WO2015161016A1 - Antagonistes du récepteur cgrp - Google Patents

Antagonistes du récepteur cgrp Download PDF

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Publication number
WO2015161016A1
WO2015161016A1 PCT/US2015/026076 US2015026076W WO2015161016A1 WO 2015161016 A1 WO2015161016 A1 WO 2015161016A1 US 2015026076 W US2015026076 W US 2015026076W WO 2015161016 A1 WO2015161016 A1 WO 2015161016A1
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Prior art keywords
methyl
phenoxy
pyridazin
halo
methylethyl
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PCT/US2015/026076
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English (en)
Inventor
Brendan CROWLEY
Mark Fraley
Chris BURGEY
Helen Mitchell
Tesfaye Biftu
Anilkumar NAIR
Cheng Wang
Xianhai Huang
Min K. Park
Jiaqiang Cai
Qingsheng LIU
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Merck Sharp & Dohme Corp.
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Publication of WO2015161016A1 publication Critical patent/WO2015161016A1/fr

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    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D409/14—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

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 bicyclic 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.
  • 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 or N
  • 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 1 is CR a ;
  • Z 7 is CR a R e ;
  • 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; is
  • Ci_6 alkyl or C 3 _ 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 _ 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 is hydrogen, halo, cyano or Ci_ 6 alkyl;
  • R 5 is hydrogen, Ci_ 6 alkyl, heterocyclyl or C 3 _ 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 , 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
  • 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 consisting of halo, cyano, oxo, R 5 , OR 5 , C 3 _6 cycloalkyl and heterocyclyl;
  • R is phenyl, heteroaryl, heterocyclyl or C 3 _ 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, 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, cycl
  • 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 and OR 5 ; 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, OR 5 and heterocyclyl;
  • R d is Ci_6 alkyl, C 3 _ 6 cycloalkyl and NR b R c ;
  • R e is selected from the group consisting of hydrogen, Ci_ 6 alkyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; m is an integer from zero to two;
  • G is CR . In a subclass of the invention, G is CH. In another class of the invention, G 1 is N.
  • G is CR . In a subclass of the invention, G is CH. In
  • G is N.
  • G is CR . In another class of the invention, G 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 4 is N.
  • G is CR . In a subclass of the invention, G 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 2 is CR 6 R 7 . In another class of the invention, A 2 is
  • A is NR .
  • a 3 is CR 6 R 7 . In a subclass of the invention, A 3 is CH 2 .
  • 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 CH.
  • Z 7 is CH.
  • W is:
  • Ci_6 alkyl which is optionally substituted with one to four substituents
  • 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 .
  • R 1 is hydrogen
  • R is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci_ 6 alkyl, heterocyclyl and C 3 _6 cycloalkyl.
  • R 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.
  • R e is Ci_ 6 alkyl.
  • Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 53, 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,
  • 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.
  • any variable e.g. R4, 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.
  • C 0 ne to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that C 0 ne to four a lkyl 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
  • 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.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the 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 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 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 -HTi B/ I D 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
  • 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-HTI B/ I D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.
  • an anti-migraine agent such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTI B/ I D agonist, in particular, sumatriptan, naratriptan, 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.
  • 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.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions and the like, containing the compounds of the present invention are employed.
  • 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 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. 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 x 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 AJ001014 was subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment.
  • 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. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Stable cell line generation was accomplished by co-transfecting 10 ⁇ g of DNA with 30 ⁇ g Lipofectamine 2000 (Invitrogen) in 75 cm flasks. CL receptor and RAMPl expression constructs were co-transfected in equal amounts.
  • FBS fetal bovine serum
  • 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/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. For 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
  • 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 & 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 IC 50 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 known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • Amine 1.4 can then be coupled to acid 1.5 in the presence of EDC and HO At (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with acetic acid at elevated temperature to afford quinazoline 1.6.
  • Other acids and dehydrating reagents may be used in the this last transformation.
  • 1.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 1.4 and 1.5 may be employed as single enantiomers or diastereomers to obtain 1.6 enriched in a single enantiomer or diastereomer.
  • Additional compounds in the present invention may be prepared according to Scheme 2. This sequence starts with reaction of aniline 1.2 with acid 2.1 in the presence of EDC and HOAt (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with sulfuric acid to afford quinolone 2.2. Other acids may be used in the this reaction. Treatment of quinolone 2.2 with phosphorous(V) oxychloride then gives chloropyridine 2.3.
  • Chloropyridine 2.3 can then be reacted with boronate (or boronic acid or other boronic acid derivative) 2.4 under palladium-catalyzed conditions to afford quinoline 2.5 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen).
  • boronate or boronic acid or other boronic acid derivative
  • a variety of different catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this coupling reaction.
  • 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 diastereomer.
  • compounds in the present invention may be prepared according to Scheme 3.
  • the sequence begins with treatment of acid 3.1 with DPPA in the presence of triethylamine to afford the corresponding aniline, which is subsequently reacted with acetyl chloride to give aryl acetamide 3.2.
  • Aryl acetamide 3.2 can then be nitrated by treatment with nitric acid in the presence of sulfuric acid followed by deacetylation of the resulant nitroaryl intermediate by treatment with sodium hydroxide to afford aniline 3.3.
  • Aniline 3.3 can then be reduced with palladium on carbon under an atmosphere of hydrogen to give dianiline 3.4.
  • Other reducing reagents can be employed in this reaction.
  • Dianiline 3.4 can then be reacted with bromoketone 3.5 in the presence of potassium carbonate to afford quinoxaline 3.6.
  • Other bases can be used in this reaction.
  • 3.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 3.4 and 3.5 may be employed as single enantiomers or diastereomers to obtain 3.6 enriched in a single enantiomer or diastereomer.
  • Heteroaryl triflate 4.4 is then coupled to boronate (or boronic acid or other boronic acid derivative) 4.5 under palladium- catalyzed conditions to afford isoquinoline 4.6 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen).
  • catalysts including other metals such as nickel
  • 4.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 4.4 and 4.5 may be employed as single enantiomers or diastereomers to obtain 4.6 enriched in a single enantiomer or diastereomer.
  • Phenol 5.3 is then coupled to aryl halide 5.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 5.5.
  • Suitable ligand can be employed in this coupling reaction. Saponification of ester 5.5 by treatement with NaOH then gives acid 1.1. If 5.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried into the coupling with 5.4.
  • 5.5 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried forward.
  • 5.2 may be employed as a single enantiomer or diastereomer to obtain 5.3 enriched in a single enantiomer or diastereomer.
  • 5.2 may be employed as a single enantiomer or diastereomer to obtain 6.3
  • Intermediates like 7.4 in the present invention may be prepared according to Scheme 7.
  • the sequence begins with coupling of acid 7.1 with acyl hydrazide 7.2 in the presence of EDC and HO At to give diacyl hydrazide 7.3.
  • Other coupling reagents, bases, and solvents can be employed for this step.
  • Diacyl hydrazide 7.3 is then treated with Lawesson's reagent to give thiadiazole 7.4.
  • Thiadiazole 7.4 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 7.4 (such as intermediate 5.4).
  • Scheme 8 which begins with coupling of boronate 8.1 with aryl (or heteroaryl) halide (or triflate) 8.2 under palladium-catalyzed conditions to afford intermediate 8.3.
  • aryl (or heteroaryl) halide (or triflate) 8.2 under palladium-catalyzed conditions to afford intermediate 8.3.
  • catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this reaction.
  • Aniline 8.3 is then treated with sodium nitrite followed by reacting the resulting diazonium species with potassium halide 8.4 to afford aryl halide 8.5.
  • Aryl halide 8.5 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 8.5 (such as intermediate 5.4).
  • 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
  • Step A A"-Acetyl-4-iodobenzohydrazide
  • Step B 2-(4-Iodophenyl)-5-methyl-l,3,4-thiadiazole
  • Step A 3-Chloro-6-(prop-l-en-2-yl)pyridazine
  • Step C 4-(6-Isopropylpyridazin-3-yl)aniline
  • Step D 3-(4-Iodophenyl)-6-isopropylpyridazine
  • Step A ( ⁇ -Methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step B ( ⁇ -Methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step C CSVMethyl 3-(4-(5-isopropyl-1 .4-t adiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
  • 2-(4-bromophenyl)-5- isopropyl-l,3,4-thiadiazole 774 mg, 2.73 mmol
  • 2,2,6,6-tetramethyl-heptane-3 5-dione (231 mg, 1.25 mmol)
  • CuCl (248 mg, 2.51 mmol
  • CS 2 CO 3 2.23 g, 6.84 mmol
  • Step D CSV3-(4-(5-Isopropyl-l .4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoic acid
  • the reaction mixture was heated at 80 °C under N 2 atmosphere for 16 h.
  • the mixture was cooled to ambient temperature, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3).
  • the combined organic phase was washed with water (30 mL x 2), dried over
  • Step B (S)-3-(4-(5 -Methyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 - yPmethyDbenzoic acid
  • Step C 4-
  • Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxopyridin-l(2H)- yl)methyl)benzoate (101.3 mg, 0.222 mmol) was dissolved in MeOH (1.50 mL)/THF (3.00 mL) at 25 °C. NaOH (0.667 mL, 0.667 mmol) was added and the reaction mixture warmed to 50 °C.
  • Step B 4- ⁇ [(6 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step B methyl 4-methoxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
  • Step C methyl 4-hydroxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
  • the reaction mixture was concentrated, diluted with DCM (100 mL), and washed with saturated aqueous NaHC0 3 (50 mL x 2) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over Na 2 S0 4 , and concentrated to give the racemic title compound as a brown solid.
  • Step E 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid
  • Step A methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate
  • Step 4 (S)-methyl 2-bromo-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
  • Step C (4S)-l -(4-amino-5-bromo-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step D 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step E (4S)-1 -[4-amino-5-(aminomethyl)-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
  • Step F (4,5 or 4i?)-l-cyclopropyl-4-(6-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step B (4S)- 1 -(4-amino-2- (4- [5 -(propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy
  • Step C (4S)-l -(4-amino-5-bromo-2- ⁇ 4-[5-(propan-2-yl)-l,3,4-thiadiazol-2-yllphenoxy
  • Step D 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • reaction mxitue was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over Na 2 S0 4 , concentrated, and purified by column chromatography (Si0 2 , PE:EtOAc, 1 : 1 to 1 :3) to give the title compound as a yellow solid.
  • Step E (461-1 -[4-amino-5-(aminomethyl)-2- (4-[5-(propan-2-yl)- 1, 3,4-thiadiazol-2- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
  • Step F (AS and 4i? -l-cvclopropyl-4-(6-(r(4y)-4-methyl-2-oxopyrrolidin-l-yl1methyl
  • Step A 3-ethoxy-N-(4- ⁇ [(46 -4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step B 6- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step D (46 -4-methyl- 1 - ⁇ (7- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step E (46 -4-methyl-l-[(7-(4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step A fert-butyl (3-[(4-methyl-2-oxopyrrolidin-l-yl) ⁇
  • Step B l-(5-amino-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step C N-(3-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
  • Step D N-(5-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-2-nmO-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
  • reaction mixture was quenched with saturated aqueous NaHC0 3 (til pH ⁇ 7) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na 2 S0 4 and concentrated to give the racemic title compound as a yellow solid.
  • Step F 1 -(4,5-diamino-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step G tert-butyl 4-(6-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-7-(4-[6-(propan-2-yl)pyridazin- 3-yllphenoxy
  • Step H (AS and 4i?)-4-methyl-l- ⁇ [2-(piperidin-4-yl)-7-(4-[6-(propan-2-yl)pyridazin-3- yllphenoxy
  • Step I (46 -4-methyl- 1 - ⁇ (7- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • reaction mixture was stirred at 60 °C for 48 h, then quenched with aqueous NaHC0 3 (10 mL), and extracted with DCM (10 mL x 2).
  • the combined organic phases were concentrated and the residue purified by preparative HPLC (C-18, 95 ⁇ 5% water/ acetonitrile with 0.1% NH 4 OH) to give the racemic title compound as colorless oil.
  • the racemate was resolved by SFC (Chiralpak AD-3, isopropanol:C0 2 (containing 0.05%> DEA), 40:60) to give the title compound as the second eluting peak and as a yellow solid.
  • Step A (4S)- 1 -(5-bromo-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step B 3- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step D 2,2-diethoxy-N-(3 - ( [(45V4-methyl-2-oxopyrrolidin- 1 -yllmethyll -4- (4-[6-(propan-2- yl)pyridazin-3-yllphenoxy
  • Step E (46 -l-[(3-hydroxy-6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • H 2 SO 4 (1 mL) was stirred at room temperature under N 2 atmosphere for 40 h.
  • Step F 7-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step G (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yl "
  • Step H (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step B (S)-methyl 5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)-2-(2-oxoethyl)benzoate
  • Step C 2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-7-(4-(6-isopropylpyridazin-3-yl)phenoxy)-6- (((S)-4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-3 ,4-dihydroisoquinolin- 1 (2H)-one (isomer 1 )

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des composés bicycliques qui sont des antagonistes du récepteur CGRP et sont utiles pour traiter ou prévenir des maladies dans lesquelles le CGRP est impliqué, telles que la migraine. Cette invention concerne également des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés et compositions pour prévenir ou traiter de telles maladies dans lesquelles le CGRP est impliqué.
PCT/US2015/026076 2014-04-17 2015-04-16 Antagonistes du récepteur cgrp WO2015161016A1 (fr)

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US11746103B2 (en) 2020-12-10 2023-09-05 Sumitomo Pharma Oncology, Inc. ALK-5 inhibitors and uses thereof
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11746103B2 (en) 2020-12-10 2023-09-05 Sumitomo Pharma Oncology, Inc. ALK-5 inhibitors and uses thereof
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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