WO2015161014A1 - Antagonistes hétérocycliques du récepteur du cgrp - Google Patents

Antagonistes hétérocycliques du récepteur du cgrp Download PDF

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WO2015161014A1
WO2015161014A1 PCT/US2015/026072 US2015026072W WO2015161014A1 WO 2015161014 A1 WO2015161014 A1 WO 2015161014A1 US 2015026072 W US2015026072 W US 2015026072W WO 2015161014 A1 WO2015161014 A1 WO 2015161014A1
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Prior art keywords
methyl
phenoxy
oxopyrrolidin
benzyl
oxadiazol
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PCT/US2015/026072
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English (en)
Inventor
Brendan CROWLEY
Mark Fraley
Craig Potteiger
John Lim
Ed SHERER
Younong Yu
Helen Mitchell
Tesfaye Biftu
Anilkumar NAIR
Cheng Wang
De-Yi Yang
Cheng Zhu
Nam Fung Kar
Xianhai Huang
Lei Chen
Wei Zhou
Min K. Park
Jiaqiang Cai
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Merck Sharp & Dohme Corp.
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Publication of WO2015161014A1 publication Critical patent/WO2015161014A1/fr

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    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • 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
    • C07D413/10—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 carbon chain containing aromatic 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D471/10—Spiro-condensed 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 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).
  • 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.
  • 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 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. N ' eurol. 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:
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin and Adrenomedullin
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extracranial 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 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, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic
  • the present invention is directed to heterocyclic 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 invention encompasses a genus of compounds of the Formula I:
  • G 1 is CR 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 or N
  • a 8 is a bond, CR 7 , O, N or NR 4 ;
  • Z 2 is CR a or N
  • Z 3 is CR a ;
  • D is phenyl or heteroaryl which is optionally substituted with R e and R e ; W is
  • R 1 is hydrogen, halo, Ci_ 6 alkyl, 0(Ci_ 6 alkyl) or NR b R c , 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 C 3 -6 cycloalkyl which may be optionally substituted with one to four
  • heteroaryl which optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R 4 , R 8 , OR 4 , NR b R c ,
  • R 1 and R 2 can be taken together with the carbon atom to which they are attached to form a C 3 _8 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 3 is hydrogen, halo, hydroxyl, cyano or Ci_ 6 alkyl
  • R 5 is hydrogen, Ci_ 6 alkyl, heterocyclyl, or C 3 _g 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 , 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 6 and R 7 can be taken together with the carbon atom or atoms to which they are attached to form a C 3 _8 cycloalkyl, C 3 _8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group
  • R 8 is phenyl, heteroaryl, heterocyclyl or C 3 _g 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, hydroxyl, cyano, R 5 , NR b R c , OR 5 and SO m R 9 ;
  • R 9 is hydrogen, cyano, Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, heterocyclyl, phenyl, heteroaryl or NR 5 R C , 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 ; or two 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 c , OR 5 , C 3 _ 6 cycloalkyl, and heterocyclyl wherein said alkyl, cycloal
  • 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 c 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
  • R d is Ci_6 alkyl, C 3 _ 6 cycloalkyl and NR b R c ;
  • G 1 is CR 3 . In a subclass of the invention, G 1 is CH. In another class of the invention, G 1 is N.
  • G 2 is CR 1 . In a subclass of the invention, G 2 is CH. In another class of the invention, G 2 is N.
  • G 3 is CR 2 . In another class of the invention, G 3 is N.
  • G 4 is CR 3 . In a subclass of the invention, G 4 is CH. In another class of the invention, G 4 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 .
  • 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.
  • a 4 is CR 6 R 7 . In another class of the invention, A 4 is S. In another class of the invention, A 4 is NR 4 . In another class of the invention, A 4 is O. In another class of the invention, 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 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 N. In another class of the invention, A 8 is O. In another class of the invention, A 8 is a bond.
  • Z 1 is CR a . In 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 CH.
  • W is:
  • W is:
  • W 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 .
  • D is oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, thiazolyl or pyrazolyl. In a subclass of the invention, D is oxadiazolyl or triazolyl.
  • 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 c 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 298, 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 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 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,
  • the absolute configuration may be determined by use of vibrational circular dichroism (VCD) spectoscopy in conjuction with computational chemistry.
  • VCD vibrational circular dichroism
  • 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 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 (IF!) and deuterium (3 ⁇ 4).
  • 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. R5, 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 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.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • Cl-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. 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, S, and Si.
  • 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
  • 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. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • 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 heteroatoms selected from the group consisting of O, N, S, SO, or S0 2 and includes bicyclic or spirocyclic groups.
  • 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,
  • 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 including migraine and cluster headache.
  • 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 antimigraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HT IB/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 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 NMD A 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
  • 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.
  • 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-HT IB/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-HT IB/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.
  • 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
  • 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.
  • suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for use in humans.
  • 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 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.
  • 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. 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 M 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% polyethyleneimine for 3 h.
  • binding buffer 10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)
  • 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. Scintillation fluid (50 ⁇ ) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the K ⁇ was determined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108).
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3' Pmel fragment. Human RAMP1 (Genbank accession number
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL- 15763 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. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.
  • 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.
  • selective medium growth medium + 300 ⁇ g/mL hygromycin and 1 ⁇ g/mL puromycin
  • ASSAY A 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 MgCl 2 , and 0.2% BSA) for 3 h at room temperature containing 10 pM I-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 MgCl 2 ). Scintillation fluid was added and the plates were counted on a Topcount (Packard).
  • Non-specific binding was determined and the data analysis was carried out with the apparent dissociation constant (Ki) determined by using a nonlinear least squares fitting the bound CPM data to the equation below:
  • Y max is total bound counts
  • Ymi 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
  • K d 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 IC 50 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.
  • HTRF 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.
  • Representative K ⁇ or IC 50 values in the recombinant receptor binding assay or recombinant receptor functional assay, respectively, for exemplary compounds of the invention are provided in the table below:
  • 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 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 product can be obtained by the other reaction conditions listed in the scheme below, including first saponifying the ester 1.1 to give the corresponding acid and then reacting it with amide oxime 1.2 in the presence of EDC and HO At followed either by adding T3P to the reaction mixture or by treating the isolated intermediate with TBAF in THF.
  • Other coupling reagents and bases can be used for this transformation.
  • 1.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 1.1 and 1.2 may be employed as single enantiomers or diastereomers to obtain 1.3 enriched in a single enantiomer or diastereomer.
  • Additional compounds in the present invention may be prepared according to
  • Amide oxime 2.3 is then reacted with ester 2.4 in the presence of potassium carbonate to afford product 2.5.
  • Other bases and solvents can be employed in this transformation.
  • product 2.5 can be obtained by reacting the corresponding acid of ester 2.4 (which, if not commercially available, can be prepared by treatement of the ester with sodium hydroxide) with amide oxime 2.3 in the presence of EDC and HO At followed either by adding T3P to the reaction mixture or by treating the isolated intermediate with TBAF in THF.
  • Other coupling reagents and bases can be used for this transformation. If 2.5 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 2.3 and 2.4 may be employed as single enantiomers or diastereomers to obtain 2.5 enriched in a single enantiomer or
  • compounds in the present invention may be prepared according to Scheme 3, in which acid 3.1 is reacted with acyl hydrazine 3.2 in the presence of EDC and HOBt.
  • Other coupling reagents and conditions can be employed to effect this transformation.
  • Other dehydrating reagents can be used for these transformations.
  • aryl halide (or boronic acid or boronic acid derivative) 5.1 is reacted with 1,3-azole (or 2-halo-l,3-azole) 5.2 under palladium-catalyzed conditions to afford product 5.3.
  • catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this reaction.
  • 5.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 5.1 and 5.2 may be employed as single enantiomers or diastereomers to obtain 5.3 enriched in a single enantiomer or diastereomer.
  • Additional compounds in the present invention may be prepared according to Scheme 6.
  • the sequence begins with coupling acid 3.1 with amine 6.1 in the presence of EDC and HO At to afford amide 6.2.
  • Other coupling reagents and conditions can be employed to effect this transformation.
  • Amide 6.2 is then treated with Dess-Martin periodinane to afford the intermediate aldehyde that is then treated with triphenylphosphine and iodine to afford oxazole 6.3.
  • oxazole 6.3 can be prepared by treatment of amide 6.2 with Deoxo-Fluor followed by BrCCl 3 and DBU.
  • oxazole 6.3 contains an ester at position W, it can then be hydro lyzed with NaOH and the resulting acid coupled with amine 6.4 in the presence of BOP and HOBt to afford product 6.5.
  • Other coupling reagents and conditions can be employed to effect this transformation.
  • ester 1.1 is first saponified with NaOH to afford acid 3.1.
  • Acid 3.1 is then reacted with amine 12.1 in the presence of EDC and HOAt followed by treating the resulting amide with AcOH at elevated temperature to afford product 12.2.
  • Other coupling reagents, bases, and solvents can be employed for step 1 and other acids and solvents can be employed for step 2.
  • the product can be obtained by the other reaction conditions listed in the scheme below, including adding T3P to the step 1 reaction mixture.
  • Additional compounds in the present invention may be prepared according to Scheme 13.
  • the sequence begins with alkylation of phenol 13.1 with benzyl bromide in the presence of sodium hydride to give the corresponding benzyl ether followed by hydrolysis of the methyl ester by treatment with NaOH to afford acid intermediate 13.2.
  • Acid 13.2 is then coupled to aniline 13.3 in the presence of HOAt and EDC to give the intermediate amide, which can then undergo cyclodehydration in the presence of acetic acid at elevated temperature to afford azabenzimidazole 13.4.
  • Intermediates like 1.1 in the present invention may be prepared according to Scheme 15.
  • the sequence begins with coupling of benzyl bromide 15.1 with intermediate 15.2 in the presence of sodium hydride followed by demethylation of the resulting alkylated intermediate by treatment with boron tribromide or HBr in acetic acid to afford intermediate phenol 15.3.
  • Phenol 15.3 is then coupled to aryl halide 15.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 1.1.
  • a variety of different catalysts including other metals such as palladium), ligands, bases, and solvents can be employed in this coupling reaction.
  • 15.3 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried into the coupling with 15.4.
  • 1.1 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 1.1.
  • 15.2 may be employed as a single enantiomer or diastereomer to obtain 15.3 enriched in a single enantiomer or diastereomer.
  • Intermediates like 1.1 in the present invention may also be prepared according to Scheme 16, which begins with coupling of phenol 16.1 with aryl halide 15.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 16.2.
  • biaryl ether 16.2 A variety of different catalysts (including other metals such as palladium), ligands, bases, and solvents can be employed in this coupling reaction.
  • Biaryl ether 16.2 is then treated with NBS and benzoyl peroxide to give benzyl bromide 16.3 that is then coupled to intermediate 16.4 in the presence of sodium hydride to afford intermediate 1.1. If ester 1.1 is a mixture of enantiomers or
  • the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 1.1.
  • 16.4 may be employed as a single enantiomer or diastereomer to obtain 1.1 enriched in a single enantiomer or diastereomer.
  • Intermediates like 17.4 in the present invention may be prepared according to Scheme 17.
  • the sequence begins with coupling of benzyl bromide 17.1 with boronic acid (or boronate ester or boronic acid derivative) 17.2 under palladium-catalyzed conditions to afford intermediate 17.3.
  • boronic acid or boronate ester or boronic acid derivative
  • a variety of different catalysts including other metals such as nickel), ligands, bases, and solvents can be employed in this reaction.
  • Ester 17.3 is then treated with HCl in methanol to afford pyridone intermediate 17.4.
  • Esters 17.3 and 17.4 can each be employed as an intermediate in schemes in the present invention that involve compounds similar to 17.3 and 17.4 (such as intermediate 1.1).
  • Ester 18.7 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 18.7 (such as intermediate 1.1).
  • the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 19.4 or 19.5 (such as 2.4).
  • 19.3 may be employed as a single enantiomer or diastereomer to obtain 19.4 enriched in a single enantiomer or diastereomer.
  • Intermediates like 20.6 in the present invention may be prepared according to Scheme 20.
  • the sequence begins with Michael addition of nitroalkane 20.2 to olefin 20.1 mediated by TBAF to give diester 20.3. This reaction can also be accomplished under acid catalyzed conditions.
  • Treatment of diester 20.3 with zinc and acetic acid gives pyrrolidinone 20.4 that can then be alkylated by treatment with sodium hydride and alkyl (or heteroalkyl or cycloalkyl or heterocycloalkyl) halide (or triflate or tosylate) 20.5 to afford ester 20.6.
  • Esters 20.6 and 20.4 can each be employed as an intermediate in schemes in the present invention that involve compounds similar to 20.6 and 20.4 (such as intermediate 2.4).
  • Interme ates e 21.6 n t e present nvent on may e prepare accor ng to
  • Nitroalkane 21.2 is then treated with Raney Ni in the presence of triethylamine under an atmosphere of hydrogen to effect ring closure and the resulting pyrrolidinone later treated with sodium hydride and alkyl (or heteroalkyl or cycloalkyl or heterocycloalkyl) iodide (or bromide or triflate or tosylate) 21.3 to give pyrrolidinone 21.4.
  • Pyrrolidinone 21.4 can then be treated with LDA and alkyl (or heteroalkyl or cycloalkyl or heterocycloalkyl) bromide (or iodide or trfilate or tosylate) 21.5 to afford pyrrolidinone 21.6.
  • oxazole 21.4 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried into the alkylation with 21.5 or carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 21.5 (such as 5.2).
  • 21.6 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 21.6 (such as 5.2).
  • Intermediates like 22.3 in the present invention may be prepared according to Scheme 22, which begins with coupling benzyl bromide 18.6 with amine 22.1 in the presence of Huenig's base to give benzyl amine 22.2. Benzyl amine 22.2 is then treated with CDI to afford imidazolone 22.3. Imidazolone 22.3 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 22.3 (such as intermediate 1.1).
  • pyrrolidinone 25.3 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 25.3 (such as 2.4).
  • 25.2 may be employed as a single enantiomer or diastereomer to obtain 25.3 enriched in a single enantiomer or diastereomer.
  • pyrrolidinone 26.4 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried forward and employed as an intermediate in schemes in the present invention that involve compounds similar to 26.4 (such as
  • thiadiazole 18.3 contains an isopropyl group at position R 4 , it can be treated with AIBN, NHS, and triphenylphospine at elevated temperature to afford tertiary alcohol 27.4.
  • Thiadiazoles 18.3 or 27.4 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 18.3 or 27.4 (such as intermediate 15.4).
  • Intermediates like 28.5 in the present invention may be prepared according to Scheme 28, which begins with coupling of boronate 28.1 with aryl (or heteroaryl) halide (or triflate) 28.2 under palladium-catalyzed conditions to afford intermediate 28.3.
  • aryl (or heteroaryl) halide (or triflate) 28.2 under palladium-catalyzed conditions to afford intermediate 28.3.
  • catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this reaction.
  • Aniline 28.3 is then treated with sodium nitrite followed by reacting the resulting diazonium species with potassium halide 28.4 to afford aryl halide 28.5.
  • Aryl halide 28.5 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 28.5 (such as intermediate 15.4).
  • Intermediates like 29.2 and 29.3 in the present invention may be prepared according to Scheme 29, which begins with treating isopropyl pyridazine 29.1 with AIBN and NHS at elevated temperature to give tertiary alcohol 29.2. Tertiary alcohol 29.2 can then be treated with DAST to afford alkyl fluoride 29.3.
  • Aryl iodides 29.1, 29.2, or 29.3 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 29.1, 29.2, or 29.3 (such as intermediate 15.4).
  • 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
  • Step B 2-(4-Iodophenyl)-5-isopropyl-l,3,4-thiadiazole
  • N-Methylmorpholine (1.68 mL, 15.3 mmol) was added to a stirring solution of 4- iodobenzohydrazide (1.00 g, 3.82 mmol), 2-methoxy-2-methylpropanoic acid (0.541 g, 4.58 mmol), EDC (1.28 g, 6.68 mmol), and HOAt (0.260 g, 1.91 mmol) in DMF (13.0 mL).
  • the resulting mixture was stirred at ambient temperature for 1 h. Excess water was added and the resulting solids filtered and washed with water. The substrate was dried under high vacuum with heat to give the title compound.
  • LC-MS m/z found 363.1 [M+l] + .
  • Step B 2-(4-Iodophenyl)-5-(2-methoxypropan-2-yl)-l,3,4-thiadiazole
  • Step A A"-Acetyl-4-iodobenzohydrazide
  • Step B 2-(4-Iodophenyl)-5-methyl-l,3,4-thiadiazole
  • Step A N , -(Cyclopropanecarbonyl)-4-iodobenzohydrazide
  • Step B 2-Cyclopropyl-5-(4-iodophenyl)-l,3,4-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. Purification of the crude mixture by silica gel chromatography (100 ⁇ 50% Hexanes/ EtOAc) provided the title compound.
  • Step A 3-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline
  • 4-bromo-3-fluoroaniline 5.00 g, 26.4 mmol
  • dioxane 80 mL
  • 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.30 g, 28.9 mmol)
  • Pd (dppf)Cl 2 (962 mg, 1.32 mmol
  • KOAc 7.70 g, 78.9 mmol
  • Step C 3-(2-Fluoro-4-iodophenyl)-6-isopropylpyridazine
  • Step A 4-(6-Ethylpyridazin-3-yl)aniline
  • Step A 3-Chloro-6-(prop-l-en-2-yl)pyridazine
  • Step C 4-(6-Isopropylpyridazin-3-yl)aniline
  • 3-chloro-6-isopropylpyridazine (10.0 g, 63.9 mmol)
  • 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (16.8 g, 76.7 mmol)
  • Pd(dppf)Cl 2 9.30 g,12.8 mmol) in toluene (100 mL) was added K 3 PO 4 (27.1 g, 0.130 mol) and water (20 mL).
  • the reaction mixture was stirred at 90 °C for 18 h and then concentrated.
  • Step D 3-(4-Iodophenyl)-6-isopropylpyridazine
  • Step A 4-Bromo-N-isobutyrylbenzohydrazide To a solution of 4-bromobenzoic acid (20.1 g, 100 mmol) in DMF (150 mL) was added HOBt (14.9 g, 110 mmol), EDC (21.1 g, 110 mmol) and TEA (20.9 mL, 150 mmol). The mixture was stirred at 25 °C for 0.5 h, and then isobutyrohydrazide (11.22 g, 110 mmol) was added. The mixture was stirred at 25 °C for 14 h, and then diluted with EtOAc and washed with H 2 0 (2x). The organics were dried over Na 2 S0 4 , and concentrated in vacuo. The residue was washed with DCM (3x) and dried to afford the title compound; LC-MS * m/z: 285.0, 287.0
  • Step A 4-tert-butyl 1 -methyl 2-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2- methylsuccinate
  • the concentrate was taken up in dioxane (3.5 mL), and HC1 (3.0 ⁇ , aqueous, 12 M, 0.04 mmol) was added. The resulting mixture was heated at 50 °C in a sealed vial for 2 d. Excess HC1 (aqueous, 12 M) was added and the mixture heated at 80 °C for 2 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by silica gel chromatography (100 ⁇ 85% DCM/ MeOH) gave the racemic title compound.
  • Step A l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide
  • Step B l-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile
  • Step A Methyl 3-((tert-butoxycarbonyl)(cyclopropyl)amino)-2-methylpropanoate
  • Step B 4-ethyl 1 -methyl 2-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)-2- methylsuccinate
  • Step C methyl l-cvclopropyl-3-methyl-5-oxopyrrolidine-3-carboxylate
  • Step A 4-(((tert-butyldimethylsilyl)oxy)methyl)- 1 -methylpyrrolidin-2-one
  • Step B 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(cvclopropylmethyl)- 1 -methylpyrrolidin-2- one
  • Step C 3 -(cvclopropylmethyl)-4-(hvdroxymethyl)- 1 -methylpyrrolidin-2-one
  • Step D methyl 4-(cvclopropylmethyl)-l-methyl-5-oxopyrrolidine-3-carboxylate
  • Step E 4-(cyclopropylmethyl)-l-methyl-5-oxopyrrolidine-3-carboxylic acid
  • Step A Methyl l-cvclopropyl-5-oxopyrrolidine-3-carboxylate
  • Step B l-Cyclopropyl-5-oxopyrrolidine-3-carboxamide
  • Methyl l-cyclopropyl-5-oxopyrrolidine-3-carboxylate (2.00 g, 10.9 mmol) was dissolved in NH 3 /MeOH (saturated, 15 mL), placed into an autoclave, and heated at 100 °C overnight. The mixture was concentrated in vacuo to give the racemic title compound.
  • Step C l-Cyclopropyl-5-oxopyrrolidine-3-carbonitrile
  • Step D 1 -Cyclopropyl-N -hydroxy-5 -oxopyrrolidine-3 -carboximidamide
  • Step E (S)- 1 -Cyclopropyl-N-hydroxy-5 -oxopyrrolidine-3 -carboximidamide
  • Racemic 1 -cyclopropyl-N'-hydroxy-5 -oxopyrrolidine-3 -carboximidamide was resolved on a ChiralPak AD-H column, eluting with supercritical carbon dioxide/methanol (55/45) containing 0.1% diethylamine.
  • First eluting enantiomer (i?)-l-cyclopropyl-N'-hydroxy- 5-oxopyrrolidine-3-carboximidamide.
  • Step A l-Cyclopropyl-4-(hydroxymethyl)pyrrolidin-2-one
  • Step B 4-(((tert-butyldiphenylsilyl)oxy)methyl)- 1 -cyclopropylpyrrolidin-2-one
  • Step C 4-(((tert-butyldiphenylsilyl)oxy)methyl)- 1 -cyclopropyl-3-methylpyrrolidin-2-one
  • Step D l-Cvclopropyl-4-(hvdroxymethyl)-3-methylpyrrolidin-2-one
  • Step E Methyl l-cyclopropyl-4-methyl-5-oxopyrrolidine-3-carboxylate
  • Step F l-Cyclopropyl-4-methyl-5-oxopyrrolidine-3-carboxamide
  • Step G l-Cyclopropyl-4-methyl-5-oxopyrrolidine-3-carbonitrile
  • Step H (Z)- 1 -Cyclopropyl-N -hydroxy-4-methyl-5 -oxopyrrolidine-3 -carboximidamide
  • Step B (E)-3-(2-bromothiazol-4-yl)prop-2-en-l-ol
  • Step C Ethyl 3-(2-bromothiazol-4-yl)pent-4-enoate To a stirred solution of (E)-3-(2-bromothiazol-4-yl)prop-2-en-l-ol (505 mg, 2.29 mmol) in 8 mL of DMF was added triethylorthoacetate (7.44 g, 45.9 mmol) and catalytic propionic acid (0.017 mL, 0.229 mmol). The reaction mixture was heated to 130 °C for 12 h and then cooled to ambient temperature. The mixture was diluted with ethyl acetate and washed with water (3x's) and saturated aqueous sodium chloride (lx).
  • Step E (S or i?)-4-(2-bromothiazol-4-yl)-l-cyclopropylpyrrolidin-2-one
  • Step B ethyl-4-nitro-3-(oxazol-4-yl)butanoate
  • the reaction mixture was quenched with water and diluted with ethyl acetate.
  • the organic layer was washed once each with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated.
  • the crude material was purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.05% NH 4 OH used as a modifier) initially, then grading to 95%
  • the aqueous phase was extracted with CH 2 CI 2 (3x), dried over MgS0 4 , filtered, and
  • Step B 3-Hvdroxy-4- ⁇ r( 6 -2-oxo-4-phenylpyrrolidin-l-yl1methyl
  • Step D 4-[5-(Methoxycarbonyl)-2- ⁇ [(46 -2-oxo-4-phenylpyrrolidin-l- vHmethyllphenoxylbenzoic acid
  • Step E Methyl 4-(r(4 ⁇ -2-oxo-4-phenylpyrrolidin-l-yl1methyl
  • T 3 P 2,4,6-tripropyl- 1,3,5, 2,4,6-trioxatriphosphorinane-2,4,6- trioxide
  • the residue was purified by silica gel chromatography eluting with CH 2 Cl 2 /MeOH (0/100 to 10/90) to afford the coupled intermediate.
  • the intermediate was taken up in 2-MeTHF (10 mL) and n-tetrabutylammonium fluoride (1.95 mL, 1.95 mmol) was added.
  • the reaction mixture was allowed to stir for 4 h.
  • the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated.
  • Step A ( ⁇ -Methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step B (5 M ethyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step C CSVMethyl 3-(4-(5-isopropyl-l,3.4-thiadiazol-2-vnphenoxy -4-((4-methyl-2- oxopyrrolidin- 1 -vDmethvDbenzoate

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Abstract

L'invention concerne des composés hétérocycliques qui sont des antagonistes des récepteurs du CGRP et qui sont utiles pour traiter ou prévenir les maladies dans lesquelles le CGRP est impliqué, notamment la migraine. L'invention concerne également des compositions pharmaceutiques contenant ces composés et l'utilisation desdits composés et compositions pour prévenir ou traiter les maladies dans lesquelles le CGRP est impliqué.
PCT/US2015/026072 2014-04-17 2015-04-16 Antagonistes hétérocycliques du récepteur du cgrp WO2015161014A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021187486A1 (fr) * 2020-03-17 2021-09-23 大日本住友製薬株式会社 Dérivé d'oxadiazole

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US6660753B2 (en) * 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US20050026963A1 (en) * 2001-12-18 2005-02-03 Cosford Nicholas D.P. Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5
US6919363B2 (en) * 2000-03-24 2005-07-19 Euro-Celtique S.A. Aryl substituted pyrazoles, triazoles and tetrazoles, and the use thereof
US20110098302A1 (en) * 2008-02-14 2011-04-28 Amira Pharmaceuticals, Inc. Cyclic diaryl ether compounds as antagonists of prostaglandin d2 receptors

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Publication number Priority date Publication date Assignee Title
US6660753B2 (en) * 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US6919363B2 (en) * 2000-03-24 2005-07-19 Euro-Celtique S.A. Aryl substituted pyrazoles, triazoles and tetrazoles, and the use thereof
US20050026963A1 (en) * 2001-12-18 2005-02-03 Cosford Nicholas D.P. Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5
US20110098302A1 (en) * 2008-02-14 2011-04-28 Amira Pharmaceuticals, Inc. Cyclic diaryl ether compounds as antagonists of prostaglandin d2 receptors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021187486A1 (fr) * 2020-03-17 2021-09-23 大日本住友製薬株式会社 Dérivé d'oxadiazole
CN115515943A (zh) * 2020-03-17 2022-12-23 住友制药株式会社 噁二唑衍生物
US11718592B2 (en) 2020-03-17 2023-08-08 Sumitomo Pharma Co., Ltd. Oxadiazole derivative

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