WO2016022644A1 - Antagonistes hétérocycliques des récepteurs cgrp - Google Patents

Antagonistes hétérocycliques des récepteurs cgrp Download PDF

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Publication number
WO2016022644A1
WO2016022644A1 PCT/US2015/043751 US2015043751W WO2016022644A1 WO 2016022644 A1 WO2016022644 A1 WO 2016022644A1 US 2015043751 W US2015043751 W US 2015043751W WO 2016022644 A1 WO2016022644 A1 WO 2016022644A1
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Prior art keywords
halo
group
optionally substituted
independently selected
cyano
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PCT/US2015/043751
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English (en)
Inventor
Ian M. Bell
Lianyun Zhao
Mark Fraley
Cheng Zhu
Tesfaye Biftu
Edward Joseph BRNARDIC
Cheng Wang
C. Blair Zartman
Steven Gallicchio
Diem Nguyen
Brendan CROWLEY
Craig Potteiger
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Merck Sharp & Dohme Corp.
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Publication of WO2016022644A1 publication Critical patent/WO2016022644A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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 three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • C07D491/12—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 three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively.
  • CGRP-alpha and CGRP-beta display similar biological properties.
  • CGRP receptor which is a heterodimer consisting of the G-protein coupled calcitonin-like receptor (CLR) in association with the single transmembrane protein known as receptor activity modifying protein 1 (RAMPi).
  • CLR G-protein coupled calcitonin-like receptor
  • RAMPi receptor activity modifying protein 1
  • CGRP receptors are predominantly coupled to the activation of adenylyl cyclase and have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
  • CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache.
  • elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al. (1990) Ann. Neurol. 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between (Bellamy et al. (2006) Headache 46, 24-33) and during attacks (Cady et al. (2009) Headache 49, 1258-1266), and CGRP itself has been shown to trigger migrainous headache (Lassen et al. (2002) Cephalalgia 22, 54-61).
  • the CGRP receptor antagonist BIBN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al. (2004) New Engl. J. Med. 350, 1104-1110) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al. (2005) Clin. Pharmacol. Ther. 77, 202-213).
  • the orally bioavailable CGRP receptor antagonist telcagepant has also shown antimigraine effectiveness in phase III clinical trials (Ho et al. (2008) Lancet 372, 2115-2123; Connor et al. (2009) Neurology 73, 970-977).
  • CGRP-mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines,
  • the middle meningeal artery the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP.
  • Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al. (1988) Ann. Neurol. 23, 193-196).
  • CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Austin Bioscience, 2000, 245-247).
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin Amylin
  • Adrenomedullin CGRP-Related Peptide
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extra-cranial pain and facial allodynia may be the result of sensitized trigeminal neurons (Burstein et al. (2000) Ann. Neurol. 47, 614-624).
  • a CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sens
  • CGRP receptor antagonists may make them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • disorders include migraine and cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261-1268; Edvinsson et al. (1994) Cephalalgia 14, 320-327); chronic tension type headache (Ashina et al. (2000) Neurology 14, 1335-1340); pain (Yu et al. (1998) Eur. J. Pharmacol. 347, 275-282); chronic pain (Hulsebosch et al.
  • the present invention is directed to heterocyclic compounds which are potent antagonists of CGRP receptors and potentially useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine.
  • the invention is also directed to
  • compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
  • A is benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, cinnolinyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrimidyl, pyrrolopyridin
  • X is NR 9 , O, S(0) m , or CR 6 R 7 ;
  • G 1 ", "G 2 ", “ G 3 " and “G 4 " are independently: CR a ; or N;
  • “1” is: hydrogen; or Ci-6 alkyl, wherein said alkyl is optionally substituted with up to three substituents which are independently for each occurrence: halo; cyano; or hydroxy; or
  • Q is -NR e -, -0-, -N(R e )CR c R d - or -CR c R d -;
  • T 1 and T 2 are independently, for each occurrence: a bond; or -CR c R d -; R 1 , R 2 , R 3 , R 4 and R 5 are independently for each occurrence:
  • QL-6 alkyl optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR 8 ; -NR 11 R 12 ; -heterocyclyl; or -OR 10 ;
  • 0-Ci_6 alkyl optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR 8 ; -NR 11 R 12 ; or -heterocyclyl;
  • C 2 -6 alkenyl optionally substituted with up to three substitutents which are independently: halogen; -OH; -CN, or -NR R 12 -;
  • R 4 and R 5 together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and wherein said ring is optionally substituted with up to three substituents which are independently: (a) halo; (b) oxo; (c) phenyl; (d) OR 8 ; or (e) R 8 ;
  • R 6 and R 7 are independently for each occurrance:
  • Ci-6 alkyl which is optionally substituted with up to three substituents which are independently: halo; hydroxy; cyano; R 10 ; or NR U R 12 ; (e) OR ;
  • R 6 and R 7 together with the carbon atom(s) to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;
  • R 8 is independently for each occurrence: hydrogen; Ci-6 alkyl; or C 3 _6 cycloalkyl, and when selected to be alkyl or cycloalkyl, said moiety is optionally substituted with up to three substituents which are independently: halo; cyano; C 3 _ 6 -cycloalkyl; phenyl; or hydroxy;
  • R 9 is independently for each occurrance:
  • R 9 and R a together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR 8 ; CN; or Ci_ 6 alkyl; (c) OR 8 ; (d) oxo; or (e) Ci_ 6 alkyl, which is optionally substituted with up to three halogen atoms; or
  • R 9 and R 1 together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR 8 ; CN; or Ci -6 alkyl; (c) OR 8 ; (d) oxo; or (e) Ci_ 6 alkyl, which is optionally substituted with up to three halogen atoms;
  • R 10 is: (i) heterocyclyl; (ii) C 3 - 6 cycloalkyl; (iii) aryl; or (iv) heteroaryl, wherein said heterocylyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with up to five substituents which are independently for each occurrence: (a) halo;
  • R 11 and R 12 are independently for each occurrence:
  • heterocyclyl optionally substituted with up to three substitutents which are independently for each occurrence: halo; cyano; OR 8 ; or R S;
  • halo; cyano; OR 8 ; or R 8 independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; (g) phenyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; or
  • heteroaryl optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; or
  • R 11 and R 12 together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally when present, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionallysubstituted with up to four substituents which are independently:
  • Ci-6 alkyl which is optionally substituted with one to three halo;
  • R a is independently for each occurrence:
  • R b is independently for each occurrence:
  • Ci_6 alkyl optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR 8 ; NR R 12 ; R 10 or OR 10 ;
  • R c and R d are each independently for each occurrence:
  • Ci-6 alky optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR 8 ; or NR R 12 ;
  • R c and R d together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionally substituted with up to four substituents which are independently:
  • Ci-6 alkyl optionally substituted with up to three halogen substituents
  • R e is independently for each occurrence:
  • n is independently for each occurrence an integer from 0 to 2.
  • Another class of the invention is directed to compounds of the formula:
  • Another class of the invention is directed to compounds of the formula:
  • A is cinnolinyl, imidazopyridinyl, naphthyridinyl,
  • pyrazolopyridinyl pyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl or quinolinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is imidazopyridinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is pyrazolopyridinyl, which is optionally substituted with 1 , R 2 , R 3 , R 4 and R 5 .
  • A is naphthyridinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is pyridinyl, which is optionally substituted with R 1 , R 2 , R 4 and R 5 .
  • A is quinolinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • X is NR 9 . In another class of the invention, X is 0.
  • G 1 is CR a . In another class of the invention, G 1 is N.
  • G 2 is CR a . In another class of the invention, G 2 is N.
  • G 3 is CR a . In another class of the invention, G 3 is N.
  • G 4 is CR a . In another class of the invention, G 4 is N.
  • B is a bond.
  • D 1 is CR 6 R 7
  • D 1 is CH 2 .
  • D 2 is a bond. In another class of the invention, D 2 is CR 6 R 7 .
  • D 3 is a bond. In another class of the invention, D 3 is CR 6 R 7 .
  • D 4 is CR 6 R 7
  • D 1 is CH 2 .
  • D 1 is OO.
  • D 5 is a bond. In another class of the invention, D 5 is CR 6 R 7 .
  • D 6 is a bond. In another class of the invention, D 6 is CR 6 R 7 .
  • Z is hydrogen
  • W and Z can be taken together with the carbon atom to which they are attached to form:
  • W and Z can be taken together
  • each X 2 is independently CR c R d . In another class of the invention, each X 2 is independently (OO).
  • each X 3 is independently CR b . In another class of the invention, each X 3 is independently N.
  • each X 4 is independently CR b . In another class of the invention, each X 4 is independently N.
  • each Y 1 is independently CR b . In another class of the invention, each Y 1 is independently N.
  • each Y 2 is independently CR b . In another class of the invention, each Y 2 is independently N.
  • each Y 3 is independently CR b . In another class of the invention, each Y 3 is independently N.
  • each Y 4 is independently CR b . In another class of the invention, each Y 4 is independently N.
  • each V 1 is independently CR b . In another class of the invention, each V 1 is independently N. In a class of the invention, each V 2 is independently CR b . In another class of the invention, each V 2 is independently N.
  • each V 3 is independently CR b . In another class of the invention, each V 3 is independently N. In a class of the invention, each V 4 is independently CR . In another class of the invention, each V 4 is independently N.
  • each U 1 is independently CR . In another class of the invention, each U 1 is independently N.
  • each U 2 is independently CR b . In another class of the invention, each U 2 is independently N.
  • each U 3 is independently CR b . In another class of the invention, each U 3 is independently N.
  • each U 4 is independently CR b . In another class of the invention, each U 4 is independently N. In a class of the invention, Q is NR e . In another class of the invention, Q is O.
  • Q is N(R e )CR c R d .
  • Q is CR c R d .
  • T 1 is a bond. In another class of the invention, T 1 is CR c R d .
  • T 2 is a bond. In another class of the invention, T 2 is CR c R d .
  • R 1 is selected from the group consisting of: (a) hydrogen,
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • OCi-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , N R N R 12 and heterocyclyl;
  • Rl is hydrogen
  • R 2 is selected from the group consisting of:
  • Ci_6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 , heterocyclyl and OR 10 ;
  • R 3 is selected from the group consisting of:
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • R3 is hydrogen
  • R 4 is selected from the group consisting of:
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • OCi-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 and heterocyclyl;
  • R4 is methyl
  • R 5 is selected from the group consisting of:
  • Qt_ 6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 , heterocyclyl and OR 10 ;
  • OCi_6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR 1X R 12 and heterocyclyl;
  • R5 is methyl
  • R 6 is selected from the group consisting of:
  • R 7 is hydrogen
  • R 9 is hydrogen
  • R 11 is selected from the group consisting of
  • heterocyclyl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 ,
  • heteroaryl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 .
  • R is hydrogen.
  • R 12 is selected from the group consisting of
  • Nh heterocyclyl C 3 . 6 cycloalkyl, phenyl and heteroaryl
  • heterocyclyl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 ,
  • heteroaryl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 .
  • each R a is independently selected from the group consisting of hydrogen, halo, cyano, Ci -6 alkyl, R 10 , OR 10 and OCi- 6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR u R 12 and R 10 .
  • R c is selected from the group consisting of
  • Ci-6 alkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 and NR R 12 ;
  • C 3- 6 cycloalkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR 8 ,
  • R c is hydrogen
  • R d is selected from the group consisting of
  • Ci-6 alkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 and NR U R 12 ;
  • OCi_6 alkyl which is optionally substituted with one to five substitutents independently sseelleecctteedd ffrrom the group consisting of halo, cyano, OR and NR R , and
  • R d is hydrogen
  • R e is hydrogen
  • Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 407, or pharmaceutically acceptable salts thereof.
  • the invention also encompasses a pharmaceutical composition which comprises an inert carrier and the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention also encompasses a method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a
  • the headache is migraine headache.
  • the invention also encompasses the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of headache.
  • the headache is migraine headache.
  • the invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which CGRP is involved, such as migraine, which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to the use of a compound of Formula I for treating diseases or disorders in which CGRP is involved, such as migraine.
  • the invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which CGRP is involved, such as migraine, comprising combining a compound of Formula I with one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the atoms may exhibit their natural isotopic
  • abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Tautomers of compounds defined in Formula I are also included within the scope of the present invention.
  • variable e.g. b, etc.
  • its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable
  • one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon.
  • size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted with one or more substituents" should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • Cone to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that Cl-4alkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl- cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
  • halo or halogen as used herein is intended to include chloro (CI), fluoro (F), bromo (Br) and iodo (I).
  • cycloalkyl or “carbocycle” shall mean cyclic rings of alkanes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to aikyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazoliny
  • benzothiazolyl benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.
  • the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • the heteroaryl contains nitrogen atoms, it is understood that the corresponding l ⁇ l-oxides thereof are also encompassed by this definition.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10- membered nonaromatic ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of 0, N, S, SO, or S0 2 and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetra hydro pyranyl, dihydropiperidinyl,
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also emcompassed by this definition.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or
  • salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the
  • salts derived from inorganic acids include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
  • Specific compounds within the present invention include a compound which may be selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • the subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors.
  • a variety of other mammals can be treated according to the method of the present invention.
  • Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.
  • the present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the terms "administration of” or “administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • the compounds of the present invention may have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; obesity; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors.
  • headache migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic
  • the subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • the present compounds may be used in conjunction with an an anti- migraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HTI B /ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTi D agonist such as PNU-142633 and a 5-HTi F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing antiinflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenopro
  • the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an interleukin inhibitor such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT 2 receptor
  • an interleukin inhibitor such as an
  • dextropropoxyphene and febtanyl an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; an antidepressant, for example amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.
  • a GABA A receptor modulator for example acamprosate calcium
  • the present compounds may be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.
  • the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine,
  • methylergonovine, metergoline, ergoloid mesylates dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-a-ergocryptine, dihydro- -ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, a-ergocryptine, ⁇ -ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
  • the present compounds may be used in conjunction with a beta-adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine,
  • a beta-adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like
  • a MAO inhibitor for example phenelzine
  • a calcium channel blocker
  • an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or divalproex sodium
  • an anti-hypertensive such as an angiotensin II antagonist, for example losartan, irbesartin, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartan and candesartan cilexetil
  • an angiotensin I antagonist an angiotensin converting enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril
  • botulinum toxin type A or B an anticonvulsant such as topiramate, zonisamide, ton
  • the present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy- ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or nonsedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine,
  • a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propy
  • brompheniramine carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine, phenylpropanolamine, or pseudoephedrine.
  • the present compounds also may be used in conjunction with anti-emetics.
  • the present compounds may be used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTi B /i D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.
  • an anti-migraine agent such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTi B /i D agonist, in particular, sumatriptan, naratriptan, zolmitrip
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, buccal or topical routes of administration
  • nasal, vaginal, rectal, sublingual, buccal or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Oral tablets may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • 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- butane diol.
  • the 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 compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • transdermal patches may also be used for topical administration.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • NATIVE RECEPTOR BINDING ASSAY The binding of 125 I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J.
  • membranes 25 pg were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCI 2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 12S I-CGRP and antagonist. After incubation at room temperature for 3 h, the assay was terminated by filtration through GFB glass fibre filter plates (PerkinElmer) that had been blocked with 0.5% polyethyieneimine for 3 h. The filters were washed three times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCI 2 ), then the plates were air dried.
  • binding buffer 10 mM HEPES, pH 7.4, 5 mM MgCI 2 and 0.2% bovine serum albumin (BSA)
  • BSA bovine serum albumin
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector plREShyg2 (BD Biosciences Clontech) as a 5'Nhel and 3' Pmel fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector plRESpuro2 (BD Biosciences Clontech) as a 5'Nhel and 3'Notl fragment.
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL-1573
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • penicillin 100 ⁇ g/mL streptomycin
  • Stable cell line generation was accomplished by co-transfecting 10 g of DNA with 30 ⁇ g Lipofectamine 2000 (Invitrogen) in 75 cm 2 flasks.
  • CL receptor and RAMP1 expression constructs were co-transfected in equal amounts.
  • a clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium was adjusted to 150 ⁇ g/mL hygromycin and 0.5 ⁇ g/mL puromycin for cell propagation.
  • RECOMBINANT RECEPTOR BINDING ASSAY Cells expressing recombinant human CL receptor/RAMPl were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and CompleteTM protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at -70°C.
  • binding assays 20 ⁇ g of membranes were incubated in 1 mL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCI 2 , and 0.2% BSA) for 3 h at room temperature containing 10 pM 125 l-hCGRP (GE Healthcare) and antagonist. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (PerkinElmer) that had been blocked with 0.05% polyethyleneimine. The filters were washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7.4, and 5 mM MgCI 2 ). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Nonspecific binding was determined and the data analysis was carried out with the apparent dissociation constant (/ ⁇ " ,) determined by using a non-linear least squares fitting the bound CPM data to the equation below:
  • Y is observed CPM bound
  • Y max is total bound counts
  • Y min is non specific bound counts
  • (Ymax - min) is specific bound counts
  • % l ma x is the maximum percent inhibition
  • % I min is the minimum percent inhibition
  • radiolabel is the probe
  • 3 ⁇ 4 is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
  • RECOMBI NANT RECEPTOR FUNCTIONAL ASSAY Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 ⁇ isobutyl-methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761; Perkin-Elmer) at a density of 2,000 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1.2 nM and incubated an additional 20 min at 37 °C.
  • cAMP dynamic 2 assay kit 62AM4PEC; Cisbio.
  • Raw data were transformed into concentration of cAMP using 33 a standard curve then dose response curves were plotted and inflection point (I P) values were determined.
  • IC 50 values in the recombinant receptor functional assay for exemplary compounds of the invention are provided in the table below:
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • Scheme 2 Another general approach for the preparation of compounds of the present invention is illustrated in Scheme 2.
  • This methodology typically relies on a palladium-catalyzed amination of intermediate 2.2 with the amine of interest (2.1).
  • intermediate 2.2 may be prepared using well-precedented methodology and several such intermediates are described herein ⁇ vide infra).
  • aryl bromide 2.2 may be replaced by a similar reactant, such as the corresponding aryl chloride or iodide.
  • Scheme 3 illustrates general methodology for the synthesis of key intermediate 1.1.
  • the amine of interest (2.1) can be reacted with 4-fluoronitrobenzene (3.1) under basic conditions to afford the nitrobenzene 3.2, which may be reduced to provide the desired arylamine intermediate 1.1.
  • Variations of this approach familiar to one skilled in the art of organic synthesis, may be employed to produce a variety of related intermediates. For example, the use of heteroaryl alternatives to 3.1 may lead to the corresponding
  • heteroarylamine analogues of 1.1 heteroarylamine analogues of 1.1.
  • the synthesis of the novel spirocyclic intermediate 6.10 is shown in Scheme 6.
  • the chloropyrimidine derivative 6.4 is synthesized from diethyl succinate (6.1) in three steps using known conditions (WO 2009/152027).
  • Treatment of 6.4 with a large excess of ieri-butylamine in a sealed vessel at elevated temperature provides ester 6.5, which may be subjected to standard saponification to the acid followed by cyclization of the corresponding HOBT ester to afford 6.6.
  • the key step is dialkylation of 6.6 with the dichloride 6.7, using cesium carbonate as base, to yield the spirocyclic compound 6.8, which may be converted to 6.10 as shown.
  • a number of known benzodiazepinone analogues may be used as amine 2.1 to provide compounds of the present invention.
  • Related analogues may be synthesized using
  • the synthesis of the ether derivative 9.4 is shown in Scheme 9.
  • the fluoronitrobenzene 9.1 may be reacted with a variety of alcohols (such as R 10 OH) under basic conditions to provide the ether derivative 9.2.
  • reduction of the nitro group provides the desired arylamine intermediate 9.4.
  • Scheme 11 illustrates an alternative strategy for the synthesis of spirocyclic
  • the indole derivative 11.1 may be protected, for example with a SEM group to give 11.2.
  • Treatment of 11.2 with pyridinium tribromide in dioxane, followed by zinc- mediated reductive debromination provides oxindole derivative 11.3.
  • This oxindole 11.3 is dialkylated with the b/s(2-iodoethyl)aniline 11.5, which is prepared in two steps from the corresponding diol 11.4 as shown, to afford the key spirocyclic intermediate 11.6.
  • catalytic hydrogenation provides the desired arylamine 11.7.
  • Scheme 13 details a similar sequence that may be used to provide 4- chloronaphthyridine intermediates such as 13.4.
  • Reaction of aminopyridine 13.1 with Meldrum's acid and triethyl orthoacetate at elevated temperature leads to the condensation product 13.2, and this may be converted to the chloronaphthyridine 13.4 using analogous chemistry to Scheme 12.
  • Similar procedures applied to other aminopyridine isomers may be used to provide alternative naphthyridine isomers.
  • Scheme 15 illustrates methodology for the synthesis of key intermediate 15.4, in which there is a substituent (R 10 ) on the aromatic ring ortho to the amino group.
  • This approach begins with the dihalonitroaromatic starting material 15.1, which contains fluoro and bromo substituents.
  • alternative halogens may be employed.
  • R 10 is introduced using standard Suzuki coupling conditions and the corresponding boronic acid R 10 B(OH) 2 to afford the nitro compound 15.2.
  • a variety of alternative conditions may be employed, as will be appreciated by one skilled in the art.
  • the amine of interest (2.1) can be reacted with 15.2 under basic conditions to afford the nitroaromatic 15.3, which may be reduced to provide the desired arylamine intermediate 15.4.
  • Alternative conditions may be employed throughout the illustrated route.
  • the nitro group in 15.3 may be hydrogenated using a number of alternative catalysts, or simply reduced using non-hydrogenation conditions, including the use of a metal such as iron, tin, or zinc under acidic conditions.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies may be employed to facilitate the reaction or to avoid unwanted
  • Step A Ethyl (3Z)-3-f(5-methoxv-2-methylphenvl)iminolbutanoate
  • Step B fe/t-Butyl ⁇ 2-f(4-chloro-2.8-dimethvlquinolin-5-vl)oxvlethyl)carbamate
  • Step A Ethyl 3-[(2-methvlphenyl)aminolbut-2-enoate
  • 2,8-Dimethylquinolin-4-ol (0.70 g, 4.0 mmol) was suspended in POCI 3 (7 mL) and the stirred reaction mixture was heated at 110 °C for 6 h, then cooled to ambient temperature. The reaction mixture was concentrated to remove most of the POCI 3 and the residue was poured onto ice with stirring. The resulting mixture was adjusted to pH 7 - 8 by addition of saturated aqueous sodium bicarbonate, and the precipitate was isolated by filtration and dried to give the title compound.
  • Step A 2,2-Dimethvl-5- ⁇ l (4-methvlpvridin-3-vl)aminolethylidene ⁇ -l,3-dioxane-4,6-dione
  • 3-amino-4-met ylpyridine (2.00 g, 18.5 mmol)
  • Meldrum's acid (3.20 g, 22.2 mmoi)
  • triethyl orthoacetate (18.0 g, 111 mmol) dropwise.
  • the resulting mixture was stirred at 100 °C for 4 h then cooled to ambient temperature and concentrated under reduced pressure.
  • Step C 4-Chloro-2,8-dimethyl-l,5-naphthvridine
  • 2,8-Dimethyl-l,5-naphthyridin-4-ol (765 mg, 4.39 mmol) was suspended in POCI 3 (20 mL) and the stirred reaction mixture was heated at 110 °C for 3 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the POCI 3 and the residue was poured onto ice with stirring, then extracted with CH 2 CI 2 (3 ⁇ 150 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH 2 CI 2 :EtOAc - 100:0 to 50:50, to give the title compound.
  • Step A 3-fl-(4-Nitrophenvl)piperidin-4-vl]-l,3,4.5-tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step B 3-[l-(4-Aminophenvl)piperidin-4-vll-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step A l',4'-Dihydro-3'H-spirofpiperidine-4,2'-quinoxalin1-3'-one
  • Step B l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiroipiperidine-4,2'-quinoxalinl-3'-one
  • Step A 1-terf-Butvl 4-methyl 4-f(2-nitropvridin-3-vl)oxvlpiperidine-l,4-dicarboxylate
  • Step B ferf-Butyl 3'-oxo-3',4'-dihvdro-lH-spirorpiperidine-4,2'-pyridof3,2-b1fl,4loxazinel-l- carboxvlate
  • Step C Spirofpiperidine-4,2'-pyridoi3.2-foiri.41oxazin1-3'(4'H)-one
  • Step D l-(4-Aminophenvl)spirofpiperidine-4,2'-pyrido[3,2-falfl,41oxazin1-3'(4'H)-one 58 Essentially following the procedures described in Intermediate 5, but using
  • Step A 1-tert-Butyl 4-methyl 4-f(2-nitropvridin-3-vl)aminolpiperidine-l,4-dicarboxylate
  • Step B ferf-Butyl 3'-oxo-3',4'-dihvdro-lH,l'H-spiro[piperidine-4,2'-pyrido[2,3-fc1pvrazine]-l- carboxylate
  • Step C l',4'-Dihvdro-3'H-spirofpiperidine-4,2'-pvridoi2,3-fe1pyrazin1-3'-one
  • Step D l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiro[piperidine-4,2'-pyridof2,3-ib1Pvrazin1-3'-one
  • Step A 5-Methoxv-l-f[2-(trimethvlsilvl)ethoxvlmethvl)-lH-pyrrolo[2,3-blPvridine
  • Step B 3,3-Dibromo-5-methoxv-l- ⁇ [2-(trimethvlsilvl)ethoxy]methvl ⁇ -l,3-dihvdro-2H-
  • Step C 5-Methoxv-l- ⁇ [2-(trimethvlsilvl)ethoxv1methvl ⁇ -l,3-dihvdro-2H-pyrrolor2,3-blPVridin-2- one
  • 3 -dibromo-5-methoxy-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -l,3- dihydro-2H-pyrrolo[2,3-jb]pyridin-2-one 3.00 g, 6.75 mmol
  • THF 44 mL
  • saturated aqueous NH 4 CI 11 mL
  • zinc 4.4 g, 67 mmol
  • reaction mixture was filtered through Celite ® , washing with EtOAc.
  • organic layer of the filtrate was separated and the aqueous phase was extracted further with EtOAc.
  • the combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • the residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 60:40, to give the title compound.
  • Step D f(4-Nitrophenyl)imino1diethane-2,l-diyl dimethanesulfonate
  • Step E /V,A/-5/s(2-iodoethvl)-4-nitroaniline
  • Step F 5'-Methoxv-l-(4-nitrophenvl)-l'- ⁇ f2-(trimethvlsilvl)ethoxv1methvl ⁇ spiroipiperidine-4,3'- pyrrolor2,3-b1pvridinl-2'(l'H)-one
  • Step G l-(4-Aminophenvl)-5'-methoxv-l'- ⁇ [2-(trimethvlsilvl)ethoxvlmethvl)spirofpiperidine-
  • Step A l-(4-nitrophenvl)-l'- ⁇ f2-(trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4.3'-pyrrolo[2,3- b1pvridinl-2'(l'H)-one
  • Step B l-(4-Aminophenvl)-5'-methoxv-l'- ⁇ f2-(trimethvlsilvl)ethoxvlmethyl ⁇ spiro[piperidine-
  • Step B l-(4-Amino-2-bromophenvl)-l'- ⁇ [2-(trimethvlsilvnethoxvlmethyl ⁇ spirofpiperidine-4,3'-
  • Step B 5'-Bromo-l-(4-nitrophenvl)-l'- ⁇ f2-(trimethylsilvl)ethoxv1methvl ⁇ spiro[piperidine-4,3'- pyrrolof2,3-i 1pvridin1-2'(l'H)-one
  • Step C l-(4-Aminophenvl)-5'-bromo-l'- ⁇ f2-(trimethvlsilvl3 ⁇ 4ethoxvlmethvl ⁇ spiro[piperidine-4,3'- pyrrolo[2,3-i 1pvridinl-2'(l' V)-one
  • Step B M-(4-Hvdroxv-2.6,8-trimethvlquinolin-7-vl)acetamide
  • Step C A/-(4-Chloro-2,6.8-trimethylquinolin-7-vl)acetamide
  • Step A 2,2,2-Trifluoro-/ ⁇ /-(2-met vl-4-nitrophenvnacetamicle
  • Step B A/-(4-Amino-2-methvlphenyl)-2,2.2-trifluoroacetamide
  • Step C A/-f4-(Acetvlamino)-2-methylphenvn-2,2,2-trifluoroacetamide To a stirred mixture of /V-(4-amino-2-methylphenyl)-2,2,2-trifluoroacetamide (7.12 g,
  • Step B 4-[(2,6,8-Trimethvlquinolin-4-yl)amino1benzoic acid 71
  • methyl 4-[(2,6,8-trimethylquinolin-4-yl)amino]benzoate (1.30 g, 4.06 mmol) in THF (60 mL) and MeOH (20 mL) was added a solution of lithium hydroxide (389 mg ; 16.2 mmol) in water (20 mL).
  • the resulting precipitate was collected by filtration and dried to afford the title compound.
  • Step B Ethyl f4-hvdroxv-2-(methylsulfanvl)pvrimidin-5-vllacetate 72
  • diethyl 2-formy!butanedioate 50.0 g, 0.247 moi
  • S- methylthiourea semisulfate (34.4 g, 0.247 mol) in water (220 mL)
  • a solution of sodium hydroxide (14.8 g, 0.37 mol) in water (55 mL).
  • the resulting mixture was stirred at 100 °C for 90 min, cooled to ambient temperature, and acetic acid (21.2 mL, 0.37 mol) was added slowly.
  • the resulting mixture was stirred at ambient temperature for 18 h and the solid was isolated by filtration, washing with water, and drying under reduced pressure to provide the title compound.
  • MS: m/z 229.1 (M + 1).
  • Step C Ethyl [4-chloro-2-(methylsulfanvl)pvrimidin-5-vnacetate
  • Step D Ethyl [4-(ferf-butvlamino)-2-(methvlsulfanyl)pvrimidin-5-vl1acetate
  • Step E 7-tert-Butvl-2-(methvlsulfanvl)-5,7-dihvdro-6H-pvrrolof2,3-cflpyrimidin-6-one
  • Step G 7'-tert-Butvlspiro[piperidine-4,5'-pvrrolo[2,3-d1pvrimidin1-6'(7'/- )-one
  • benzyl 7'-iert-butyl-2'-(methylsulfanyl)-6'-oxo-6',7 , -dihydro-lH- spiro[piperidine-4,5'-pyrrolo[2,3--/]pyrimidine]-l-carboxylate (1.10 g, 2.50 mmol) in EtOH (20 mL) was added aney 3 ⁇ 4 Nickel (slurry in water, ca.
  • Step H 7'-ferf-Butvl-l-(4-nitrophenyl)spiroipiperidine-4,5'-pvrrolo[2,3-c/lpvrimidin1-6'(7'H)-one
  • Step I l-(4-Aminophenvl)-7'-fert-butvlspirofpiperidine-4,5'-pvrrolo[2,3-- lPvrimidinl-6'(7'H)- one
  • Step B 2-(2-Bromo-6-nitrophenvl)ethyl methanesulfonate
  • Step D ferf-Butyl 4- ⁇ r2-(2-bromo-6-nitrophenyl)ethvllamino ⁇ piperidine-l-carboxvlate
  • Step E ferf-Butyl 4-(r2-(2-amino-6-bromophenvl)ethyllamino ⁇ piperidine-l-carboxvlate
  • Step F ferf-Butyl 4-(6-bromo-2-oxo-1.2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl)piperidine-l- carboxvlate
  • Step G tert-Butyl 4-(6-cvano-2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidine-l- carboxylate
  • Step H 2-Oxo-3-(piperidin-4-yl)-2,3,4,5-tetrahvdro-lH-l,3-benzodiazepine-6-carbonitrile
  • Step I 3-[l-(4-Nitrophenvl)piperidin-4-vll-2-oxo-2,3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
  • Step J 3-[l-(4-Aminophenvl)piperidin-4-vll-2-oxo-2 J 3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
  • Step A A/-(4-Bromophenvl)-2,6-dimethvlpyridin-4-amine
  • Step B A/-(4-Bromophenvl)-A/,2,6-trimethvlpyridin-4-amine
  • Step B l-(4-Nitro-3-phenoxvphenvl)spirofpiperidine-4,3'-Pvrrolo[2,3-felPvridin1-2'(l'H)-one
  • Step C l-(4-Amino-3-phenoxvphenvl)spirofpiperidine-4,3'-pyrrolo[2,3--?lpvridinl-2'(l'H)-one A mixture of l-(4-nitro-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-Jb]pyridin]-
  • Step A tert-Butyl 5-bromo-2,3-dihvdro-lH-indole-l-carboxylate
  • Step B fe/t-Butyl 5-i4-(2-oxo-l,2,4,5-tetrahvdro-3W-l,3-benzodiazepin-3-yl)piperidin-l-vn-2,3- dihvdro-lH-indole-l-carboxylate
  • Step C 3-fl-(2,3-Dihvdro-lH-indol-5-vl)piperidin-4-vn-l,3,4,5-tetrahydro-2 -/-l,3- benzodiazepin-2-one
  • Step A Benzyl 2'-oxo-l'- ⁇ r2-(trimethvlsilvl)ethoxv1methvl)-l',2'-dihvdro-lH-spirorpiperidine-
  • Step B l'- ⁇ [2-(Trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4,3'-Pvrrolor2,3-fe1pyridin1-2'(l'H)- one
  • a mixture of benzyl Z'-oxo-l'-iia-itrimethylsilylJethoxyJmethylJ-l' ⁇ '-dihydro-lH- spiro[piperidine-4,3'-pyrrolo[2,3-ib]pyridine]-l-carboxylate (5.50 g, 11.8 mmol) and 10% Pd/C (1.00 g, 0.94 mmol) in EtOAc (30 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The resulting mixture was filtered through Celite ® , washing with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification.
  • Step C l-(6-Chloropvridazin-3-vl)-l'-(f2-(trimethvlsilvl)ethoxvlmethyl)spirofpiperidine-4,3'- pvrrolo[2,3-blpvridin]-2'(l'H)-one
  • DIEA 3,5,5-dichloropyridazine
  • Step A /V-(3-Formvlpyridin-2-vl)pivalamide
  • Step B 3-(Piperidin-4-vl)-l,8-naphthyridin-2(lH)-one hydrochloride
  • Step D 3-[l-(5-Aminopvridin-2-vl)piperidin-4-vll-l,8-naphthyridin-2(lti)-one
  • Step B fe/t-Butyl 4-f5-oxo-lH-l,2,4-triazol-4(5H)-vnpiperidine-l-carboxylate
  • EtOH 2-(ethoxymethylene)hydrazinecarboxylate
  • ieri-butyl 4-aminopiperidine-l-carboxylate (0.12 g, 0.60 mmol) and the reaction mixture was heated at 50 °C for 64 h.
  • MeOH MeOH (2 mL)
  • sodium methoxide 0.324 g, 6.00 mmol
  • Step C 4-(Piperidin-4-yl)-l /-1.2,4-triazol-5(4H)-one trifluoracetate
  • Step D 4-ri-(5-Nitropyridin-2-vl)piperidin-4-vll-lH-l,2,4-triazol-5(4fV)-one
  • Step A fe/t-Buty) 3-[(2-aminopvridin-3-yl)aminolazetidine-l-carboxvlate
  • Step B fert-Butyl 3-(2-oxo-2,3-dihvdro-lH-imidazof4,5-b1pyridin-l-vl)azetidine-l-carboxvlate To a stirred solution of te/t-butyl 3-[(2-aminopyridin-3-yl)amino]azetidine-l-carboxylate
  • Step C l-(Azetidin-3-yl)-lW-imidazof4,5-blpvridin-2(3H)-one hydrochloride
  • Step D l-fl-(5-Aminopvridin-2-vl)azetidin-3-vn-lH-imidazor4,5-b1pyridin-2(3H)-one
  • Step A 2'-Chloro-l-methvl-5'-nitro-3,4'-bipyridin-6(lH)-one
  • Step B l-Methvl-5'-nitro-2'-r4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl3 ⁇ 4piperidin- l-vll-3.4'-bipyridin-6(l/V)-one
  • Step C 5'-Amino-l-methvl-2'-f4-(2-oxo-l,2,4.5-tetrahydro-3H-l,3-benzodiazepin-3- vl)piperidin-l-vn-3,4'-bipyridin-6(lH)-one
  • Step B Methyl /V-(ferf-butoxvcarbonvl)-A/-(2-nitrobenzyl)glvcinate
  • Step C Methyl N-(2-aminobenzyl)-/V-(1 ⁇ 2rr-butoxvcarbonvl)glvcinate
  • Step D ferr-Butyl 2-oxo-l,2.3.5-tetrahydro-4H-l,4-benzodiazepine-4-carboxvlate
  • Step E l,3,4,5-Tetrahydro-2H-l,4-benzodiazepin-2-one
  • a stirred mixture of ie/t-butyl 2-oxo-l,2,3,5-tetrahydro-4H-l,4-benzodiazepine-4- carboxylate (3.1 g, 12 mmol), and trifluoroacetic acid (7.0 mL, 91 mmol) in CH 2 CI 2 (100 mL) was stirred at ambient temperature for 2 h.
  • the reaction mixture was concentrated in vacuo, the residue was triturated with ether and the resulting solid was isolated by filtration and dried in vacuo to give the title compound in sufficient purity for use in the next step.
  • MS: m/z 163.1 (M + l).
  • Step F te/t-Butvl 4-(2-oxo-1.2,3,5-tetrahvdro-4H-l,4-benzodiazepin-4-yl)piperidine-l- carboxylate
  • Step G 4-(Piperidin-4-yl)-l,3,4,5-tetrahvdro-2H-l,4-benzodiazepin-2-one
  • tert-butyl 4-(2-oxo-l,2,3,5-tetrahydro-4W-l,4-benzodiazepin-4- yl)piperidine-l-carboxylate (1.8 g, 5.2 mmol) in CH 2 CI 2 (50 mL)
  • TFA 10 mL, 25 mmol
  • Step A 5-(5-Fluoro-2-nitrophenvl)-2-(trifluoromethyl)pvridine
  • Step B 3-(l- ⁇ 4-Nitro-3-i6-(trifluoromethvl)pvridin-3-vllphenvl ⁇ piperidin-4-vl)-l,3,4,5- tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step C 3-(l- ⁇ 4-Amino-3-r6-(trifluoromethvl)pvridin-3-vnphenyl)piperidin-4-vl)-l.3.4,5- tetrahydro-2tf-l,3-benzodiazepin-2-one
  • Step A 5-Bromo-2-chloro-4-f4-(methvlsulfonyl)phenvnpvridine
  • Step B 6-Chloro-A/-(2,6-dimethvlpvridin-4-vl)-4-[4-(methylsulfonvl)phenvllpvridin-3-amine
  • a deoxygenated mixture of 5-bromo-2-chloro-4-[4-(methylsulfonyl)phenyl]pyridine (500 mg, 1.4 mmol), 4-amino-2,6-dimethylpyridine (260 mg, 2.1 mmol) and chloro(2- dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ll)- methyl-ferr-butyl ether adduct ( uPhos precatalyst) (120 mg, 0.14 mmol) in 1,4-dioxane (15 mL) was treated with sodium iert-butoxide (2.0 M in THF, 1.4 mL, 2.9 mmol) and the resulting mixture was heated at 40 °C for 18 h.
  • Step A 5-Bromo-2-chloro-4-(4-fluorophenvl)pyridine
  • 4-fluorophenyl)boronic acid (0.92 g, 6.9 mmoi)
  • tris-(3-suifonatophenyl)phosphine-hydrate sodium salt (0.30 g, 0.47 mmol)
  • pailadium(ll) acetate 35 mg, 0.16 mmol
  • DMF 24 mL
  • water (7.9 mL) was added diisopropylamine (2.7 mL, 19 mmol).
  • Step B 4- ⁇ l-f5-Bromo-4-(4-fluorophenvl)pvridin-2-yllpiperidin-4-vl)-l,3,4,5-tetrahvdro-2H-l,4- benzodiazepin-2-one
  • Step A A/-(2,6-Dimethylpvridin-4-vl)-2,2-dimethvlpropanamide
  • Step B A/-(3-Bromo-2,6-dimethvlpvridin-4-vl)-2,2-dimethylpropanamide
  • Step C / ⁇ /- ⁇ 3-[(£)-2-Ethoxvethenvn-2,6-dimethvlpvridin-4-vl ⁇ -2,2-dimethylpropanamide
  • Step D 4,6-Dimethvl-l/-7-pvrrolo[3,2-c1pyridine
  • Step A 4-(2-Chloro-5-nitropyridin-4-vl)thiomorpholine 1,1-dioxide
  • Step B 3- ⁇ l-r4-(l,l-Dioxidothiomorpholin-4-vl)-5-nitropyridin-2-vnpiperidin-4-vl ⁇ -l,3,4.5- tetrahydro-2H-l,3-benzodiazepin-2-one
  • a mixture of 4-(2-chloro-5-nitropyridin-4-yl)thiomorpholine 1,1-dioxide 450 mg, 1.54 mmol
  • 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (435 mg, 1.54 mmol)
  • DIEA (0.81 mL, 4.63 mmol
  • Step C 3- ⁇ l-f5-Amino-4-(l,l-dioxidothiomorpholin-4-vl)pyridin-2-vnpiperidin-4-vl)-l, 3.4.5- tetrahydro-2H-1.3-benzodiazepin-2-one
  • Step A 5-Nitro-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-1.3-benzodiazepin-3-yl)piperidin-l-
  • Step B 5-Amino-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidin-l- vnpyridine-4-carbonitrile
  • Step A 4-(4,4,5,5-Tetramethvl-l,3,2-dioxaborolan-2-vl)-2-(trifluoromethvl)pyridine
  • Step C 2-(l,4-Dioxa-8-azaspirof4.51dec-8-vl)-5-nitro-2'-(trifluoromethyl)-4,4'-bipvridine
  • Step D 6-(l,4-Dioxa-8-azaspiroi4.5ldec-8-vl)-2'-(trifluoromethvl)-4,4'-bipvridin-3-amine
  • Step E / ⁇ /-(2,6-Dimethvlpvridin-4-vl)-6-(l,4-dioxa-8-azaspiro[4.51dec-8-vl)-2'-(trifluoromethyl)-
  • Step F l- ⁇ 5-f(2,6-Dimethvlpvridin-4-vl)amino)-2'-(trifluoromethvl)-4,4'-bipvridin-2-yl ⁇ piperidin- 4-one
  • ⁇ /-(2,6- ⁇ -4- ⁇ )-6-(1,4- ⁇ 3-8-3 ⁇ 35 ⁇ [4.5] ⁇ €-8- yi)-2'-(trifluoromethyl)-4,4'-bipyridin-3-amine 260 mg, 0.536 mmol
  • H 2 0 (1 mL) was added cone.
  • HCI (0.44 mL, 5.36 mmol).
  • Step B 4-Chloro-2-(fluoromethvl)-6-methylpvridine hydrochloride
  • Step A (lZ,4g)-l-Hvdroxv-5-methoxv-l-fl-(trifluoromethvl)cvclopropvnpenta-l,4-dien-3-one
  • reaction mixture was quenched with saturated NH 4 CI (20 mL), concentrated under reduced pressure to remove THF and the residue was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na 2 S0 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 100:0 to 50:1, to give the title compound.
  • Step B 2-fl-(Trifluoromethyl)cvclopropvll-4H-pvran-4-one
  • Step C 2-ri-(Trifluoromethvl)cvclopropyl]pvridin-4(l/Tf)-one
  • Step D 4-Bromo-2-Fl-(trifluoromethyl)cvclopropvnpvridine
  • Step E A/-(2,6-Dimethvlpyridin-4-vl)-6-(l,4-dioxa-8-azaspirof4.51dec-8-vl)-2'-fl- (trifluoromethvl)cyclopropvll-4,4'-bipvridin-3-amine
  • Step F A/-(2,6-Dimethylpvridin-4-vl)-6-(l,4-dioxa-8-azaspiror4.5ldec-8-yl)-/ ⁇ /-methvl-2'-fl- (trifluoromethyl)cvclopropvll-4,4'-bipvridin-3-amine
  • Step G l- ⁇ 5-i(2,6-Dimethvlpvridin-4-vl)(methvl)aminol-2'-il-(trifluoromethvl)cyclopropvn-4,4'- bipyridin-2-vl ⁇ piperidin-4-one

Abstract

la présente invention concerne des composés bicycliques qui sont des antagonistes des récepteurs CGRP et qui peuvent être utiles dans le traitement ou la prévention de maladies dans lesquelles CGRP est impliqué, telles que la migraine. L'invention concerne également des compositions pharmaceutiques comprenant lesdits composés, et l'utilisation de ces composés et compositions dans la prévention ou le traitement de maladies dans lesquelles CGRP est impliqué.
PCT/US2015/043751 2014-08-06 2015-08-05 Antagonistes hétérocycliques des récepteurs cgrp WO2016022644A1 (fr)

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EP3556760A1 (fr) * 2018-04-19 2019-10-23 F. Hoffmann-La Roche AG Spirocomposés
WO2020168927A1 (fr) * 2019-02-19 2020-08-27 四川科伦博泰生物医药股份有限公司 Composé cyclique condensé contenant de l'azote, son procédé de préparation et son utilisation
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
JP2021506978A (ja) * 2017-12-22 2021-02-22 ラヴェンナ ファーマシューティカルズ，インコーポレイテッド ホスファチジルイノシトールリン酸キナーゼ阻害剤としてのアミノピリジン誘導体
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
CN114630825A (zh) * 2019-11-01 2022-06-14 先正达农作物保护股份公司 杀有害生物活性的稠合二环杂芳香族化合物
US11584748B2 (en) 2018-04-16 2023-02-21 C4 Therapeutics, Inc. Spirocyclic compounds
US11976067B2 (en) 2022-01-18 2024-05-07 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
JP2021506978A (ja) * 2017-12-22 2021-02-22 ラヴェンナ ファーマシューティカルズ，インコーポレイテッド ホスファチジルイノシトールリン酸キナーゼ阻害剤としてのアミノピリジン誘導体
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
US11584748B2 (en) 2018-04-16 2023-02-21 C4 Therapeutics, Inc. Spirocyclic compounds
EP3556760A1 (fr) * 2018-04-19 2019-10-23 F. Hoffmann-La Roche AG Spirocomposés
WO2020168927A1 (fr) * 2019-02-19 2020-08-27 四川科伦博泰生物医药股份有限公司 Composé cyclique condensé contenant de l'azote, son procédé de préparation et son utilisation
CN114630825A (zh) * 2019-11-01 2022-06-14 先正达农作物保护股份公司 杀有害生物活性的稠合二环杂芳香族化合物
US11976067B2 (en) 2022-01-18 2024-05-07 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use

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