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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to bisarylimidazolyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions affected by inhibiting fatty acid amide hydrolase.
• Neuropathic pain is caused by injury to nerves as the result of many factors including physical damage (e.g., trauma, surgery), drugs such as Zidovudine (AZT), Carmustine (BCNU) and disease (e.g., diabetes, herpes zoster).
• drugs such as Zidovudine (AZT), Carmustine (BCNU) and disease (e.g., diabetes, herpes zoster).
• ZCT Zidovudine
• BCNU Carmustine
• diabetes herpes zoster
• the prevalence in the United States of neuropathies associated with diabetes, herpes and amputation is estimated at 1.5 million.
• the worldwide prevalence of diabetic neuropathy alone is expected to reach 12 million by 2007.
• Nerve injury can result in both allodynia and hyperalgesia.
• NSAIDs non-steroidal anti- inflammatory drugs
• other analgesics as well as anticonvulsants (e.g., carbamazepine, gabapentin) and tricyclic antidepressants (e.g., amitryptiline).
• Effective treatment of pain with current therapies is limited by adverse effects and a lack of efficacy against all components of pain.
• cannabinoids The analgesic properties of cannabinoids have been known for many years and to many cultures. Cannabinoids are active in many pre-clinical models of pain, including neuropathic pain. Within the last few years, several endogenous cannabinoids, including the fatty acid amides arachidonylethanolamide (anandamide), and arachidonyl amino acids such as N-arachidonylglycine, homo- ⁇ - linolenyl-ethanolamide and docosatetraenyl-ethanolamide, as well as 2-arachidonyl- glycerol, have been shown to induce analgesia in laboratory animals (DeVane, W. A. et.
• cannabinoid receptor antagonists and cannabinoid receptor antisense to induce hyperalgesia in animals suggests that endogenous cannabinoids regulate the nociceptive threshold (Hargreaves, K. M. et al., Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia J. Neurosci. 18: 451-457, 1998; Piomelli, D. et. al, Control of Pain Initiation By Endogenous Cannabinoids, Nature 394: 277-281, 1998; Fields, H. L. et. al., An Analgesia Circuit Activated By Cannabinoids, Nature 395: 381-383, 1998).
• Elevation of levels of neuroactive fatty acid amides such as anandamide may provide a unique mechanism to achieve analgesia.
• the mechanisms by which endogenous cannabinoids are synthesized are not well understood; therefore, targets for drugs aimed at increasing the synthesis of these compounds are slow to be identified.
• FAAH fatty acid amide hydrolase
• R 1 are R 2 are each independently H, C 1-3 alkyl or halo;
• R 3 is Ci-C 3 alkyl or C 3-7 cycloalkyl
• A is C 1-12 alkylene or L
• L is -phenyl-O-C 1-4 alkylene wherein said C 1-4 alkylene is attached to D; provided that if A is L, then D is X(O)O and A-D is not interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene;
• X is C and is attached to A
• Y is N and is attached to A;
• G is H, C 1-5 alkyl, C 1-5 haloalkyl, C 3-7 cycloalkyl, phenyl, -C 1-2 alkylene-phenyl, C-pyridyl or N-pyridyl, said phenyl or -C 1-2 alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO 2 , CN, -C(O)O-C 1-3 -alkyl, C 1-3 alkyl, hydroxy and C 1-3 alkoxy;
• G' is H, C 1-5 alkyl or C 1-5 haloalkyl; wherein A-D is optionally interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene; wherein Z is O or S and is attached to A;
• J is CH and is attached to A, D and J' ;
• J' is C 1-4 alkyl or phenyl; and provided that if A-D is interrpted with -Z-phenyl-, then A is C ⁇ -5 alkylene; if A-D is not interrpted with -Z-phenyl-, then A is C 5-1 2 alkylene.
• compounds of Formula (I) according to the first embodiment of the first aspect wherein R and R are each fluoro. According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R 3 is methyl. According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R is ethyl.
• compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C 3-1 oalkylene According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C 7-1 oalkylene.
• G is phenyl or -C 1- alkylene-phenyl, said phenyl or phenyl of said - C 1-2 alkylene-phenyl are optionally substituted with the same or different substitutents selected from the group consisting of halo, CN, -C(O)O-C 1-3 -alkyl, C 1-3 alkyl and C ⁇ . 3 alkoxy.
• compounds of Formula (I) according to the first embodiment of the first aspect wherein G is phenyl or -C 1- alkylene-phenyl, said phenyl or phenyl of said - C 1-2 alkylene-phenyl are substituted with halo, -C(O)O-C 1-3 -alkyl, C 1-3 alkyl or Q. 3 alkoxy.
• R 1 and R 2 are each H, R 3 is C 1-3 alkyl, A is C 7-1 oalkylene, D is X(O)O and A-D is not interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• R 1 and R 2 are each H, R 3 is C 1-3 alkyl, A is Ci-salkylene, D is X(O)O and A-D is interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• compounds of Formula (I) according to the first embodiment of the first aspect wherein R 1 and R 2 are each H, R 3 is C 1-3 alkyl, A is C -1 oalkylene, D is X(O)N(G') and A-D is not interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• compounds of Formula (I) according to the first embodiment of the first aspect wherein R 1 and R 2 are each H, R 3 is C 1-3 alkyl, A is C -1 oalkylene, D is X(O)N(G') and A-D is not interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• R and R are each H, R is C 1-3 alkyl, A is C 1-5 alkylene, D is X(O)N(G') and A-D is interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• R and R are each H, R is C 1-3 alkyl, A is C 7-1 oalkylene, D is HYC(O)O and A-D is not interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• HYC(O)O and A-D is interrupted with J-J', -Z-phenyl- or -Z-C 1-3 alkylene.
• 3-Pyridinecarboxaldehyde O-[6-(2-methyl-4,5-diphenyl-lH-imidazol-l- yl)hexyl] amino] carbonyl] oxime; ⁇ 4-[3-(2-Methyl-4,5-diphenyl-imidazol-l-yl)-propoxy]-phenyl ⁇ -carbamic acid 3,4- difluoro-phenyl ester;
• a third aspect of the present invention are provided methods of treating conditions the treatment of which can be effected by the inhibitition of FAAH by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
• a method of treating pain, more particularly chronic pain, acute pain and neuropathic pain by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
• a pharmaceutical composition comprising
• a pharmaceutical composition comprising
• a method of providing neuroprotection and contraception and yet further methods of psychomotor disorder, hypertension, cardiovascular disease, eating disorder, nausea, AIDS-related complex, glaucoma, inflammation, psoriasis and multiple sclerosis by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
• Raphael Mechoulam "Looking Back at Cannabis Research," Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1313-1322 (p. 1319); Sumner H. Burstein, "Ajulemic Acid (CT3): A Potent Analog of the Acid Metabolites of THC," Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1339-1345 (p.
• halo or halogen
• alkyl or “alkylene” includes straight or branched chain configurations.
• the compounds of this invention can exist in the form of pharmaceutically acceptable salts.
• Such salts include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid.
• the acidic group can exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt and a calcium salt; and salts with organic bases such as a triethylammonium salt and an arginine salt.
• the compounds of the present invention may be hydrated or non-hydrated.
• the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
• the compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts.
• the compounds can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice.
• Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
• the dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level which will produce effective beneficial effects without causing any harmful or untoward side effects.
• reaction mixture was let stirred at -78°C for 1 hr, then warming up to room temperature and let stirred for 18 hrs. The next day, analysis by TLC indicated consumption of starting material.
• the reaction was quenched with aqueous Ammonium Chloride (10 ml).
• the aqueous layer was extracted with Ethyl Acetate (3x25 ml).
• the organic layers obtained were combined, dried over Sodium Sulfate and filtered .
• the resultant filtrate was concentrated in vacuo. Purification by flash column chromatography using Hexane/Ethyl Acetate (4: 1) gave rise to product (150 mg, 45%).
• the reaction mixture was let stirred at room temperature for 10 minutes under Nitrogen, then at 108°C for 90 minutes.
• the reaction was let cooled to room temperature, to which 2- Fluorophenol (0.03 ml, 0.038g, 0.338 mmole) was added.
• the reaction mixture was let stirred at room temperature for 30 minutes, then at 100°C for 18 hrs.
• analysis by TLC (Dichloromethane/Ethyl Acetate 3:1) indicated consumption of starting material.
• the reaction was let cooled to room temperature, where the solvent was removed by rotorvap.
• the crude material was purified by flash column chromatography using Dichloromethane/Ethyl Acetate (6:1 to 3:1). Product was obtained (110 mg, 71%).
• the reaction mixture was let stirred at room temperature for 10 minutes under Nitrogen, then at 108°C for 90 minutes.
• the reaction was let cooled to room temperature, to which 2- Fluorophenol (0.03 ml, 0.038g, 0.338 mmole) was added.
• the reaction mixture was let stirred at room temperature for 10 minutes, then at 100°C for 18 hrs.
• analysis by TLC (Dichloromethane/Ethyl Acetate 3:1) indicated consumption of starting material.
• the reaction was let cooled to room temperature, where the solvent was removed by rotorvap.
• the crude material was purified by flash column chromatography using dichloromethane/Ethyl Acetate (6:1 to 3:1). Product was obtained (58 mg, 33.1%).
• H4-FAAH cells Homogenates of crude membranes were prepared from H4 cells that express transfected human FAAH (H4-FAAH cells). Briefly, cells were grown in DMEM supplemented with 10% FBS and Geneticin at a final concentration of 500 ⁇ g/ml(Gibco BRL, Rockville, MD). Confluent cultures of H4-FAAH cells were rinsed twice with phosphate-buffered saline [138 mM NaCl, 4.1 mM KC1, 5.1 mM Na 2 PO 4 , 1.5 mM KH 2 PO 4 (pH 7.5), 37°C] and incubated for 5-10 min. at 4°C in lysis buffer [1 mM sodium bicarbonate].
• example 1 was active in phase I (acute phase) and phase II (chronic phase) of the rat formalin test.
• phase I acute phase
• phase II chronic phase
• the number of paw flinches was reduced by nearly 40% in the first 10 minutes after administration of formalin. Paw flinches were reduced by approximately 30% over the following 50 minutes.
• the effect of example 1 was similar to that seen with a 3 mg/kg, i.p. dose of morphine.
• Example 1 Morphine Example 1 Morphine mg/kg, i.v. mg/kg, i.p. mg/kg, i.v. mg/kg, i.p.
• HARGREAVES TEST (Acute Thermal Pain): In animals that received Example 1, the latency to paw withdrawal was increased significantly. The present results confirm, the activity of Example 1 against acute pain.
• Example 1 was examined in the Chung model of neuropathic pain where animals exhibit a pain response (paw withdrawal) to a normally innocuous stimulus (light touch). In animals with a neuropathic injury, the threshold for withdrawal of the injured paw was increased (toward normal) in a dose-dependent fashion by Example 1. The anti-neuropathic effect observed with 20 mg/kg Example 1 exhibited earlier onset of action compared to 100 mg/kg gabapentin (reference compound) with similar peak efficacy.

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