WO2003065989A2 - (oxime)carbamoyl fatty acid amide hydrolase inhibitors - Google Patents

(oxime)carbamoyl fatty acid amide hydrolase inhibitors Download PDF

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Publication number
WO2003065989A2
WO2003065989A2 PCT/US2003/003222 US0303222W WO03065989A2 WO 2003065989 A2 WO2003065989 A2 WO 2003065989A2 US 0303222 W US0303222 W US 0303222W WO 03065989 A2 WO03065989 A2 WO 03065989A2
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phenyl
oxime
amino
carbonyl
compound
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French (fr)
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WO2003065989A3 (en
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Sing-Yuen Sit
Kai Xie
Hongfeng Deng
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to JP2003565415A priority Critical patent/JP2005516986A/ja
Priority to EP03737600A priority patent/EP1472215A4/en
Priority to AU2003210824A priority patent/AU2003210824A1/en
Publication of WO2003065989A2 publication Critical patent/WO2003065989A2/en
Publication of WO2003065989A3 publication Critical patent/WO2003065989A3/en
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C271/60—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups having oxygen atoms of carbamate groups bound to nitrogen atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention Yelates to novel (oxime)carbamoyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions which can be effected by inhibiting fatty acid amide hydrolase.
  • 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 (anandamid ⁇ ), 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.
  • FAAH fatty acid amide hydrolase
  • A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
  • R is C-i -16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with C ⁇ -4 alkyl; phenoxy; phenyl-C ⁇ - alkyloxy-; pyridyloxy; pyridyl-C ⁇ -4 alkyloxy-; -N(H)-C(0)-C 1-16 alkyl; or -C(O)-N(H)-C ⁇ . ⁇ 6 alkyl;
  • R 1 is a bond or a C 1 - 3 branched or linear aliphatic hydrocarbon
  • B is C- ⁇ - 4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzohienyl, fluorenyl, carbazolyl, naphthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of C ⁇ -4 branched or linear aliphatic hydrocarbon, C 1 . 4 alkoxy, halo, haloalkyl, nitro and (C ⁇ -3 alkyl) 0-2 amino-; or represented by Formula III, or Formula IV:
  • R 2 is hydrogen, halo or C ⁇ -4 alkyl
  • R 3 is Ci- 4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo,tician C 1-4 haloalkyI and nitro
  • X is CH or nitrogen
  • R 4 is Ci- 4 branched or linear aliphatic hydrocarbon, C ⁇ - alkoxy, halo, haloalkyl, nitro or amino
  • b is 0 to 3, provided that if R 2 is halo, then R 3 is not halo; and if R 3 is halo, the R 2 is not halo.
  • A is dibenzofuranyl.
  • R is C- ⁇ - 4 alkoxy optionally substituted with phenyl, phenoxy, pyridyloxy, or amido optionally substituted with CM 6 alkyl,
  • R 1 is a bond
  • B is represented by Formula III:
  • R 2 is hydrogen
  • R 3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • R 2 is hydrogen or methyl
  • R 3 is methyl or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • R 2 is hydrogen or methyl; and R 3 is methyl, or phenyi optionally substituted with one or more halo, haloalkyl or nitro.
  • B is represented by Formula IV:
  • R 2 is hydrogen, or methyl
  • R 3 is Ci- 4 alkyl, pyridyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro, X is CH or nitrogen,
  • R 4 is C- ⁇ - 4 branched or linear aliphatic hydrocarbon, C1- 4 alkoxy, halo, haloalkyl or amino, and b is 0 to 3.
  • R 2 is hydrogen or methyl
  • R 3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • compounds of Formula VI according to the first embodiment of the second aspect wherein R 2 is hydrogen and R 3 is phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • compounds of Formula VI according to the first embodiment of the second aspect wherein R 2 is methyl and R 3 is methyl.
  • compounds of Formula VI according to the first embodiment of the second aspect, a member selected from the group consisting of pyridine-3-carbaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl] oxime; pyridine-3-carbaIdehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
  • 4-trifluoromethyl-benzaldehyde 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime; benzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime;
  • 4-fluorobenzaldehyde 0-[[[4-(2-phenylethoxy)phenyl]amino] carbonyl]oxime; 2-fluoro-5-trif luoromethyl-benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime;
  • 3-pyridinecarboxaldehyde 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl] amino]carbonyl]oxime; benzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime;
  • 3-pyridinecarboxaldehyde 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime;
  • 4-fluorobenzaldehyde 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime;
  • R is C-1-12 alkoxy; R 4 is halo;
  • X is CH or nitrogen; and b is 0 to 2, with the proviso that when X is nitrogen then b is 0.
  • R 1 is a C ⁇ - 3 branched or linear aliphatic hydrocarbon
  • R 4 is phenyl, C ⁇ -3 alkoxy or halo
  • X is CH or nitrogen; and b is 2.
  • R is C ⁇ -12 alkoxy;
  • R 1 is a C- ⁇ - 3 branched or linear aliphatic hydrocarbon;
  • X is CH or nitrogen.
  • a seventh aspect of the present invention a method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating neuropathic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating acute pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating chronic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • an eleventh aspect of the present invention a method of treating emesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating anxiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of altering feeding behaviors in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating movement disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method treating glaucoma in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating brain injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a pharmaceutical composition for treating a condition or disorder requiring inhibition of a fatty acid amidohydrolase comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.
  • A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
  • R is C ⁇ -16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with C ⁇ - alkyl; phenoxy; phenyl-C ⁇ -4 alkyloxy-; pyridyloxy; pyridyl-C ⁇ -4 alkyloxy-; -N(H)-C(0)-C ⁇ - ⁇ 6 alkyl; or -C(0)-N(H)-C ⁇ - ⁇ 6 alkyl;
  • R 1 is a bond or a C ⁇ -3 branched or linear aliphatic hydrocarbon
  • B is C- ⁇ -4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzothienyl, fluorenyl, carbazolyl, napthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of Ci- 4 branched or linear aliphatic hydrocarbon, C ⁇ -4 alkoxy, halo, haloalkyl, nitro and (C ⁇ -3 alkyl) 0- 2 amino- or represented by Formula III or Formula IV:
  • R 2 is hydrogen, methyl
  • R 3 is C- ⁇ - 4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, C ⁇ -4 haloalkyl and nitro
  • X is CH or nitrogen
  • R 4 is C- ⁇ - 4 branched or linear aliphatic hydrocarbon, C ⁇ -4 alkoxy, halo, haloalkyl, nitro or amino
  • b is 0 to 3.
  • A is represented by Formula II:
  • R is C ⁇ - ⁇ 2 alkoxy; phenoxy; pyridyloxy; or amido optionally substituted with Ci.-i ⁇ alkyl; and R 1 is a bond.
  • R 2 is preferably hydrogen or methyl, and R 3 is preferably methyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • B is represented by Formula IV:
  • X is preferably CH, R 4 is preferably halo, and b is 1.
  • X is nitrogen, however, b is preferably 0.
  • B is represented by Formula V:
  • X is preferably nitrogen.
  • a dependnent embodiment describes a variable as being "phenyl or pyridyl", wherein said phenyl and pyridyl were described in the independent embodiment as being “optionally substituted”, then the phenyl and pyridyl of the dependent embodiment will also be optionally substituted.
  • halo or “halogen” includes fiuoro, chloro, bromo and iodo.
  • 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 that will produce effective beneficial effects without causing any harmful or untoward side effects.
  • Scheme 1A Reaction conditions: (i) R-halide, NaH, DMF, room temp.; (ii) NaOH, EtOH, room temp., (iii) (a) N 3 P(O)(OPh) 2 , Et 3 N, toluene at room temp, following by 90 min. at reflux, (b) addition of oxime C at room temp, with stirring for 1 hr., heating to 85°C; n is 0 to 3; R, and R 2 are as defined above.
  • 2,4-Difluoro-benzaldehvde oxime (Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCI salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K 2 C0 3 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes).
  • reaction mixture was stirred at r.t. for 10 min. and then at 80 °C for 1 h.
  • the mixture was diluted with EtOAc, washed with H 2 0.
  • the residue was purified by by preparative HPLC (YMC 30X100 mm (5 uM packing), 10% MeOH/90% water/01 % TFA as mobile phase A, 90% MeOH/10%water/0.1% TFA as mobile phase B).
  • 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 NaCI, 4.1 mM KCI, 5.1 mM Na 2 P0 4 , 1.5 mM KH 2 P0 4 (pH 7.5), 37°C] and incubated for 5 to 10 minutes at 4°C in lysis buffer [1 mM sodium bicarbonate].
  • Example 5 (40 mg/kg, i.p.) suppressed the development of thermal hyperalgesia induced by paw carrageenan. Paw carrageenan injection (0, 0:45 hr, Carr) produced strong thermal hyperalgesia as evidenced by the short escape latencies seen in vehicle treated rats (0, 2:15 hr, Carr) as compared to the long baseline latencies (0:00 hr).
  • Example 5 Animals pretreated with Example 5 (#1, 0:15 hr) failed to exhibit hyperalgesic responses (compare 0 to ⁇ at 2:15 hr) and instead the latencies for drug treated animals were comparable to baseline.
  • Example 5 Inflammation-induced Edema
  • Example 5 inhibited swelling by 26% at 40 mg/kg (Ex. 5 - 40, ip administered at -30 min and +2hr relative to carrageenan) but showed no efficacy at 20 mg/kg (Ex. 5 - 20, ip).
  • the reference agent dexamethasone (Dex, 1 mg/kg, ip) inhibited swelling by 70%. Table IV, below, summarizes the data.

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US7851473B2 (en) 2004-11-18 2010-12-14 Takeda Pharmaceutical Company Limited Amide compound
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US11377426B2 (en) 2017-12-05 2022-07-05 Suzhou Pengxu Pharmatech Co., Ltd. Processes to produce elagolix

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