(12) United States Patent
`Chaturvedula et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,384,930 B2
`Jun. 10, 2008
`
`USOO7384930B2
`
`(54) CONSTRAINED COMPOUNDS AS
`CGRP-RECEPTOR ANTAGONSTS
`
`(75) Inventors: Prasad V. Chaturvedula, Cheshire, CT
`(US); Stephen E. Mercer, Middletown,
`CT (US); Haiquan Fang Madison, CT
`s
`s
`s
`
`(US)
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`-
`0
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 247 days.
`
`(*) Notice:
`
`(21) Appl. No.: 11/247,697
`
`(22) Filed:
`
`Oct. 11, 2005
`9
`
`(65)
`
`O
`O
`Prior Publication Data
`US 2006/OO94707 A1
`May 4, 2006
`
`(56)
`
`Related U.S. Application Data
`(60) Provisional application No. 60/624,655, filed on Nov.
`3, 2004, provisional application No. 60/678,099, filed
`on May 5, 2005.
`(51) Int. Cl
`(2006.01)
`CO7D 487/04
`(2006.01)
`CO7D 40/4
`(2006.01)
`C07D 519/00
`(2006.01)
`A6IP 25/06
`(2006.01)
`A6 IK3I/55
`(52) U.S. Cl. .................................. 514/212.06; 540/521
`(58) Field of Classification Search ................ 540/521;
`514/212.06
`See application file for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`6,313,097 B1
`1 1/2001 Eberlein et al.
`6,344,449 B1
`2/2002 Rudolf et al.
`6,521,609 B1
`2/2003 Doods et al.
`6,552,043 B1
`4/2003 Patchett et al.
`2001/0036946 A1
`11/2001 Rudolf et al.
`2003. O1394.17 A1
`7/2003 Eberlein et al.
`2003. O181462 A1
`9, 2003 Doods et al.
`2003/019 1068 A1 10, 2003 Trunk et al.
`2003/0212057 A1 11, 2003 Rudolf et al.
`2003/0236282 A1 12/2003 Hurnaus et al.
`2004.0002495 A1
`1/2004 Sher et al.
`2004/0014679 A1
`1/2004 Trunk et al.
`2004/OO63735 A1
`4/2004 Chaturvedula et al.
`2004/0076587 A1
`4/2004 Kruss et al.
`2004/O132716 A1
`7/2004 Rudolf et al.
`2004/0192729 A1
`9, 2004 Rudolf et al.
`2004/0204397 A1 10, 2004 Chaturvedula et al.
`2004/0214819 A1 10, 2004 Rudolf et al.
`2004/0229861 A1 11/2004 Burgey et al.
`2004/024881.6 A1 12/2004 Doods et al.
`2005/OO32783 A1
`2/2005 Doods et al.
`2005, OO65094 A1
`3/2005 Davidai
`2005/O153959 A1
`7/2005 Luo et al.
`2005/0215546 A1
`9, 2005 Hurnaus et al.
`
`9/2005 Degnan et al.
`2005/0215576 A1
`2005/0227968 A1 10/2005 Lustenberger et al.
`2005/0233980 A1 10, 2005 Doods et al.
`2005/0234054 A1 10, 2005 Mueller et al.
`2005/0234067 A1 10, 2005 Mueller et al.
`2005/0250763 A1 11/2005 Mueller et al.
`2005/0256098 A1 11/2005 Burgey et al.
`2005/0256099 A1 11/2005 Mueller et al.
`2005/0272955 A1 12/2005 Zimmer et al.
`FOREIGN PATENT DOCUMENTS
`2387 613
`5, 2001
`2 503 455
`4/2005
`1 227 090 A1
`T 2002
`WO 97/09046
`3, 1997
`WO 98.09630
`3, 1998
`WO 98,11128
`3, 1998
`WO 98.56779
`12/1998
`WO 99, 52875
`10, 1999
`WOOOf 18764
`4/2000
`WOOO,55154
`9, 2000
`WO O1/32648
`3, 2001
`WO O1/25228
`4/2001
`WO O1/32649
`5, 2001
`WO O1? 49676
`T 2001
`WO O2/10140
`2, 2002
`WO 03/027252
`4/2003
`WO O3 O70753
`8, 2003
`WO O3,O76432
`9, 2003
`(Continued)
`OTHER PUBLICATIONS
`U.S. Appl. No. 1 1/291,670, filed Dec. 1, 2005, Chaturvedula, et al.
`(Continued)
`Primary Examiner Bruck Kifle
`(74) Attorney, Agent, or Firm—James Epperson
`
`CA
`CA
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`ABSTRACT
`(57)
`The invention encompasses constrained bicyclic and tricy
`clic CGRP-receptor antagonists, methods for identifying
`them, pharmaceutical compositions comprising them, and
`methods for their use in therapy for treatment of migraine
`and other headaches, neurogenic vasodilation, neurogenic
`inflammation, thermal injury, circulatory shock, flushing
`associated with menopause, airway inflammatory diseases,
`Such as asthma and chronic obstructive pulmonary disease
`(COPD), and other conditions the treatment of which can be
`effected by the antagonism of CGRP-receptors.
`
`3
`R
`R4 Vx1 R4
`/
`W
`
`I
`
`(()n
`
`-N
`R
`
`-YS-R
`X
`
`R5
`
`O
`
`13 Claims, No Drawings
`
`EX2016
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01423
`
`1
`
`

`

`US 7,384,930 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`12/2003
`WO O3/104236
`WO
`1, 2004
`WO WO 2004/002960 A1
`5, 2004
`WO WO 2004/O37810
`9, 2004
`WO WO 2004/0826O2 A2
`9, 2004
`WO WO 2004/082605 A2
`9, 2004
`WO WO 2004/082678 A1
`9, 2004
`WO WO 2004/083.187 A1
`WO WO 2004/087649 A2 10, 2004
`WO WO 2004/091514 A2 10, 2004
`WO WO 2004/092.166 A2 10, 2004
`WO WO 2004/092.168 A1 10, 2004
`WO WO 2005,000807
`1, 2005
`WO WO 2005/OO9962
`2, 2005
`WO WO 2005/O13894
`2, 2005
`WO WO 2005/056550
`6, 2005
`WO WO2005/065779
`7/2005
`WO WO 2005, O723O8
`8, 2005
`WO WO2005/084672
`9, 2005
`WO WO 2005/09288O
`10/2005
`WO WO 2005/095383
`10/2005
`WO WO, 2005/10O343
`10/2005
`WO WO, 2005/10O352
`10/2005
`WO WO, 2005/100360
`10/2005
`WO WO 2005,102322
`11/2005
`WO WO 2005,103037
`11/2005
`WO WO, 2005/121078
`12/2005
`
`OTHER PUBLICATIONS
`Ashina, M., et al., “Evidence for increased plasma levels of
`calcitonin gene-related peptide in migraine outside of attacks'.
`Pain, 2000, 86(1-2):133-138.
`Brain, S.D., et al., "CGRP receptors: a headache to study, but will
`antagonists prove therapeutic in migraine?', TiPS, 2002, 23(2):
`51-53.
`Carlström, A.-S. and Fred, T., Palladium-Catalyzed Synthesis of
`Didehydroamino Acid Derivatives, Synthesis, 1989, 6, 414-418.
`Carlström, A.-S. and Fred, T., “Palladium-Catalyzed Bis-coupling
`of Dihaloaromatics with 2-Amidoacrylates'. J. Org. Chem., 1991,
`56: 1289-1293.
`Chu, D.Q., et al., “The calcitonin gene-related peptide (CGRP)
`antagonist CGRP8-37 blocks vasodilatation in inflamed rat skin:
`involvement of adrenomedullin in addition to CGRP” Neuroscience
`Letters, 2001, 310:169-172.
`De Vries, P. et al., “Pharmacological aspects of experimental
`headache models in relation to acute antimigraine therapy.” Euro
`pean Journal of Pharmacology, 1999, 375: 61-74.
`Doods, H., et al., “Pharmacological profile of BIBN4096BS, the
`first selective Small molecule CGRPantagonist.” British Journal of
`Pharmacology, 2000, 129: 420-423.
`Dygos, J.H., “A Convenient Asymmetric Synthesis of the Unnatural
`Amino Acid 2,6-Dimethyl-L-tyrosine”. Synthesis, 1992, 741-743.
`Edvinsson, L. “Calcitonin Gene-Related Peptide (CGRP) and the
`Pathophysiology of Headache', CNS Drugs, 2001, 15(10):745-753.
`Escott, K.J., et al., “Trigeminal ganglion stimulation increases facial
`skin blood flow in the rat: a major role for calcitonic gene-related
`peptide', Brain Research, 1995, 669: 93-99.
`Escott, K.J., et al., “Effect of a calcitonin gene-related peptide
`antagonist (CGRP8-37) on skin vasodilatation and oedema induced
`by stimulation of the rat Saphenous nerve”. British Journal of
`Pharmacology, 1993, 110, 772-776.
`Evans, B.N. et al., “CGRP-RCP, a Novel Protein Required for
`Signal Transduction at Calcitonin Gene-related Peptide and
`Adrenomedullin Receptors'. J. Biol. Chem., 2000, 275(4): 31438
`3.1443.
`
`Gallai, V., et al. “Vasoactive peptide levels in the plasma of young
`migraine patients with and without aura assessed both interictally
`and ictally”. Cephalalgia, 1995; 15: 384-390.
`Goadsby, P.J., et al., “Vasoactive peptide release in the extracerebral
`circulation of humans during migraine headache'. Annals of Neu
`rology, 1990, 28(2):183-187.
`Grant, A.D., “Evidence of a role for NK1 and CGRP receptors in
`mediating neurogenic vasodilatation in the mouse ear. British
`Journal of Pharmacology, 2002, 135: 356-362.
`Hall, J.M. and Brain, S.D., “Interaction of amylin with calcitonin
`gene-related peptide receptors in the microvasculature of the ham
`ster cheek pouch in vivo.” British Journal of Pharmacology, 1999,
`126: 280-284.
`Hall, J.M., et al., “Interaction of human adrenomedullin 13-52 with
`calcitonin gene-related peptide receptors in the microvasculature of
`the rat and hamster.” British Journal of Pharmacology, 1995, 114:
`592-597.
`Juaneda, C. et al. “The molecular pharmacology of CGRP and
`related peptide receptor Subtypes'. TiPS, 2000, 21: 432-438.
`Lassen, L.H. et al. “CGRP may play a causative role in migraine”
`Cephalalgia, 2002, 22(1):54-61.
`Mallee, J.J., et al. “Receptor Activity-modifying Protein 1 Deter
`mines the Species Selectivity of Non-peptide CGRP Receptor
`Antagonist”. J. Biol. Chem., 2002, 277(16): 14294-14298.
`Mclatchie, L.M. et al., “RAMPs regulate the transport and ligand
`specificity of the calcitonin-receptor-like receptor', Nature, 1998,
`393: 333-339.
`Olesen, J. et al., "Calcitonin Gene-Related Peptide Receptor
`Antagonist BIBN 4096 BS for the Acute Treatment of Migraine'.
`New England.J. of Medicine, 2004, 350 (11): 1104-1110.
`Pasternak, A., et al., “Potent, orally bioavailable somatostatin
`agonists: good absorption achieved by urea backbone cyclization'.
`Bioorganic & Medicinal Chemistry Letters, Oxford GB, vol. 9, No.
`3, Feb. 8, 1999, p. 491-496.
`Poyner, D.R. et al., “Pharmacological characterization of a receptor
`for calcitonin gene-related peptide on rat, L6 myocytes'. British
`Journal of Pharmacology, 1992, 105: 441-447.
`Rosenfeld, M.G., et al., “Production of a novel neuropeptide
`encoded by the calcitonin gene via tissue-specific RNA processing'.
`Nature, 1983, 304: 129-135.
`Rudolf, K., et al., “Development of Human Calcitonin Gene
`Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selec
`tive Small Molecule CGRP Antagonists. 1-N-3,5-Dibromo-N-
`4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-
`piperidinylcarbonyl-D-tyrosyl
`L-lysyl-4-(4-
`pyridinyl)piperazine: The First CGRP Antagonist for Clinical Trials
`in Acute Migraine”. J. Med. Chem. 2005, 48: 5921-5931.
`Shen, Y-T. et al., “Functional Role of O-Calcitonin Gene-Related
`Peptide in the Regulation of the Cardiovascular System”. J. Pharm.
`Exp. Ther..., 2001, 298: 551-558.
`Van Valen, F. et al., "Calcitonin gene-related peptide (CGRP)
`receptors are linked to cyclic adenosine monophosphate production
`in SK-N-MC human neuroblastoma cells'. Neuroscience Letters,
`1990, 119: 195-198.
`Williamson, D.J. and Hargreaves, R.J., “Neurogenic Inflammation
`in the Context of Migraine”, Microsc. Res. Tech., 2001, 53: 167-178.
`Williamson, D.J., et al., “Intravital microscope studies on the effects
`of neurokinin agonists and calcitonin gene-related peptide on dural
`vessel diameter in the anaesthetized rat,” Cephalalgia, 1997, 17:
`518-524.
`Williamson, D.J., et al., “Sumatriptan inhibits neurogenic vasodila
`tion of dural blood vessels in the anaesthetized rat-intravital micro
`scope studies,” Cephalalgia, 1997, 17: 525-531.
`Xin, Z. et al., “Potent, Selective Inhibitors of Protein Tyrosine
`Phosphatase IB”, Bioorg. Med. Chem. Lett., 2003, 13: 1887-1890.
`
`2
`
`

`

`US 7,384,930 B2
`
`1.
`CONSTRAINED COMPOUNDS AS
`CGRP-RECEPTOR ANTAGONSTS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of U.S. provisional
`application Ser. Nos. 60/624,655 filed Nov. 3, 2004 and
`60/678,099 filed May 5, 2005.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`10
`
`Calcitonin gene-related peptide (CGRP) is a naturally
`occurring 37-amino-acid peptide first identified in 1982
`(Amara, S. G. etal, Science 1982, 298, 240-244). Two forms 15
`of the peptide are expressed (C,CGRP and BCGRP) which
`differ by one and three amino acids in rats and humans,
`respectively. The peptide is widely distributed in both the
`peripheral (PNS) and central nervous system (CNS), prin
`cipally localized in sensory afferent and central neurons, and 20
`displays a number of biological effects, including vasodila
`tion.
`When released from the cell, CGRP binds to specific cell
`Surface G protein-coupled receptors and exerts its biological
`action predominantly by activation of intracellular adenylate 25
`cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105,
`441-7: Van Valen, F. etal, Neurosci Lett 1990, 119, 195-8.).
`Two classes of CGRP receptors, CGRP, and CGRP, have
`been proposed based on the antagonist properties of the
`peptide fragment CGRP(8-37) and the ability of linear 30
`analogues of CGRP to activate CGRP receptors (Juaneda,
`C. et al. TiPS2000, 21, 432-438). However, there is lack of
`molecular evidence for the CGRP receptor (Brain, S. D. et
`al, TiPS 2002, 23, 51-53). The CGRP receptor has three
`components: (i) a 7 transmembrane calcitonin receptor-like 35
`receptor (CRLR); (ii) the single transmembrane receptor
`activity modifying protein type one (RAMP1); and (iii) the
`intracellular receptor component protein (RCP) (Evans B. N.
`et al., J Biol Chem. 2000, 275, 31438-43). RAMP1 is
`required for transport of CRLR to the plasma membrane and 40
`for ligand binding to the CGRP-receptor (McLatchie, L. M.
`etal, Nature 1998, 393,333-339). RCP is required for signal
`transduction (Evans B. N. et al., J Biol Chem. 2000, 275,
`31438-43). There are known species-specific differences in
`binding of small molecule antagonists to the CGRP-receptor 45
`with typically greater affinity seen for antagonism of the
`human receptor than for other species (Brain, S. D. et al.
`TiPS2002, 23, 51-53). The amino acid sequence of RAMP1
`determines the species selectivity, in particular, the amino
`acid residue Trp74 is responsible for the phenotype of the 50
`human receptor (Mallee et al. J Biol Chem 2002, 277,
`14294-8).
`Inhibitors at the receptor level to CGRP are postulated to
`be useful in pathophysiologic conditions where excessive
`CGRP receptor activation has occurred. Some of these 55
`include neurogenic vasodilation, neurogenic inflammation,
`migraine, cluster headache and other headaches, thermal
`injury, circulatory shock, menopausal flushing, and asthma.
`CGRP receptor activation has been implicated in the patho
`genesis of migraine headache (Edvinsson L. CNS Drugs 60
`2001; 15(10):745-53: Williamson, D. J. Microsc. Res. Tech.
`2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol. 2002,
`135, 356-362). Serum levels of CGRP are elevated during
`migraine (Goadsby PJ, et al. Ann Neurol 1990; 28: 183-7)
`and treatment with anti-migraine drugs returns CGRP levels 65
`to normal coincident with alleviation of headache (Gallai V.
`et al. Cephalalgia 1995; 15: 384–90). Migraineurs exhibit
`
`2
`elevated basal CGRP levels compared to controls (Ashina
`M, et al., Pain 2000, 86(1-2): 133-8.2000). Intravenous
`CGRP infusion produces lasting headache in migraineurs
`(Lassen L. H. et al. Cephalalgia 2002 February; 22(1):54
`61). Preclinical studies in dog and rat report that systemic
`CGRP blockade with the peptide antagonist CGRP(8-37)
`does not alter resting systemic hemodynamics nor regional
`blood flow (Shen, Y-T. et al, J Pharmacol Exp Ther 2001,
`298, 551-8). Thus, CGRP-receptor antagonists may present
`a novel treatment for migraine that avoids the cardiovascular
`liabilities of active vasoconstriction associated with non
`Selective 5-HT1, agonists, triptans (e.g., Sumatriptan).
`A number of non-peptidic, small molecule CGRP-recep
`tor antagonists have been recently reported. WO 04/091514,
`WO 04/092.166 and WO 04/092.168 disclose cyclic com
`pounds containing an amide bond in the ring as CGRP
`antagonists. WO 97/09046 and equivalents disclose inter
`alia quinine and quinidine related compounds which are
`ligands, in particular antagonists, of CGRP-receptor. WO
`98/09630 and WO 98/56779 and equivalents disclose inter
`alia variously substituted, nitrobenzamide compounds as
`CGRP-receptor antagonists. WO 01/32649, WO 01/49676,
`and WO 01/32648 and equivalents disclose interalia a series
`of 4-oxobutanamides and related cyclopropane derivatives
`as CGRP-receptor antagonists. WO 00/18764, WO
`98/11128 and WO 00/55154 and equivalents disclose inter
`alia benzimidazolinyl piperidines as antagonists to CGRP
`receptor. Unrelated to CGRP, a series of somatostatin
`antagonists have been disclosed in WO99/52875 and WO
`01/25228 and equivalents. See also U.S. Pat. Nos. 6,344,
`449, 6,313,097, 6,521,609, 6,552,043, US 20030181462,
`US20030191068 and WO 03/076432 and related applica
`tions. Thus, novel CGRP-receptor antagonists effective for
`the treatment of neurogenic inflammation, migraine and
`other disorders would be greatly advantageous.
`
`DESCRIPTION OF THE INVENTION
`
`The invention encompasses compounds of Formula I and
`II which are CGRP antagonists. The invention also encom
`passes compositions incorporating these compounds and
`methods of using these compounds in therapeutic treatment.
`One aspect of the invention is a compound of Formula I
`
`R3
`R4 y R'
`
`/
`
`W
`
`(()n
`R11
`
`N
`
`Y,
`
`x1 s
`
`R6
`
`O
`
`R5
`
`wherein:
`R" is Calkyl, Coalkenyl, C-cycloalkyl, Cs, cycloalk
`enyl,
`C (C3-7cycloalkyl)alkyl, Chaloalkyl, C-(C-galkoxy)
`alkyl, C-(Ar")alkyl,
`C (NR7R)alkyl, N-(R)-pyrrolidinyl or N-(R)-pip
`eridinyl:
`R is hydrogen, halo, hydroxy, Coalkyl, Calkenyl, ben
`zyloxy, or NR7R:
`
`3
`
`

`

`3
`R is hydrogen, hydroxy, halo, Calkyl, or Coalkenyl:
`or R and R taken together are CHNNR;
`R" is hydrogen, halo or C-alkyl, or C2-alkenyl:
`R is hydrogen or C-alkyl;
`R is hydrogen, C-alkyl,
`or NR'R' taken together is
`
`O
`
`NH
`
`C X=0, or
`N4
`
`N
`H
`
`O
`
`1N
`
`21
`
`NH
`-l
`N
`H
`
`O;
`
`r
`Z
`N 10
`Riv,
`
`N
`
`H N
`
`O A.
`
`O
`
`NH
`
`s
`
`O,
`
`NH
`
`A.
`
`NH 30
`
`NS
`
`Ar,
`
`A, H
`
`N
`
`O
`
`35
`
`40
`
`45
`
`N
`
`O
`
`N
`
`NH
`
`O, or
`
`50
`
`NH
`
`55
`
`R’ is hydrogen or Calkyl;
`R is hydrogen or C-alkyl; or
`NR'R' taken together is selected from the group consisting 60
`of pyrrolidinyl, piperidinyl, N-(R)-piperazinyl, mor-
`pholinyl, and thiomorpholinyl:
`R is hydrogen, Coalkyl, Coalkylcarbonyl, or Calkoxy-
`carbonyl:
`R" is phenyl, naphthyl, pyridinyl, pyridinyl N-oxide, quino- 65
`linyl, quinolinyl N-oxide, isoquinolinyl, or isoquinolinyl
`N-oxide, and is substituted with 0-2 substituents selected
`
`US 7,384,930 B2
`
`4
`from the group consisting of halo, Calkyl, Cha
`loalkyl, Calkoxy, hydroxy, and phenyl:
`or R' is selected from the group consisting of
`
`5
`
`10
`
`15
`
`2O
`
`A.
`
`AleX
`
`R11,
`
`R11
`O
`
`A.,
`r
`:-
`
`R11,
`
`R11
`O
`
`ls
`
`NH
`
`N
`
`N
`
`N
`AX
`R11
`R11,
`O
`
`N
`
`N
`
`SN
`d
`%2
`R11,
`R11
`O
`
`N
`1.
`%2
`R11
`R11,
`O
`
`N
`1.
`A.
`R11,
`R11
`O
`
`NH
`
`NH
`
`r
`
`1.
`RII
`
`R11
`
`R11
`O
`
`NH
`
`NN
`Á2.
`O
`s
`
`N
`
`NH
`N
`CeX
`R11
`RI1,
`
`r
`
`d
`R11
`
`R11
`
`R11
`O
`
`R11
`
`NH
`
`N
`As R11
`O
`s
`
`NH
`NN
`d
`AleX
`R11,
`R11
`
`N
`
`4
`
`

`

`US 7,384,930 B2
`
`6
`
`-continued
`
`-continued
`
`O
`
`O
`
`NH
`
`N
`
`N r
`
`M2 AX
`R
`RI,
`
`O
`
`ls
`N
`NH,
`
`N
`
`r
`
`Na
`R11
`
`R11
`
`,
`
`O
`
`NH,
`
`N
`
`R11
`
`R11
`
`R11
`
`R11
`
`
`
`
`
`s
`
`N
`e N
`NH,
`
`S.
`
`O
`
`O
`
`A-. A.
`
`1. s
`O
`N
`\?
`
`NH, and
`N
`Ar2
`
`O N A
`
`Ar?:
`
`R' is hydrogen, halo, Calkyl, Chaloalkyl, or
`Coalkoxy,
`Ar' is phenyl, naphthyl, pyridinyl, or imidazolyl, and is
`substituted with 0-2 substituents selected from the group
`consisting of halo, Calkyl, and Chaloalkyl;
`Ar’ is phenyl, naphthyl, or pyridinyl, and is substituted with
`0-2 substituents selected from the group consisting of
`halo, Calkyl, and Chaloalkyl;
`X-Y is aminocarbonyl, oxycarbonyl, methylenecarbonyl,
`ethylene, or amino (cyano)iminomethyl;
`Z is N or CH; and
`n is 0 or 1;
`or a pharmaceutically acceptable salt or Solvate thereof.
`Another aspect of the invention is a compound of Formula
`Ia.
`
`Ia
`
`Another aspect of the invention is a compound of Formula
`Ib.
`
`
`
`Ib
`
`5
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5
`
`

`

`7
`Another aspect of the invention is a compound of Formula
`II.
`
`US 7,384,930 B2
`
`8
`
`
`
`5 A N
`
`H
`
`10
`
`15 A.
`
`Another aspect of the invention is a compound of Formula
`IIa.
`
`2O
`
`
`
`IIa
`
`NH
`NS
`
`Ar,
`
`A N
`
`H
`
`N
`
`O,
`
`NH
`
`s
`
`O,
`
`NH
`
`25 A.
`
`30
`
`NH
`
`O, or
`
`N
`
`O
`
`NH
`
`Another aspect of the invention is a compound of Formula
`IIb.
`
`35
`
`Another aspect of the invention is a compound of Formula
`I or II where R' is selected from the group consisting of
`
`
`
`IIb
`
`40
`
`45
`
`50
`
`O
`
`ls
`A. N
`NH
`SS
`A.
`
`R11
`
`11,
`
`O
`
`ls
`
`NH
`
`N
`
`O
`
`ls
`N
`NH
`
`n
`
`N
`x
`
`R11
`
`O
`
`N
`
`N
`
`AleX
`R11
`R11,
`
`Another aspect of the invention is a compound of Formula
`I or II where R is chloro, fluoro, or methyl.
`Another aspect of the invention is a compound of Formula 55
`I or II where NRR taken together is
`
`N
`
`A. x
`RN R11,
`
`O
`
`O
`
`Another aspect of the invention is a compound of Formula
`I or II where NRR taken together is
`
`65
`
`A.Sa d
`R11
`R11,
`
`4. X
`R11
`R11,
`
`6
`
`

`

`9
`
`-continued
`
`US 7,384,930 B2
`
`
`
`10
`
`-continued
`
`n N
`
`RI,
`
`AleX
`RI,
`
`RI,
`
`R11
`
`R11,
`
`OR
`
`n N
`
`a
`
`R s
`
`N H
`
`N
`
`RI
`
`O
`
`H
`X N
`
`N
`
`X, l NH,
`
`NH,
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`NH, and
`
`7
`
`

`

`12
`
`R3
`
`R2
`
`R4
`
`Y.
`
`x1 s
`
`R6
`
`O
`
`R5
`
`N
`
`R11
`
`
`
`US 7,384,930 B2
`
`10
`
`15
`
`25
`
`11
`Another aspect of the invention is a compound of Formula
`I or II where R' is hydrogen, chloro, fluoro, or methyl.
`Another aspect of the invention is a compound of Formula
`I or II where Z is CH.
`Another aspect of the invention is a compound of Formula
`I where n is 1.
`Another aspect of the invention is that any scope of
`variables R. R. R. R. R. R. R. R. R. R. R'', Ar",
`Ar, X-Y, Z, and n can be used with any scope of the
`remaining variables
`“Alkyl,” “hydroxyalkyl,” “alkoxy' and related terms with
`an alkyl moiety include straight and branched isomers.
`“Alkenyl' means a straight or branched alkyl group with at
`least one double bond. A term Such as C(R)alkyl means a
`straight or branched alkyl group of one to six carbons
`substituted with the substituent R. A term such as N—(R)-
`pyrrolidinyl indicates that the nitrogen is substituted with the
`substituent R. “Haloalkyl and “haloalkoxy' include all
`halogenated isomers from monohalo Substituted alkyl to
`perhalo substituted alkyl. "Aryl includes carbocyclic and
`heterocyclic aromatic ring systems. “Amino” includes
`includes primary, secondary, and tertiary moieties. “Carbo
`nyl' means CO. “Oxy' means —O—. “Aminocarbonyl
`30
`means —N(R)C(=O)—. “Oxycarbonyl means —OC
`(=O)—. "Methylenecarbonyl” means —CHC(=O)—.
`“Amino(cyano)iminomethyl means —NHC(=NCN)—.
`The invention includes all pharmaceutically acceptable
`salt forms of the compounds. Pharmaceutically acceptable
`salts are those in which the counter ions do not contribute
`significantly to the physiological activity or toxicity of the
`compounds and as such function as pharmacological equiva
`lents. These salts can be made according to common organic
`techniques employing commercially available reagents.
`Some anionic salt forms include acetate, acistrate, besylate,
`bromide, chloride, citrate, fumarate, glucouronate, hydro
`bromide, hydrochloride, hydroiodide, iodide, lactate, male
`ate, mesylate, nitrate, pamoate, phosphate. Succinate, Sul
`fate, tartrate, tosylate, and Xinofoate. Some cationic salt
`forms include ammonium, aluminum, benzathine, bismuth,
`calcium, choline, diethylamine, diethanolamine, lithium,
`magnesium, meglumine, 4-phenylcyclohexylamine, pipera
`Zine, potassium, Sodium, tromethamine, and zinc.
`The invention also includes all solvated forms of the
`compounds, particularly hydrates. Solvates do not contrib
`ute significantly to the physiological activity or toxicity of
`the compounds and as Such function as pharmacological
`equivalents. Solvates may form in Stoichiometric amounts or
`may form from adventitious solvent or a combination of
`both. One type of solvate is hydrate, and some hydrated
`forms include monohydrate, hemihydrate, and dihydrate.
`Some compounds of the invention may exist in Stereoi
`someric forms, one example of which is shown below. The
`invention includes all stereoisomeric and tautomeric forms
`of the compounds.
`
`Synthetic Methods
`
`The compounds described in the present invention can be
`synthesized according to Schemes 1-4 as well as other
`procedures known in the art. Starting materials are commer
`cially available or synthesized by common synthetic proce
`dures. Variations of the compounds and the procedures to
`make them which are not illustrated are within the skill of
`the art.
`Scheme 1 describes how to make certain compounds of
`the invention. Regiospecific introduction of iodine on a
`appropriately substituted aromatic ring can be accomplished
`using iodine monochloride. Aryl iodides (II) are good cou
`pling partners in palladium-mediated Heck reactions. The
`Heck products (III) can be reduced with hydrogen mediated
`by number of asymmetric catalysts to produce enationeri
`cally pure materials (IV). Subsequent hydrolysis of acetate
`functionality with methanolic potassium carbonate followed
`by treatment of alcohol (V) with thionyl chloride can
`produce benzylic chlorides (VI). Treatment of benzylic
`chlorides with various amines in acetonitrile can deliver
`requisite amines (VII).
`The amines (VII) can be converted into desired azepino
`nes (VIII) in refluxing toluene mediated by catalytic acetic
`acid. The azepinone intermediates VIII (X=NH, CH, O)
`can in turn be elaborated into final products. Hydrogenolysis
`of VIII (X=NH) under 10% Pd on carbon produces amine
`intermediate IX (Scheme II). The amine functionality can be
`transformed to the desired urea functionality (X) with the
`assistance of phosgene or N,N'-disuccinimyl dicarbonate
`and various amines (Scheme 2). Alternatively, the Succinic
`ester VIII (X=CH-) can be converted to carboxylic acid
`(XI) with lithium hydroxide, followed by reaction with an
`appropriate amine under TBTU coupling conditions to give
`desired amides (XII) (Scheme 3).
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`
`

`

`13
`
`US 7,384,930 B2
`
`R3
`R2
`A
`\ A
`/R4
`/
`
`I
`
`—>
`A020
`DMAP
`
`OH
`
`1
`
`I
`
`R3
`R2
`A
`\ A
`I /
`/
`
`OAc
`
`I
`
`11
`
`Pd(OAc)2
`Bu4NCl—
`
`ROZC\ AL
`
`X
`
`COZMe
`
`R3
`R2
`/\
`\ A
`/R4
`/
`
`l
`
`R3
`R2
`/\
`\ A
`/R4
`/
`
`l
`
`14
`
`R3
`R2
`(A
`/R4
`/
`
`l
`
`OAc \
`
`COZMe
`
`X
`
`OR
`
`T0
`
`111
`
`X : NH, CH2, 0, s
`
`Asymmetric H
`reduction
`
`R3
`R2
`/\
`\ A
`/R4
`/
`
`l
`
`C1
`
`COZMe
`
`4—
`SOClz
`CH2C12
`
`OH
`
`COZMe
`
`K2C03MeOH
`
`OAc
`
`COZMe
`
`X\”/OR0
`
`VI
`
`HZNRliCH3CN
`
`R2
`
`l
`
`R3A
`\/\W
`/R4
`/
`
`NHRl
`
`COzMe
`
`HOAc
`toluene
`
`/N
`
`X\”/OR0
`
`VIII
`
`Sghemel
`
`10% Pd—C
`MeOH
`
`X\”/OR0
`
`V
`
`RZA R3
`\ A
`| /
`/
`
`o
`
`XJ<OR
`
`VIII
`
`50
`
`55
`
`60
`
`65
`
`X\”/OR0
`
`IV
`
`R2
`R3
`/\
`\ A
`| /
`/
`
`O
`
`—>
`
`Rl/N
`
`0
`
`X—<
`
`R6
`
`I|\I/
`R5
`
`-continued
`
`/\
`\ \ A/R4
`
`/
`
`Rl/N
`
`NH2
`
`0
`R
`
`HN/
`5
`
`R
`
`6
`
`Phosgene or
`N,N'-disuccinimidyl
`carbonate
`
`9
`
`

`

`US 7,384,930 B2
`
`16
`
`-continued
`
`-continued
`
`*i-s/
`Xsé
`2
`
`5
`
`O
`
`10
`
`LiOH
`THF-HO
`
`15
`
`25
`
`30
`
`XIII
`
`R % XSAS
`2
`
`O
`
`OH
`
`N
`
`R
`
`O
`
`XI
`
`R6
`Y
`TBTU
`
`I
`Rs
`
`“ia R3
`Xsé -R4
`2
`
`R N
`
`O
`
`O
`
`-R
`
`Rs
`
`XII
`
`In a manner similar to urea formation, cyanoguanidine
`XIII can be prepared using diphenyl N-cyanocarboimidate
`and various Substituted amines (Scheme 4).
`
`10% Po-C
`MeOH
`
`NCN
`
`OPh
`
`10
`
`

`

`17
`Biological Methods
`
`US 7,384,930 B2
`
`18
`In the Table 4, results are denoted as follows: A 0.1-10
`nM; B=10-100 nM; C=100-1000 nM; D>1000 nM.
`
`CGRP Binding Assay. Tissue Culture. SK-N-MC cells
`were grown at 37°C. in 5% CO as a monolayer in medium
`consisting of MEM with Earle's salts and L-glutamine 5
`(Gibco) supplemented with 10% fetal bovine serum (Gibco).
`Cell Pellets. The cells were rinsed twice with phosphate-
`buffered saline (155 mM NaCl, 3.3 mM NaHPO, 1.1 mM
`KHPO, pH 74), and incubated for 5-10 min. at 4°C. in
`hypotonic lysis buffer consisting of 10 mM Tris (pH 7.4) and
`5 mM EDTA. The cells were transferred from plates to
`polypropylene tubes (16x100 mm) and homogenized using
`a polytron. Homogenates were centrifuged at 32,000xg for
`30 min. The pellets were resuspended in cold hypotonic lysis 15
`buffer with 0.1% mammalian protease inhibitor cocktail
`(Sigma) and assayed for protein concentration. The SK-N-
`MC homogenate was then aliquoted and stored at -80° C.
`until needed.
`Radioligand Binding Assay. The compounds of invention 20
`were solubilized and carried through serial dilutions using
`100% DMSO. Aliquots from the compound serial dilutions
`were further diluted 25 fold into assay buffer (50 mM Tris-Cl
`pH 7.5, 5 mM MgCl, 0.005% Triton X-100) and transferred
`(volume 50 yul) into 96 well assay plates. 'I-CGRP is
`(Amersham Biosciences) was diluted to 60 pM in assay
`buffer and a volume of 50 ul was added to each well.
`SK-N-MC pellets were thawed, diluted in assay buffer with
`fresh 0.1% mammalian protease inhibitor cocktail (Sigma),
`and homogenized again. SK-N-MC homogenate (5 g/well) 30
`was added in a volume of 100 ul. The assay plates were then
`incubated at room temperature for 2 h. Assays were stopped
`by addition of excess cold wash buffer (20 mM Tris-Cl pH
`7.5, 0.1% BSA) immediately followed by filtration over
`glass fiber filters (Whatman GF/B) previously soaked in 35
`0.5% PEI. Non-specific binding was defined with 1 uM
`beta-CGRP Protein bound radioactivity was determined
`using a gamma or Scintillation counter. The ICso was defined
`as the concentration of a compound of invention required to
`displace 50% of radioligand binding.
`Cyclic AMP Functional Antagonism Assay. Antagonism
`of the compounds of invention was determined by measur-
`ing the formation of cyclic AMP (adenosine 3',5'-cyclic
`monophosphate) in SK-N-MC cells that endogenously
`express the human CGRP receptor. CGRP receptor complex 45
`is coupled with Gs protein and CGRP binding to this
`complex leads to the cyclic AMP production via Gs-depen-
`dent activation of an adenylate cyclase (Juaneda C et al.,
`TiPS, 2000: 21:432-438; incorporated by reference herein).
`Consequently, CGRP receptor antagonists inhibit CGRP- 50
`induced cyclic AMP formation in SK-N-MC cells (Doods H
`et al., Br J Pharmacol, 2000; 129(3):420-423); incorporated
`by reference herein). For cyclic AMP measurements SK-N-
`MC cells were incubated with 0.3 nMCGRP alone or in the
`presence of various concentrations of the compounds of 55
`invention for 30 min at room temperature. Compounds of
`invention were pre-incubated with SK-N-MC cells for 15
`min before the addition of CGRP to allow receptor occu-
`pancy (Edvinsson et al., Eur J Pharmacol, 2001, 415:39-44:
`incorporated by reference herein). Cyclic AMP was 60
`extracted using the lysis reagent and its concentration was
`determined by radioimmunoassay using RPA559 cAMP
`SPA Direct Screening Assay Kit (Amersham Pharmacia
`Biotech). IC50 values were calculated using Excel fit. The
`tested compounds of invention were determined to be 65
`antagonists as they exhibited a dose-dependent inhibition
`of the CGRP induced cyclic AMP production.
`
`40
`
`C
`B
`B
`p
`B
`B
`A.
`p
`B
`A.
`p
`B
`A.
`A.
`f
`B
`C
`A.
`s
`C
`B
`D
`5
`C
`B
`B
`
`TABLE 4
`CGRP Binding and cAMP Functional Data
`CGRP binding
`cAMP Function
`ICso (nM)
`ICso (nM)
`B
`B
`C
`:
`:
`:
`B
`:
`:
`B
`B
`A
`:
`:
`A.
`:
`A.
`A.
`A.
`A
`B
`:
`A.
`B
`:
`B
`:
`:
`:
`:
`B
`B
`B
`A.
`f
`A.
`A.
`A.
`f
`:
`A.
`A.
`A
`A.
`A.
`:
`:
`:
`:
`:
`:
`:
`:
`:
`
`Example
`1
`2
`:
`5
`6
`7
`
`10
`11
`12
`t
`15
`16
`s
`19
`2O
`21
`3.
`24
`25
`26
`5.
`29
`30
`31
`3.
`34
`35
`36
`3.
`39
`40
`3.
`43
`44
`45
`is
`48
`49
`50
`s
`53
`S4
`55
`s
`58
`59
`60
`2.
`63
`64
`65
`66
`3.
`69
`70
`71
`
`B
`A.
`f
`A.
`A.
`A.
`f
`B
`A.
`A.
`
`A.
`A.
`C
`
`C
`C
`D
`E.
`C
`D
`D
`B
`
`B
`C
`C
`
`:
`:
`:
`:
`
`11
`
`

`

`US 7,384,930 B2
`
`19
`
`TABLE 4-continued
`
`CGRP Binding and cAMP Functional Data
`CGRP binding
`cAMP Function
`ICso (nM)
`ICso (nM)
`
`Example
`
`72
`73
`74
`75
`76
`77
`78
`79
`8O
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`OO
`O1
`O2
`O3
`O4
`05
`O6
`O7
`O8
`09
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`2O
`
`Pharmaceutical Compositions and Methods of
`Treatment
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`The compounds of Formula I inhibit the CGRP receptor.
`AS Such, they are useful for treating disorders associated
`with aberrant CGRP levels or where modulating CGRP
`55
`levels may have therapeutic benefit.
`Accordingly, another aspect of the invention is a phar
`maceutical composition comprising a compound of Formula
`I with a pharmaceutically acceptable adjuvant, carrier, or
`diluent.
`60
`Compounds are generally given as pharmaceutical com
`positions comprised of a therapeutically effective amount of
`a compound of Formula I, or a pharmaceutically acceptable
`salt, and a pharmaceutically acceptable carrier and may
`contain conventional exipients. A therapeutically effective
`amount is the amount needed to provide a meaningful
`patient benefit as determined by practitioners in that art.
`
`65
`
`20
`Pharmaceutically acceptable carriers are those convention
`ally known carriers having acceptable safety profiles. Com
`positions encompass all common Solid and liquid forms
`including capsules, tablets, losenges, and powders as well as
`liquid Suspensions, syrups, elixers, and solutions. Solid
`compositions may by formed in timed or Sustained released
`formulations. Compositions are made using common for
`mulation techniques and conventional excipients (such as
`binding and wetting agents) and vehicles (such as water and
`alcohols).
`Solid compositions are normally formulated in dosage
`units providing from about 1 to about 1000 mg of the active
`ingredient per dose. Some examples