WO2005065779A1 - Antagonistes du recepteur peptidique lie au gene de la calcitonine - Google Patents

Antagonistes du recepteur peptidique lie au gene de la calcitonine Download PDF

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WO2005065779A1
WO2005065779A1 PCT/US2003/038799 US0338799W WO2005065779A1 WO 2005065779 A1 WO2005065779 A1 WO 2005065779A1 US 0338799 W US0338799 W US 0338799W WO 2005065779 A1 WO2005065779 A1 WO 2005065779A1
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Prior art keywords
oxo
dihydro
piperidine
methyl
ethyl
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PCT/US2003/038799
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English (en)
Inventor
Andrew P. Degnan
Ling Chen
Rita Civiello
Gene M. Dubowchik
Xiaojun Han
Xiang Jun J. Jiang
John E. Macor
George Tora
Guanglin Luo
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Bristol-Myers Squibb Company
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34748456&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005065779(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP03819270A priority Critical patent/EP1689493A4/fr
Priority to JP2005513137A priority patent/JP2007524568A/ja
Priority to BRPI0318637-7A priority patent/BR0318637A/pt
Priority to YUP-2006/0382A priority patent/RS20060382A/sr
Priority to AU2003297694A priority patent/AU2003297694A1/en
Priority to CA002549330A priority patent/CA2549330A1/fr
Priority to PCT/US2003/038799 priority patent/WO2005065779A1/fr
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to UAA200607510A priority patent/UA81563C2/xx
Priority to CNB200380111030XA priority patent/CN100558428C/zh
Priority to TW093137052A priority patent/TWI284534B/zh
Priority to ARP040104530A priority patent/AR046788A1/es
Priority to PE2004001196A priority patent/PE20051036A1/es
Publication of WO2005065779A1 publication Critical patent/WO2005065779A1/fr
Priority to IS8482A priority patent/IS8482A/is
Priority to IL176018A priority patent/IL176018A0/en
Priority to NO20062648A priority patent/NO20062648L/no
Priority to HR20060236A priority patent/HRP20060236A2/xx

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    • 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
    • A—HUMAN NECESSITIES
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel small molecule antagonists of calcitonin gene-related peptide receptors ("CGRP-receptor”), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP- receptors.
  • CGRP-receptor novel small molecule antagonists of calcitonin gene-related peptide receptors
  • pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic o
  • Calcitonin gene-related peptide is a naturally occurring 37-amino- acid peptide first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed ( ⁇ CGRP and ⁇ CGRP) which differ by one and three amino acids in rats and humans, respectively.
  • the peptide is widely distributed in both the peripheral (PNS) and central nervous system (CNS), principally localized in sensory afferent and central neurons, and displays a number of biological effects, including vasodilation.
  • CGRP When released from the cell, CGRP binds to specific cell surface G protein- coupled receptors and exerts its biological action predominantly by activation of intracellular adenylate cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105, 441-1; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.).
  • Two classes of CGRP receptors, CGRPi and CGRP 2 have been proposed based on the antagonist properties of the peptide fragment CGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP 2 receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438).
  • the CGRPj receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR); (ii) the single transmembrane receptor activity modifying protein type one (RAMPl); and (iii) the intracellular receptor component protein (RCP) (Evans B. N. et al., J Biol Chem. 2000, 275, 31438-43).
  • RAMP1 is required for transport of CRLR to the plasma membrane and for ligand binding to the CGRP-receptor (McLatchie, L. M.
  • RCP is required for signal transduction (Evans B. N. et al., J Biol Chem. 2000, 275, 31438-43).
  • RAMP 1 The amino acid sequence of RAMP 1 determines the species selectivity, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al. J Biol Chem 2002, 277, 14294-8).
  • Inhibitors at the receptor level to CGRP are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP receptor activation has been implicated in the pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001;15(10):745-53; Williamson, D. J. Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol. 2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine (Goadsby PJ, et al.
  • CGRP- receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5- HT IB/ID agonists, 'triptans' (e.g., sumatriptan).
  • 'triptans' e.g., sumatriptan
  • the method of the present invention procedure being inter alia a non-invasive survival model in primates measuring exogenous CGRP-induced changes in facial blood flow and demonstrating pre- and post-treatment effects of peptide and small molecule CGRP antagonists in spontaneously breathing isoflurane anesthetized marmosets who recover from the procedure offers significant advantages.
  • a number of non-peptidic, small molecule CGRP-receptor antagonists have been recently reported.
  • WO 97/09046 and equivalents disclose inter ⁇ li ⁇ quinine and quinidine related compounds which are ligands, in particular antagonists, of CGRP- receptor.
  • WO 98/09630 and WO 98/56779 and equivalents disclose inter ⁇ li ⁇ variously substituted, nitrobenzamide compounds as CGRP-receptor antagonists.
  • WO 01/32649, WO 01/49676, and WO 01/32648 and equivalents disclose / «ter ⁇ li ⁇ a series of 4-oxobutanamides and related cyclopropane derivatives as CGRP-receptor antagonists.
  • WO 00/18764, WO 98/11128 and WO 00/55154 and equivalents disclose wter ⁇ li ⁇ benzimidazolinyl piperidines as antagonists to CGRP-receptor.
  • Unrelated to CGRP a series of somatostatin antagonists have been disclosed in WO 99/52875 and WO 01/25228 and equivalents. See also U.S. 6,344,449, U.S.
  • V is -N(R')(R 2 ) or OR 4 ;
  • R 4 is H, C 1-6 alkyl, C ]-4 haloalkyl or R 4 is C 3- cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydro furanyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl
  • R 4 is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, hydroxy, amino, C -7 cycloalkyl, C ⁇ - alkylamino, Ci. dialkylamino, (C ⁇ -3 alkyl)o -2 ureido, phenyl and benzyl; and R 4 optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure ofR 4' ; R 1 and R 2 are each independently L 1 , wherein L 1 is selected from the group consisting of H, C ⁇ -6 alkyl, C -6 alkenyl, C 2-6 alkynyl, -Ci.
  • R and R are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C ⁇ . 4alkyl, hydroxy, amino, C 3- 10 cycloalkyl, C ⁇ -3 alkylamino, Cj -3 dialkylamino, (Ci.
  • R 1 and R 2 optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising R 1 and R 2 ; 15 wherein L 1 is optionally and independently interrupted from the nitrogen to which it is attached by L 2 , wherein L 2 is independently C ⁇ -3 alkylene or C ] -3 alkylidene; or R 1 and R 2 together with the nitrogen to which they are attached form
  • X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y 25 is dioxolanyl, C ⁇ - alkyl, C 2-9 alkenyl, C - alkynyl, Ci- 4alkoxy, C 3- cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, 30 imidazolinyl, imidazolidinyl, imidazolidinyl
  • X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon atom and together form a spirocyclic moiety;
  • Q is Q* or Q"; wherein Q' is (S y ) s R 3 ;
  • Q" is NH(S y ) s R 3 , NHC(O)(S y ) s R 3 , NHC(O)O(S y ) s R 3 , NHC(O)NH(S y ) s R 3 , O(S y ) s R 3 , (S y ) s NHR 3 , (S y ) s NHC(O)R 3 , (S y ) s NHC(O)OR 3 , (S y ) s NHC(O)NHR 3 or (S y ) s OR 3 ; wherein S y is C ⁇ -3 alkylene or C ⁇ -3 alkylidene and s is 0 or 1; U is CH 2 or NH; provided that if Q is Q", then U is CH 2 ; R 3 is R 3a or R 3b wherein
  • R 3a is (i) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings; (ii) a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; (iii) C 3-7 cycloalkyl;
  • R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C].
  • R 3 is R 3a but is not phenyl, 1 -naphthyl, 2-naphthyl, 1 ,2,3,4- tetrahydro- 1-naphthyl, lH-indol-3-yl, 1 -methyl- 1H- indol-3-yl, l-formyl-lH-indol-3-yl, 1-(1,1- dimethylethoxycarbonyl)- 1 H-indol-3-yl, 4- imidazolyl, 1 -methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl,
  • a x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle;
  • a y is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; wherein A x and A y are optionally substituted with Ci.
  • GJA' is A x or A y ; and GJA" is A x or A y ; provided that
  • a x is not a 1,3-diaza-fused heterocycle
  • A is not a 1,3-diaza-heterocycle; and further provided that ifQ is Q", then R 3 is R 3a ; and if Q is Q', then R 3 is R 3b ; or
  • R 3 is R 3a , p is 0 and G, J and A together form GJA".
  • Q is Q' and R 3 is R 3 .
  • compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S y ) s R 3 and s is 0. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S y ) s R 3 , S y is C ⁇ -3 alkylene and s is l.
  • compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S ) s R 3 , S y is C ⁇ -3 alkylidene and s is 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S y ) s R 3 .
  • compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S y ) s R 3 , S y is C 1-3 alkylidene and s is 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S y ) s R 3 .
  • compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S y ) s R 3 , S y is C,. 3 alkylene and s is 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S y ) s R 3 , S y is C ⁇ -3 alkylidene and s is 1.
  • R 4 is H, C 1-6 alkyl, Ci ialoalkyl, (C ]-4 alkylene) 0-1
  • R 4' R 4 is C 3- cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridy
  • R 4 is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, hydroxy, amino, C 3- cycloalkyl, C ⁇ -3 alkylamino, C ⁇ _ 3dialkylamino, (C ⁇ -3 alkyl) 0-2 ureido, phenyl and benzyl;
  • R 4 optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure ofR 4' ;
  • R 1 and R 2 are each independently L 1 , wherein L 1 is selected from the group consisting of H, Ci- ⁇ alkyl, -C 1-6 alkylene-amino(C ⁇ .
  • R and R are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Ci. 10 4 alkyl, hydroxy, amino, C 3- 7 cycloalkyl, C ⁇ -3 alkylamino, C ⁇ -3 dialkylamino, (Cj.
  • R 1 and R 2 optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a 15 member of the heterocycles comprising R 1 and R 2 ; wherein L 1 is optionally interrupted from the nitrogen to which it is attached by L 2 , wherein L 2 is C ⁇ -3 alkylene; or R 1 and R 2 together with the nitrogen to which they are attached form
  • X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y 25 is dioxolanyl, C ⁇ _
  • X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon atom and together form a spirocyclic moiety.
  • R 4 is H, C ⁇ -6 alkyl, or (C ⁇ -4 alkylene)o- ⁇ R 4 ;
  • R 4 is C 3-7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,
  • R 4 is H, C 1-6 alkyl, or (C ⁇ -4 alkylene)o- ⁇ R 4 ;
  • R 4 is C 3- cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thi
  • N is - ⁇ (R )(R )
  • R 1 and R 2 are each independently L 1 , wherein L 1 is selected from the group consisting of H, C ⁇ -6 alkyl, 3alkyl) 2 , C 3-7 cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyrid
  • X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C 3- cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyridyl
  • N is - ⁇ (R )(R )
  • R 1 and R 2 are each independently L 1 , wherein L 1 is selected from the group consisting of H, C ⁇ -6 alkyl, or
  • X wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, or piperidinyl; and wherein X and Y optionally share one carbon atom and together form a spirocyclic moiety.
  • V is -N(R')(R 2 ) and wherein R 1 and R 2 are each independently L 1 , wherein L 1 is selected from the group consisting of H, C) -6 alkyl.
  • V is -N(R')(R 2 ) and wherein
  • X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, or piperidinyl; and wherein X and Y optionally share one carbon atom and together form a spirocyclic moiety.
  • X is piperidinyl; wherein X is substituted with Y, wherein Y is dioxolanyl; and wherein X and Y share one carbon atom and together form a spirocyclic moiety.
  • compounds according to the first embodiment of the first aspect of the present invention wherein X and Y are not interrupted with Z.
  • R 3a is a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S.
  • R 3a is a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings.
  • R 3a is a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings; wherein R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C 1-3 alkylphenyl, -C ⁇ -3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C 1-3 mono-bi-tri-haloalkyl, C ⁇ -3 mono-bi-tri-haloalkyloxy, .
  • R 3a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S.
  • R 3a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle.
  • R 3a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; wherein R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C ⁇ -3 alkylphenyl, -C ⁇ , 3 alkylene-OC(O)- phenyl, cyano, amino, nitro, halo, C ⁇ -3 mono-bi-tri-haloalkyl, C ⁇ -3 mono-bi-tri- haloalkyloxy, C ⁇ -6 alkoxy, (C ⁇ -3 alkyl
  • R 3a is C 3-7 cycloalkyl.
  • R 3a is C 3-7 cycloalkyl; wherein R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C 1-3 alkylphenyl, -C 1- alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C 1-3 mono-bi-tri-haloalkyl, C ⁇ -3 mono-bi-tri-haloalkyloxy, Ci.
  • R 3a is carbazolyl, fluorenyl, phenyl, -O-phenyl, -O-Ci. 4 alklylene-phenyl, or napthyl.
  • R 3a is carbazolyl, fluorenyl, phenyl, -O-phenyl, -O-Ci.
  • R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, - O-phenyl, -O-C ⁇ -3 alkylphenyl, -C ⁇ -3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C ⁇ -3 mono-bi-tri-haloalkyl, C ⁇ -3 mono-bi-tri-haloalkyloxy, C ⁇ - 6 alkoxy, (Ci- 3 alkyl) ]-2 amine, -OR 3' , -C(O)R 3' , -C(O)O-R 3' , -O-C(O)R 3' , -N(R 3' ) 2 , -C(O)N(R 3' ) 2 , -N(R 3' )C(O)(R 3' )(R 3' )(R)(R 3'
  • R 3a is C 1-8 alkyl, C 2 . 7 alkenyl, -C(O)R 3' , -C(O)O-R 3' or C 2- alkynyl.
  • R 3a is C 1-8 alkyl, C 2-7 alkenyl, -C(O)R 3' , -C(O)O-R 3' or C 2- 7 alkynyl; wherein R 3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-Ci.
  • R 3 is R 3a and R 3a is phenyl, hydroxyphenyl, azetidinyl, napthyl, Cj- alkyl, C 2-6 alkenyl, C 2-6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, quinolinyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, isoquinolinyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, indazolyl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro- benzthiazol
  • R 3 is R a and R 3a is phenyl, napthyl, indazolyl, benzimidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, benzdioxolanyl, dihydroindolonyl, indolyl, furanyl, thienyl, pyridyl, purinyl, carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl; optionally substituted as provided in the first embodiment of the first aspect.
  • R 3 is R 3a and R 3a is dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl or indazolyl; optionally substituted as provided in the first embodiment of the first aspect.
  • R 3 is R 3a and R 3a is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidine, halopurinyl, C ⁇ -3 alkyl- nitroaminopyrimidine, triazolopyrimidinyl, pyridyl, indazolyl, phenyl or benzdioxolanyl; optionally substituted as provided in the first embodiment of the first aspect.
  • R 3 is R 3a and R 3a is naphthyl, phenyl-O-phenyl, or thienyl; optionally substituted as provided in the first embodiment of the first aspect.
  • T y is H, F, CI, Br or nitrile.
  • R is R and R is azetidinyl, C ⁇ -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, 1 H- indazol-5-yl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenon
  • R 3 isR 3b and R 3b is dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, 1H- indazol-5-yl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl
  • R 3 isR 3b and R 3b is azetidinyl, Ci- ⁇ alkyl, C -6 alkenyl, C 2- alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, 1H- indazol-5-yl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothi
  • R 3 isR 3b and R 3 is azetidinyl, Cj- ⁇ alkyl, C 2-6 alkenyl, C 2- 6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, lH-indazol-5-yl, indolizinyl, isoindolyl, in
  • R 3 is R 3b and R 3b is benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl; optionally substituted as provided in the first embodiment of the first aspect.
  • R 3 is R 3b and R 3b is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C 1-3 alkyl- nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, lH-indazol-5-yl, phenyl or benzdioxolanyl.
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 1 ; and G, J and E together form A x or A y . According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 1 ; and G, J and E together form A x .
  • a x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle.
  • a x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S.
  • a x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S and wherein A x is substituted with phenyl.
  • a x is a fused heterocycle described herein.
  • a y is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle.
  • a y is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S.
  • a y is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; and wherein A y is substituted with phenyl.
  • a y is a 4 to 6 membered heterocycle described herein.
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA'.
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA".
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA' and GJA' is A x .
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA' and GJA' is A y .
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA" and GJA" is A y .
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranony
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranony
  • first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein said heterocycle is optionally substituted with cyano,
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranony
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl and dihydrobenzoxazinonyl.
  • compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl and dihydrobenzoxazinyl.
  • compositions comprising compounds of Formula (I) as defined herein.
  • methods of treating inflammation particularly neurogenic inflammation
  • headache particularly migraine
  • pain thermal injury
  • circulatory shock diabetes, Reynaud's syndrome
  • peripheral arterial insufficiency e.g., arachnoid/ cranial hemorrhage
  • tumor growth e.g., arachnoid/ cranial hemorrhage
  • flushing associated with menopause effected by the antagonism of the CGRP receptor
  • a fourth aspect of the present invention are uses of the compounds of the present invention selected from the group consisting of (a) immune regulation in gut mucosa (b) protective effect against cardiac anaphylactic injury (c) stimulating or preventing interleukin- lb(IL-lb)-stimulation of bone resorption (d) modulating expression of NK1 receptors in spinal neurons and (e) airway inflammatory diseases and chronic obstructive pulmonary disease including asthma. See (a) Calcitonin Receptor-Like Receptor Is Expressed on
  • an in vivo non-terminal method of identifying anti-migraine compounds comprising administering a CGRP-receptor agonist to a mammal in an amount capable of inducing an increase in blood flow, followed by administering a test compound in an amount capable of reversing said CGRP-induced increase in blood flow, wherein said mammal is a transgenic mammal with humanized RAMP1 having T 74 or a mammal endogenously expressing RAMP1 having T ⁇ 74.
  • an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a test compound prior to the delivery of a CGRP-receptor agonist wherein said CGRP-receptor agonist is administered in an amount capable of inducing an increase in blood flow and wherein said test compound is administered in an amount capable of suppressing said CGRP-induced increase in blood flow, wherein said mammal is a transgenic mammal with humanized RAMPl having T ⁇ 74 or a mammal endogenously expressing RAMPl having T ⁇ 74.
  • an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a CGRP-receptor agonist in an amount capable of inducing an increase in peripheral artery diameter, followed by administering a test compound in an amount capable of reversing said CGRP-induced increase in peripheral artery diameter, wherein said mammal is a transgenic mammal with humanized RAMPl having T ⁇ 74 or a mammal endogenously expressing RAMPl having T ⁇ 74.
  • an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a test compound prior to the delivery of a CGRP-receptor agonist wherein said CGRP-receptor agonist is administered in an amount capable of inducing an increase in peripheral artery diameter and wherein said test compound is administered in an amount capable of suppressing said CGRP- induced increase in peripheral artery diameter, wherein said mammal is a transgenic mammal with humanized RAMPl having T ⁇ 74 or a mammal endogenously expressing RAMPl having T ⁇ 74.
  • inventions of the present invention may comprise a suitable combination of two or more of the embodiments and/or aspects disclosed herein.
  • Intravenous delivery of i.v. h ⁇ CGRP induces comparable percent increases (100- 120% of baseline) in rat middle meningeal artery diameter and rat facial blood flow (left and right striped bars, respectively).
  • Pretreatment with the peptide antagonist CGRP(8-37) produces a 50% inhibition of subsequent i.v. h ⁇ CGRP administration for both measures (filled bars).
  • heterocyclic or “heterocycle” includes cyclic moieties containing one or more heteroatoms, (e.g., O, N or S) said heterocycles include those that are aromatic and those that are not, i.e., "alicyclic", unless otherwise specified.
  • fused bicyclic system when describing for example a 5.6-fused bicyclic system containing 1 to 4 nitrogen atoms includes aromatic and alicyclic systems, e.g. indolizine, indole, isoindole, 3H-indole, indoline, indazole or benzimidazole.
  • a substitutent is named generically, then any and all species of that genus comprise that aspect of the invention.
  • a substituent generically named as “pyrrolonyl” (the radical of "pyrrolone", a pyrrole having a carbonyl) includes pyrrol-2-onyls wherein the carbonyl is adjacent to the nitrogen and pyrrol-3-onyls wherein the carbonyl and nitrogen have an intervening methylene.
  • the present invention comprises that a substituent may be attached at any and all suitable points of attachement on said substituent unless otherwise specified.
  • the compounds encompassed by the present invention are those that are chemically stable, i.e., heteroalicyclic substituents of the present invention should not be attached in such a way that a heteroatom in said heteroalicyclic substituent is alpha to a point of attachment wherein said point of attachment is also a heteroatom.
  • alkylene means a divalent alkane, i.e., an alkane having two hydrogen atoms removed from said alkane (said hydrogen removed from two different carbon atoms when said alkane contains more than one carbon atom), e.g., -CH CH CH 2 - .
  • alkylidene means an alkane having two hydrogen atoms removed from one carbon atom in said alkane, e.g. , It should be understood that the alternating double bond designations in the six-membered ring of the 5, 6-membered fused structure represented in Formula (I) are relative and represent the delocalized ⁇ orbital electrons of said ring.
  • aryl or “ar-” includes phenyl or napthyl.
  • heterocyclic or “heterocyclo” includes both heteroaryl and heteroalicyclic.
  • halo or “halogen” includes fluoro, chloro, bromo and iodo and further means one or more of the same or different halogens may be substituted on a respective moiety.
  • acyclic hydrocarbons such as alkyl, alkoxy, alkenyl and alkynyl may be branched or straight chained.
  • T ⁇ 74 means that the 74 th residue in RAMP 1 is tryptophan
  • anti-migraine compound includes any compound, peptide or peptide fragment (modified or unmodified) capable of reversing or attenuating CGRP-receptor mediated vasodilation, (e.g., CGRP-receptor antagonists).
  • test compound includes any compound, peptide or peptide fragment (modified or unmodified) being tested to determine if it is capable of reversing or attenuating CGRP-receptor mediated vasodilation, (e.g., putative CGRP- receptor antagonists).
  • CGRP-receptor agonist includes any compound, peptide or peptide fragment (modified or unmodified) capable of inducing CGRP-receptor mediated vasodilation particularly by example ⁇ CGRP or ⁇ CGRP; other members of the calcitonin family, e.g, adrenomedullin; N-terminal CGRP fragments, e.g, CGRP(1-12) CGRP(1-15) and CGRP(l-22); C-terminal amide (NH2) versions of CGRP e.g., CGRP(l-8+NH2), CGRP(1-13+NH2) or CGRP(1-14+NH2); and non- naturally occurring CGRP analogues e.g., [Ala 1 CH2NH)Cys 2 ]hCGRP which contains a pseudopeptide bond between Ala 1 and Cys 2 .
  • the compounds of this invention may exist in the form of pharmaceutically acceptable salts.
  • Such salts may include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid.
  • the acidic group may exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt and a calcium salt; and salts with organic bases such as a triethylammonium salt and an arginine salt.
  • a saccharin salt or maleate salt may be of particular benefit.
  • the compounds of the present invention may be hydrated or non-hydrated.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts.
  • the compounds can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice.
  • Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
  • the dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level which will produce effective beneficial effects without causing any harmful or untoward side effects.
  • a compound of Formula II which is an amino acid with a protected amino terminus.
  • Common amino protecting groups include BOC, CBZ, and FMOC and their addition and removal are well known in the field.
  • the carboxylic acid moiety of a Formula II compound is coupled 1 7 with an amine of formula HNR R using standard peptide coupling reagents to form an amide of Formula III.
  • the amino protecting group is removed resulting in a Formula IV compound.
  • This compound is then coupled with an amine of Formula V (see below) in a mixed urea or urea isostere reaction, generating a Formula I compound.
  • urea formation is conveniently carried using phosgene, disuccinimidyl carbonate, carbonyl diimidazole or other equivalents. Formation of urea isosteres, such as cyanoguanidines and sulfonylguanidines, are known in the literature.
  • the synthesis described by Scheme 2 begins with a compound of Formula V, which is an amino acid with a protected carboxylate terminus.
  • the protection is generally a methlyl ester, but other protecting groups such as ethyl, t-butyl, and benzyl esters may also be used.
  • the Formula V compound is coupled with an amine of Formula VIII (see below) in a mixed urea or urea isostere reaction, as above, to generate a Formula VI compound.
  • the Formula VI compound is converted to a free acid compound of Formula VII which is then coupled with an amine of Formula HNR'R 2 to generate a Formula I compound.
  • Formula VIII and HNR R amines are commercially available, made by literature methods or described herein.
  • Such reductions can result from transfer hydrogenation from hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using gaseous hydrogen, both in the presence of a suitable catalyst.
  • Compounds of Formula II are prepared by acid or base hydrolysis of the ester.
  • Compounds of Formula V are prepared by removal of the protecting group (PG) using methods well known in the art.
  • compounds of Formula XIV are nucleophilic compounds such as amines or alcohols that are able to participate in a Michael Reaction with a compound of Formula XIII as shown.
  • Scheme 7 also starts with commercially available or synthesized aldehydes. These are reacted with dimethyl succinate in the presence of bases to give compounds of Formula XXI.
  • the double bond of the Formula XXI compound is reduced to give compounds of Formula XXII.
  • Reduction can be carried out to give either a racemate or by use of a stereoselective catalyst to give either enantiomer of Formula XXII.
  • Such reductions can result from transfer hydrogenation from hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using gaseous hydrogen, both in the presence of a suitable catalyst.
  • Amide coupling with amines of Formula VIII lead to compounds of Formula XXIII using well known amide synthesis protocols.
  • Hydrolysis of methyl ester leads to Formula XXIV compounds, which are further coupleded with various amines or alcohols to give amides of Formula I and esters of Formula I, respectively.
  • the resulting compounds of Formula XXVIII are then reacted with a variety of electrophilic reagents to generate Formula I compounds.
  • they can be coupled with halo-aromatic compounds using known methods involving heating at various temperatures or by catalysis with transition metals such as palladium or copper, either in stoichiometric amounts or as catalysts. They can also react with various aldehydes or ketones under reductive alkylation conditions, well described in the art. They can also react with isocyanates, acyl chlorides, or carbamoyl chlorides to generate urea, amide or carbamate derivatives, respectively. It is understood that the sequence of the modifications described above can be changed depending on the selection of protecting groups and the order of their removal.
  • Solvent A- was: 10% methanol/90% water/0.1% trifluoroacetic acid
  • solvent B was 90% methanol/10% water/0.1% trifluoroacetic acid with a UV detector set at 220 nm.
  • Polyphosphoric acid 113 g was heated to 100-110°C and stirred while 1- benzyl-piperidin-4-one (9.27 ml, 50 mmol) was added. Immediately afterwards, phenyl urea (9.55 g, 70. mmol) was added in portions small enough to avoid excessive foaming. The mixture was heated at 150-160°C overnight. Water (200 mL) was then added slowly to the mixture which had been allowed to cool to 100- 110°C (at lower temperatures the mixture becomes too viscous to stir). The resulting solution was neutralized with 1 ON NaOH to ca. pH 8, and then extracted wth chloroform.
  • the filtrate was concentrated to ca 50 mL, ethyl acetate/hexanes (1 :3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 min and filtered through a pad of celite. Solvents were removed in vacuo and the residue was loaded onto a pre-wetted column with silica gel (300 mL) using 1:3 ethyl acetate/hexanes as the eluent. Solvents were removed and the title compound was obtained as a light tan liquid (41.9g, 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize decomposition.
  • aqueous ammonium chloride 200 mL was added, and the mixture was extracted with ethyl acetate (300 mL). After separation, the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), and dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using 1:1.5 methylene chloride hexanes as eluent to afford the title compound as a white solid (15.8 g, 79%).
  • 1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)- ⁇ -phophonoglycine trimethyl ester (1.88g, 5.69 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 15 min and cooled to -78°C, and a solution of l-(2- trimethylsilanyl-ethanesulfonyl)-lH-indole-5-carbaldehyde (L6g, 5.17 mmol) in tetrahydrofuran (15 mL) was added slowly.
  • the 2-benzyloxycarbonylamino-3-[l-(2- trimethylsilanyl-ethanesulfonyl)-lH-indazol-5-yl]-acrylic acid methyl ester (1.75 g, 3.40 mmol) was weighed into a second AIRFREE ® (Schlenk) reaction flask equipped with stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in a mixture of anhydrous methanol (75 mL ) and anhydrous methylene chloride (15 mL). Both solvents were deoxygenated prior to addition by sparging with nitrogen for at least 1 h. Once in solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles.
  • the dehydroamino acid solution was introduced into the AIRFREE ® (Schlenk) reaction flask containing the catalyst via cannula.
  • the reaction mixture was subjected to 5 vacuum/hyrogen purge cycles before opening the flask to 1 atm. of hydrogen (balloon). After 16 h, the reaction mixture was purged with 3 vacuum/nitrogen purge cycles .
  • the 2-benzyloxycarbonylamino-3-[7- methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl]-acrylic acid methyl ester (2.03 g, 3.83 mmol) was weighed into a second AIRFREE ® (Schlenk) reaction flask equipped with stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in anhydrous methanol (80 mL, deoxygenated prior to addition by sparging with nitrogen for at least 1 h). Once in solution, it was again subjected to 3 vacuum/nitrogen purge cycles.
  • the dehydroamino acid solution was transferred via cannula to the AIRFREE ® (Schlenk) reaction flask containing the catalyst.
  • the reaction mixture was purged with 5 vacuum/hydrogen purge cycles before opening the flask to a balloon of hydrogen (1 atm). After 2.5 h, the reaction mixture was purged with 3 vacuum/nitrogen purge cycles.
  • the reaction mixture was stirred at 0°C for 6 h and then placed in the freezer for a further 16 h.
  • the solvents were removed in vacuo and the residue dissolved in water (15 mL).
  • the pH of the aqueous solution was adjusted to ca. 1 with IN hydrochloric acid.
  • the resulting white solid precipitated was collected by filtration. The solid was dried under vacuum to give the title compound (108 mg, 80%).
  • the reaction mixture was stirred at 0°C for 2 h and then placed in the freezer at -15°C for 16 h. While cooling the reaction mixture with an ice bath, the p ⁇ was increased to ca. 7 by addition of IN hydrochloric acid (3.8 mL). Organic solvents were removed under vacuum. The resulting aqueous solution was extracted with ethyl acetate after additon of more IN hydrochloric acid (0.5 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give 684 mg (90%) of the title compound as a white solid.
  • reaction mixture was stirred for 16 h at room temperature. All solvent was removed using high vacuum. The residue was subjected to flash column chromatography using methylene chloride/methanol/ triethylamine (93:5:2) to give the title compound as a white solid (67 mg, 56% yield).
  • 5-Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to -70°C and a solution of .yec-butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes.
  • dimethylformamide (10 mL) was added over several minutes. The mixture was allowed to warm to room temperature and was stirred overnight. It was then cooled to 0°C and carefully treated with IN hydrochloric acid (60 mL). After a few minutes, solid sodium bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted with 0.8M sodium hydrogen sulfate (3 x 125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL) and then the pH was adjusted to ca. 10 with solid sodium hydroxide.
  • the solution was cooled to 0°C, treated with aqueous 1 M potassium hydrogen sulfate (60 ⁇ L, 2.0 equiv), and concentrated to give the crude acid which was immediately used without purification.
  • the crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (10.1 mg, 2 equiv), diisopropylethylamine (10 ⁇ L, 2 equiv), and PyBOP ® (16.5 mg, 1.1 equiv). The solution was stirred 30 min and concentrated. The product was purified by column chromatography to give 14.7 mg (77%, 2 steps).
  • the solution was cooled to 0°C, treated with aqueous 1 M potassium hydrogen sulfate (60 ⁇ L, 2.0 equiv), and concentrated to give the crude acid which was immediately used without purification.
  • the crude acid was dissolved in dimethylformamide (0.4 mL), cooled to 0°C, and sequentially treated with methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), diisopropylethylamine (12 ⁇ L, 2.3 equiv.), and PyBOP ® (19 mg, 1.2 equiv). The solution was stirred for 15 min at 0°C, warmed to room temperature, stirred 1.5 h, and concentrated.
  • 1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114. lg, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to -78°C. A solution 3,4-dinitro- benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at -78°C for 2h and then allowed to warm to room temperature overnight.
  • the solution was cooled to 0°C, treated with aqueous 1 M potassium hydrogen sulfate (60 ⁇ l, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification.
  • the crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (11 mg, 2 equiv), diisopropylethylamine (12 ⁇ L, 2 equiv), and PyBOP ® (19 mg, 1.1 equiv). The solution was stirred 30 min and concentrated. The product was purified by column chromatography to give 17.6 mg (85%, 2 steps).
  • the solution was cooled to 0°C, treated with aqueous IM potassium hydrogen sulfate (75 ⁇ l, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification.
  • the crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 ⁇ L, 2 equiv), and PyBOP ® (22 mg, 1.1 equiv). The solution was stirred 1.5 h and concentrated.
  • the product was purified by column chromatography to give a product which was tainted with HOBT.

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Abstract

La présente invention concerne des composés représentés par la formule (I) qui sont utiles en tant qu'antagonistes des récepteurs du peptide lié au gène de la calcitonine (récepteur CGRP), des compositions pharmaceutiques comprenant ces composés, des méthodes d'identification de ces derniers, des méthodes de traitement dans lesquelles on les utilise et leur utilisation en thérapie pour le traitement de la vasodilatation neurogène, de l'inflammation neurogène, de la migraine et d'autres maux de tête, des brûlures thermiques, des chocs circulatoires, des bouffées de chaleur liées à la ménopause, des maladies inflammatoires des voies aériennes telles que l'asthme et la broncho-pneumopathie chronique obstructive (BPCO) et d'autres états qui peuvent être traités par l'antagonisme des récepteurs CGRP. Formule (I)
PCT/US2003/038799 2003-12-05 2003-12-05 Antagonistes du recepteur peptidique lie au gene de la calcitonine WO2005065779A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
UAA200607510A UA81563C2 (en) 2003-12-05 2003-12-05 Antagonists of calcitonin gene-related peptide receptors
CNB200380111030XA CN100558428C (zh) 2003-12-05 2003-12-05 降钙素基因相关肽受体拮抗剂
JP2005513137A JP2007524568A (ja) 2003-12-05 2003-12-05 カルシトニン遺伝子関連ペプチドレセプターアンタゴニスト
YUP-2006/0382A RS20060382A (en) 2003-12-05 2003-12-05 Calcitonin gene related peptide receptor antagonists
AU2003297694A AU2003297694A1 (en) 2003-12-05 2003-12-05 Calcitonin gene related peptide receptor antagonists
CA002549330A CA2549330A1 (fr) 2003-12-05 2003-12-05 Antagonistes du recepteur peptidique lie au gene de la calcitonine
PCT/US2003/038799 WO2005065779A1 (fr) 2003-12-05 2003-12-05 Antagonistes du recepteur peptidique lie au gene de la calcitonine
EP03819270A EP1689493A4 (fr) 2003-12-05 2003-12-05 Antagonistes du recepteur peptidique lie au gene de la calcitonine
BRPI0318637-7A BR0318637A (pt) 2003-12-05 2003-12-05 antagonistas de receptores de peptìdios relacionados com o gene de calcitonina
TW093137052A TWI284534B (en) 2003-12-05 2004-12-01 Calcitonin gene related peptide receptor antagonists
ARP040104530A AR046788A1 (es) 2003-12-05 2004-12-03 Antagonistas del receptor peptido relacionado con el gen de calcitonina
PE2004001196A PE20051036A1 (es) 2003-12-05 2004-12-06 Antagonistas del receptor peptido relacionado con el gen de calcitonina
IS8482A IS8482A (is) 2003-12-05 2006-05-26 Kalsítóníngen-skyldir peptíðviðtaka antagónistar
IL176018A IL176018A0 (en) 2003-12-05 2006-05-30 Calcitonin gene related peptide receptor antagonists
NO20062648A NO20062648L (no) 2003-12-05 2006-06-08 Calcitonin gen relaterte peptid reseptor antagonister
HR20060236A HRP20060236A2 (en) 2003-12-05 2006-07-04 Calcitonin gene related peptide receptor antagonists

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JP (1) JP2007524568A (fr)
CN (1) CN100558428C (fr)
AR (1) AR046788A1 (fr)
AU (1) AU2003297694A1 (fr)
BR (1) BR0318637A (fr)
CA (1) CA2549330A1 (fr)
IL (1) IL176018A0 (fr)
IS (1) IS8482A (fr)
NO (1) NO20062648L (fr)
PE (1) PE20051036A1 (fr)
RS (1) RS20060382A (fr)
TW (1) TWI284534B (fr)
UA (1) UA81563C2 (fr)
WO (1) WO2005065779A1 (fr)

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WO2007074130A2 (fr) * 2005-12-24 2007-07-05 Boehringer Ingelheim International Gmbh 3-(4-piperidinyl)-2,3,4,5-tetrahydro-1,3-benzodiazepine-2(1h)-one
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
JP2009511621A (ja) * 2005-10-21 2009-03-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 選抜されたｃｇｒｐアンタゴニスト、それらの調製方法及び医薬組成物としてのそれらの使用
US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
US7772244B2 (en) 2004-03-29 2010-08-10 Bristol-Myers Squibb Company Therapeutic agents for the treatment of migraine
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
EP2251338A2 (fr) 2007-11-22 2010-11-17 Boehringer Ingelheim International GmbH Composés organiques
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
US8168592B2 (en) 2005-10-21 2012-05-01 Amgen Inc. CGRP peptide antagonists and conjugates
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US9688660B2 (en) 2015-10-30 2017-06-27 Heptares Therapeutics Limited CGRP receptor antagonists
US9802935B2 (en) 2015-10-30 2017-10-31 Heptares Therapeutics Limited CGRP receptor antagonists
US9808457B2 (en) 2015-10-30 2017-11-07 Heptares Therapeutics Limited CGRP receptor antagonists
WO2023034466A1 (fr) * 2021-09-02 2023-03-09 Pfizer Ireland Pharmaceuticals Antagonistes du cgrp pour le traitement du psoriasis

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US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7314883B2 (en) 2002-06-05 2008-01-01 Bristol-Myers Squibb Company Anti-migraine treatments
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
US7754732B2 (en) 2002-06-05 2010-07-13 Bristol-Myers Squibb Company Spirocyclic anti-migraine compounds
US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
US7772244B2 (en) 2004-03-29 2010-08-10 Bristol-Myers Squibb Company Therapeutic agents for the treatment of migraine
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
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IS8482A (is) 2006-05-26
EP1689493A4 (fr) 2008-04-23
CA2549330A1 (fr) 2005-07-21
AR046788A1 (es) 2005-12-21
CN100558428C (zh) 2009-11-11
TWI284534B (en) 2007-08-01
EP1689493A1 (fr) 2006-08-16
RS20060382A (en) 2008-09-29
TW200529835A (en) 2005-09-16
NO20062648L (no) 2006-08-02
CN1917921A (zh) 2007-02-21
UA81563C2 (en) 2008-01-10
BR0318637A (pt) 2007-02-13
IL176018A0 (en) 2006-10-05
AU2003297694A1 (en) 2005-08-12
JP2007524568A (ja) 2007-08-30
PE20051036A1 (es) 2005-12-11

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