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WO2004030629A2 - Nouveaux antagonistes de la neurokinine et leurs procedes d'utilisation - Google Patents

Nouveaux antagonistes de la neurokinine et leurs procedes d'utilisation Download PDF

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WO2004030629A2
WO2004030629A2 PCT/US2003/031153 US0331153W WO2004030629A2 WO 2004030629 A2 WO2004030629 A2 WO 2004030629A2 US 0331153 W US0331153 W US 0331153W WO 2004030629 A2 WO2004030629 A2 WO 2004030629A2
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compound
pharmaceutical composition
treat
group
amount effective
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WO2004030629A3 (fr
Inventor
Oren Becker
Dale S. Dhanoa
Silvia Noiman
Anurag Sharadendu
Venkitasamy Kesavan
Pradyumna Mohanty
Yael Marantz
Ori Kalid
Dongli Chen
Sacham SHARON
Raphael Nudelman
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PREDIX PHARMACEUTICALS
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PREDIX PHARMACEUTICALS
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Publication of WO2004030629A3 publication Critical patent/WO2004030629A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention generally relates to the field of neurokinin antagonists, and more particularly to new compounds which are neurokinin antagonists and use of these compounds in the treatment and prevention of neurokinin-related conditions.
  • tachykinin neuropeptides in a variety of biological activities including vasodilation, smooth muscle contraction, bronchoconstriction, immune system activation (inflammatory pain), and neurogenic inflammation.
  • vasodilation smooth muscle contraction
  • bronchoconstriction immune system activation (inflammatory pain)
  • neurogenic inflammation a detailed understanding of the physiological role of these compounds has been severely hampered by a lack of selective, high affinity, metabolically stable neurokinin receptor antagonists that possess both good bioavailability and CNS penetration.
  • tachykinin receptor antagonists have been described, most have been developed through modifying and/or deleting one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
  • NKi receptor antagonists A number of high-affinity nonpeptide antagonists have been reported, e.g., FK 888, CP 96345 and RP 67580 (NKi receptor antagonists), and SR 48969 (NK 2 ). Most of the nonpeptide tachykinin receptor antagonists described to date directly or indirectly arose out of large compound collection screening using a robust radioligand binding assay as the primary screen. International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 discuss certain nonpeptide tachykinin receptor antagonists.
  • Substance-P is widely distributed throughout the peripheral and central nervous systems. It is believed to mediate a variety of biological actions via an interaction with NKi, NK 2 , and NK 3 receptors, including smooth muscle contraction, pain transmission, neuronal excitation, saliva secretion, angiogenesis, bronchoconstriction, immune system activation, and neurogenic inflammation.
  • neurokinin receptor antagonists e.g., compounds capable of antagonizing substance-P effects at NKi receptors will be useful in treating or preventing a variety of brain disorders such as pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders; inflammatory diseases like arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including Parkinson's disease, multiple sclerosis, and Alzheimer's disease; and ophthalmic diseases including scleroderma.
  • brain disorders such as pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders
  • inflammatory diseases like arthritis, asthma, and psoriasis
  • gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety
  • allergic responses such as eczema and rhin
  • such compounds may be used as anti-angiogenic agents for treating conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth; and as agents for imaging NKi receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
  • the present invention relates to the discovery of new neurokinin antagonists that can be used for treating, preventing or curing neurokinin-related conditions.
  • neurokinin antagonist compounds include certain substituted triazole compounds having the formula of Formula I:
  • ⁇ Ri, A] and A 2 are independently aromatic or heteroaromatic groups; ⁇ n is 1, 2 or 3; and
  • ⁇ m and q are individually 1 , 2, 3, 4, 5 or 6.
  • the Ri, A] and A 2 aromatic or heteroaromatic groups may be unco ⁇ jugated, e.g., phenyl, pyrazole, and thiophene; or conjugated, e.g., naphthyl, biphenyl, benzothiazole, benzothiophene, and benzoxazole.
  • the Ri, Ai and A 2 aromatic or heteroaromatic groups are mono-, di- or tri-substituted.
  • the substituents may include OH, O-lower alkyl, F, Cl, Br, I, CF 3 , OCF 3 , CN, N0 2 , NH 2 , NR 2 , NCO-lower alkyl, NCO-aryl, lower alkyl (e.g., C ⁇ -C 5 or Ci-Ce), 2,3-methylenedioxy, 3,4-methylenedioxy, COOH, COO-lower alkyl, COOCH 2 C 6 H 5 , CONH 2 , CONH-lower alkyl, and CON(lower alkyl) 2 .
  • the Ai and A 2 aromatic or heteroaromatic groups are mono-, di- or tri-substituted.
  • substituted hexahydropyrimidine-sulfonamide compounds are found to be effective neurokinin antagonists, such neurokinin antagonist compounds include those having the formula of Formula IT:
  • Ri may be H, (C ⁇ -C6)alkyl or cycloalkyl; O-(C ⁇ -C ⁇ ) alkyl or cycloalkyl; aryl or heteroaryl; OCF 3 ; halo, e.g., Cl, Br, or F; or CN or NO 2 .
  • the aryl group may be phenyl, naphthyl, and biphenyl, and may be substituted or unsubstituted.
  • Aryl group substituents include mono-, di-, or tri-substituted phenyl, naphthyl, or biphenyl with methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy, phenoxy, benzyloxy, phenylethoxy, fluoro, chloro, bromo, iodo, amino, dimethylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy,
  • the heteroaryl group may be thiazole, oxazole, be
  • Heteroaryl group substituents include mono-, di-, or tri-substituted thiazole, oxazole, benzothiazole, benzoxazole, pyrazole, indole, and indazole with methyl, ethyl, propyl, allyl, n- butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy, phenoxy, benzyloxy, phenylethoxy, fluoro, chloro, bromo, iodo, amino, dimethylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methyl
  • R 2 and R 3 are substituted aryl and or heteroaryl groups. These groups may be substituted or unsubstituted.
  • Aryl groups include phenyl, biphenyl, and naphthyl groups.
  • Heteroaryl groups include thiazole, imidazole, indazole, and oxazole groups.
  • Ri may advantageously be (C]-C 6 ) alkyl, (CpC 7 ) cycloalkyl; O-(C ⁇ -C 6 ) alkyl, O-(Cj-C 7 ) alkyl; OCF 3 ; halo, e.g., F, Cl, or Br; CN or N0 2 ; or tetrazole groups.
  • substituted tetrahydro beta-carboline compounds are found to be effective neurokinin antagonists, such neurokinin antagonist compounds include those having the formula of Formula IE:
  • Z may be c or CH 2 ; n is 0, 1 , 2 or 3; R ⁇ may be H, halo, e.g., Cl, Br, or
  • R 2 F; OMe; OCF ; (C ⁇ -C 4 )alkyl; or aryl, e.g., phenyl; or heteroaryl, e.g., thiophenyl or furanyl.
  • halo e.g., Cl, Br, or F
  • OMe e.g., OMe
  • OCF 3 e.g., OMe, OCF 3 ;
  • Aryl groups include mono-, di-, or tri-
  • substituted phenyl with (C ⁇ -C )alkyl halo, e.g., Cl, Br, or F; OMe; OCF 3 ; ;
  • R 3 may advantageously be (C ⁇ -C 4 )
  • cycloalkyl e.g., F, Cl, or Br
  • OMe e.g., F, Cl, or Br
  • substituted tetrahydro beta-carboline compounds are found to be effective neurokinin antagonists, such neurokinin antagonist compounds include those having the formula of Formula IN: or a pharmaceutically acceptable salt thereof.
  • Z may be CH 2 , O or S.
  • n and m may individually be 0, 1, 2, 3, 4 or 5.
  • Rj may be H; (C ⁇ -C 6 )alkyl (advantageously (C ⁇ -C 4 )alkyl) or cycloalkyl; halo, e.g., Cl, Br, or F; and Ri may be mono-, di-, or tri-substituted on the benzyl ring; O-Ar, OMe or OCF 3 ; aryl, e.g., substituted or unsubstituted phenyl; or heteroaryl, e.g., thiophenyl or furanyl.
  • R 2 may be H; (C ⁇ -C ⁇ )alkyl or cycloalkyl; O-(C ⁇ -C6)alkyl; halo, e.g., Cl, Br, or F; OMe or OCF 3 ; 3,4-methylenedioxy; 3,4- dichlorobenzyl; 3,4-difluorobenzyl; and 3,5-ditrifluoromethylbenzyl.
  • R 3 and t may independently be methyl, ethyl, propyl, or isopropyl; n-, sec-, or tert-butyl; (C ⁇ -C 6 )alkyl; halo, e.g., Cl, Br, or F; OMe or OCF 3 ; or aryl, e.g., substituted or unsubstituted phenyl or naphthyl.
  • Ri is desirably H, methoxyphenyl, chlorophenyl, and fluorophenyl;
  • R 2 is desirably methoxyphenyl or 3,4-methylenedioxyphenyl;
  • n and m are desirably 0;
  • R 3 and R_ are desirably chlorophenyl, fluorophenyl, and trifluoromethylphenyl;
  • Z is desirably CH 2 .
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating eye diseases in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat allergies in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating allergies in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective to treat migraine in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating migraine in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of compound according to Formula I-IN effective to treat pain arising from neurogenic inflammation or inflammatory pain.
  • Another aspect of the invention is a method for treating pain such as pain arising from neurogenic inflammation in inflammatory pain comprising administering a therapeutically effective amount of a compound according to Formula I-IN.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I-IN effective in treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth.
  • Another aspect of the invention is a method of treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth comprising administering a therapeutically effective amount of a compound according to Formula I-IV.
  • Another aspect of the invention is using the compounds according to Formula I-IN as imaging agents for imaging ⁇ Ki receptors in vivo.
  • G-protein coupled receptor includes the NKi, NK 2 , and NK 3 receptors.
  • Neurokinin includes substance-P, neurokinin A, and neurokinin B.
  • Neurokinin antagonist includes compounds having such effect at the NKi, NK 2 , and
  • Alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octy
  • Alkyl further includes alkyl groups which have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms.
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., C ⁇ -C 6 for straight chain, C 3 -C ⁇ for branched chain), and more preferably four or fewer.
  • preferred cycloalkyls have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure.
  • “Ci-C ⁇ ” includes alkyl groups containing one to six carbon atoms.
  • alkyl also includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • “Alkyl” also includes the side chains of natural and unnatural amino acids.
  • Aryl includes groups with aromaticity, including 5- and 6-membered “unconjugated”, or single-ring, aromatic groups that may include from zero to four heteroatoms, as well as “conjugated”, or multicyclic, systems with at least one aromatic ring.
  • aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tefrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 - C 6 for branched chain.)
  • cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing two to six carbon atoms.
  • alkenyl also includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C - C ⁇ for branched chain).
  • C 2 -Ce includes alkynyl groups containing two to six carbon atoms.
  • alkynyl also includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • Acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group.
  • Substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, aryl
  • Acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • Aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • Alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • heterocyclyl or “heterocyclic group” include closed ring structures, e.g., 3- to 10-, or 4- to 7-membered rings, which include one or more heteroatoms.
  • Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamo
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkylamino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkylamino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino
  • alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • amide or "aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • Polycyclyl or “polycyclic radical” refers to two or more cyclic rings ⁇ e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • Heteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • the structure of some of the compounds of the invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry ⁇ e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate.
  • Polymer includes molecules formed by the chemical union of two or more combining subunits called monomers.
  • Monomers are molecules or compounds which usually contain carbon and have relatively low molecular weight and simple structure. A monomer can be converted to a polymer by combination with itself or other similar molecules or compounds.
  • a polymer may be composed of a single identical repeating subunit or multiple different repeating subunits ("copolymers"). Polymers include substituted and unsubstituted vinyl, acryl, styrene and carbohydrate-derived polymers and copolymers and salts thereof.
  • aliphatic group is intended to include organic compounds characterized by straight or branched chains, typically having between 1 and 22 carbon atoms. Aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups. In complex structures, the chains can be branched or cross-linked. Alkyl groups include saturated hydrocarbons having one or more carbon atoms, including straight-chain alkyl groups and branched-chain alkyl groups. Such hydrocarbon moieties may be substituted on one or more carbons with, for example, a halogen, a hydroxyl, a thiol, an amino, an alkoxy, an alkylcarboxy, an alkylthio, or a nitro group.
  • lower aliphatic as used herein means an aliphatic group, as defined above (e.g., lower alkyl, lower alkenyl, lower alkynyl), but having from one to six carbon atoms.
  • Representative of such lower aliphatic groups, e.g., lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, 2-chloropropyl, n-butyl, sec-butyl, 2-aminobutyl, isobutyl, tert-butyl, 3-thiopentyl, and the like.
  • amino means -NH 2 ; the term “nitro” means -N0 2 ; the term “halogen” designates -F, -Cl, -Br or -I; the term “thiol” means SH; and the term “hydroxyl” means -OH.
  • alkylamino as used herein means an alkyl group, as defined above, having an amino group attached thereto.
  • alkylthio refers to an alkyl group, as defined above, having a sulfhydryl group attached thereto.
  • alkylcarboxyl as used herein means an alkyl group, as defined above, having a carboxyl group attached thereto.
  • alkenyl and “alkynyl” refer to unsaturated aliphatic groups analogous to alkyls, but which contain at least one double or triple bond respectively.
  • alicyclic group is intended to include closed ring structures of three or more carbon atoms.
  • Alicyclic groups include cycloparaffins or naphthenes which are saturated cyclic hydrocarbons, cycloolefins which are unsaturated with two or more double bonds, and cycloacetylenes which have a triple bond. They do not include aromatic groups.
  • Examples of cycloparaffins include cyclopropane, cyclohexane, and cyclopentane.
  • cycloolefins include cyclopentadiene and cyclooctatetraene.
  • Alicyclic groups also include fused ring structures and substituted alicyclic groups such as alkyl substituted alicyclic groups.
  • such substituents can further comprise a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF 3 , -CN, or the like.
  • An "anionic group,” as used herein, refers to a group that is negatively charged at physiological pH.
  • Prefe ⁇ ed anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof.
  • "Functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents. Classical and non-classical bioisosteres are known in the art (see, e.g., Silverman, R. B.
  • aryl aldehyde refers to a compound represented by the formula Ar-C(0)H, in which Ar is an aryl moiety (as described above) and -C(O)H is a formyl or aldehydo group.
  • the aryl aldehyde is a (substituted or unsubstituted) benzaldehyde.
  • a variety of aryl aldehydes are commercially available, or can be prepared by routine procedures from commercially available precursors.
  • Procedures for the preparation of aryl aldehydes include the Nilsmeier-llaack reaction (see, e.g., Jutz, Adv. Org. Chem. 9, pt. 1, 225-342 (1976)), the Gatterman reaction (see Truce, Org. React. 9, 37-72 (1957)), the Gatterman-Koch reaction (see Crounse, Org. React. 5, 290-300 (1949)), and the Reimer-Tiemann reaction (see Wynberg and Meijer, Org. React. 28, 1-36 (1982)).
  • heterocyclic group is intended to include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, or oxygen or sulfur.
  • Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine.
  • Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF , -C ⁇ , or the like.
  • the present invention relates to the discovery of new neurokinin antagonists that can be used for treating, preventing or curing neurokinin-related conditions.
  • neurokinin antagonist compounds include certain substituted triazole compounds having the formula of Formula I:
  • ⁇ Ri, Ai and A 2 are independently aromatic or heteroaromatic groups
  • ⁇ n is 1, 2 or 3; and ⁇ m and q are individually 1 , 2, 3, 4, 5 or 6.
  • the Ri, Ai and A 2 aromatic or heteroaromatic groups may be unconjugated, e.g., phenyl, pyrazole, and thiophene; or conjugated, e.g., naphthyl, biphenyl, benzothiazole, benzothiophene, and benzoxazole. Desirably the Ri, A ⁇ and A 2 aromatic or heteroaromatic groups are mono-, di- or tri-substituted.
  • the substituents may include OH, O-lower alkyl, F, Cl, Br, I, CF 3 , OCF 3 , CN, N0 2 , NH 2 , NR 2 , NCO-lower alkyl, NCO-aryl, lower alkyl (e.g., C 1 -C 5 or C ⁇ -C 6 ), 2,3-methylenedioxy, 3,4-methylenedioxy, COOH, COO-lower alkyl, COOCH 2 C 6 H 5 , CONH 2 , CONH-lower alkyl, and CON(lower alkyl) 2 .
  • the Ai and A 2 aromatic or heteroaromatic groups are mono-, di- or tri-substituted.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating eye diseases in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat allergies in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating allergies in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat migraine in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating migraine in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of compound according to Formula I effective to treat pain arising from neurogenic inflammation or inflammatory pain.
  • Another aspect of the invention is a method for treating pain such as pain arising from neurogenic inflammation in inflammatory pain comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective in treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth.
  • Another aspect of the invention is a method of treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth comprising administering a therapeutically effective amount of a compound according to Formula I.
  • Another aspect of the invention is using the compounds according to Formula I as imaging agents for imaging NKi receptors in vivo.
  • Processes for preparing the compounds of Formula I and their novel intermediates are also included in the invention.
  • neurokinin antagonist compounds include those having the formula of Formula II:
  • Ri may be H, (C ⁇ -C 6 )alkyl or cycloalkyl; 0-(C ⁇ -C 6 ) alkyl or cycloalkyl; aryl or heteroaryl; OCF 3 ; halo, e.g., Cl, Br, or F; or CN or NO 2 .
  • the aryl group may be phenyl, naphthyl, and biphenyl, and may be substituted or unsubstituted.
  • Aryl group substituents include mono-, di-, or tri-substituted phenyl, naphthyl, or biphenyl with methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy, phenoxy, benzyloxy, phenylethoxy, fluoro, chloro, bromo, iodo, amino, dimethylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy,
  • the heteroaryl group may be thiazole, oxazole, be
  • Heteroaryl group substituents include mono-, di-, or tri-substituted thiazole, oxazole, benzothiazole, benzoxazole, pyrazole, indole, and indazole with methyl, ethyl, propyl, allyl, n- butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy, phenoxy, benzyloxy, phenylethoxy, fluoro, chloro, bromoj iodo, amino, dimethylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methyl
  • R 2 and R 3 are substituted aryl and/or heteroaryl groups. These groups may be substituted or unsubstituted.
  • Aryl groups include phenyl, biphenyl, and naphthyl groups.
  • Heteroaryl groups include thiazole, imidazole, indaole, and oxazole groups.
  • the benzene group of Formula II may be mono-, di-, or trisubstituted with, e.g., (C ⁇ -C 6 ) alkyl, (C ⁇ -C 7 ) cycloalkyl; 0-(C ⁇ -C 6 ) alkyl, O-(C_-C 7 ) alkyl; OCF 3 ; halo, e.g., F, Cl, or Br; CN or NO 2 ; or tefrazole groups.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula II effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula II effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula ⁇ effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula ⁇ effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating eye diseases in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula II effective to treat allergies in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating allergies in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula H
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula ⁇ effective to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula II effective to treat migraine in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating migraine in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of compound according to Formula ⁇ effective to treat pain arising from neurogenic inflammation or inflammatory pain.
  • Another aspect of the invention is a method for treating pain such as pain arising from neurogenic inflammation in inflammatory pain comprising administering a therapeutically effective amount of a compound according to Formula II.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula II effective in treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth.
  • Another aspect of the invention is a method of treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth comprising administering a therapeutically effective amount of a compound according to Formula ⁇ .
  • Another aspect of the invention is using the compounds according to Formula II as imaging agents for imaging NKi receptors in vivo.
  • neurokinin antagonist compounds include those having the formula of Formula IH:
  • R 2 F; OMe; OCF ; (C]-C )alkyl; or aryl, e.g., phenyl; or heteroaryl, e.g., thiophenyl or furanyl.
  • Aryl groups include mono-, di-, or tri-
  • substituted phenyl with (C ⁇ -C 4 )alkyl halo, e.g., Cl, Br, or F; OMe; OCF 3 ; ;
  • R 3 may advantageously be (C ⁇ -C 4 )
  • cycloalkyl e.g., F, Cl, or Br
  • OMe e.g., F, Cl, or Br
  • the benzyl group of Formula HI to which R 3 is attached may be mono-, di-, or trisubstituted by R 3 .
  • compounds of Formula III include l-[3-(4-Phenyl-piperazin- l-ylmethyl)-phenyl]-2,3,4,9-tetrahydro-lH-b-carboline and
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IH effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula III.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula DI effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula III.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula III effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula in.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IH effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating eye diseases in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula in.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula HI effective to treat allergies in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating allergies in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula El.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IE effective to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IE.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula IE effective to treat migraine in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating migraine in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IE.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of compound according to Formula El effective to treat pain arising from neurogenic inflammation or inflammatory pain.
  • Another aspect of the invention is a method for treating pain such as pain arising from neurogenic inflammation in inflammatory pain comprising an amount of compound according to Formula IE.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula El effective in treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth.
  • Another aspect of the invention is a method of treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth comprising an amount of compound according to Formula IE.
  • Another aspect of the invention is using the compounds according to Formula IH as imaging agents for imaging NKi receptors in vivo.
  • Processes for preparing the compounds according to Formula HI and their novel intermediates are also included in the invention.
  • neurokinin antagonist compounds include those having the formula of Formula IN:
  • Z may be CH 2 , O or S.
  • n and m may individually be 0, 1, 2, 3, 4 or 5.
  • Ri may be H; (C ⁇ -C 6 )alkyl (advantageously (C ⁇ -C 4 )alkyl) or cycloalkyl; halo, e.g., Cl, Br, or F; and Ri may be mono-, di-, or tri-substituted on the benzyl ring; O-Ar, OMe or OCF 3 ; aryl, e.g., substituted or unsubstituted phenyl; or heteroaryl, e.g., thiophenyl or furanyl.
  • R 2 may be H; (C ⁇ -C 6 )alkyl or cycloalkyl; 0-(C ⁇ -C 6 )alkyl; halo, e.g., Cl, Br, or F; OMe or OCF 3 ; 3,4-methylenedioxy; 3,4- dichlorobenzyl; 3,4-difluorobenzyl; and 3,5-ditrifluoromethylbenzyl.
  • R 3 and R may independently be methyl, ethyl, propyl, or isopropyl; n-, sec-, or tert-butyl; (C ⁇ -C 6 )alkyl; halo, e.g., Cl, Br, or F; OMe or OCF 3 ; or aryl, e.g., substituted or unsubstituted phenyl or naphthyl.
  • Ri is desirably H, methoxyphenyl, chlorophenyl, and fluorophenyl;
  • R 2 is desirably methoxyphenyl or 3,4-methylenedioxyphenyl;
  • n and m are desirably 0;
  • R 3 and R_ ⁇ are desirably chlorophenyl, fluorophenyl, and trifluoromethylphenyl; and
  • Z is desirably CH 2 .
  • compounds of Formula IV include
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IV effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IN effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IV effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IV effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating eye diseases in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula IN effective to treat allergies in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating allergies in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IV effective to treat diseases of the central nervous system in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating diseases of the central nervous system in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula IV effective to treat migraine in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating migraine in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula IN.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of compound according to Formula IV effective to treat pain arising from neurogenic inflammation or inflammatory pain.
  • Another aspect of the invention is a method for treating pain such as pain arising from neurogenic inflammation in inflammatory pain comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound according to Formula IV effective in treating conditions associated with abe ⁇ ant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth.
  • Another aspect of the invention is a method of treating conditions associated with aberrant neovascularization: rheumatoid arthritis, atherosclerosis, and tumor cell growth comprising administering a therapeutically effective amount of a compound according to Formula IV.
  • Another aspect of the invention is using the compounds according to Formula IV as imaging agents for imaging NKi receptors in vivo.
  • Processes for preparing the compounds according to Formula IN and their novel intermediates are also included in the invention.
  • the compounds of the invention are valuable for treating a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, e.g., substance P, activity.
  • an excess of neurokinin activity is implicated in a variety of disorders of the central nervous system.
  • disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recu ⁇ ent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar ⁇ disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia
  • Neurokinin activity is also involved in nociception and pain.
  • the compounds of the invention will therefore be useful in preventing or treating diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynecological pain, for example, dysmenorrhea, and labor pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often refe ⁇ ed to as
  • Neurokinin antagonists may also be useful in treating respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
  • respiratory diseases particularly those associated with excess mucus secretion
  • Neurokinin antagonists may also be useful in treating neoplasms, including breast tumors, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
  • Neurokinin antagonists may also be useful in treating gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations in intercranial pressure, gastro-esophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal
  • Neurokinin antagonists may also be useful in treating a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially pain transmission in migraine.
  • the compounds of the invention are also valuable in treating a combination of the above conditions, in particular in the treatment of combined post-operative pain and postoperative nausea and vomiting.
  • the compounds of the invention are particularly useful in treating emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of the invention are useful in treating emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
  • emesis including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
  • chemotherapeutic agents include alkylating agents like nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nifrosoureas, cisplatin and dacarbazine; antimetabohtes, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
  • alkylating agents like nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nifrosoureas, cisplatin and dacarbazine
  • antimetabohtes for example, folic acid, purine or pyrimidine antagonists
  • mitotic inhibitors for example, vinca alkaloids and derivatives of podophyllotoxin
  • cytotoxic antibiotics include cytotoxic antibiotics.
  • chemotherapeutic agents are described, for example, by D. J. Stewart in “Nausea and Vomiting: Recent Research and Clinical-Advances", Eds. J. Kucharczyk, et al., CRC Press Inc., Boca Raton, Fla., USA (1991), pages 177-203, especially page 188.
  • chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil [R. J. Gralla, et al., Cancer Treatment Reports, 68(1), 163-172 (1984)].
  • the compounds of the invention are also useful in treating emesis induced by radiation including radiation therapy such as in cancer treatment, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
  • radiation therapy such as in cancer treatment, or radiation sickness
  • another pharmacologically active agent for treating certain conditions it may be desirable to employ the compound of the invention in conjunction with another pharmacologically active agent.
  • the compounds of the invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
  • a further aspect of the invention comprises compounds of the invention in combination with a 5-HT antagonist, such as ondansetron, granisetron, tropisetron or zatisetron, or other anti-emetic medicaments, for example, dexamethasone or a dopamine antagonist such as metoclopramide.
  • a 5-HT antagonist such as ondansetron, granisetron, tropisetron or zatisetron, or other anti-emetic medicaments
  • dexamethasone such as metoclopramide
  • the compounds of the invention may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone.
  • the compounds of the invention may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above.
  • chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above.
  • the compounds of the invention are also particularly useful for treating pain or nociception and/or inflammation and disorders associated therewith, such as neuropathy, e.g., diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteoarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
  • neuropathy e.g., diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteoarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
  • the invention further provides the compounds of the invention for therapeutic use.
  • the invention provides compounds of the invention for use in the manufacture of a medicament for the treatment or prevention of physiological disorders associated with neurokinin excess.
  • the invention also provides methods for treating or preventing physiological disorders associated with neurokinin excess, which method comprises administration to a patient in need thereof of a tachykinin-reducing amount of a compound of the invention or a composition comprising a compound of the invention.
  • a compound according to the invention for treating certain conditions it may be desirable to employ a compound according to the invention in conjunction with another pharmacologically active agent.
  • the compound of the invention may be used in conjunction with a bronchodilator, such as a ⁇ 2 -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors.
  • a bronchodilator such as a ⁇ 2 -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors.
  • the compound of the invention and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
  • the compound of the invention may be used in conjunction with a tachykinin antagonist which acts at neurokinin-2 receptors, or with tachykinin receptor antagonist which acts at both neurokinin- 1 and neurokinin-2 receptors.
  • the compounds of the invention may be employed with a leukotriene antagonist, such as a leukotriene D antagonist such as disclosed in European patent specification nos. 0 480 717 and 0 604 114, and in U.S. Pat. Nos. 4,859,692 and 5,270,324.
  • a leukotriene antagonist such as a leukotriene D antagonist such as disclosed in European patent specification nos. 0 480 717 and 0 604 114, and in U.S. Pat. Nos. 4,859,692 and 5,270,324.
  • This combination is particularly useful in treating respiratory diseases such as asthma, chronic bronchitis and cough.
  • the invention accordingly provides a method for treating a respiratory disease, e.g., asthma, which method comprises administration to a patient in need thereof of an effective amount of the compound of the invention and an effective amount of a bronchodilator.
  • a respiratory disease e.g., asthma
  • the invention also provides a composition comprising the compound of the invention, a bronchodilator, and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT ⁇ agonists, especially sumatriptan or rizatriptan.
  • other anti-migraine agents such as ergotamines or 5-HT ⁇ agonists, especially sumatriptan or rizatriptan.
  • the compounds of the invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMD A), such as dizocilpine.
  • NMD A N-methyl D-aspartate
  • the compounds of the invention may be used in conjunction with an anti-inflammatory agent such as a bradykinin receptor antagonist.
  • the invention also provides a composition comprising a compound of the invention, a bronchodilator, and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAEDs and, in particular, opioid analgesics, especially morphine.
  • analgesics such as acetaminophen (paracetamol), aspirin and other NSAEDs and, in particular, opioid analgesics, especially morphine.
  • opioid analgesics especially morphine.
  • Specific anti- inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac.
  • Suitable opioid analgesics of use in conjunction with a compound of the invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, afenantil, buprenorphine, buto ⁇ hanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
  • Prefe ⁇ ed salts of these opioid analgesics include mo ⁇ hine sulfate, mo ⁇ hine hydrochloride, mo ⁇ hine tarfrate, codeine phosphate, codeine sulfate, dihydrocodeine bitartrate, diacetylmo ⁇ hine hydrochloride, hydrocodone bitartrate, hydromo ⁇ hone hydrochloride, levo ⁇ hanol tarfrate, oxymo ⁇ hone hydrochloride, afenantil hydrochloride, bupreno ⁇ hine hydrochloride, buto ⁇ hanol tarfrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulphonic acid (1 :1) monohydrate), and pentazocine hydrochloride.
  • a pharmaceutical composition comprising a compound of the invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
  • a product comprising a compound of the invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
  • the compounds of the invention may be used in combination with an antidepressant agent or anti-anxiety agent.
  • Suitable classes of antidepressant agents of use in the invention include: norepinephrine reuptake inhibitors, selective serotonin include: norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors, corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists and atypical antidepressants.
  • CRF corticotropin releasing factor
  • antidepressant agent of use in the invention are noradrenergic and specific serotonergic antidepressants, such as mirtazapine.
  • norepinephrine reuptake inhibitors include amitripdyline, clomipramine, doxepine, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, reboxetine and protriptyline and pharmaceutically acceptable salts thereof.
  • Suitable examples of selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline and pharmaceutically acceptable salts thereof.
  • Suitable examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromain and selegiline, and pharmaceutically acceptable salts thereof.
  • Suitable examples of reversible monoamine oxidase inhibitors include moclobemide, and pharmaceutically acceptable salts thereof.
  • Suitable examples of serotonin and noradrenaline reuptake inhibitors include venlafaxine, and pharmaceutically acceptable salts thereof.
  • Suitable examples of corticotropin releasing factor (CRF) antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
  • atypical antidepressants include bupropion, lithium, nefazoedone, sibutramine, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
  • Other antidepressants of use in the invention include adinozolam, alaproclate, amineptine, amitryptyline/chlordiazepoxide combination, atipamezole, azamianserin, apelinaprine, fefuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dasepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, setazolam, etoperidone, fem
  • Preferred antidepressant agents include selective serotonin reuptake inhibitors, in particular, fluoxetine, fluvoxamine, paroxetine, and sertraline and pharmaceutically acceptable salts thereof.
  • Suitable classes of anti-anxiety agents of use in the invention include benzodiazepines and 5-HTj A agonists or antagonists, especially 5-HTI A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • benzodiazepines include nonbenzodiazepine sedative-hypnotic drugs such as zolpidem; mood- stabilizing drugs such as clobazam, gabapentin, lamofrigine, loreclezole, oxcarbamazepine, stiripentol and vigabatrin; and barbiturates.
  • Suitable benzodiazepines of use in the invention include alprazolam, chlordizepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorezepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
  • Suitable examples of 5-HT IA agonists or antagonists of use in the invention include, in particular, the 5- HT IA partial agonists buspirone, flesinoxan, gepirone, ipsapirone and pindolol, and pharmaceutically acceptable salts thereof.
  • Suitable examples of corticotropin releasing factor (CRF) antagonists include those compounds described in International Patent Specification Nos.
  • WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677 Another class of anti-anxiety agent of use in the invention are compounds having muscarinic cholinergic activity. Suitable compounds in this class include m 1 muscarinic cholinergic receptor antagonists such as those compounds described in European Patent Specification Nos. 0 709 093, 0 709 094 and 0 773 021 and International Patent Specification No. WO 96/12711.
  • Another class of anti -anxiety agent of use in the invention are compounds acting on ion channels.
  • Suitable compounds in this class include carbamazepine, lamofrigine and valproate, and pharmaceutically acceptable salts thereof. Therefore, in a further aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention and an antidepressant or an anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • Suitable antipsychotic agents of use in combination with the compounds of the invention include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
  • Suitable examples of phenothiazines include chlo ⁇ romazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, pe ⁇ henazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlo ⁇ rothixene and thiothixene.
  • Suitable examples of dibenzazepines include clozapine and olanzapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other antipsychotic agents include loxapine, sulpiride and risperidone.
  • the antipsychotic agents when used in combination with the compounds of the invention may be in the form of a pharmaceutically acceptable salt, for example, chlo ⁇ romazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flu ⁇ henazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlo ⁇ romazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flu ⁇ henazine enathate, fluphenazine decanoate, trifluoperazin
  • Pe ⁇ henazine, chlo ⁇ rothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • Other classes of antipsychotic agnet of use in combination with the compounds of the invention include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists.
  • An example of a D3 dopamine receptor antagonist is the compound PNU-99194A.
  • An example of a D4 dopamine receptor antagonist is PNU-101387.
  • An example of a muscarinic ml receptor agonist is xanomeline.
  • Another class of antipsychotic agent of use in combination with the compounds of the invention is the 5-HT 2A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with the compound of the invention are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT 2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone. Therefore, in a further aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • SDAs serotonin dopamine antagonists
  • the compounds of the invention and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term “combination” further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
  • the compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. In the treatment of a condition associated with an excess of tachykinins, an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day which may be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.01 to 5 mg/kg per day.
  • a compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.01 to 1 mg/kg per day.
  • the compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.01 to 1 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the amount of the compound of the invention required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
  • compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methyl cellulose, polyvinylpy ⁇ olidone or gelatin.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Methods for preparing the compounds of this invention are illustrated in the following Example(s). The following examples are given for the pu ⁇ ose of illustrating the invention, but not for limiting the scope or spirit of the invention.
  • Medrum's acid 2 is acylated with formic acid activated by carbonyl diimidazole to give the intermediate 3.
  • Reductive amination of 3 with ammonium acetate with sodium triacetoxy borohydride gives the aminated derivative 4 which in turn is sulfonylated with a wide range of sulfonyl chlorides in the presence of triethyl amine in dichloromethane to produce the sulfonamide derivative 5.
  • Treatment of 5 with thiourea under reflux conditions followed by Raney nickel reduction gives the hexahydropyrimidinyl sulfonamide 6.
  • the key intermediate is then converted into the target compounds 1 by either its reductive amination with a variety of aldehydes or with its alkylation with a wide range of alkylating agents such as arylalkyl bromides.

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Abstract

La présente invention a trait à des antagonistes du récepteur de la tachynine, la famille de la famille de récepteurs de la tachynine comprenant la substance P des neurokinines (SP), de la neurokinine A. et de la neurokinine B et des neuropeptides qui sont largement répartis dans le système nerveux central et périphérique. La présente invention décrit de nouveaux antagonistes de la neurokinine représentés par les formule I-IV, et leur synthèse et utilisations pour le traitement de maladies provoquées directement ou indirectement par les récepteurs de la tachynine. De telles conditions comprennent les troubles du système nerveux central tels que l'anxiété, la douleur, la dépression, le vomissement, par exemple le vomissement induit par la chimiothérapie anticancéreuse, les maladie respiratoires et intestinales inflammatoires et d'autre troubles gastriques, l'asthme, la schizophrénie, les maladies ophtalmiques telles que le glaucome, l'hypertension oculaire, la lésion neuronale, l'accident vasculaire cérébral, les troubles cardiaques, le psoriasis et la migraine. L'invention a également trait à des procédés de préparation et de nouveaux intermédiaires et de sels pharmaceutiques desdits antagonistes.
PCT/US2003/031153 2002-10-01 2003-09-30 Nouveaux antagonistes de la neurokinine et leurs procedes d'utilisation Ceased WO2004030629A2 (fr)

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US7488736B2 (en) 2004-05-17 2009-02-10 Epix Delaware, Inc. Thienopyridinone compounds and methods of treatment
US7982040B2 (en) 2004-05-17 2011-07-19 Nanotherapeutics, Inc. Thienopyridinone compounds and methods of treatment
US7576211B2 (en) 2004-09-30 2009-08-18 Epix Delaware, Inc. Synthesis of thienopyridinone compounds and related intermediates
US7598265B2 (en) 2004-09-30 2009-10-06 Epix Delaware, Inc. Compositions and methods for treating CNS disorders
US7407966B2 (en) 2004-10-07 2008-08-05 Epix Delaware, Inc. Thienopyridinone compounds and methods of treatment
US8163788B2 (en) 2004-11-19 2012-04-24 Rheinische Friedrich-Wilhelms Universitat Bonn Low-molecular inhibitors of cytohesin-family guanine nucleotide exchange factors
WO2006053903A3 (fr) * 2004-11-19 2006-12-07 Univ Bonn Inhibiteurs a faible poids moleculaire de facteurs d'echange de nucleotide guanine de la famille de la cytohesine
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8114894B2 (en) 2008-12-03 2012-02-14 Nanotherapeutics, Inc. Bicyclic compounds and methods of making and using same
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
WO2018130123A1 (fr) * 2017-01-11 2018-07-19 南京圣和药业股份有限公司 Composé pentacyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation
CN108299420A (zh) * 2017-01-11 2018-07-20 南京圣和药业股份有限公司 作为选择性雌激素受体下调剂的五环类化合物及其应用
CN108299420B (zh) * 2017-01-11 2021-10-15 南京圣和药业股份有限公司 作为选择性雌激素受体下调剂的五环类化合物及其应用
WO2019051185A1 (fr) * 2017-09-08 2019-03-14 Symberix, Inc. Composés, compositions et méthodes d'inhibition sélective des beta-glucuronidases et d'atténuation des effets secondaires associés à une diarrhée provoquée par un traitement médicamenteux
US12017994B2 (en) 2017-09-08 2024-06-25 Symberix, Inc. Compounds, compositions, and methods for selectively inhibiting β-glucuronidases and alleviating side effects associated with drug treatment induced diarrhea

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