., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, and the like).
  • 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 heterocyde, chloro, cyano, hydroxy, (C ⁇ -C 3 )alkoxy, aryloxy, amino, (C-i-C ⁇ Jalkyl amino, di-(C ⁇ -C )alkyl amino, aminocarboxylate (i.e., (CrC 3 )alkyl-0-C(0)-NH-), hydroxy(C 2 - C 3 )alkylamino, or keto (oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituent selected from (C ⁇ -C 3 )alkyl, (C 3 -C 6 )cycloalkyl,
  • 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.
  • carbocyclic ring is generally a 3- to 8-membered ring (preferably, 3- to 6-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 (CrC 3 )alkyl, (C 2 -C- 3 )alkenyl, (C ⁇ - C ⁇ jalkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocyde, chloro, fluoro, cyano, hydroxy, (C- ⁇ -C 3 )alkoxy, aryloxy, amino, (C ⁇ -Ce)alkyl amino, di-(Cr C )alkyl amino, aminocarboxylate (i.e., (CrC 3 )alkyl-0-C(0)-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 heterocyde, fluoro, (C ⁇ -C 3 )alkoxy, (C- ⁇ -C
  • 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 heterocyde”) 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 independently selected from sulfur, oxygen 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 heterocyde 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-dihydrobenzofuranyI, 2,3- dihydroindolyl, 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc.).
  • the heterocyde group is preferably substituted with 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 - C 4 )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocyde, chloro, fluoro, cyano, hydroxy, (C ⁇ -C 3 )alkoxy, aryloxy, amino, (C ⁇ -Ce)alkyl amino, di-(d- C 3 )alkyl amino, aminocarboxylate (i.e., (CrC 3 )alkyl-0-C(0)-NH-), or keto (oxo), and more preferably with 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C ⁇ jaryl, 6-membered-heteroaryl, 3- to 6- membered heterocyde, or fluoro.
  • the heterocyclic group may be attached to the chemical entity or moiety by any one of the ring atoms within the heterocyclic ring system.
  • any heterocyde portion of a group e.g., heterocycle-substituted alkyl, heterocyde 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 When indicated as being “optionally substituted,” 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 (CrC 4 )alkyl, (C 2 -C 3 )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocyde, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C ⁇ -C 4 )alkoxy, aryloxy, amino, (C ⁇ -C ⁇ )alkyl amino, di-(CrC 3 )alkyl amino, or aminocarboxylate (i.e., (Ci-C 3 )alkyl-0-C(0)-NH-), and more preferably, 1 or 2 substituents independently selected from (C ⁇ -C 4 )alkyl, chloro, fluoro, cyano, hydroxy, or (C ⁇ -C 4 )alkoxy.
  • 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 aromatic 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, indazolyl,
  • 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 heterocyde, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C ⁇ -C 4 )alkoxy, aryloxy, amino, (CrC 6 )alkyl amino, di-(C ⁇ -C 3 )alkyl amino, or aminocarboxylate (i.e., (C 1 -C 3 )alkyl-0-C(0)- NH-), and more preferably, 1 or 2 substituents independently selected from (C ⁇ -C 3 )alkyl-
  • 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
  • a heteroaroyl or heteroaroyloxy i.e., (heteroaryl)-C(O)-O-
  • acyl refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocyde, aryl, and heteroaryl substituted carbonyl groups.
  • acyl includes groups such as (C- ⁇ -C 6 )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-carbonyI, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl,
  • alkyl, cycloalkyl, heterocyde, 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, heterocyde, 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 (CrC 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 - C 6 )alkenyl, (C ⁇ -C 6 )alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocyde, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C- ⁇ -C 6 )alkoxy, aryloxy, sulfhydryl (mercapto), (C ⁇ -C 6 )alkylthio, arylthio, amino, mono- or di- (CrC 6 )alkyl amino, quaternary ammonium salts, amino(C ⁇ -C 6 )alkoxy, aminocarboxylate (i.e., (CrC 6 )alkyl-0-C(0)-NH-), hydroxy(C 2 -C 6 )alky
  • substituted combinations such as "substituted aryl(Cr C ⁇ jalkyl"
  • 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.).
  • halo refers to a chloro, bromo, fluoro or iodo group.
  • 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.
  • 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.
  • protecting group 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 alkyl, -CH 2 CH 2 S0 2 Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • T. W For a general description of protecting groups and their use, see T. W.
  • 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. A preferred animal is a human.
  • 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), (II), (III) and (IV), 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.
  • DETAILED DESCRIPTION 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. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • BOC t- butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9- fluorenylmethyleneoxycarbonyl
  • the pyrazolone (1a) can then be treated with phosphorus oxychloride in a polar solvent (e.g., dimethylformamide (DMF)) to produce the chloroaldehyde (1 b).
  • a polar solvent e.g., dimethylformamide (DMF)
  • the chloro aldehyde derivatives can be synthesized using procedures analogous to those described in Journal of Heterocyclic Chemistry, 27(2), 2434-5 (1990).
  • the chloroaldehyde (1 b) can be reacted with alkyl or aryl organometallic reagent, such as dialkylzinc, alkylmagnesium chloride or bromide, and arylmagnesium chloride or bromide, to provide an intermediate alcohol derivative which can be oxidized to the ketone (1c) using oxidizing reagents, such as pyridinium chlorochromate (PCC), Cr0 3 , Swern oxidation conditions and others well known to chemists skilled in the art.
  • oxidizing reagents such as pyridinium chlorochromate (PCC), Cr0 3 , Swern oxidation conditions and others well known to chemists skilled in the art.
  • PCC pyridinium chlorochromate
  • Cr0 3 pyridinium chlorochromate
  • Swern oxidation conditions and others well known to chemists skilled in the art.
  • the conditions for the addition of organometallic reagents
  • the oxidation conditions are as described in Heterocvdes, 29(10), 381-386 (1989).
  • the hydrazone (1d) can then be formed from chloroaldehyde intermediate (1b) or ketone (1c) by reacting the chloroaldehyde (1 b) or ketone (1c) with a protected hydrazine using procedures analogous to those described in Pharmazie, 54(2), 106-111 (1999).
  • Preferred protecting groups include t-butylcarbamoyl, benzyl, benzyloxy carbamoyl, acetyl, and the like. Use of t-butyl carbamoyl is preferred because of ease of deprotection during cyclization.
  • the hydrazone (1d) can then be heated to 60°-100°C in the presence of acids (e.g., acetic acid, HCI, or pTsOH) in solvents such as DMF, dioxane, or toluene to provide the pyridazinone (1e).
  • acids e.g., acetic acid, HCI, or pTsOH
  • solvents such as DMF, dioxane, or toluene
  • the pyridazinone (1e) can then be reacted with a suitable aryl boronic acid, according to the procedures described in
  • aryl substituted pyridazinone (1f) Tetrahedron, 56, 5499 (2000), using tetrakistriphenylphosphine as a catalyst to provide the desired aryl substituted pyridazinone (1f).
  • Other Suzuki reaction conditions can also be used to prepare the aryl pyridazinone (1f) (see, e.g., Chem. Rev. 2457 (1995) and references cited therein).
  • the pyridazinone (1f) can be treated with alkyl halides in the presence of base in a solvent such as DMF, THF, DMSO, NMP, etc to provide pyridazinone (1g).
  • the alkyl halides are generally commercially available.
  • the aldehyde or ketone intermediate (2a), prepared as described in Scheme I, can be converted to the acid (2b) by reacting with a suitable base (e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide) in an alcoholic solvent (e.g., ethanol).
  • a suitable base e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide
  • an alcoholic solvent e.g., ethanol
  • the acid (2b) can be reacted with a chlorinating agent (e.g., oxalyl chloride or thionyl chloride) to generate an intermediate acyl chloride derivative which can be treated in situ with an appropriately substituted alkyl hydrazine derivative to provide the pyridazinone intermediate (2c).
  • Cross-coupling of intermediate (2c) with an arylboronic acid in the presence of a palladium catalyst e.g., t ⁇ trakistriphenylphosphine
  • Intermediate (3a) can be prepared by treating the appropriate amine having the desired R 2 group with trimethylaluminum under inert atmospheric conditions followed by condensation with the appropriate cyanide having the desired R 1 group.
  • Suitable amines include substituted phenyl amines (e.g., 4- chlorophenyl amine, 4-fluorophenyl amine, 4-bromophenyl amine, 4- iodophenyl amine, 4-cyanophenyl amine, and the like) pyridin-2-yl amine, pyridin-3-yl amine, pyridin-4-yl amine, substituted pyridinyl amines (e.g., 2- dimethylaminopyridin-5-yl amine, 2-methoxypyridin-5-yl amine, 5- c loropyridin-2-yl amine, 5-methylpyridin-2-yl, 5-methoxypyridin-2-yl amine, 3- chloropyridin-4-y
  • Suitable cyano compounds include substituted benzonitriles (e.g., 2-chlorobenzonitrile, 2-fluorobenzonitrile, 2- methoxybenzonitrile, 2-methylbenzonitrile, 2,4-dichlorobenzonitrile, 2,4- difluorobenzonitrile, 2-chloro-4-fluorobenzonitrile, 2-chloro-4- methylbenzonitrile, 2,4-dimethoxybenzonitrile, 2-methyl-4-chlorobenzonitrile, and the like), cyano-substituted pyridines (e.g., 4-cyano-3-chloropyridine) and other commercially available or easily synthesized substituted or unsubstituted aryl or heteroaryl nitriles.
  • substituted benzonitriles e.g., 2-chlorobenzonitrile, 2-fluorobenzonitrile, 2- methoxybenzonitrile, 2-methylbenzonitrile, 2,4-dichlorobenz
  • Intermediate (3a) can then be condensed with a 3-bromo-2-oxo- propionic acid ester to produce the cyclized 4-hydroxy-4,5-dihydro-1 H- imidazole ester (3b) using procedures analogous to those described by Khanna, I.K., et al., in J. Med. Chem., 40, 1634 (1997).
  • the amidine intermediate (3a) is refluxed in a polar solvent (e.g., isopropanol) in the presence of a mild base (e.g., sodium bicarbonate).
  • a mild base e.g., sodium bicarbonate
  • intermediate (3b) can be treated with methanesulfonyl chloride in the presence of a base (e.g., triethylamine) to provide (3c).
  • a base e.g., triethylamine
  • Intermediate (3d, where L 1 is a halogen) can be synthesized from imidazole ester (3c) using a halogenating agent such as bromine, N- bromosuccinimide, iodine, or N-iodosuccinamide in a suitable protic solvent such as glacial acetic acid or trifluoroacetic acid or an aprotic solvent such as acetonitrile, ether or THF, at reaction temperatures ranging from 35° - 100°C.
  • a halogenating agent such as bromine, N- bromosuccinimide, iodine, or N-iodosuccinamide
  • a suitable protic solvent such as glacial acetic acid or trifluoroacetic acid or an aprotic solvent such as acetonitrile, ether or THF
  • intermediate l-3c is treated with bromine in glacial acetic acid at room temperature.
  • intermediate (3e) may be prepared directly from (3c) by treatment with Vilsmeier reagent (prepared from an equivalent of POCI 3 or POBr 3 and an equivalent of DMF) in a solvent such as DMF or CH 2 CI 2 , followed by hydrolysis.
  • the aldehyde intermediate (3e) can be reacted with aqueous hydrazine in a polar solvent (e.g., ethanol) at refluxing temperatures to give intermediate (3f) which can be cyclized to (3g) in a non-polar solvent (e.g., benzene, toluene) under refluxing conditions in the presence of an acid catalyst (e.g., p- TsOH, HOAc).
  • a polar solvent e.g., ethanol
  • an acid catalyst e.g., p- TsOH, HOAc
  • Scheme IV illustrates an alternative method for synthesizing aldehyde intermediate (3e).
  • the 5-hydroxymethylimidazolyl derivative (4d) can be treated with oxalyl chloride, DMSO and a tertiary amine base such as triethylamine or diisopropylethylamine in a halogenated solvent such as CH 2 CI 2 or CHCI 3 .
  • the intermediate (4d) can be oxidized using Mn0 2 in a polar or non-polar solvent such as MeOH, acetone, dioxane, ether, CH 2 CI 2 , or CHCI 3 .
  • Compounds of Formula (ll-B) or (IV-B) where R 3 is an alkyl or aryl group can be prepared by the route shown in Scheme V.
  • Reaction of (5a) with an appropriately substituted hydrazine derivative in a polar solvent e.g., ethanol
  • a polar solvent e.g., ethanol
  • salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound, 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, lactobionate, and laurylsulfonate salts, and the like.
  • the salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as 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), (II), (III) or (IV), 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 ⁇ -C 8 )alkyl, (C 2 -C ⁇ 2 )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 ca on atoms, 1-(N-(N-C 8 )alkyl, (C 2 -C ⁇ 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C- ⁇ -C 2 )alkylamino(C 2 - C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(C ⁇ -C 2 )alkyl, N,N-di(Cr C 2 )alkylcarbamoyl-(C ⁇ -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2 - C 3 )alkyl.
  • 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 )alkanoyloxy)ethyl, 1-methyl-1-((Cr C 6 )alkanoyloxy)ethyl, (C ⁇ -C 6 )alkoxycarbonyloxymethyl, N-(Cr C 6 )alkanoyloxymethyl, 1-((C C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Cr C 6 )alkanoyloxy)ethyl, (C ⁇ -C 6 )alkoxycarbonyloxymethyl, N-(Cr C 6 )alkanoyloxymethyl, 1-((C C 6 )alkanoyloxymethyl, 1-((C C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Cr C 6 )alkanoyloxy)eth
  • each ⁇ -aminoacyl group is selected from the naturally occurring L-amino acids, P(0)(OH) 2 , P(0)(0(CrC 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • 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 (C ⁇ -C ⁇ .0 )alkyl, (C 3 - C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl-natural ⁇ -aminoacyl, -C(OH)C(0)OY' wherein Y' is H, (d-C 6 )alkyl or benzyl, -C(OY 0 )Y ⁇ wherein Y 0 is (C 1 -C 4 ) alkyl and Y-t is (CrC 6 )alkyl, carboxy(C ⁇ -C 6 )alkyl, amino(C ⁇ -C 4 )alkyl or mono-
  • 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 transforms, 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 intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • a specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • 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, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C,
  • 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.
  • 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.
  • Positron emitting isotopes such as 15 0, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • 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 herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Another aspect of the present invention is 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, 11 ⁇ - hydroxy steroid dehydrogenase-1 (11 ⁇ -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 agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonist
  • anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ - hydroxy steroid dehydrogenase-1 (11 ⁇ -HS
  • anorectic agents such as a bombesin agonist
  • Neuropeptide-Y antagonists e.g., NPY Y5 receptor antagonists, such as the spiro compounds described in US Patent Nos. 6,566,367; 6,649,624; 6,638,942; 6,605,720; 6,495,559; 6,462,053; 6,388,077; 6,335,345; and 6,326,375; US Publication Nos. 2002/0151456 and 2003/036652; and PCT Publication Nos. WO 03/010175.
  • thyromimetic agents dehydroepiandrosterone or an analog thereof, 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 proteins (AGRP), 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
  • human agouti-related proteins AGRP
  • ghrelin receptor antagonists histamine 3 receptor antagonists or inverse agonists
  • neuromedin U receptor agonists and the like thyromimetic agents, dehydroepiandrosterone
  • 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, pseudoephedrine, PYY 3-3 6 or an analog thereof, and 2-oxo-N-(5- phenylpyrazinyl)spiro-[isobenzofuran-1 (3H),4'-piperidine]-1 '-carboxamide.
  • 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; PYY 3-36 (including analogs thereof) can be prepared as described in US Publication No.
  • NPY Y5 receptor antagonist 2-oxo-N-(5- phenylpyrazinyl)spiro[isobenzofuran-1 (3H),4'-piperidine]-1 '-carboxamide can be prepared as described in US Publication No. 2002/0151456.
  • Other useful NPY Y5 receptor antagonists include those described in PCT Publication No.
  • 03/082190 such as 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran- 1 (3H), 4'-piperidine]-1 '-carboxamide; 3-oxo-N-(7-trifluoromethylpyrido[3,2- b]pyridin-2-yl)-spiro-[isobenzofuran-1 (3H), 4'-piperidine]-1 '-carboxamide; N- [5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1 (3H), [4 1 - piperidine]-1 '-carboxamide; fra/?s-3'-oxo-N-(5-phenyl-2-pyrimidinyl)] spiro[cydohexane-1 ,1 '(3'H)-isobenzofuran]-4-carboxamide; frans-3'
  • tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the trade name 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
  • antihypertensive agents include antihypertensive agents; 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) and GLP-1 (7-36)-NH 2 ; sulfonylureas and analogs thereof: chlorpropamide, glibendamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepiride
  • 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 e.g., anti-obesity agent
  • the dosage range of an antiobesity 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 0 mg per kilogram body weight of the individual per day.
  • some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like.
  • the determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
  • another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • a compound of the present invention may be administered in combination with at least one additional pharmaceutical agent (referred to herein as a "combination") which is also preferably administered in the form of a pharmaceutical composition.
  • a compound of the present invention or a combination can be administered in any conventional oral, rectal, transdermal, parenteral, (for example, intravenous, intramuscular, or subcutaneous) intracisternal, intravaginal, intraperitoneal, intravesical, local (for example, powder, ointment or drop), or buccal, or nasal, dosage form.
  • the compound of the present invention and at least one other pharmaceutical agent e.g., anti-obesity agent described above
  • a combination When a combination is administered, such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred.
  • the combination 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 the compound of the present invention and the additional pharmaceutical agent can be by the same or by different methods.
  • a typical formulation is prepared by mixing a compound of the present invention and a excipient, diluent or carrier. Suitable excipients, diluents and carriers 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.
  • 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 dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray-dried dispersion, such as those described by Takeuchi, H., et al. in "Enhancement of the dissolution rate of a poorly water- soluble drug (tolbutamide) by a spray-drying solvent depostion method and disintegrants" J. Pharm. Pharmacol., 39, 769-773 (1987).
  • compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions.
  • the compositions generally include sterile excipients, diluents or carriers for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous excipients, diluents or carriers 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 pharmaceutically acceptable excipient, diluent or carrier.
  • Suitable excipients, diluents, or carriers include sodium citrate or dicalcium phosphate, or (a) fillers or extenders (e.g., starches, lactose, sucrose, mannitol, silicic acid and the like); (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like); (c) humectants (e.g., glycerol and the like); (d) disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate and the like); (e) solution retarders (e.g., paraffin and the like); (f) absorption accelerators (e.g., quaternary ammonium compounds and the like); (g) wetting agents (e.g., cetyl alcohol, glycerol mono
  • 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 excipients, diluents or carriers.
  • Suitable excipients, diluents or carriers include additives 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.
  • additives such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benz
  • suitable additives include 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, diluents, 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, diluents, 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 condition with a pharmaceutically acceptable excipient, diluent or 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 compound of the present invention or combination 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 then 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 following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals.
  • the administration of a compound of the present invention or combination i.e., a compound of the present invention with at least one additional pharmaceutical agent
  • 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 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 with an excipient, diluent or 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.
  • 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.
  • Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM). Low-resolution mass spectral data (El) were obtained on a Automass 120 (JEOL) mass spectrometer. Liquid Chromatography data was collected on a Hewlett Packard 1100 Liquid Chromatography/ Mass Selective Detector (LC/MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml/minute running a gradient of 50% 0.1 % aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes.
  • the ionization type for the mass detector of the Mass Spectrophotometer was atmospheric pressure electrospray in the positive ion mode with a fragmentor voltage of 50 volts.
  • THF tetrahydrofuran
  • CH 2 CI 2 dichloromethane (DCM)
  • NaHC0 3 sodium bicarbonate
  • HCI hydrogen chloride
  • DME dimethoxyethane
  • n-BuLi n-butyllithium
  • DMF dimethylformamide
  • DCE dichloroethane
  • reaction mixture was cooled to room temperature, concentrated down to -50 ml, quenched with 800 ml of ice water (CAUTION: significant heat and gas evolution occurred), and extracted with ethyl acetate (3x300ml). The combined organic extracts were dried and concentrated under vacuum to give the crude product.
  • the heterogenous mixture was heated at 80°C for 17 hours, cooled to room temperature, diluted with CHCI 3 /methanol (2:1 ), and poured over a slurry of silica gel.
  • the filter cake was washed with additional CH 2 CI 2 /MeOH (2:1 ).
  • the combined filtrates were concentrated in vacuo, and the resulting yellow solid was triturated with hexanes/ether (2:1).
  • the product h ⁇ a (25.1 g, 66%) was used without further purification.
  • reaction mixture was stirred at -78 °C for 2.5 hours, quenched with saturated aqueous NH CI (10 ml), allowed to slowly warm to room temperature, and finally poured into saturated aqueous NaCI.
  • the aqueous solution was extracted with Et 2 0 (3x) and the combined organic extracts were dried (Na 2 S0 4 ) and concentrated in vacuo.
  • Example 1 illustrates the preparation of 2,6-dihydro-pyrazolo[3,4- d]pyridazin-7-one analogs having the general Formulae (I) and (III).
  • 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.
  • 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.
  • 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.
  • 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.
  • drug buffer (0.5% BSA, 10% DMSO, and 80.5% TME)
  • 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.
  • 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 m 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
  • 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.
  • Cannabinoid agoinists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and 5-(1 ,1 -dimethyl-heptyI)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol have been shown to affect four characteristic behaviors in mice, collectively known as the Tetrad.
  • Tetrad mice
  • Negative numbers indicate a potentiation of the agonist activity or non-antagonist activity. Positive numbers indicate a reversal of activity for that particular test.
  • mice were pre-treated with test compound (sc, po, ip, or icv). Fifteen minutes later, the mice were challenged with 5-(1 ,1-dimethyl-heptyl)-2- [5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol (sc). Twenty-five minutes after the agonist injection, the mice were placed in clear acrylic cages (431.8 cm x 20.9 cm x 20.3 cm) containing clean wood shavings. The subjects were allowed to explore surroundings for a total of about 5 minutes and the activity was recorded by infrared motion detectors (available from Coulbourn InstrumentsTM, Allentown, PA) that were placed on top of the cages.
  • infrared motion detectors available from Coulbourn InstrumentsTM, Allentown, PA
  • test compounds sc, po, ip or iv
  • each mouse was tested for reversal of analgesia using a standard hot plate meter (Columbus Instruments).
  • the hot plate was 10" x 10" x 0.75" with a surrounding clear acrylic wall. 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.
  • 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.
  • Food was provided to the rats 30 minutes after dosing and the Oxymax automated food intake system (Columbus Instruments, Columbus, Ohio) was started. Individual rat food intake was recorded continuously at 10-minute intervals for a period of two hours. When required, food intake was recorded manually using an electronic scale; food was weighed every 30 minutes after food was provided up to four hours after food was provided. Compound efficacy was determined by comparing the food intake pattern of compound-treated rats to vehicle and the standard positive control.
  • 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 (17-19 g) mice were individually housed upon arrival 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.
  • 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 300-380g 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. s.c, i.p., i.v.).
  • 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

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) et (II), ainsi que leurs utilisations dans le traitement de maladies liées à la médiation des récepteurs cannabinoïdes (notamment le récepteur CB-1) chez l'animal.
PCT/IB2004/004017 2003-12-16 2004-12-06 Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations Ceased WO2005061504A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52990903P 2003-12-16 2003-12-16
US60/529,909 2003-12-16

Publications (1)

Publication Number Publication Date
WO2005061504A1 true WO2005061504A1 (fr) 2005-07-07

Family

ID=34710147

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/004017 Ceased WO2005061504A1 (fr) 2003-12-16 2004-12-06 Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2005061504A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2909090A1 (fr) * 2006-11-23 2008-05-30 Sanofi Aventis Sa Derives de 2,5-dihydro-3h-pyrazolo[4,3-c]pyridazin-3-one substitues,leur preparation et leur application en therapeutique.
US7728141B2 (en) 2003-11-04 2010-06-01 Merck Sharp & Dohme Corp. Substituted naphthyridinone derivatives
WO2011097553A1 (fr) * 2010-02-08 2011-08-11 Allergan, Inc. Agonistes du cannabinoïde-2

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3244715A (en) * 1964-10-30 1966-04-05 Smith Kline French Lab Phenylimidazo [4, 5-d] pyridazines
US4656171A (en) * 1983-12-23 1987-04-07 Dr. Karl Thomae Gmbh 2-phenyl-imidazo-pyrazines, useful as cardiotonics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3244715A (en) * 1964-10-30 1966-04-05 Smith Kline French Lab Phenylimidazo [4, 5-d] pyridazines
US4656171A (en) * 1983-12-23 1987-04-07 Dr. Karl Thomae Gmbh 2-phenyl-imidazo-pyrazines, useful as cardiotonics

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BARTH F: "Cannabinoid receptor agonists and antagonists", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 8, no. 3, March 1998 (1998-03-01), pages 301 - 313, XP002150850, ISSN: 1354-3776 *
GOYA P ET AL: "RECENT ADVANCES IN CANNABINOID RECEPTOR AGONISTS AND ANTAGONISTS", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 10, no. 10, 2000, pages 1529 - 1538, XP001036546, ISSN: 1354-3776 *
PALMER S L ET AL: "Review: Cannabinergic ligands", CHEMISTRY AND PHYSICS OF LIPIDS, LIMERICK, IR, vol. 121, 2002, pages 3 - 19, XP002977255, ISSN: 0009-3084 *

Cited By (9)

* 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
FR2909090A1 (fr) * 2006-11-23 2008-05-30 Sanofi Aventis Sa Derives de 2,5-dihydro-3h-pyrazolo[4,3-c]pyridazin-3-one substitues,leur preparation et leur application en therapeutique.
WO2008068424A3 (fr) * 2006-11-23 2008-07-24 Sanofi Aventis Derives de 2, 5-dihydro-3h-pyrazolo [4, 3-c] pyridazin-3-one substitues, leur preparation et leur utilisation comme ligands des recepteurs cb1 des cannabinoides
US7915258B2 (en) 2006-11-23 2011-03-29 Sanofi-Aventis Substituted 2,5-dihydro-3H-pyrazolo[4,3-C]pyridazin-3-one derivatives, preparation thereof and therapeutic use of the same
WO2011097553A1 (fr) * 2010-02-08 2011-08-11 Allergan, Inc. Agonistes du cannabinoïde-2
JP2013518907A (ja) * 2010-02-08 2013-05-23 アラーガン インコーポレイテッド カンナビノイド−２作動薬として有用なピリダジン誘導体
US9062004B2 (en) 2010-02-08 2015-06-23 Allergan, Inc. Cannabinoid-2 agonists
EP2957560A1 (fr) * 2010-02-08 2015-12-23 Allergan, Inc. Dérivés de pyridazine utiles en tant qu'agonistes du cannabinoïde-2
US9670216B2 (en) 2010-02-08 2017-06-06 Allergan, Inc. Cannabinoid-2 agonists

Similar Documents

Publication Publication Date Title
EP1622903B1 (fr) Ligands de recepteurs cannabinoides et leurs applications
US7232823B2 (en) Cannabinoid receptor ligands and uses thereof
US7354929B2 (en) Cannabinoid receptor ligands and uses thereof
US7145012B2 (en) Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) Cannabinoid receptor ligands and uses thereof
US20040259887A1 (en) Cannabinoid receptor ligands and uses thereof
WO2004099157A1 (fr) Ligands de recepteurs cannabinoides et leurs applications
US20050026983A1 (en) Imidazole compounds and uses thereof
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
WO2005061504A1 (fr) Composes bicycliques de pyridazinone utiles en tant que ligands des recepteurs cannabinoides et leurs utilisations
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
US20070213334A1 (en) Cannabinoid receptor ligands and uses thereof

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): 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 LT 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