EP1799637A1 - Sulfonamidopropionamides substitues et procedes d'utilisation - Google Patents

Sulfonamidopropionamides substitues et procedes d'utilisation

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Publication number
EP1799637A1
EP1799637A1 EP05797852A EP05797852A EP1799637A1 EP 1799637 A1 EP1799637 A1 EP 1799637A1 EP 05797852 A EP05797852 A EP 05797852A EP 05797852 A EP05797852 A EP 05797852A EP 1799637 A1 EP1799637 A1 EP 1799637A1
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EP
European Patent Office
Prior art keywords
amino
sulfonyl
butanamide
tetrahydro
naphthalenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05797852A
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German (de)
English (en)
Inventor
Jr Ben C. Askew
Toshihiro Aya
Kaustav Biswas
Guolin Cai
Jian J. Chen
Christopher H. Fotsch
Nianhe Han
Jason Brooks Human
Aiwen Li
Qingyian Liu
Tanya Peterkin
Wenyuan Qian
Babak Riahi
Chester Chenguang Yuan
Jiawang Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
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Publication date
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Publication of EP1799637A1 publication Critical patent/EP1799637A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/38—Halogen atoms or nitro radicals
    • 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating inflammation-related disorders, including pain.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but they are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, increased cardiovascular risk, and confusion.
  • Pain is a perception based on signals received from the environment and transmitted and interpreted by the nervous system (for review, see M. Millan, Prog. Neurobiol. 57:1-164 (1999)).
  • Noxious stimuli such as heat and touch cause specialized sensory receptors in the skin to send signals to the central nervous system ("CNS").
  • This process is called nociception, and the peripheral sensory neurons that mediate it are nociceptors.
  • a person may or may not experience a noxious stimulus as painful. When one's perception of pain is properly calibrated to the intensity of the stimulus, pain serves its intended protective function.
  • tissue damage causes a phenomenon, known as hyperalgesia or pronociception, in which relatively innocuous stimuli are perceived as intensely painful because the person's pain thresholds have been lowered. Both inflammation and nerve damage can induce hyperalgesia.
  • hyperalgesia a phenomenon in which relatively innocuous stimuli are perceived as intensely painful because the person's pain thresholds have been lowered. Both inflammation and nerve damage can induce hyperalgesia.
  • persons afflicted with inflammatory conditions such as sunburn, osteoarthritis, colitis, carditis, dermatitis, myositis, neuritis, inflammatory bowel disease, collagen vascular diseases (which include rheumatoid arthritis and lupus) and the like, often experience enhanced sensations of pain.
  • BK and kallidin the active peptides, BK and kallidin, are quickly degraded by peptidases in the plasma and other biological fluids and by those released from a variety of cells, so that the half-life of BK in plasma is reported to be approximately 17 seconds (1).
  • BK and kallidin are rapidly metabolized in the body by carboxypeptidase N, which removes the carboxyterminal arginine residue to generate des-Arg BK or des-Arg kallidin.
  • Des-Arg-kallidin is among the predominant kinins in man and mediate the pathophysiological actions of kinins in man.
  • des-Arg-BK or des-Arg-kallidin is known to induce vasodilation, vascular permeability, and bronchoconstriction (for review, see Regoli and Barabe, Pharmacological Rev, 32(1), 1-46 (1980)).
  • des-Arg-BK and des-Arg-kallidin appear to be particularly important mediators of inflammation and inflammatory pain as well as being involved in the maintenance thereof.
  • Bl and B2 The membrane receptors that mediate the pleiotropic actions of kinins are of two distinct classes, designated Bl and B2. Both classes of receptors have been cloned and sequenced from a variety of species, including man (Menke, et al, J. Biol. Chem. 269, 21583- 21586 (1994); Hess et al, Biochem. Biophys. Res. Commun. 184, 260-268 (1992)). They are typical G protein coupled receptors having seven putative membrane spanning regions. In various tissues, BK receptors are coupled to every known second messenger. B2 receptors, which have a higher affinity for BK, appear to be the most prevalent form of bradykinin receptor. Essentially all normal physiological responses and many pathophysio-logical responses to bradykinin are mediated by B2 receptors.
  • Bl receptors have a higher affinity for des-Arg-BK compared with
  • BK whereas des-Arg-BK is inactive at B2 receptors.
  • Bl receptors are not normally expressed in most tissues. Their expression is induced upon injury or tissue damage as well as in certain kinds of chronic inflammation or systemic insult (F. Marceau, et al.,
  • LPS inflammatory cytokines
  • B 1 receptors inflammatory cytokines
  • the pain-inducing properties of kinins coupled with the inducible expression of B 1 receptors make the Bl receptor an interesting target in the development of anti-inflammatory, antinociceptive, antihyperalgesic and analgesic agents that may be directed specifically at injured tissues with minimal actions in normal tissues.
  • this invention is directed to a class of compounds useful in treating inflammation and pain and having the structure of Formula (I):
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • R 4 is H, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents independently selected from Ci ⁇ alkyl, Ci_ 3 haloalkyl, -OQ ⁇ alkyl, -NH 2 , -NHC M alkyl, and -N(C 1-4 alkyl)C M alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I;
  • R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R 6 , R 7 or R 8 independently selected from basic moie
  • R b is independently, at each instance, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and -C ⁇ aHcyl, - C 1-3 haloalkyl, -OC ⁇ alkyl, -NH 2 , -NHC M alkyl, -N(C M alkyl)C M alkyl; R d is independently at each instance -Ci -8 alkyl, halo, cyano, nitro,
  • R e is independently at each instance -Ci- ⁇ alkyl substituted by 0, 1, 2 or 3 substituents independently selected from R d and additionally substituted by 0 or 1 substituents selected from R g ;
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • R 4 is H, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents independently selected from Q ⁇ alkyl, -OC M alkyl, -NH 2 , and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I;
  • R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R 6 , R 7 or R 8 independently selected from basic moieties, and additionally substituted by 0, 1 , 2 or 3 substituents independently selected from R 6 , R 7 and R 8 which are selected from R g
  • R b is independently, at each instance, phenyl, benzyl or -Ci. 6 alkyl, the phenyl, benzyl and -Ci- ⁇ alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, -Q ⁇ alkyl, - Ciohaloalkyl, -OC M alkyl, -NH 2 , -NHC ⁇ alkyl, -N(C M alkyl)C M alkyl; R d is independently at each instance -C]. 8 alkyl, -C ⁇ haloalkyl, halo, cyano, nitro,
  • R e is independently at each instance -Ci_ ⁇ alkyl substituted by 0, 1, 2 or 3 substituents independently selected from R d and additionally substituted by 0 or 1 substituents selected from R 8 ;
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • the basic moieties are independently selected from amino, cycloalkylamino- (Ci-C6)alkyl, cycloalkyl(Ci-C 6 ) alkylamino(Ci-C6)alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyc IyI(C i -C 6 )alkyl-amino(C i -C 6 )alkyl, arylamino(C i -Ce)alkyl, aryl(C i -C 6 )alkylamino- (Ci -C 6 )alkyl, (Ci -C 6 )alkylamino(Ci -C 6 )alkoxy, (Q -C 6 )alkylamino(C, -C 6 )alkoxy(Ci -C 6 )- alkoxy, amino(Ci-C 6 )
  • the basic moieties are independently selected from amino, mono-C M - alkylamino-C 1 . 4 -alkyl, di-C 1 ⁇ -alkylamino-C 1 ⁇ -alkyl, mono-C 1 ⁇ - alkylamino-C 2-4 -alkenyl, di-Ci. 4 -alkylamino-C 2-4 -aUcenyl, 5-8 membered nitrogen-containing heterocyclyl-C 2-4 -alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl or 5-8 membered nitrogen-containing heterocyclyl-C M -alkyl.
  • the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, ⁇ -butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N- ⁇ -butyl-N- methylaminomethyl, N-wo-butyl-N-methylaminomethyl, N- ⁇ -butyl-N
  • R 1 is H
  • R 1 is -Ci -8 alkyl.
  • R 1 is -C 3- SaIlCyI. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is -CH 3 .
  • R 1 is substituted by 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is -CF 3 .
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -C ]-2 alkyl or -CF 3 .
  • R la is H and R lb F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 .
  • R la is F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 and R lb is H.
  • R la and R lb are each independently, H or F.
  • R lc is H or F.
  • R la , R lb , and R lc are H.
  • R 2 is selected from 2-naphthyl, 1-naphthyl, phenyl, 3-chlorophenyl, 4- chlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4,6-trichlorophenyl, 3 -fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl, 3-chloro-4-methylphenyl, 4-chloro-3- methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3- methylphenyl, [2.1.3]-benzoxadiazol-4-yl, thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl.
  • R 3 is H.
  • R 4 is phenyl, benzyl or -C ⁇ aUcyl, the phenyl, benzyl and C ⁇ alkyl being substituted by 0, 1, 2 or 3 substituents selected from C i ⁇ alkyl, -OC l-4 alkyl, -NH 2 , -NHC M alkyl, and -N(Ci. 4 alkyl)C M alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I.
  • R 5 is:
  • R and R are H; and wherein R 7 is selected from amino, aminomethyl, isopropylaminomethyl, /-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(pi ⁇ eridin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N- ⁇ -butyl-N- methylaminomethyl, N- ⁇ o-butyl-N-methylaminomethyl, N- ⁇ o-butyl-N-methylaminomethyl,
  • R 7 and R 8 are H; and R 6 is selected from amino, aminomethyl, isopropylaminomethyl, f-butylaminomethyl, 2-7-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-f-butyl-N- methylaminomethyl, N-w ⁇ -butyl-N-methylaminomethyl, N-£-
  • R 6 and R 7 are H; and R 8 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-r-butyl-N- methylaminomethyl, N-zs ⁇ -butyl-N-methylaminomethyl, N-t
  • R is:
  • R 5 is:
  • R 3 and R 4 together may additionally be C 2-3 alkylene.
  • a substituent on R 2 that is vicinal to the -SO 2 -R 2 bond together with R 3 may additionally be
  • R la , R lb , R 3 , and R 4 are hydrogen; and R lc is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen.
  • R lc is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen.
  • R 2 is phenyl, naphthenyl, 5- or 6-membered monocyclic saturated or unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, O and S, or 9- or 10- membered unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, O and S, preferably phenyl, benzodioxinyl, quinolinyl, isoquinolinyl, napthalenyl, 2,3- dihydrobenzofuranyl, tetrahydrofuranyl, 2,3-dihydroindolyl, 3,4-dihydro-2H- benzo[b][l,4]dioxepinyl, or 3,4-dihydro-2H-benzo[b][l,4]oxazine substituted with 0, 1, 2, or three substitutents independently selected from halo, C M haloalkyl, nitro, -OH, - NH 2 , R
  • R 5 is unsaturated 10-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, preferably 1 (R)-1, 2,3, 4-tetrahydronaphthalen-l-yl or 4(Z?)-chroman-4-yl, substituted with cycloalkylamino-(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino(C]-C 6 )alkyl, Ci -6 - alkylamino-Ci.
  • heterocyclyl ring optionally contains an oxygen or nitrogen ring atom and is substituted with 0, 1, or 2 substitutents independently selected from halo, -OH, or -Ci, 6 alkyl and additionally with 0 or 1 substitutuent selected from halo or nitro.
  • a family of specific compounds of particular interest within Formula (I) consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or any pharmaceutically-acceptable salt or hydrate thereof and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treating a disease in a patient mediated by the Bl receptor comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or any pharmaceutically-acceptable salt or hydrate thereof and a pharmaceutically acceptable excipient.
  • the compounds of the present invention are useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed- vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and
  • the invention also provides for the use of the compounds of the present invention for the prevention or for the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic aicononsm, stroke, thalamic pain syn ⁇ rome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed- vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia
  • this invention is directed to the use of one or more of the compounds of the present invention in the manufacture of a medicament.
  • the medicament is useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed- vascular and non ⁇ vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions,
  • a disorder such as
  • the compounds of this invention may also act as inhibitors of other receptors or kinases, and thus be effective in the treatment of diseases associated with other protein kinases. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • C a _palkyl means an alkyl group having a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein ⁇ and ⁇ represent integers as indicated in the claims unless otherwise indicated.
  • the alkyl groups described in this section may also contain one or two double or triple bonds.
  • alkenyl When the alkyl group has a double bond it is also referred to herein as alkenyl.
  • alkynyl When the alkyl group has a triple bond it is also referred to herein as alkynyl. Examples include, but are not limited to, the following:
  • alkylamino denotes amino groups which have been substituted with one alkyl radical and with two alkyl radicals, including terms “N-alkylamino” and "NN- dialkylamino". More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable “alkylamino” may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino and the like.
  • N-aralkyl-N-alkylamino and “N-alkyl-N-arylamino” denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
  • aminoalkyl embraces linear or branched alkyl radicals having one to ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
  • alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom independently substituted with an alkyl radical. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N- methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.
  • aminoalkenyl embraces linear or branched alkyl radicals having two to ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkenyl radicals are "lower aminoalkenyl” radicals having two to six carbon atoms and one or more amino radicals. Examples of such radicals include aminoethenyl, aminopropenyl, aminobutenyl and aminohexenyl. Even more preferred are lower aminoalkenyl radicals having two or three carbon atoms.
  • alkylaminoalkenyl embraces aminoalkenyl radicals having the nitrogen atom independently substituted with an alkyl radical. More preferred alkylaminoalkenyl radicals are "lower alkylaminoalkenyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkenyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkenyl radicals may be mono or dialkyl substituted, such as N-methylaminovinyl, N,N-dimethyl-aminovinyl, N,N-diethylaminovinyl, and the like.
  • alkoxy embrace linear or branched oxy-containing radicals (-OR) having alkyl portions of one to ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fiuoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.
  • alkoxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more alkoxyl radicals. More preferred alkoxyalkyl radicals are "lower alkoxyalkyl” radicals respectively having one to six carbon atoms. Examples of such radicals include methoxymethyl, methoxyethyl, and the like. Even more preferred are lower alkoxyalkyl radicals respectively having one to three carbon atoms alkyl radicals.
  • aminoalkoxy embraces alkoxy radicals substituted with an amino radical. More preferred aminoalkoxy radicals are "lower aminoalkoxy” radicals having alkoxy radicals of one to six carbon atoms. Suitable aminoalkoxy radicals may be aminoethoxy, aminoethoxy, aminopropoxy and the like.
  • alkylaminoalkoxy embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy” radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
  • alkylaminoalkoxyalkoxy embraces alkoxy radicals substituted with alkylaminoalkoxy radicals as defined above. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy” radicals independently having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms.
  • Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxymethoxy, N,N- dimethylaminoethoxymethoxy, N ⁇ V-diethylaminomethoxymethoxy, and the like.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl.
  • the "aryl” group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino unless otherwise indicated.
  • aralkyl embraces aryl substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
  • arylalkenyl embraces aryl substituted alkenyl radicals.
  • Preferable arylalkenyl radicals are "lower arylalkenyl” radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl.
  • the aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy unless otherwise indicated.
  • N-arylaminoalkyl denotes aminoalkyl radicals substituted with an aryl radical. More preferred arylaminoalkyl radicals are "lower N-arylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are phenylaminoalkyl radicals having one to three carbon atoms. Examples of such radicals include N-phenylaminomethyl and N-phenylaminoethyl.
  • aralkylaminoalkyl embraces aralkyl radicals as described above, attached to an aminoalkyl radical as defined herein. More preferred are lower arylalkylaminoalkyl radicals independently having alkyl radicals of one to three carbon atoms.
  • basic moiety or “basic moieties” means a chemical moiety that has a measured or calculated pK a of from about 7 to about 13.
  • the term also can include a chemical moiety that is protonable, to some extent, between a pH range of from about 7 to about 10.
  • Examples of basic moieties include, but are not limited to, amino, cycloalkylamino-
  • the basic moiety is selected from cycloalkylamino(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkyl- amino(Ci -Ce)alkyl, heterocyclylamino(Ci -C 6 )alkyl, heterocyclyl(C i -C6)alkylamino- (d-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (C r C 6 )alkyl amino(C i -C 6 )alkoxy, (C i -C 6 )alkylamino(C i -C 6 )alkoxy(C i -C6)alkoxy, amino(C i -Ce)alkoxy, amino(Ci-C 6 )alkyl, (Ci
  • the basic moiety is selected from cycloalkylamino(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino- (C i -C 6 )alkyl, heterocyclylamino(C i -C 6 )alkyl, heterocyclyl(C i -C 6 )alkylamino(C i -C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (Ci-Ce)alkyl amino(Ci-C 6 )alkoxy, (C i -C 6 )alkylamino(C i -Ce)alkoxy(C i -C 6 )alkoxy, amino(C i -C 6 )alkoxy, amino(C i -Ce)alkoxy, amino(
  • the basic moiety is amino, aminomethyl, isopropylaminomethyl, ⁇ -butylaminomethyl, 2- ⁇ -butylaminoethyl, 2-tert- butylamino-1 -methyl-ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, 1- (piperidin-l-yhnethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2- dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N- methylaminomethyl, N-/-butyl-N-methylaminomethyl, N-jso-butyl-N-methylaminomethyl, N-t- butyl-N-ethylaminomethyl, N-isobutyl-N
  • cycloalkyl includes saturated carbocyclic groups.
  • Preferred cycloalkyl groups include C 3 -C 6 rings. More preferred compounds include cyclopentyl, cyclopropyl, and cyclohexyl.
  • cycloalkylaminoalkyl refers to aminoalkyl radicals where the nitrogen atom of the amino group is independently substituted, respectively, with one cycloalkyl radical, or two cycloalkyl radicals and therefore includes "N-cycloalkylaminoalkyl” and 1 WW- dicycloalkylaminoalkyl". More preferred cycloalkylaminoalkyl radicals are "lower cycloalkylaminoalkyl” radicals having alkyl radicals with one to six carbon atoms. Even more preferred are lower cycloalkylaminoalkyl radicals having alkyl radicals with one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N- cyclohexylaminomethyl, and N-cyclopentylaminoethyl.
  • cycloalkylalkylaminoalkyl embraces cycloalkyl radicals as described above, attached to an alkylaminoalkyl radical. More preferred are lower cycloalkyl-alkylaminoalkyl radicals independently having alkyl radicals of one to three carbon atoms.
  • Halo or "halogen” means a halogen atoms selected from F, Cl, Br and I.
  • C ⁇ _ ⁇ haloalkyl means an alkyl group as described above, unless otherwise indicated, wherein any number—at least one—of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.
  • Heterocycle or “heterocyclyl” means a ring comprising at least one carbon atom and at least one other atom selected from ⁇ , O and S.
  • the term heterocycle embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -O-O- or -S-S- portions.
  • the heterocycle ring contains 3 to 10 ring atoms.
  • Unsaturated heteroatom-containing ring radicals as used herein means a heterocycle containing at least one aromatic ring.
  • Unsaturated heteroatom-containing ring radicals are also referred to herein as heteroaryl.
  • Partially saturated heteroatom-containing ring radicals as used herein means a heterocycle containing one or more double bonds provided that it is not aromatic. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
  • heterocyclylaminoalkyl embraces heterocyclyl radicals as described above, attached to an aminoalkyl radical as defined herein.
  • heterocyclylalkylaminoalkyl embraces heterocyclylalkyl radicals as described below, attached to an aminoalkyl radical. More preferred are lower heterocyclylalkylaminoalkyl radicals having, independently, alkyl radicals of one to three carbon atoms.
  • heterocyclylalkyl embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl” radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridinylmethyl and thienylmethyl.
  • heterocyclylalkenyl embraces heterocyclyl-substituted alkenyl radicals.
  • Preferable heterocyclylalkenyl radicals are "lower heterocyclylalkenyl” radicals having heterocyclyl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include pyridinylethenyl.
  • the heterocyclyl ring contains 4 to 8 ring atoms having at least a nitrogen ring atom it is referred to herein as 4-8 membered nitrogen containing heterocyclylalkenyl.
  • heterocyclyloxy embraces optionally substituted heterocyclyl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include piperidyloxy.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • partially saturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring means a hydrocarbon ring that is not completely aromatic e.g., tetrahydronaphthyl, tetrahydrochromenyl, dihydroindolyl, and the like.
  • unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring means a hydrocarbon ring that is aromatic.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • therapeutically-effective is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • effective pain therapeutic agents relieve the pain sensation of the patient.
  • effective therapeutic agents for the treatment of inflammation minimize the damage from the inflammation, and the like.
  • treatment includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals).
  • the compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below:
  • the invention expressly includes all tautomeric forms of the compounds described herein.
  • the compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • Substituents on ring moieties may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen).
  • the compounds of this invention may contain heterocyclic ring systems attached to another ring system. Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
  • Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof.
  • the compounds of the present invention as depicted or named, may exist as the racemate, a single enantiomer, or any uneven (i.e. non 50/50) mixture of enantiomers. All such isomeric forms are within the scope of the invention.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column, such as, for example, a CHIRAL-AGP column, optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • Preferred compounds of the invention have an R configuration at the carbon that is attached to the amide bond as shown below:
  • compositions of Formula (I) are also included in the family of compounds of Formula (I) and the pharmaceutically- acceptable salts thereof.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopent
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N- ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula (I)
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as de
  • organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1994); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers); Organic Reactions, Volumes 1-46 (John Wiley and Sons, 2003), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 0 C.
  • Compounds of formula 1 are either commercially available or they can be prepared by methods well known in the art.
  • Compounds of formula 2 are either commercially available or they can be prepared by methods well known in the art.
  • Reaction of acid 3 with an amine of formula 4 where R 4 and R 5 are as defined in the Summary of the invention under standard peptidic coupling reaction conditions provide a compound of Formula (I).
  • the reaction is carried out in the presence of a coupling agent such as are coupled with the substituted amine 2 using standard peptide coupling conditions coupling agent (e.g., benzotriazol-1-yloxy- trispyrrolidinophosphonium hexafluorophosphate (PyBOP ® .), l-(3-dimethylamino-propyl)-3- ethylcarbodiimide hydrochloride (EDCI), CKT-azabenzotrizol-l-yl)-!,! ⁇ , tetra- methyluroriium-hexafluoro- phosphate (HATU), O-berizotriazol-l-yl-N,N,N,N-tetramethyl- uronium hexafluorophosphate (HBTU), l ⁇ -dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt
  • Amines of formula 2 are commercially available or may be prepared by methods well known in the art. A detailed description of syntheses of amines is provided in working examples below.
  • Compounds of Formula (I) can also be prepared by reacting compound 3 with a an amine of formula 5 where PG is a precursor group to R 5 group. Conversion of the PG group to R 5 group then provides a compound of Formula (I).
  • the aldehyde can first treated with an unsubstituted amine and then the amine can be alkylation under standard alkylation reaction conditions or treated with an aldehyde under reductive amination reaction conditions.
  • the above compounds can also be prepared from a corresponding compound of formula 6 carrying an alkene group by first converting the alkyne group to an aldehyde under ozonolysis reaction conditions and then proceeding as described above.
  • the aldehyde can be first converted to a ketone by treating it with a Grignard reagent and then reacted with amine to provide compounds of Formula (I) where the carbon atom alpha to the amino group is substituted.
  • Compounds of Formula (I) where R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring substituted with 5-6 membered heterocyclyloxy can be prepared from a corresponding compound of formula 6 where PG is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring substituted with a hydroxyl group by reacting it with heterocyclyl halide under alkylating reaction conditions.
  • Salts of a compound of Formula (I) with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula (I) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid molecules for example a dihalogenide of a compound of Formula (I)
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • the compounds of Formula (I), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates). All such forms are within the scope of this invention.
  • the compound of Formula (I) are Bl receptor antagonists and hence are useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed-vascular and non- vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and
  • the in vitro binding affinity of the compounds of the invention to the human Bl and B2 bradykinin receptors can be tested using the radioligand binding assay described in Biological Example 1 below.
  • the antagonistic activity of the compounds of the invention for the human Bl and B2 bradykinin receptors can be tested using the calcium flux assay, Rabbit endothelial cell Bl -specific PGI 2 secretion Assay, and umblical vein Assay described in Biological Examples 2 and 3 below.
  • the antinociceptive activity of the compounds of the invention was determined using the rat and monkey pain models described in Example 4 below.
  • the antiinflammatory activity of the compounds of the invention was determined using the Green Monkey LPS inflammation model described in Example 5 below.
  • the present invention also embraces pharmaceutical compositions comprising the active compounds of Formula (I) in association with one or more non-toxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients.
  • carrier non-toxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants
  • the compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • the pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg or 5 to 1000 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
  • the amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • a daily dose of about 0.01 to 500 mg/kg, preferably between about 0.1 and about 50 mg/kg, and more preferably about 0.1 and about 20 mg/kg body weight may be appropriate.
  • the daily dose can be administered in one to four doses per day.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled- release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Topical preparation of compounds of this invention In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g. , liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
  • a suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily.
  • the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
  • the active ingredients When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.
  • transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsif ⁇ ers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
  • Formulations for parenteral administration may be in the form of aqueous or non ⁇ aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (i.e., Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (i.e., Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
  • Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the present compounds may also be used in combination therapies with opioids and other anti-pain analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non- addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin- 1 receptor antagonists, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, and darecoxib, NSAID's, and sodium channel blockers, among others.
  • opioids and other anti-pain analgesics including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non- addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin
  • the present compounds may also be used in co-therapies with other treatments for inflammation, e.g. steroids, NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, LTB 4 receptor antagonists and LTA 4 hydrolase inhibitors.
  • steroids e.g., NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, LTB 4 receptor antagonists and LTA 4 hydrolase inhibitors.
  • Step A Synthesis of 5(iS)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
  • BH 3 -SMe 2 was added (17 mL, 180 mmol, Aldrich), followed by a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in THF (200 mL) was added over 5 h using a syringe pump. After the addition was complete, the reaction mixture was stirred for an additional 1 h. The reaction mixture was poured into an addition funnel, and the reaction mixture was added to MeOH (200 mL), cooled in a ice-salt bath, over 30 min at such a rate that the internal temp, was kept below 0 0 C. The reaction mixture was concentrated in vacuo.
  • Step B Synthesis of 5(R)-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester
  • Step A Synthesis of 2-trifluoromethanesulfonic acid 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl ester To a 1 -L round-bottomed flask charged with 6-hydroxy- 1 -tetralone (Aldrich, 21.97 g,
  • Step C Synthesis of 2-trifluoromethanesulfonic acid 5(i?)-azido-5,6,7,8-tetrahydro-naphthalen- 2-yl ester
  • 2-trifluoromethanesulfonic acid 5(5)-hydroxy-5,6,7,8-tetrahydro- naphthalen-2-yl ester (11.2 g, 37.9 mmol, 1.0 eq) in THF (150 mL) at RT was added DPPA (Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq).
  • Step E Synthesis of 2-trifluoromethanesulfonic acid 5(/?)-tert-butoxycarbonyl-amino-5,6,7,8- tetrahydro-naphthalen-2-yl ester
  • Step G Synthesis of 6-( 1 -piperidin- 1 -ylmethylvinyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
  • TFA 3 mL
  • the reaction mixture was stirred at RT for 4 h and then concentrated in vacuo.
  • the crude was neutralized with 10% Na 2 CO 3 until the aqueous phase is basic, extracted with CH 2 Cl 2 .
  • the organic solution was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide the title compound.
  • Step A Synthesis of (i?)-tert-butyl 6-(hydroxymethyi)-l,2,3,4-tetrahydronaphthalen-l-yl- carbamate
  • Triethylamine (27.7 mL, 199 mmol) and di-tert-butyl-dicarbonate (17.4 g, 79.6 mmol) were added consecutively to a solution of (5(/?)-amino-5,6,7,8-tetrahydronaphthalen-2-yl)- methanol (7.05 g, 39.8 mmol) in a mixed solvent of ethyl acetate (100 mL), methanol (100 mL), and dichloromethane (100 mL) and the reaction mixture was stirred at RT for 2 h. The solvents were removed in vacuo, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate.
  • Step C Synthesis of (R)-tert-butyl 6-((tert-butylamino)methyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate
  • Step D Synthesis of (/?)-6-((tert-butylamino)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
  • Step A Synthesis of (R)-tert-buty ⁇ 6-(piperidin-l -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1- ylcarbamate.
  • Step B Synthesis of (R)- ⁇ -(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine
  • Step B Synthesis of 7-(tert-butylamino-methyl)-6-chloro-chroman-4-one
  • Step D Synthesis of 4(/?)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine
  • Step C Synthesis of (R)-tert-butyl 6-(2-oxoethyl)- 1 ,2,3,4-tetrahydronaphthalen-l -ylcarbamate
  • Step D Synthesis of (/?)-tert-butyl-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylcarbamate
  • (R)-tert-butyl 6-(2-oxoethyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate (2.02 g, 7 mmol)
  • piperidine (1.79 g, 21 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (2.97 g, 14 mmol).
  • Step E Synthesis of ( ⁇ )-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine
  • Step B Synthesis of 3-(tert-butyldiphenylsilyloxy)-propanamidine To a suspension OfNH 4 Cl (5.35 g, 0.1 mol) in dry benzene (60 mL) at 0 0 C was slowly added a solution of trimethylaluminum in toluene (50 mL, 2M).
  • reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased.
  • a solution of 3-(tert-butyldiphenylsilyloxy)propanenitrile (9.27 g, 0.03 mol) in dry benzene (20 mL) was added to the aluminum amide reagent and the resulting mixture was heated up to 80 0 C for 20 h.
  • the reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1 :2).
  • Step C Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one
  • Step D Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-ol
  • a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one (2.16 g, 5 mmol) in dry MeOH (30 mL) was treated with NaBH 4 (189 mg, 5 mmol). After 5 min, the reaction was quenched with 5 mL of sat. NH 4 Cl solution. The MeOH was evaporated and the residue was extracted with DCM, dried over Na 2 SO 4 and evaporated.
  • Step F Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5- amine
  • Step G Synthesis of 2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol
  • a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5- amine (570 mg, 1.32 mmol) in THF (10 mL) at 0 0 C was treated with a IM TBAF solution in THF (1.56 mL, 1.56 mmol).
  • Step A Synthesis of 1 -(2-hydroxyethyl)-6,7-dihydro- 1 H-indazol-4(5H)-one
  • Step B Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-lH-indazol-4(5H)- one
  • Step C Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4-ol
  • Step D Synthesis of 4-azido-l-(2-(tert-butyldimethyl silyloxy)ethyl)-4,5,6,7-tetrahydro-lH- indazole
  • Step E Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4- amine
  • Step A Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoroniethyl)phenylsulfonamido)butanoate
  • Step B Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid A mixture of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate
  • (/?)-4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid was prepared from (i?)-ethyl 3-amino-4,4,4-trifluorobutanoate (prepared according to literature procedure: Soloshonok, V.A.; Ono, T.; Soloshonok, LV. J. Org. Chem. 1997, 62, 7538-39).
  • the following sulfonylated acids were prepared similarly:
  • Step A Synthesis of (5',E)-l-phenyl-N-(2,2,2-trifluoroethylidene)ethanamine
  • Step B Synthesis of (2/?,3/?)-2-(benzyloxy)-4-((/?)-l-phenylethyl)-3-(trifluoromethyl)- cyclobutanone
  • Step A Synthesis of (2R,3S)-methyl 4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoro- methyl)phenylsulfonarnido)butanoate
  • Step B Synthesis of (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoromethyl)- phenylsulfonamido)butanoic acid
  • Step A Synthesis of (5)-ethyl 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoate
  • Step B Synthesis of (5)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoic acid
  • Step A Synthesis of ( ⁇ )-2,2,2-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)acetamide
  • Step B Synthesis of (/?)-(5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)- methylacetate
  • Step C Synthesis of (i?)-(l-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate and (i?)-(3-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate
  • (/?)-(5-(2,2,2-trifluoroacetamido)-5 ,6,7,8-tetrahydronaphthalen-2-yl)- methyl acetate 160 mg, 0.508 mmol
  • MeCN 2 mL
  • Step F Synthesis of ( ⁇ -trifluoro-N-CT-nitro- ⁇ -Cpiperidin-l-yhnethyO-l ⁇ -tetrahydro- naphthalen- 1 -yl)acetamide
  • (i?)-2,2,2-trifluoro-N-(6-formyl-7-nitro-l ,2,3,4-tetrahydronaphthalen- l-yl)acetamide 350 mg, 1.1 mmol
  • 1,2-dichloroethane (6 mL)
  • piperidine 187 mg, 2.2 mmol
  • NaBH(OAc) 3 350 mg, 1.65 mmol
  • Step G Synthesis of (/?)-7-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l- amine
  • Step A Synthesis of (/?)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l,2,3,4-tetrahydro- naphthalen- 1 -yl)acetamide
  • Step B Synthesis of (i?)-2,2,2-trifluoro-N-(6-formyl-5-nitro-l,2,3,4-tetrahydronaphthalen-l- yl)acetamide
  • (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l ,2,3,4-tetrahydro- naphthalen-l-yl)acetamide 440 mg, 1.38 mmol
  • DCM 50 mL
  • Step C Synthesis of ( ⁇ )-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ybnethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)acetamide
  • Step D Synthesis of (/?)-5-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - amine
  • a solution of (/?)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ymiethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)acetamide 230 mg, 0.6 mmol
  • NaOH 48 mg, 1.2 mmol
  • Step A Synthesis of (5)-N-((R)-6-(hydroxymethyl)-l ,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
  • Step B Synthesis of (5)-N-((/?)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3-(trifluoro- methyl)phenylsulfonamido)butanamide
  • Step C Synthesis of (S)-N-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3- (3 -(trifluoromethyl)phenylsulfonamido)butanamide
  • Step A Synthesis of (/?)-4,4,4-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide A mixture of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
  • Step B Synthesis of (i?)-4,4,4-trifluoro-N-(6-formyl-l ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
  • Step C Synthesis of ( ⁇ )-4,4,4-trifluoro-N-(6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen- 1 -yl)-3-(3-(trifluoromethyl) phenylsulfonamido)butanamide
  • Step A Synthesis of [6-(l-hydroxy-ethyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-carbamic acid tert-butyl ester
  • Step A Synthesis of 3,4-dichloro-N-((2R,3R)-2-methyl-5-oxo-tetrahydrofuran-3-yl)benzene- sulfonamide
  • Step B Synthesis of (3/?,4i?)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6- (hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide
  • Step C Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-N-((i?)-6-formyl-l,2,3,4- tetrahydronaphthalen- 1 -yl)-4-hydroxypentanamide (3i?,4 ⁇ )-3-(3,4-Dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6-(hydroxymethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)pentanamide (0.12 g) in DCM (300-400 mL) was stirred with MnO 2 at RT for 2 h. The reaction mixture was filtered through a pad of celite.
  • Step A Synthesis of methyl 3-(4-fluorophenylamino)propanoate To a 30-mL microwave vial containing methyl 3-bromopropanoate (6.2 mL, 57 mmol,
  • Step C Synthesis of 3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)propanoic acid To a 100-mL round-bottomed flask containing methyl 3-(N-(4-fluorophenyl)-3-
  • Step D Synthesis of (/?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- (hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide
  • oxalyl chloride 10 mL, 21 mmol, 2.0M, Aldrich.
  • Step E Synthesis of (S)-N-(4-fluorophenyl)-N-(4-(6-formyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide
  • Step F Synthesis of (i?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- ((4-fiuoropiperidin- 1 -yl)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)propanamide
  • Step B Synthesis of methyl 3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanoate
  • N-methyl-3-(trifluoromethyl) benzenesulfonamide 1.5 g, 6.3 mmol, Step A
  • DMF 10 mL
  • methyl 3-bromo- propanoate 28 mL, 257 mmol, Aldrich
  • K 2 CO 3 2.3 g, 17 mmol, Aldrich
  • Step D Synthesis of (i?)-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3-(2V- methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide
  • Step E Synthesis of (R)-N-(6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(N-methyl-3- (trifluoromethyl)phenylsulfonamido)propanamide
  • Step F Synthesis of (/?)-N-(6-((4-fluoropiperidin-l-yl)methyl)-l,2,3,4-tetrahydronaphthalen- l-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide.
  • Step A Synthesis of N-cyclopro ⁇ yl-3-(trifluoromethyl) benzenesulfonamide
  • Step B Synthesis of f ⁇ r/-butyl 3-(N-cyclopropyl-3-(trifluoromethyl)phenyl- sulfonamido)propanoate.
  • N-cyclopropyl-3-(trifluoromethyl) benzenesulfonamide 1.7 g, 6.2 mmol, step A
  • DMF 10 mL
  • Step C Synthesis of 3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido) ⁇ ropanoic acid.
  • Step D Synthesis of (/?)-3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide.
  • Step A Synthesis of methyl 3-(3-bromo-saccharinyl)propanoate To a 100-mL round-bottomed flask containing 3-bromosaccharin (1.0 g, 3.8 mmol,
  • Step C Synthesis of (/?)-3-(3-bromo-saccharinyl-N-(6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)propanamide
  • Step A Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate

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Abstract

Cette invention touche le domaine des agents pharmaceutiques et concerne spécifiquement des composés, des compositions, des utilisations et des méthodes de traitement de troubles liés à l'inflammation et notamment de la douleur.
EP05797852A 2004-09-23 2005-09-19 Sulfonamidopropionamides substitues et procedes d'utilisation Withdrawn EP1799637A1 (fr)

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