WO2015161011A1 - Antagonistes benzamides des récepteur cgrp - Google Patents

Antagonistes benzamides des récepteur cgrp Download PDF

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Publication number
WO2015161011A1
WO2015161011A1 PCT/US2015/026067 US2015026067W WO2015161011A1 WO 2015161011 A1 WO2015161011 A1 WO 2015161011A1 US 2015026067 W US2015026067 W US 2015026067W WO 2015161011 A1 WO2015161011 A1 WO 2015161011A1
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Prior art keywords
methyl
phenoxy
benzamide
oxopyrrolidin
fluoro
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PCT/US2015/026067
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English (en)
Inventor
Brendan CROWLEY
Mark Fraley
Craig Potteiger
Robert Gilfillan
Mehul Patel
Ken ARRINGTON
Helen Mitchell
Kathy Schirripa
Melody Mcwherter
Tesfaye Biftu
Anilkumar NAIR
Cheng Wang
De-Yi Yang
Cheng Zhu
Nam Fung Kar
Xianhai Huang
Lei Chen
Wei Zhou
Qingsheng LIU
Jiaqiang Cai
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Merck Sharp & Dohme Corp.
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Publication of WO2015161011A1 publication Critical patent/WO2015161011A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • 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
    • C07D401/02—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
    • C07D401/12—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 chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D471/04—Ortho-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
    • C07D471/02—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
    • C07D471/06—Peri-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
    • C07D471/02—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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • CGRP Calcitonin Gene-Related Peptide
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system.
  • CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation.
  • 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 When released from the cell, CGRP initiates its biological responses by binding to the 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, 1 104-1 1 10) 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, 21 15-2123; 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, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9).
  • the middle meningeal arteiy the principal 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).
  • Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP receptor antagonist (Williamson et al. (1997) Cephalalgia 17, 525-531).
  • Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al. (1995) Brain Res. 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP receptor antagonist BIBN4096BS (Doods et al. (2000) Br. J. Pharmacol. 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP receptor antagonist.
  • 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
  • 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 sensitization.
  • CGRP receptor antagonists 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.
  • disorders may 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.
  • Urology 166, 1720-1723 allergic dermatitis (Wallengren (2000) Contact Dermatitis 43, 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al. (1999) Neurobiol. Dis. 6, 1 -34); skin diseases (Geppetti and Holzer, Eds., Neurogenic
  • the present invention is directed to benzamide compounds which are potent antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which the CGRP receptor is involved, such as migraine.
  • the invention is also directed to pharmaceutical 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.
  • the present invention is directed to compounds of Formula I:
  • G 1 isCR 3 orN;
  • G 2 is CR 1 orN
  • G 3 is CR 2 orN
  • G 4 is CR 3 orN
  • G 5 is CR 3 orN
  • E 1 is N or CH
  • a 4 is a bond, CR 6 R 7 , O, S or NR 4 ;
  • E 2 is N or C
  • a 5 is CR 6 orN
  • a 8 is a bond, CR 7 , O, N or NR 4 ;
  • Z 1 is CR a or N
  • Z 2 is CR a orN
  • Z 3 is CR a ;
  • Ci-6 alkyl which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo and hydroxyl, or
  • R 1 is hydrogen, halo, Ci -6 alkyl, 0(Ci_6 alkyl) or NR b R°, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
  • Ci-6 alkyl or C3.6 cycloalkyl which may be optionally substituted with one to four
  • R and R can be taken together with the carbon atom to which they are attached to form a C 3 .
  • cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to two substituents independently selected from the group consisting of cyano, R 4 , R 8 , halo, oxo and OR 4 ;
  • R is hydrogen, halo, hydroxyl, cyano or C
  • R 5 is hydrogen, Ci. 6 alkyl, heterocyclyl, or C 3 skill 8 cycloalkyl, which is optionally substituted with one to three halo;
  • R 6 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl or NR b R c ;
  • R 7 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl, 0(Ci_6 alkyl), NR b R°, C 3-6 cycloalkyl, heterocyclyl, heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl groups are optionally substituted with one to three substituents independently selected form the group consisting of halo, hydroxyl, R 8 , R 5 , and OR 5 ; or R° and R' can be taken together with the carbon atom or atoms to which they are attached to form a C 3 . 8 cycloalkyl, C 3 .
  • R 8 is phenyl, heteroaryl, heterocyclyl or C3.8 cycloalkyl, wherein said phenyl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, hydroxy., cyano, R 5 , NR b R c , OR 5 and SO m R 9 ;
  • R 9 is hydrogen, Ci -6 alkyl, C 3 . 8 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and OR 5 ;
  • R 4 groups or an R 4 and R 8 group can be taken together with the atom to which they are attached to form a C 3 . 8 cycloalkyl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NR b R°, OR 5 , C 3 _6 cycloalkyl, and heterocyclyl wherein said alkyl, cycloalkyl and heterocyclyl rings are optionally substituted with one to four substituents independently selected from the group consisting of oxo, Ci-6 alkyl, halo and hydroxyl;
  • R a is selected from the group consisting of hydrogen, halo, cyano, Ci_6 alkyl and OR 5 , wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
  • R° is hydrogen or Ci_ 6 alkyl, which is optionally substituted with one to three subsitituents independently selected from the group consisting of halo, OR 5 and hydroxyl; or R b and R c can be taken together with the atom to which they are attached to form a heterocyclyl ring which is optionally substituted with one to three substituents independently selected from the group consisting of R 5 , halo, oxo, hydroxyl, OR 5 and heterocyclyl;
  • R d is C,. 6 alkyl, C 3 - 6 cycloalkyl and NR b R c ;
  • n is an integer from zero to two;
  • G is CR 3 .
  • G 1 is CH.
  • G is N.
  • G is CR .
  • G 2 is CH.
  • G is CR .
  • G 3 is CR 2 . In another class of the invention, G 3 is N. In a class of the invention, G 4 is CR 3 . In a subclass of the invention, G 4 is CH. In another class of the invention, G is N.
  • G 5 is CR 3 . In a subclass of the invention, G 5 is CH. In another class of the invention, G 5 is N.
  • Y is O. In another class of the invention, Y is CR 5 R 6 . In another class of the invention, Y is NR b . In another class of the invention, Y is SO m .
  • E 1 is CH. In another class of the invention, E 1 is N.
  • E 2 is C. In another class of the invention, E 2 is N.
  • a 1 is CHR 6 . In a subclass of the invention, A 1 is CH 2 .
  • a z is CR 6 R 7 .
  • A is NR .
  • a J is CR 6 R 7 .
  • a 5 is CH 2 .
  • a 3 is NR 4 .
  • a 3 is O.
  • a 3 is S.
  • a 4 is CR 6 R 7 .
  • a 4 is S.
  • a 4 is NR 4 .
  • a 4 is O.
  • a 4 is a bond.
  • a 5 is CR 6 . In a subclass of the invention, A 5 is CH. In another class of the invention, A 5 is N.
  • a 7 is CR 6 . In another class of the invention, A 7 is CR 7 . In a subclass of the invention, A 7 is CH. In another class of the invention, A 7 is C-O. In another class of the invention, A 7 is NR 4 .
  • a 8 is CR 7 . In a subclass of the invention, A 8 is CH. In another class of the invention, A 8 is NR 4 . In another class of the invention, A 8 is O. In another class of the invention, A is a bond.
  • Z 1 is CR a . hi a subclass of the invention, Z 1 is CH. In another class of the invention, Z 1 is N.
  • Z 2 is CR a . In another class of the invention, Z 2 is N.
  • Z 3 is CR a . In a subclass of the invention, Z 3 is CH.
  • W 1 is:
  • W 1 is:
  • W 1 is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, R 4 , OR 4 and R 8 .
  • W is hydrogen
  • R 1 is hydrogen
  • R 2 is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci -6 alkyl, heterocyclyl and C3.6 cycloalkyl.
  • R 3 is hydrogen
  • R a is hydrogen or halo.
  • R b is hydrogen or Ci -6 alkyl.
  • R° is hydrogen or Ci -6 alkyl.
  • R d is Ci. 6 alkyl.
  • Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 397, 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 potential method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • 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 potential 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 earners.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,
  • 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 chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • 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 iso topic 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 (lH) and deuterium ( ⁇ H).
  • 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.
  • any variable e.g. R.4, etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds.
  • Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
  • 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 ordinaiy 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.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • Ci -4-alkyl is defined to identify the group as having 1 , 2, 3 or 4 carbons in a linear or branched arrangement, such that Ci -4-alkyl 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.
  • alkenyl As described above with respect to alkyl, 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.
  • cycloalkenyl or shall mean cyclic rings of alkenes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e.,
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.
  • 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 O, 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, pyridinonyl, pyrimidinyl, pyrroly
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 4- to 10-membered nonaromatic ring, unless otherwise specified, containing from 1 to 4
  • Heterocyclyl therefore includes, but is not limited to the following:
  • 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 complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • 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 conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as 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. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • 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. In addition to primates, especially humans, 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 earner.
  • 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. In general, such 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.
  • 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-HTJB/ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTID agonist such as PNU-142633 and a 5-HTi F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective migraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HTJB/ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTID agonist
  • cyclooxygenase-2 inhibitor for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone,
  • 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 granzyn e B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT
  • an interleukin inhibitor such as an
  • 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-P-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, a-ergocryptine, ⁇ -ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
  • ergot alkaloids other than ergotamine and dihydroergotamine for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine, dihydroergocristine
  • 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, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or
  • 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 non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine
  • 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-HTIB/ID 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-HTIB/ID agonist, in particular, sumatriptan, naratriptan, zolmitriptan,
  • 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. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, 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 glyceiyl 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 monooleate.
  • 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.
  • 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • 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 laiown 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.
  • compositions and methods 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 , 25 I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 ⁇ g) were incubated in 1 mL of binding buffer [ 10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 125 I-CGRP and antagonist.
  • binding buffer 10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)
  • the assay was terminated by filtration through GFB glass fibre filter plates (PerkinElmer) that had been blocked with 0.5% polyethyleneimine for 3 h.
  • the filters were washed three times with ice- cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCl 2 ), then the plates were air dried.
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences).
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL- 1573) were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ⁇ g mL streptomycin, and maintained at 37 °C and 95% humidity.
  • FBS fetal bovine serum
  • 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 RAMPl expression constructs were co-transfected in equal amounts. Twenty-four hours after transfection the cells were diluted and selective medium (growth medium + 300 ⁇ g/mL hygromycin and 1 ⁇ g/mL puromycin) was added the following day. 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.
  • ASSAY A Cells expressing recombinant human CL receptor/RAMP 1 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.
  • Yobsd (YTM, - Yn,inX%I mm . -% mi n / 100) + Yjnin + fYmav - . Yn ⁇ 100-%W10 ⁇ »
  • Y max is total bound counts
  • Y m j n is non specific bound counts
  • (Ymax - Ymin) is specific bound counts
  • % I max is the maximum percent inhibition
  • % I min is the minimum percent inhibition
  • radiolabel is the probe
  • Ki is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
  • ASSAY B RECOMBINANT RECEPTOR FUNCTIONAL ASSAY
  • cAMP dynamic 2 assay kit 62AM4PEC; Cisbio.
  • Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.
  • ASSAY C RECOMBINANT 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 3,500 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 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 a standard curve then dose response curves were plotted and IC50 values were determined.
  • DMEM Dulbecco's Modified Eagle Medium (High Glucose)
  • 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 loiown 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 1 illustrates the general strategy for preparing the compounds of the present invention by coupling of a carboxylic acid intermediate (1.1) to an amine (1.2) to give the desired product amide 1.3.
  • carboxylic acid intermediates such as those described herein ⁇ vide infra
  • the carboxylic acid 1.1 may be activated as an acid chloride or anhydride, for example, to facilitate reaction with the amine of interest.
  • Activation of the amine 1.2 for example with trimethylaluminum, followed by treatment with an ester derivative of carboxylic acid 1.1, may also be a useful strategy in cases where the amine is relatively unreactive.
  • various protecting group strategies familiar to one skilled in the art of organic synthesis may be employed to allow preparation of a particular compound of the present invention.
  • SFC or normal phase or reverse-phase chromatography employing a chiral or achiral stationary phase
  • intermediates such as ester 4.8 in Scheme 4, can be resolved using similar conditions and the individual stereoisomers may be elaborated to prepare the final compounds of interest.
  • Scheme 2 Another general approach for the preparation of compounds of the present invention is illustrated in Scheme 2.
  • This methodology relies on a palladium-catalyzed arylation of intermediate 2.1 with a boronic acid (2.2).
  • a boronic acid 2.2
  • the aryl boronic acid 2.2 may be replaced by a similar reactant, such as the corresponding aryl stananne or trifluoroboronate salt and the aryl bromide 2.1 may be replaced with the corresponding chloride or iodide to effect the formation of similar biaryl products.
  • aryl bromide 2.1 may be converted to the boronic acid via treatment with bis(pinacolato)diboron in the presence of a suitable palladium catalyst, ligand, and base (e.g., Pd 2 (dba)3, X-phos and KOAc) and subsequently coupled with a suitable aryl or heteroaryl halide to afford target 2.3.
  • a suitable palladium catalyst, ligand, and base e.g., Pd 2 (dba)3, X-phos and KOAc
  • Scheme 3 describes a number of methods in which the amide from Scheme 1 may be alkylated or acylated to afford derivatives such as 3.3.
  • the Boc group (or other suitable protecting group) from intermediate 3.1 is removed under acidic conditions to provide amine 3.2, which may then be treated with a base (e.g. NaH) and an alkylating agent (R 4 -X) to afford the substituted amine 3.3.
  • Amine 3.2 may alternatively undergo reductive amination with a ketone or aldehyde under standard conditions to afford 3.3. Reaction of amine 3.2 with an epoxide in the presence of a mild base (TEA) may afford amine 3.3.
  • treating 3.2 with an acylating agent in the presence of a base may afford an amide variant of 3.3.
  • Other functionalization of the amine may include sulphonylation, urea or carbamate formation, and N-arylation.
  • intermediate acids of the type 1.1 may be prepared using well- precedented methodology and several such intermediates are described herein ⁇ vide infra). Variations of these approaches, familiar to one skilled in the art of organic synthesis, may be employed to produce a variety of related intermediates.
  • Scheme 4 describes one such method wherein acid 4.1 is esterified, followed by treatment of 4.2 with NBS and a radical initiator (AIBN or benzoyl peroxide) in a suitable solvent to afford benzyl bromide 4.3. Treatment of this bromide with the anion of 4.4 may be used to provide the alkylated product 4.5.
  • LiHMDS LiHMDS
  • the methyl ether of 4.5 is cleaved with BBr 3 or HBr, followed by re-esterification of the carboxylic acid product, if required.
  • the resulting phenol 4.6 is then treated with aryl iodide (or bromide) 4.7 in the presence of a copper source, a suitable base, and a ligand to afford the ether 4.8.
  • aryl iodide or bromide
  • 4.7 is a heteroaryl bromide (or fluoride) or aryl fluoride
  • treatment of phenol 4.6 with NaH or Cs 2 C0 3 in DMF followed by reaction with 4.7 may afford the corresponding ether as well.
  • ether 4.8 is a mixture of isomers, it may be convenient to separate the isomers at this stage using SFC or reverse or normal phase chromatography employing an achiral or chiral stationary phase, prior to saponification of the ester to afford acid 4.9.
  • SCHEME 4
  • Acid intermediates of type 6.6 may be prepared as shown in Scheme 6, using similar methodology to that described in Scheme 4. Phenol 5.1 is transformed into ether 6.2 under Ullmann or direct displacement conditions, depending upon the nature of halide 6.1. Bromination of the tolyl group in 6.2 followed by alkylation as described ⁇ vide supra), and ester hydrolysis affords intermediate 6.6.
  • Scheme 7 describes a synthetic route to acid intermediates of the type 7.6.
  • Chloride 6.2 is converted to boronate 7.1 using standard conditions (Pd 2 (dba)3, X-Phos, KOAc, B 2 (Pin) 2 ) and then subsequent bromination affords bromide 7.2.
  • Alkylation of a suitable substrate, such as pyrazinone 7.3, with bromide 7.2 is followed by Suzuki coupling and hydroylsis to afford acid 7.6.
  • acid intermediates represented by 8.9 can by synthesized by the route described in Scheme 8.
  • Ullmann coupling of phenol 5.1 with iodoester 8.1 affords ether 8.2.
  • base catalyzed displacement may also afford ether 8.2.
  • Bromination, alkylation, and deprotection of the terf-butyl ester under acidic conditions affords acid 8.5.
  • a synthetic route to acid intermediate 9.15 is depicted in Scheme 9.
  • silyl ether 9.3 is brominated with excess NBS to afford 9.4, which can undergo silver mediated hydrolysis to provide aldehyde 9.5.
  • Fluoride mediated removal of the silyl group is followed by heating of 9.6 with trimethylorthoformate in the presence of acid to form acetal 9.7.
  • Coupling of the phenol with aryl iodide 9.8 under Ullmann conditions, followed by acidic deprotection of the acetal and reduction of the subsequent aldehyde with a reducing agent such as sodium tnacetoxyborohydride affords alcohol 9.11.
  • the alcohol can be converted to the benzyl bromide 9.12 through treatment with carbon tetrabromide and triphenylphosphine, and then used to alkylate an agent such as pyrimidinone 9.13 to afford, after saponification, acid 9.15.
  • Scheme 10 illustrates the preparation of acid intermediate 10.4.
  • Benzyl bromide 9.12 can undergo a palladium-mediated coupling with boronic acid 10.1, for example, to fonn ester 10.2.
  • the methyl ether is cleaved with HBr in water with heat and then saponification of the ester affords acid 10.4.
  • Scheme 1 1 depicts a synthetic route to acid intermediate 11.5, which begins by palladium catalyzed cross-coupling of benzyl bromide 4.3 with boronic acid 10.1. Removal of the methyl ethers is effected by treatment with HBr in water. Ullmann coupling of phenol 11.2 with iodide 11.3, followed by saponification, affords 11.5.
  • Scheme 12 describes the preparation of pyridazinone acid intermediate 12.2 condensation of aldehyde 9.10 with dihydropyridazinone 12.1 under basic conditions.
  • Scheme 13 describes the preparation of urea containing intermediate 13.2 via alkylation of benzyl bromide 9.12 with a diamine such as 13.1, followed by cyclization with CDI and ester hydrolysis.
  • Scheme 14 illustrates a method to install a benzylic methyl group to afford intermediates such as 14.6.
  • Bromide 14.1 is treated with vinylpyrrolidinone 14.2 under Heck coupling conditions (Pd(OAc) 2 , X-Phos, dicyclohexylmethylamine) to afford 14.3.
  • the benzyl ether is removed under hydrogenolysis conditions (H 2 , Pd/C) to afford phenol 14.4.
  • Ullmann coupling followed by saponification affords the acid 14.6.
  • Scheme 15 illustrates a method to prepare substituted thiadiazoles of the type 15.4. lodoacid 15.1 is coupled with the substituted acylhydrazide 15.2 using EDC/HOAt to give intermediate 15.3, which is subsequently heated with Lawesson's reagent to afford thiadiazole 15.4.
  • Acid 15.1 may also be transformed into an oxadiazole as shown in Scheme 16, starting with the coupling of N-hydroxyamidine 16.1 to give intermediate 16.2.
  • This intermediate may be heated with 2,4,6-tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), or isolated and treated with TBAF, to afford oxadiazole 16.3.
  • SCHEME 16 2,4,6-tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
  • pyridazine 17.4 The synthesis of pyridazine 17.4 is outlined in Scheme 17. Palladium catalyzed cross-coupling between chloropyridazine 17.1 and pinacol boronate 17.2 affords aminobiaryl 17.3. The amino group is then converted into an iodide under Sandmeyer conditions to afford iodide 17.4.
  • Schemes 18-20 illustrate methods to prepare substituted amines that are useful for the preparation of compounds of the present invention.
  • piperidinyl amine 18.1 is bisalkylated with benzyl bromide to afford 18.2.
  • Standard removal of the Boc group gives 18.3, which can then undergo reductive alkylation with an aldehyde or ketone (18.4) to afford 18.5.
  • product 18.5 is a mixture of stereoisomers, they may be separated utilizing techniques such as chiral SFC or reverse or normal phase chromatography prior to removal of the benzyl groups under hydrogenolysis conditions to afford 18.7a and 18.7b.
  • a method to prepare substituted amines of the type 20.10 is outlined in Scheme 20.
  • 1,4-Addition of amine 20.1 to ethyl 4,4,4-trifiuorobut-2-enoate 20.2 affords amine 20.3.
  • Other unsaturated esters may be used as alternatives to 20.2 to provide other products.
  • Acylation with 20.4 in the presence of base provides diester 20.5, which may be cyclized and then decarboxylated by sequential treatments with base and then acid, respectively, to give ketone 20.6.
  • the ketone may undergo reductive amination with benzylamine, and the resulting piperidinone 20.7 can be reduced with LAH to provide amine 20.8.
  • the stereoisomers may be separated using SFC or reverse or normal phase chromatography
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • various protecting group strategies may be employed to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable intermediate, followed by processing of the single isomers individually.
  • alternative methodologies may also be employed in the synthesis of these key intermediates.
  • Asymmetric methodologies e.g. chiral catalysis, auxiliaries
  • Oxalyl chloride (508 mg, 4.00 mmol) was added dropwise to a solution of 4- iodobenzoic acid (500 mg, 2.0 mmol) in CH2CI2 (5 mL) at 0 °C containing 3 drops of DMF. The mixture was stirred at 0 °C for 1 h and warmed up to 23 °C and stirred for 2 h. The CH 2 C1 2 was then removed, and the residue was dissolved in 6 mL dry pyridine.
  • N-Methylmorpholine (17.7 mL, 161 mmol) was added to a stirring solution of 4- iodobenzoic acid (10.0 g, 40.3 mmol), acetylhydrazide (3.00 g, 40.3 mmol), EDC (13.5 g, 70.6 mmol), and HOAt (2.70 g, 20.2 mmol) in DMF (81 mL).
  • the resulting mixture was stirred at 50 °C for 30 min. The mixture was cooled to ambient temperature, and excess water was added. The resulting solids were filtered, washed with water, and dried under high vacuum to give the title compound.
  • LC-MS m/z found 305.1 [M+l].
  • Step B 2-Cyclopropyl-5-(4-iodophenyl)-L3,4-thiadiazole
  • Lawesson's Reagent (25.4 g, 62.8 mmol) was added to a solution of N- (cyclopropanecarbonyl)-4-iodobenzohydrazide (15.6 g, 47.3 mmol) in THF (475 mL) and the resulting mixture was stirred at 50 °C for 2 h. The mixture was concentrated to dryness.
  • 2,4,6-Tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (5.88 mL, 50% in DMF, 10.1 mmol) was added to a vial containing 4-iodobenzoic acid (1.00 g, 4.03 mmol), tetrahydro-2H-pyran-4-carbohydrazide (0.640 g, 4.44 mmol), and TEA (1.69 mL, 12.1 mmol) in EtOAc (4 mL).
  • the vial was sealed and the resulting mixture was heated at 80 °C for 18 h. The reaction was concentrated.
  • Step A 2-Fluoi -4-iodo-N'-isobutvi lbenzohvdrazide
  • Step B 2-(2-Fluoro-4-iodophenyl)-5-isopropyl-l,3,4-thiadiazole
  • AIBN 0.055 g, 0.33 mmol
  • l-hydroxypyrrolidine-2,5-dione 0.096 g, 0.83 mmol
  • 2-(4-bromo-2-fluorophenyl)-5-isopropyl-l ,3,4-thiadiazole 1.00 g, 3.32 mmol
  • MeCN MeCN
  • Step A 3-Fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline
  • Step B 3-Fluoro-4-(6-isopropylpyridazin-3-yl)aniline
  • Step A 4-(6-Ethylpyridazin-3-yl)anilme
  • Step B 3-Ethyl-6-(4-iodophenyl)pyridazine
  • Step A 2-Amino-l-(4-bromophenyl)ethanone hydrobromide
  • Step B N-(2-(4-Bromophenyl)-2-oxoethyl)acetamide
  • Step C 6-(4-Bromophenyl)-3-methyl-4,5-dihydro-L2,4-triazine
  • Step D 6-(4-Bromophenyl)-3-m ethyl- 1 ,2,4-triazine
  • Step A 3-Chloro-6-(prop-l-en-2-yl)pyridazine
  • Step C 4-(6-Isopi pylpyridazin-3-yl)aniline
  • Step A 3,5-Difluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline
  • Step B 3,5-Difluoro-4-(6-isopropylpwidazin-3-yl)aniline
  • Step C 3-(2,6-Difluoro-4-iodophenylV6-isopropylpyridazine
  • Step A 4-Bromo-N'-isobutyrylbenzohvdrazide To a solution of 4-bromobenzoic acid (20.1 g, 100 mmol) in DMF (150 mL) was added HOBt (14.9 g, 1 10 mmol), EDC (21.1 g, 1 10 mmol) and Et 3 N (20.9 mL, 150 mmol). The mixture was stirred at 25 °C for 0.5 h, and then isopropylhydrazide (1 1.2 g, 1 10 mmol) was added. The reaction mixture was stirred at 25 °C for 14 h, and then diluted with EtOAc (300 mL) and washed with H 2 0 (100 mL x 2).
  • Step B 2-(4-Bromophenyl)-5-isopropyl-l ,3,4-thiadiazole
  • Step B Methyl 3-(3-ethoxy-3-oxo- N-(tetrahydro-2H-pyran-4-yl)propanamido)butanoate
  • Step B 6-Methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidine-2,4-dione
  • Step C 4-((4-Methoxybenzyl)amino)-6-methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidin-2-one
  • Step D N-(4-methoxybenzyl)-2 -methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine
  • Step E Benzyl 4-methoxybenzyl(2-methyl-l-(tetrahvdro-2H-pyran-4-yl piperidin-4-yl)carbamate
  • Step F (2R, R)-N-Benzyl-2 -methyl- l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine and (2R.4S)- N-benzyl (2-methyl-l -(tetrahvdro-2H-pyran-4-yl)piperidin-4-vncarbamate and (2S,4R)-N-benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate and (2S,4S)-N-benzyl (2- methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate
  • Step G (2R, ⁇ R)-2-Methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine and (2R,4S)-2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine and (2S, R)-2-methyl- 1 -(tetrahvdro-2H-pyran-4- yl)piperidin-4-amine and (2S, S)-2-methyl- 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine
  • Step A Ethyl 4,4,4-trifluoro-3-((tetrahvdro-2H-pyran-4-yl)amino)butanoate
  • Step B Ethyl 3-(3-ethoxy-3-oxo- N-(tetrahvdro-2H-pyran-4-yl)propanamido)-4A4- trifluorobutanoate
  • Step C 1 -(Tetrahvdro-2H-pyran-4-yl)-6-(trifluoromethyl)piperidine-2,4-dione
  • Step D 4-(Benzylamino)-l -(tetrahvdro-2H-pyran-4-yl)-6-(trifluoromethyl)piperidin-2-one
  • Step E (2S, R)-N-Benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine and (2R. ⁇ R)-N-benzyl-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine and (2R, S)-N-benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine and (2S, S)-N-benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine
  • Step F (2S, R)-l-(Tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-amine and (2S, ⁇ S)-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-amine and (2R, ⁇ S)-l-
  • Benzyl chloroformate (0.90 mL, 6.3 mmol) was added to a suspension of 4- amino- l -cyclopropyl-2-pyiTolidinone hydrochloride (1.00 g, 5.66 mmol) and K 2 CO 3 (4.75 g, 34.4 mmol) in THF (1 15 mL) at 0 °C and the reaction mixture was stirred for 4 h.
  • Benzyl chloroformate (0.90 mL, 6.3 mmol) was added and the reaction mixture was stirred for 18 h. Water (1 mL) was added, the reaction was filtered, and the filtrate was concentrated.
  • Step B (R)-4-Amino- 1 -cvclopropylpyrrolidin-2-one and (S)-4-amino-l-cvclopropylpyrrolidin-2- one
  • Step A /erf-Butyl (l-(4,4-difluorocvclohexyl)piperidin-4-yl)carbamate
  • Step A ter -Butyl (l -(2-methylcvclohexyl)piperidin-4-yl)carbamate
  • Step B l -(2-Methylcyclohexyl)piperidin-4-amine
  • Step C Benzyl ( 1 -(2-methylcyclohexyl)piperidin-4-yl)carbamate
  • Benzyl chloroformate (2.50 g, 14.5 mmol) was added dropwise to a solution of 1- (2-methylcyclohexyl)piperidin-4-amine (1.3 g, 4.8 mmol) and Na 2 C0 3 (3.1 g, 29 mmol) in THF (25 mL) and water (5 mL) at 0 °C.
  • the reaction mixture was warmed to 23 °C and stirred for 18 h.
  • the reaction was concentrated, the residue was diluted with water (30 mL), and then extracted with EtOAc (20 mL x 3).
  • Step C l-(2-Methylcvclohexyl)piperidin-4-amine (Isomers 1 and 2)
  • Step A /er/-Butyl 4-(((benzyloxy)carbonyl)amino)piperidine-l -carboxylate
  • Benzyl chloroformate (28 g, 0.17 mol) was added to a solution of ieri-butyl-4- aminopiperidine-l-carboxylate (30 g, 0.15 mol) and K 2 C0 3 (41 g, 0.30 mol) in THF (250 mL) and H 2 0 (125 mL) and the resulting mixture was stirred at 23 °C for 18 h. The THF was removed and the resulting aqueous phase was extracted with EtOAc (70 mL x 3).
  • Step B Benzyl piperidin-4-ylcarbamate hydrochloride
  • Step B (R)-l -(Tetrahydroraran-3-yl)piperidin-4-amine and (S)- l -(tetrahydrofuran-3-yl)piperidin- 4-amine

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Abstract

Cette invention concerne des composés de benzamide qui sont des antagonistes des récepteurs CGRP et qui sont utiles dans le traitement ou la prévention de maladies dans lesquelles le CGRP est impliqué, telles que la migraine. Cette 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 le CGRP est impliqué.
PCT/US2015/026067 2014-04-17 2015-04-16 Antagonistes benzamides des récepteur cgrp WO2015161011A1 (fr)

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WO2018016547A1 (fr) * 2016-07-22 2018-01-25 キッセイ薬品工業株式会社 Dérivé de pyrrolidine
CN107922385A (zh) * 2015-08-12 2018-04-17 伊莱利利公司 Cgrp受体拮抗剂
WO2019093284A1 (fr) * 2017-11-07 2019-05-16 キッセイ薬品工業株式会社 Composé hétérocyclique condensé
WO2020215094A1 (fr) 2019-04-18 2020-10-22 The Johns Hopkins University Dérivés de 2-amino-pyrazolyl-[1,2,4]triazolo[1,5 a] pyridine substitués et leur utilisation
CN114456059A (zh) * 2022-03-04 2022-05-10 丽珠集团新北江制药股份有限公司 一种制备阿福拉纳中间体的方法
WO2024033374A1 (fr) 2022-08-11 2024-02-15 Syngenta Crop Protection Ag Nouveaux composés arylcarboxamide ou arylthioamide

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CN107922385A (zh) * 2015-08-12 2018-04-17 伊莱利利公司 Cgrp受体拮抗剂
CN107922385B (zh) * 2015-08-12 2020-09-08 伊莱利利公司 Cgrp受体拮抗剂
WO2018016547A1 (fr) * 2016-07-22 2018-01-25 キッセイ薬品工業株式会社 Dérivé de pyrrolidine
CN109476639A (zh) * 2016-07-22 2019-03-15 橘生药品工业股份有限公司 吡咯烷衍生物
CN109476639B (zh) * 2016-07-22 2021-02-26 橘生药品工业股份有限公司 吡咯烷衍生物
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WO2020215094A1 (fr) 2019-04-18 2020-10-22 The Johns Hopkins University Dérivés de 2-amino-pyrazolyl-[1,2,4]triazolo[1,5 a] pyridine substitués et leur utilisation
CN114456059A (zh) * 2022-03-04 2022-05-10 丽珠集团新北江制药股份有限公司 一种制备阿福拉纳中间体的方法
CN114456059B (zh) * 2022-03-04 2024-01-02 丽珠集团新北江制药股份有限公司 一种制备阿福拉纳中间体的方法
WO2024033374A1 (fr) 2022-08-11 2024-02-15 Syngenta Crop Protection Ag Nouveaux composés arylcarboxamide ou arylthioamide

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