WO2013138418A2 - Process for making cgrp receptor antagonists - Google Patents

Process for making cgrp receptor antagonists Download PDF

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WO2013138418A2
WO2013138418A2 PCT/US2013/030696 US2013030696W WO2013138418A2 WO 2013138418 A2 WO2013138418 A2 WO 2013138418A2 US 2013030696 W US2013030696 W US 2013030696W WO 2013138418 A2 WO2013138418 A2 WO 2013138418A2
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formula
compound
group
yield
process according
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PCT/US2013/030696
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English (en)
French (fr)
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WO2013138418A3 (en
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Kevin M. Belyk
Edward Cleator
Shen-Chun Kuo
Peter Emmanuel MALIGRES
Bangping Xiang
Nobuyoshi Yasuda
Jianguo Yin
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Merck Sharp & Dohme Corp.
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Priority to KR1020147025146A priority Critical patent/KR102071278B1/ko
Priority to CA2865944A priority patent/CA2865944C/en
Priority to BR112014022542A priority patent/BR112014022542A8/pt
Priority to KR1020217005005A priority patent/KR20210022150A/ko
Priority to AU2013232196A priority patent/AU2013232196C1/en
Priority to KR1020247001330A priority patent/KR20240010553A/ko
Priority to MX2014011000A priority patent/MX346252B/es
Priority to EP13760317.1A priority patent/EP2825044B1/en
Priority to KR1020227041223A priority patent/KR20220164616A/ko
Priority to KR1020217029942A priority patent/KR20210116717A/ko
Priority to US14/384,624 priority patent/US9487523B2/en
Priority to KR1020207001976A priority patent/KR102220242B1/ko
Priority to RU2014141158A priority patent/RU2672056C2/ru
Priority to JP2015500541A priority patent/JP6212534B2/ja
Priority to CN201380013890.3A priority patent/CN104168768B/zh
Publication of WO2013138418A2 publication Critical patent/WO2013138418A2/en
Publication of WO2013138418A3 publication Critical patent/WO2013138418A3/en

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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to a process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine.
  • This class of compounds is described in U.S. Patent Application Nos. 13/293,166 filed November 10, 2011 , 13/293, 177 filed November 10, 2011 and 13/293,186 filed November 10, 2011, and PCT International Application Nos. PCT/US11/60081 filed November 10, 2011 and PCT/US 11/60083 filed November 10, 2011.
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messehger RNA and is widely distributed in the central and peripheral nervous system.
  • CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation.
  • CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively.
  • CGRP-alpha and CGRP-beta display similar biological properties.
  • CGRP When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase.
  • CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
  • CGRPi CGRP2
  • CGRP2 CGRP2
  • Human oc-CGRP-(8-37) a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRP l
  • the linear analogue of CGRP diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP)
  • Cys(ACM)2,7]CGRP diacetoamido methyl cysteine CGRP
  • CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache.
  • CGRP-mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9).
  • the middle meningeal 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, Ann. Neurol., 1988, 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 antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).
  • Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 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 antagonist BIBN4096BS (Doods et al., Br. J.
  • CGRP vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist.
  • CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Austin Bioscience, 2000, 245-247).
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin Amylin
  • Adrenomedullin CGRP-Related Peptide
  • 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., Ann. Neurol. 2000, 47, 614-624).
  • a CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sens
  • CGRP antagonists make them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • disorders include migraine and cluster headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175);
  • non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al, Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al., Crit.
  • Urology 2001, 166, 1720-1723
  • allergic dermatitis Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143
  • psoriasis encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,
  • the present invention describes a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists.
  • the invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine, utilizing a highly effective spiroacid synthesis.
  • the invention encompasses a process for making a compound of Formula I
  • Y is CH or N
  • R1 is selected from the group consisting of Ci ⁇ alkyl, cyclopropylmethyl, cyclobutylmethyl and
  • R2 is hydrogen, methyl, F, CI, or Br; comprising initiating the reaction of a compound of Formula F
  • E 1 is selected from the group consisting of halogen, -C(0)-0-R", -CN, -CONRR', -NRR', -CI3 ⁇ 4-
  • R and R' are independently selected from the group consisting of hydrogen, C ⁇ .galkyl, aryl, heteroaryl or benzyl and R" is hydrogen or a carbon containing substituent capable of being solubilized to a carboxylic acid, is a functional group that has leaving ability
  • PG is a nitrogen protecting group, in an organic phase, in the presence of a mono- or bis-quaternary cinchona alkaloid salt and an inorganic base in an aqueous phase, to form a biphasic medium comprising the aqueous phase and organic phase, to make a compound of Formula G
  • Rl is Ci__j.alkyl, optionally substituted with 1 to 3 F or hydroxy, or both.
  • Rl is selected from the group consisting of isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3- trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.
  • Rl is 2,2,2-trifluoroethyl.
  • the cinchona alkaloid salts of the invention encompass all stereoisomers, including cinchonine, cinchonidine, quinine, quinidine, dihydrocinchonine, dihydrocinchonidine, dihydroquinidine, and dihydroquinine.
  • R A means pure ethyl, pure vinyl or a mixture of ethyl and vinyl.
  • the cinchona alkaloid salts function as phase transfer catalysts in the asymmetric synthesis described herein. See Takashi Ooi and Keiji Maruoka, Recent Advances in Asymmetric Phase-Transfer Catalysis, Angew. Chem. Int. Ed. 2007, 46, 4222-4266.
  • the invention encompasses the process described herein wherein the cinchona alkaloid salt is bis-quaternary and has the chemical structure of Formula II:
  • RB is selected from the group consisting of hydrogen and methoxy
  • RC and R ⁇ are each independently selected from the group consisting of C ⁇ alkyl, C2_ 6alkenyl, C2-6 a lkynyl, C3_6cycloalkyl, aryl, heteroaryl, -Cj ⁇ alkyl-aryl and -Ci ⁇ alkyl- heteroaryl, wherein Cj.galkyl, C2_6alkenyl, C2-6alkynyl, C3_6cycloalkyl, aryl, heteroaryl and the aryl and heteroaryl portions of -Ci_4alkyl-aryl and -C ⁇ alkyl-heteroaryl are optionally substituted with one to five substituents independently selected from RF,
  • R E is selected from the group consisting of hydrogen, C(0)R, C(0)OR, CONRR', and Ci.galkyl,
  • RF is selected from the group consisting of Ci-4alkyl, aryl, Ci_4alkoxy, hydroxy, CN, CO2R, CONRR', SR, S0 2 R, SO3R, PR3, PO(OR) 2 , PO(OR) (NRR), PO(NRR') 2 , P(OR) 2 ,
  • each R, R' and R" is independently selected from the group consisting of hydrogen, Cj.galkyl, hydroxyl, C ⁇ .galkoxy, aryl, heteroaryl, -CH 2 -aryl, -CH 2 -heteroaryl, and each Xi and X 2 are independently anions selected from the group consisting of halide, OH, HSO4, SO4, BF4, SbFg, carboxylate, carbonate, hydrogencarbonate, NO3, sulfonate, hexafluorophosphate, phosphate, hydrogen phosphate and perchlorate.
  • E ⁇ is -NRR'
  • the amino group can be converted into halogens via Sandmeyer reaction or directly converted into either carboxylic acid or ester via diazonium in the transition metal mediated carbonylation.
  • E ⁇ is -CH2-OR
  • carboxylic acid or ester can be introduced by oxidation.
  • E 1 is OR
  • OR group can be converted into halogens or O-sulfonates (such as tosylate, triflurate) and then further converted into either carboxylic acid or ester with transition metal mediated carbonylation.
  • E ⁇ is halogen.
  • the invention encompasses the process described herein wherein carbonylation of the compound of Formula G is via palladium catalyzed reaction with carbon monoxide whereby the compound of Formula G is reacted with carbon monoxide in the presence of a palladium catalyst, a first base and a ligand to yield a compound of Formula H.
  • the ligand is a phosphine ligand.
  • the ligand is selected from DCPE and DCPP.
  • the base is for example potassium carbonate.
  • the invention encompasses the process described herein wherein carbonylation of the compound of Formula G wherein E* is halogen is via Grignard reagent formation whereby the compound of Formula G is reacted with magnesium or lithium followed by CO2 and an acid to yield a compound of Formula H.
  • a "carbon containing substituent capable of being solubilized to a carboxylic acid” is for example methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, allyl, hexyl, octyl, cyclohexyl, benzyl and phenyl.
  • nitrogen protecting group means a substituent that protects a nitrogen atom in a reaction from a reagent or chemical environment.
  • Nitrogen protecting groups are well known in the art and include for example, t-butyl, vinyl, phenyl, benzyl, >-methoxybenzyl, 3,4- dimethoxybenzyl, -nitrobenzyl, benzhydryl, trityl, trialkylsilyl, methoxymethyl ether, (2,2,2- trichloroethoxy)methyl and 2-(trimethylsilyl)ethoxy)methyl.
  • Methods for deprotecting a nitrogen are also well within the skill of one having ordinary skill in the art.
  • the invention encompasses the process described herein wherein PG is selected from the group consisting of: Ci _g alkyl, vinyl, C(0)-0-L, C(0)-L, aryl, hetroaryl, benzyl, benzhydryl, trityl, anthranyl and Ci _6alkoxymethyl, wherein aryl, heteroaryl, benzyl, benzyhydryl and trityl optionally are substituted with 1 to 3 substituents independently selected from methoxy and nitro, Ci _6alkoxymethyl is optionally substituted with trimethylsilyl and L is Ci .galkyl, aryl or benzyl.
  • the term "functional group that has leaving ability” means an atom or atom group that leaves from a substrate in a substitution or elimination reaction, that is a leaving group, and includes for example halogen and sulfonate.
  • the invention encompasses the process described herein wherein is selected from the group consisting of: halogen, OMs,
  • the invention encompasses the process described herein wherein the organic phase is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, ethyl ether, isopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, isopropyl acetate, ethyl acetate, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, acetonitrile, acetone, methyl ethyl ketone, butanol and amyl alcohol.
  • the organic phase is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, ethyl ether, isopropyl ether, tetrahydrofuran, 2-
  • the invention encompasses the process described herein wherein the inorganic base is selected from the group consisting of: sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium hydroxide, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium phosphate and potassium phosphate.
  • the invention encompasses the process described herein wherein the organic phase is toluene and the inorganic base is sodium hydroxide.
  • the invention encompasses the process described herein wherein the compound of Formula C is isolated as a salt selected from HC1, H2SO4, Na, K, Li, H3PO4 and HBF4.
  • Conditions for an amide bond formation between an acid and amine include for example reacting the compounds of Formulas B (after salt break) and C with an amide coupling reagent and optionally an additive and a base in a non-reactive solvent.
  • Amide coupling reagents include for example EDC, CDI, SOCI2, (COCl)2, DCC, T 3 P, DPPA, and the like.
  • Additives include HOBT, HOAt, HATU, HOPO, and HOSu, pyridine, pyridine derivatives and the like.
  • Appropriate bases include amines having formula N(R X )3 9 wherein each R x is independently hydrogen, alkyl and aryl, inorganic bases, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, lithium carbonate, cesium carbonate, potassium phosphate, and the like.
  • Conditions for an amide bond formation between an acid or ester and amine also include utilizing activated acyl via mixed carbonic anhydride intemediates. Examples include pivaloyl chloride, alkyl chloroformate plus a base.
  • Further examples of peptide coupling reagents in organic synthesis are well known in the art and described for example in Han, et al., Tetrahedron 60 (2004) 2447-2467.
  • the invention encompasses the process described herein wherein, in the bis-quaternary cinchona alkaloid salt of Formula II, RC and R ⁇ are
  • the bis-quaternary cinchona alkaloid salt of Formula ⁇ , RB is methoxy.
  • RF is selected from the group consisting of halogen and methoxy.
  • the invention encompasses the process described herein wherein the bis-quaternary cinchona alkaloid salt is of the formula In another embodiment, the invention encompasses the process described herein further comprising making a compound of Formula F by reacting a compound of Formula J
  • R4-Z1 or a salt thereof wherein and are independently functional groups that have leaving ability, with R4-Z1 or a salt thereof and HC(0)-N(R5)2 wherein R4 is C ⁇ alkyl, is magnesium halide or lithium and each R ⁇ is independently H or Cj.galkyl, to yield a compound of Formula K
  • Step (a) - coupling the compound of Formula N with a compound of Formula O
  • the invention encompasses the process described herein wherein the compound of Formula N is made by reacting the compound of Formula M with R.6- or a salt thereof and HC(0)-N(R 7 )2 wherein R.6 is C ⁇ galkyl, Z 2 is magnesium halide or lithium and each R 7 is independently H or C ⁇ .galkyl, to yield a compound of Formula N.
  • R ⁇ and R > are independently isopropyl or s-butyl, the optional salt
  • R4-Z! and R ⁇ -Z ⁇ i each instance is lithium and each R ⁇ and R? is methyl.
  • alcohol protecting group means a substituent that protects an alcohol/oxygen atom in a reaction from a reagent or chemical environment.
  • Alcohol protecting groups are well known in the art. Introduction and removal of alcohol protecting groups are well within the skill of the ordinarily skilled artisan. See, e.g., Philip J. Koceienski, Protecting Groups, 3 rd Ed., Thieme, 2005.
  • the invention encompasses the process described herein wherein APG is selected from the group consisting of THP, tetrahydrofuryl, SEM, MOM, BOM, TMS, TES, TBDMS, TIPS and benzyl which is optionally substituted with 1 to 3 substituents independently selected from halogen, methyl, methoxy and nitro.
  • APG is selected from the group consisting of THP, tetrahydrofuryl, SEM, MOM, BOM, TMS, TES, TBDMS, TIPS and benzyl which is optionally substituted with 1 to 3 substituents independently selected from halogen, methyl, methoxy and nitro.
  • reducing agent means an agent capable of delivering hydrogen and are well know to one having ordinary skill in the art.
  • the invention encompasses the process described herein wherein the first reducing agent and second reducing agent are independently selected from the group consisting of 3 ⁇ 4, HC0 2 H, HCO 2 NH4, NaBH4, L1BH4 and L1AIH4.
  • the invention encompasses the process described herein wherein the second base is selected from the group consisting of: DBU, N,N- Diisopropylethylamine, TEA, morpholine and N-methylmorpholine.
  • the invention encompasses the process described herein wherein the second base is an inorganic base.
  • the replacement of the alcohol with the appropriate leaving group can be accomplished by techniques well known to those skilled in the art.
  • the alcohol can be replaced with chloride by reaction with thionyl chloride.
  • activating agent means an agent capable of replacing the alcohol with a leaving group for example mesyl chloride, tosyl chloride, (PhO)2POCl, oxalyl chloride, SOCI2 and phosgene.
  • the invention encompasses a compound selected from the following group:
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • C1 -6 alkyl (or “C1-C6 alkyl”) refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl.
  • Ci-4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • Ci-3 alkyl refers to n-propyl, isopropyl, ethyl and methyl.
  • acyl means -C(0)-alkyl where alkyl is as defined above.
  • alkoxy means -O-alkyl where alkyl is as defined above.
  • alkenyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and at least one carbon-carbon double bond, and otherwise carbon-carbon single bonds.
  • Alkenyl includes for example ethenyl, 1-methylethynyl, 2-propenenyl, 2-butenyl, 1,4-pentadienyl and the like.
  • alkynyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and at least one carbon-carbon triple bond, and otherwise carbon-carbon double or single bonds.
  • Alkynyl includes for example 2-propynyl, 1-butynyl, 3-hexen-5-ynyl and the like.
  • cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C3_6 cycloalkyl (or “C3-C6 cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and "C3.5
  • cycloalkyl refers to cyclopropyl, cyclobutyl, and cyclopentyl.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • aryl refers to phenyl, naphthyl, and anthranyl.
  • heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or (ii) is a heterobicyclic ring selected from indolyl, quinolinyl, isoquinolinyl, and quinoxalinyl.
  • Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.
  • Examples of 4- to 7-membered, saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl.
  • Examples of 4- to 7-membered, unsaturated heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).
  • any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
  • a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms.
  • an aryl or heteroaryl described as optionally substituted with "from 1 to 4 substituents” is intended to include as aspects thereof, an aryl or heteroaryl substituted with 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent.
  • substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.
  • the compounds of the invention contain chiral centers and, as a result of the selection of substituents and substituent patterns, can contain additional chiral centers, and thus can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.
  • tautomers e.g., keto-enol tautomers
  • substituents and substituent patterns provide for the existence of tautomers (e.g., keto-enol tautomers) in the compounds of the invention
  • all tautomeric forms of these compounds are within the scope of the present invention.
  • Compounds of the present invention having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present.
  • Boc fert-butoxycarbonyl
  • BOP (benzotriazole-l-yloxy)-tris(dimethylamino)phosphonium
  • CDI l,l'-carbonyldiimidazole
  • CPME cyclopentyl methyl ether
  • DCPE l,3-bis(dicyclohexylphosphino)ethane
  • DCPP l,3-bis(dicyclohexylphosphino)propane
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • DPP A diphenylphosphoryl azide
  • EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N'N'-tetramethyluronium HC1
  • LiHMDS lithium bis(trimethylsilyl)amide
  • Ph phenyl
  • TBDMS fert-butyldimethylsilyl
  • TIPS triisopropylsilyl
  • Scheme 1 illustrates a route to 3-aminopiperidinone intermediates of type 1.5 which may be used to prepare compounds of the present invention.
  • Aryl acetone 1.1 can be alkylated using the iodoalanine derivative 1.2 under basic conditions to provide keto ester 1.3.
  • Reductive amination followed by cyclization and epimerization provides primarily cis- substituted lactam 1.4 as a racemic mixture.
  • Chiral resolution using normal-phase liquid chromatography, for example, and removal of the Boc protecting group with HCl in EtOAc furnishes 3-aminopiperidinone 1.5 as a hydrochloride salt.
  • a synthetic route to 3-aminopiperidinone intermediates of type 4.4 is shown in Scheme 4.
  • Aryl acetonitrile 4.1 can be alkylated using the iodoalanine derivative 1.2 under basic conditions to provide cyano ester 4.2.
  • Reductive cyclization using hydrogen and palladium hydroxide on carbon or Raney nickel, epimerization, and chiral resolution affords cis lactam 4.3 as a single enantiomer.
  • N-Alkylation and removal of the Boc protecting group then provides 4.4 as a hydrochloride salt.
  • Scheme 5 illustrates an alternative route to 3-aminopiperidinone intermediates of type 4.4.
  • the arylacetonitrile 5.1 may be condensed with acrylate 5.2 at elevated temperature to give the 4-cyanobutanoate ester 5.3.
  • Hydrogenation of nitrile 5.3 using Raney nickel catalyst and an ethanolic solution of ammonia affords the corresponding amine product, which typically cyclizes in situ to provide piperidinone 5.4.
  • N-Alkylation of lactam 5.4 may be accomplished by a variety of methods known to those skilled in the art of organic synthesis, the exact choice of conditions being influenced by the nature of the alkylating agent, RlX.
  • Electrophilic azidation of the resulting substituted lactam 5.5 can be accomplished using similar methodology to that described by Evans and coworkers (Evans et al. (1990) J. Am. Chem. Soc. 112, 4011-4030) to provide the azide 5.6 as a mixture of diastereoisomers, which can be separated by
  • pyridin-2(lH)-one 3.1 may be converted to the N-substituted pyridinone 6.1 by treatment with a suitable electrophile (RlX) under basic conditions.
  • Pyridinone 6.1 can then be subjected to Suzuki-Miyaura coupling with the boronic acid 6.2, and the resulting 5- arylpyridinone 6.3 may be hydrogenated using, for example, platinum(IV) oxide catalyst to afford the corresponding 5-arylpiperidinone 6.4, which is usually obtained as predominantly the cis isomer.
  • piperidinone 6.4 may be achieved using analogous methodology to that described in Scheme 5. Specifically, electrophilic azidation followed by one-pot reduction and Boc protection leads to carbamate 6.6, and the desired enantiomer may be obtained using chiral chromatography.
  • the desired diastereomer of azide 6.5 may be isolated as a racemic mixture of the (3S,5S,6R)- and (3 ?,5i?,65)-isomers following silica gel chromatography of the crude product, and this mixture may be elaborated as outlined in Scheme 6. In other cases, it may be advantageous to take a mixture of diastereomers of azide 6.5 forward to the corresponding carbamate 6.6.
  • the mixture of carbamate 6.6 diastereomers may be epimerized under basic conditions, such as potassium carbonate in EtOH, to afford a mixture that is significantly enriched in the desired (3S,5S,6R)- and (3R,5R,6S)-isomers, further purification may be employed to obtain the enantiomer of interest as outlined herein.
  • Useful derivatives of the intermediates described herein may be prepared using well-precedented methodology.
  • One such example is illustrated in Scheme 10, in which the azaoxindole intermediate 7.4 is converted to the corresponding nitrile derivative 10.2, which may be used to prepare compounds of the present invention.
  • Bromination of 7.4 with N- bromosuccinimide in boron trifluoride dihydrate provides the bromo derivative 10.1, which may be converted to the desired nitrile 10.2 using zinc cyanide and a palladium catalyst as shown.
  • Useful derivatives of the intermediates described herein may be prepared using well-precedented methodology.
  • One such example is illustrated in Scheme 14, in which the azaoxindole intermediate 11.17 is converted to the corresponding nitrile derivative 14.2, which may be used to prepare compounds of the present invention.
  • Treatment of 11.17 with bromine in acetic acid provides the bromo derivative 14.1, which may be converted to the desired nitrile 14.2 using zinc cyanide and a palladium catalyst as shown.
  • Scheme 15 illustrates conditions that can be used for the coupling of 3- aminopiperidinone intermediates, such as 15.1, and carboxylic acid intermediate 15.2, to produce, in this instance, amides 15.3. These standard coupling conditions are representative of the methods used to prepare the compounds of the present invention.
  • the process of the instant invention utilizes a transaminase induced dynamic kinetic resolution providing high diastereoselectivity at positions C5 and C6. N-mono-trifluoroethylation was discovered and developed. Cis and trans isomer at the alpha position of the amine was successfully controlled by crystallization in the presence of arylaldehyde derivatives. Overall, synthetic steps are shorter, practical and efficient and yield is dramatically improved.
  • the compound 6 is a mixture of two pair of diastereomers 6-1 and 6-2, partially separable by flash chromatography on silica gel with ethyl acetate and heptane as a eluant (1: 10).
  • the phases were separated, the organic layers were combined and washed with DI water (0.5 L).
  • the HPLC based assay yield in the organic layer was 8 (114.6 g) with >60:1 dr at the positions C5 and C6.
  • the ratio of stereoisomers at position C2 was ⁇ 1:1.
  • the extract was concentrated and dissolved in CH 2 C1 2 .
  • the organic solution was washed with water then saturated aqueous NaCl, concentrated and crystallized from MTBE/rc-hexane (2:3).
  • the crystal was filtered at room temperature and washed with MTBE/n-hexane (2:3) and dried to afford a cis and trans mixture ( ⁇ 1 :1.2) of the lactam 8 (99.6 g, 80.0 %) as crystals.
  • the phases were separated.
  • the aqueous phase was extracted with heptane (4 L).
  • the combined organic phase was washed with water (2 L).
  • the solution was concentrated to a volume of about 1 L under vacuum between 25 and 50 °C.
  • the crude material was passed through a short silica gel plug with heptane/ethyl acetate.
  • the resulting solution was concentrated under vacuum until distillation stopped at a temperature below 50 °C, dissolved in IPAc (2 L) and used for the next processing step.
  • the assay yield of 9 for both cis and trans isomers was 85% in the ratio of ⁇ 8 to 1.
  • the aqueous layer was separated and extracted with toluene (20 mL).
  • the combined organic layer contained 87% of 9, 6% of 10 and 6% of 8 by HPLC and yield for the desired product 9 was 87%.
  • the organic layer was then stirred with 3N HC1 solution (80 ml) and tetrabutylammoniium bromide (0.8 g) for about 3 h until HPLC analysis indicated selective removal of the Boc group in the unreacted 8 was completed.
  • the aqueous layer was removed.
  • the organic layer containing 9 and 10 was then concentrated under vacuum at 60 °C to remove most of solvent. The residue was dissolved in MTBE (60 mL), and 5N HC1 solution (65 mL) was added.
  • the diphasic solution was agitated vigorously at 50 °C for about 5 h until the deprotection of 9 was completed while 10 was mainly intact.
  • heptane (30 mL)
  • the organic layer was separated at 45 °C.
  • the aqueous layer was diluted with water (60 mL) and resulting aqueous and washed with heptane (30 mL) at 45 °C.
  • the aqueous solution was then mixed with MTBE (100 mL) and basified with 10 N NaOH solution until the pH of the mixture was about 10.
  • the organic layer was separated and the aqueous layer was back-extracted with MTBE (60 mL).
  • the combined organic layers were washed with brine (60 mL).
  • the mixture was quenched with 0.2 N HC1 (70 ml), followed by addition of heptane (80 ml).
  • the organic layer was separated and aqueous layer extracted with heptane (30 ml).
  • the combined organic layers were washed with 15%) aquoeus citric acid (50 mL) and 5%> aqueous NaHC0 3 (50 mL).
  • the solution was concentrated under vacuum at 40 °C and the resulting oil was dissolved in iPAc (30 mL). The solution was used directly in the next step without further purification.
  • iPAc solution of 22 (529 g assayed, 1.2 mol), obtained from previous step, was diluted to 6 L with iPAc, /j-toluenesulfonic acid monohydride (343 g, 1.8 mol) was added and the solution was heated to 55 °C. After 4 h, the reaction completed (>99% conversion).
  • Aqueous K 2 C0 3 (530 g in 3 L of water) was charged into the solution after cooled to 15-25 °C. The aqueous layer was separated and was back-extracted with iPAc (2 L). The iPAc solutions were combined and the total volume was adjudted to 10 L by adding iPAc. The solution was heated to 50-60 °C.
  • N-acetyl L-phenylalanine was added and the solution was agitated for 15 min or until solids precipitated out.
  • the remaining N-acetyl L-phenylalanine (total 250 g, 1.2 mol) was charged slowly and 2-hydroxy-5-nitrobenzaldehyde (2 g) was charged.
  • the suspension was agitated for 12 h at 20 °C and then cooled to 0 °C for 3 h.
  • the suspension was filtrated, washed with iPAc three times and dried to give 23 (583g, 89% yield) as crystals.
  • a thick salt suspension was agitated at 55-60 °C for another 18 h and then was allowed to cool to ambient temperature.
  • the salt was filtered and washed with isopropyl acetate. After drying at 60 °C in a vacuum oven with nitrogen purge for 8 hours, 25 (2.97 g, 91.4%) was obtained as crystals.
  • the reaction was agitated for 1 hour at -55 to -45 and then quenched by adding AcOH (25.7 mL, 445 mmol) and then water (150 mL). After warmed to room temperature, the aqueous layer was seperated. The aqueous solution was extracted with MTBE (200 mL x 1) and the combined organic layers were washed with brine (100 mL x 1). The organic layer was concentrated at 25-35 °C. The residue was flashed with heptane (100 mL x 1) and concentrated to dryness and give 30 (87.94 g, 90.2 wt%, 98% yield, and >99% HPLC purity) as an oil. !
  • the hydroxy ketone 30 (7.69 g, 35.2 mmol) and 95% H 2 S0 4 (26.2 mL, 492.8 mmol) were pumped at 2.3 and 9.2 mL/min respectively into the flow reactor.
  • the temperature on mixing was controlled at 22-25 °C by placing the reactor in a water bath (21 °C).
  • the effluent was quenched into a a mixture of cold water ( 106 g) and heptane/DPAc ( 1 : 1 , 92 mL) in a j acketed reactor cooled at 0 °C; the internal temperature of the quench solution was ⁇ 7 °C during the reaction.
  • the layers in the quench reactor were separated and the organic layer was washed with 10% NaH 2 P0 4 /Na 2 HP0 4 (1 : 1, 50 mL). The pH of the final wash was 5-6. Solka flock (3.85 g, 50 wt%) was added to the organic solution. The resulting slurry was concentrated and solvent- switched to heptanes at 25-30 °C. The mixture was filtered, rinsed with heptanes (50 mL x 1). The combined filtrates were concentrated under vacuum to give 31 as an light yellow oil (6.86 g, 90 wt%, 87% yield), which solidified in a freezer.
  • Salt 39 (0.25 g, 0.58 mmol) was partitioned between IPAC (2.5 mL) and 5 wt% aqueous solution of K 3 P0 4 (2.5 mL), and washed twice with 5 wt% aqueous K 3 P0 4 . The organic layer was washed with brine, dried over Na 2 S0 4 and concentrated to give a crude 40. Crude 40 was dissolved in MeCN (1.75 mL) and H 2 0 (1.0 mL). To this was added acid 14 (0.17 g, 0.53 mmol), HOBT (0.11 g, 0.70 mmol) and EDC HC1 (0.17 g, 0.87 mmol).
  • the heterogeneous mixture was aged at 20-25°C for 16 h.
  • the homogeneous reaction was partitioned between IPAC and saturated aqueous NaHC0 3 , and washed twice with saturated aqueous NaHC0 3 .
  • the organic layer was washed with 15 wt% aqueous citric acid solution, saturated aqueous NaHC0 3 and brine.
  • the organic layer was dried over Na 2 S0 4 and concentrated to give product 41 (0.29 g, 89 % yield).
  • Salt 49 (0.60 g, 1.27 mmol) was partitioned in IPAC (6 mL) and a 5 wt% aqueous K3PO4 (6 mL), and washed twice with 5 wt% aqueous K3PO4. The organic layer was washed with brine, dried with Na 2 S0 4 and concentrated to give crude 50. Crude 50 was then dissolved in MeCN (4.2 mL) and H 2 0 (2.4 mL). To this solution was added acid 14 (0.32 g, 1.12 mmol), HOBT (0.22 g, 1.42 mmol) and EDC HCl (0.34 g, 1.77 mmol). The heterogeneous mixture was aged at 20-25 °C for 16 h.
  • the resulting slurry was aged at 22 °C for 1 to 2 h, filtered, rinsed with AcOEt (2 x 24 ml), then hexane (2 x 24 ml). The solid was dried under vacuum to give powder as a mixture of bis-salts (bis-quinidine salt 61 and bis-dihydroquinidine salt). (Total 19.7 g, 94% yield).
  • the authentic sample of 61 was purified by SFC (IC column, 20 x 250 mm, 60% MeOH/C0 2 , 50 mL/min, 100 bar, 35°C, 220 nm, sample concentration: 133 mg/mL in MeOH; desired peak: 3 to 4.5 min).
  • the solution was kept under CO (100 psi) at 60 °C for 18 h in the presence of 5 mol% of Pd(dppf)Cl 2 .
  • the solvent was removed and the residue was transferred onto silica gel (60 g) on a filter funnel.
  • the mixture was rinsed with a mixture of 10% ethyl acetate in hexane (400 mL).
  • the resulting solution was concentrated to give crude 64 (29.2 g, 98% LCAP, 84% wt, 100% yield) as an oil, which was used directly in the next step without further purification.
  • the reaction mixture was acidified with 6N HCl solution in IPA (17 mL). The resulting solution was heated at 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with MTBE (100 mL) and 5% brine (50 mL). The organic layer was washed with water (50 mL) and dried over MgS0 4 . The solution was concentrated under vacuum at 50 °C and residue crystallized from hexane (30 mL), to give 56 (3.75 g, 67% from 65) as crystals.
  • the bis-quaternary catalyst is much more active and efficient as compared to the mono-quaternary catalyst for the spirocyclization reaction shown.
  • the bis-quaternary catalysts contained ⁇ 12 to 15% of the double bond saturated compounds hydroquinidine or hydrocinchonine.
  • Tables 2 and 3 show a SAR study of bis-quaternary PTC catalysts for spirocyclization. Both bis-quaternary quinidine and cinchonine catalysts are very efficient (Entries 2 to 5). Bis-quaternary Quinidine catalyst is relatively better than bis-quatnary cinchonine catalyst (Entry 2 and 3). 2-Bromo-5-methoxy-benzyl group is one of the most effective groups for this reaction. Table 2
  • Table 4 shows a study of different functional groups.

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EP2849568A4 (en) * 2012-05-09 2016-04-13 Merck Sharp & Dohme METHOD FOR MANUFACTURING CGRP RECEPTOR ANTAGONISTS
US11400081B2 (en) 2017-05-17 2022-08-02 The University Of Sheffield Compounds
WO2024134683A1 (en) * 2022-12-21 2024-06-27 Msn Laboratories Private Limited, R&D Center Novel process for the preparation of intermediate compounds used in the treatment of migraine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037210A (zh) * 2015-05-27 2015-11-11 江苏大学 一种α，β-脱氢-α-氨基酸的合成方法

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0102616D0 (sv) * 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
ATE520661T1 (de) * 2003-06-27 2011-09-15 Univ Maryland Heterocyclische verbindungen mit quaternärem stickstoff zum nachweis von wässrigen monosacchariden in physiologischen flüssigkeiten
AU2005208834B2 (en) * 2004-01-29 2009-10-08 Merck Sharp & Dohme Corp. CGRP receptor antagonists
US7994325B2 (en) * 2005-03-14 2011-08-09 Merck Sharp & Dohme Corp. CGRP receptor antagonists
CA2650932C (en) * 2006-05-09 2013-01-22 Merck & Co., Inc. Substituted spirocyclic cgrp receptor antagonists
US7951795B2 (en) * 2006-12-08 2011-05-31 Merck Sharp & Dohme Corp. Constrained spirocyclic compounds as CGRP receptor antagonists
US8097750B2 (en) * 2006-12-20 2012-01-17 Brandeis University Cinchona alkaloid-catalyzed asymmetric mannich reactions
AU2008241500A1 (en) * 2007-04-16 2008-10-30 Merck Sharp & Dohme Corp. Aryl heterocyclic CGRP receptor antagonists
WO2008153849A1 (en) * 2007-06-05 2008-12-18 Merck & Co., Inc. Carboxamide heterocyclic cgrp receptor antagonists
JP5233457B2 (ja) * 2007-07-17 2013-07-10 セントラル硝子株式会社 新規な含フッ素ジカルボン酸およびそれを用いた新規な高分子化合物
KR101098335B1 (ko) * 2008-07-18 2011-12-26 성균관대학교산학협력단 신코나 기재 이작용성 유기 촉매 및 이를 이용한 메소-고리산무수물의 비대칭 고리 열림 반응을 통한 키랄성헤미에스터의 제조방법
JP2012511500A (ja) * 2008-08-20 2012-05-24 メルク・シャープ・エンド・ドーム・コーポレイション Ｃｇｒｐ受容体アンタゴニストとしての分岐末端を有する非アミドリンカー
CA2771226A1 (en) * 2008-08-22 2010-02-25 James Madden New bradykinin b1 antagonists
CA2735821A1 (en) * 2008-09-08 2010-03-11 Merck Sharp & Dohme Corp. Monocyclic amide cgrp receptor antagonists
EP2438067B1 (de) * 2009-06-05 2015-08-26 Boehringer Ingelheim International GmbH Spirolactame als cgrp-antagonisten
WO2011005731A2 (en) * 2009-07-08 2011-01-13 Merck Sharp & Dohme Corp. Process for making cgrp receptor antagonist
WO2011014383A1 (en) * 2009-07-27 2011-02-03 Merck Sharp & Dohme Corp. Radiolabeled cgrp antagonists
AU2011326455A1 (en) 2010-11-12 2013-05-23 Merck Sharp & Dohme Corp. Piperidinone carboxamide indane CGRP receptor antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None
See also references of EP2825044A4

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2849568A4 (en) * 2012-05-09 2016-04-13 Merck Sharp & Dohme METHOD FOR MANUFACTURING CGRP RECEPTOR ANTAGONISTS
US20160130273A1 (en) * 2012-05-09 2016-05-12 Merck Sharp & Dohme Corp. Process for Making CGRP Receptor Antagonists
US9850246B2 (en) * 2012-05-09 2017-12-26 Merck Sharp & Dohme Corp. Process for making CGRP receptor antagonists
US10106541B2 (en) 2012-05-09 2018-10-23 Merck Sharp & Dohme Corp. Intermediates for preparing CGRP receptor antagonists
US11400081B2 (en) 2017-05-17 2022-08-02 The University Of Sheffield Compounds
WO2024134683A1 (en) * 2022-12-21 2024-06-27 Msn Laboratories Private Limited, R&D Center Novel process for the preparation of intermediate compounds used in the treatment of migraine

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CA2865944C (en) 2020-12-08
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JP2015516946A (ja) 2015-06-18
CN104168768B (zh) 2017-03-01
RU2672056C2 (ru) 2018-11-09
KR20210022150A (ko) 2021-03-02
CN104168768A (zh) 2014-11-26
JP6743256B2 (ja) 2020-08-19
MX2014011000A (es) 2014-10-13
EP2825044A4 (en) 2015-12-02
JP2019206586A (ja) 2019-12-05
RU2014141158A (ru) 2016-05-10
EP2825044A2 (en) 2015-01-21
MX346252B (es) 2017-03-10
WO2013138418A3 (en) 2014-05-30
KR20240010553A (ko) 2024-01-23
EP2825044B1 (en) 2018-08-15
BR112014022542A8 (pt) 2023-04-11
KR20140138705A (ko) 2014-12-04
BR112014022542A2 (pt-PT) 2017-06-20
KR20200011559A (ko) 2020-02-03
KR102071278B1 (ko) 2020-03-03
JP2018030858A (ja) 2018-03-01
KR20220164616A (ko) 2022-12-13
KR20210116717A (ko) 2021-09-27
KR102220242B1 (ko) 2021-02-25
CA2865944A1 (en) 2013-09-19
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