Classifications

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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
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  • A61P25/06—Antimigraine agents
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • 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
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—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
  • C07D471/20—Spiro-condensed systems

Definitions

• the disclosure generally relates to the novel compounds of formula I, including pharmaceutically acceptable salts, which are CGRP -receptor antagonists.
• the disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine 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).
• CGRP related disorders including migraine 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).
• COPD chronic obstructive pulmonary disease
• Calcitonin gene-related peptide is a naturally occurring 37-amino- acid peptide first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed (aCGRP and CGRP) 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), principally localized in sensory afferent and central neurons, and displays a number of biological effects, including vasodilation.
• CGRP 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 cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al, Neurosci Lett 1990, 1 19, 195-8.).
• Two classes of CGRP receptors, CGRPl and CGRP2 have been proposed based on the antagonist properties of the peptide fragment CGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP2 receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438).
• the CGRP1 receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR); (ii) the single
• transmembrane receptor activity modifying protein type one RAMP1
• RAMP1 transmembrane receptor activity modifying protein type one
• RCP intracellular receptor component protein
• RAMP 1 is required for transport of CRLR to the plasma membrane and for ligand binding to the CGRP -receptor (McLatchie, L. M. et al, Nature 1998, 393, 333-339).
• RCP is required for signal transduction (Evans B. N. et al, J Biol Chem. 2000, 275, 31438-43).
• 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 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 pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001 ; 15(10):745-53; Williamson, D. J. Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J.
• Serum levels of CGRP are elevated during migraine (Goadsby PJ, et al. Ann Neurol 1990;28: 183-7) and treatment with antimigraine drugs returns CGRP levels to normal coincident with alleviation of headache (Gallai V. et al. Cephalalgia 1995; 15: 384-90).
• Migraineurs exhibit 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 LH, et al. Cephalalgia 2002 Feb;22(l):54-61).
• CGRP- receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5- HT1B/1D agonists, 'triptans' (e.g., sumatriptan).
• CGRP antagonists have shown efficacy in human clinical trials. See Davis
• CGRP receptor antagonists have been disclosed in PCT publications WO 2004/092166, WO 2004/092168, and WO 2007/120590.
• the invention provides technical advantages, for example, the compounds are novel and inhibit CGRP. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
• the invention encompasses a series of CGRP antagonist compounds including pharmaceutically acceptable salts, compositions, methods of making them, and methods of using them in therapeutic treatment.
• One aspect of the invention is a compound of formula I
• R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;
• R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of
• R 3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
• R 4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
• R 5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
• R 9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
• R 10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl; or R 10 and R 11 taken together is O or N-OH; provided that at least one of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , or R 11 is not hydrogen;
• Ar 1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSC ⁇ ;
• X is O, CH 2 , or H; and Y is a bond, O, CH 2 , or NH; or a pharmaceutically acceptable salt thereof.
• R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;
• R 3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
• R 4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
• R 5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
• R 6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
• R 8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
• R 9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;
• R 11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; or R 10 and R 11 taken together is oxo; provided that at least one of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , or R 11 is not hydrogen;
• Ar 1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSC ⁇ ;
• X is O, CH 2 , or H
• Y is a bond, O, CH 2 , or NH; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I with the designated stereochemistry.
• Another aspect of the invention is a compound of formula I where
• R 1 is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino
• R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of
• R" is hydrogen or halo
• R is hydrogen or halo
• R is hydrogen
• R 7 is hydrogen
• R 8 is hydrogen
• R 9 is hydrogen or hydroxy;
• R is hydrogen, hydroxy, azido, amino, alkylamino, or dialkylamino;
• R is hydrogen; or R 10 and R 11 taken together is oxo; provided that at least one of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , or R 11 is not hydrogen;
• Ar 1 is phenyl substituted with 0-2 halo substituents;
• X is O, CH 2 , or H; and
• Y is O; or a pharmaceutically acceptable salt thereof.
• R 1 is hydrogen
• R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of
• R 5 is hydrogen or hydroxy;
• R 6 is hydrogen;
• R 7 is hydrogen;
• R 8 is hydrogen;
• R 9 is hydrogen or hydroxy;
• R 10 is hydroxy, azido, or amino;
• R 11 is hydrogen; or
• Ar 1 is phenyl or difluorophenyl;
• X is O, CH 2 , or NH; and
• Y is O; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I where R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl.
• R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl.
• R 2 is N- piperidinyl and is 4-substituted.
• Another aspect of the invention is a compound of
• formula I where the substituent is Another aspect of the invention is a compound of formula I where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen, R 10 is hydroxy, azido, or amino, and R 11 is hydrogen; or where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen or hydroxy, and R 10 and R 11 taken together is oxo; or where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydroxy, R 10 is hydrogen or hydroxy, and R 11 is hydrogen; or where R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen, R 10 is hydrogen, and R 11 is hydrogen.
• Another aspect of the invention is a compound of formula I where Ar 1 is phenyl substituted with 2 halo substituents.
• Another aspect of the invention is a compound of formula I where Ar 1 is 2, difluorophenyl.
• Another aspect of the invention is a compound of formula I where X is O.
• any instance of a variable including R , R , R , R , R , R , R , R 9 , R 10 , R 11 , Ar 1 , X, and Y, can be used independently with the scope of any other instance of a variable substituent.
• the invention includes combinations of the different aspects.
• Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons, preferably 1 to 3 carbons.
• Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
• Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
• Hydroxyl means a straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety.
• Haloalkyl and haloalkoxy include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl.
• Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art.
• a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
• 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 equivalents. 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, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
• Some compounds of the invention may exist in stereoisomeric forms, one example of which is shown below.
• the invention includes all stereoisomeric and tautomeric forms of the compounds.
• the invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. Synthetic Methods
• the compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that there are a number of methods available for the synthesis of these compounds and that their synthesis is not limited to the methods provided in the following examples. Variations of the compounds and the procedures to make them which are not illustrated are within the skill of the art. The variables describing general structural formulas and features in the synthetic schemes are distinct from and should not be confused with the variables in the claims or the rest of the specification. These variables are meant only to illustrate how to make some of the compounds of the invention.
• Formula I compounds can be synthesized through the following general schemes. Previous known structure II could be arylated with various aryl bromide to generated III. Ill could be deprotected and further processed to keto analogs of formula I. The ketone group of III could be alpha-hydroxylated to VII, which could be further converted to hydroxylketone and diol derivatives of formula I.
• the ketone group of III could be reduced to the alcohol IV, which could be either directly converted to hydroxyl analogs of formula I, or converted to halogenated analogs V. V could be converted to halogenated intermediates V.
• example 4 The stereochemistry of example 4 was proved and its stereospecific synthesis was achieved by experiments shown in Scheme 2.
• Simple reduction of the ketone with sodium borohydride produced two compounds, 2 and 3.
• Treatment of the mixture with TBAF at room temperature only deprotected the major component 2 to compound 4, which was easily separated from 3.
• Single crystals were obtained for x- ray analysis, where the cis-diol was confirmed.
• Treatment of 3 with TBAF under elevated temperature generated the trans-diol 5, whose structure was also confirmed by x-ray analysis.
• Diastereoselective reduction of the ketone group was achieved, and after acetate protection and TIPS deprotection, the intermediate 7 could be converted to example 4, whose spectroscopic properties matched that from previous non-stereospecific synthesis.
• Scheme 2 :
• Scheme 3a illustrates an alternative synthesis of example 8.
• Example 2 Example 15
• Example 16 The azide group of intermediate 9 could be reduced to amine 21 and protected with Boc as shown in Scheme 9. After deprotection, the alcohol group can react with isocyanates such as 24, which was prepared in one step from known aniline 26, to afford carbamate intermediate 25. Upon deprotection, example 17 can be obtained.
• Scheme 9 :
• intermediate 23 could also be converted to the ketone intermediate 32 through Swern oxidation.
• the ketone was converted to the unsaturated ester 33 by Wittig reaction.
• Intermediate 33 after hydrogenation, afforded two separable isomers 34 and 35. Both 34 and 35 was hydrolyzed by aqueous LiOH to afford the intermediate acids 36 and 37, respectively.
• intermediate 36 and 37 were converted to examples 19 and 20, respectively.
• Example 20 was converted to example 21 by treatment with TFA.
• SK-N-MC cells were grown at 37 °C in 5% CO 2 as a monolayer in medium consisting of MEM with Earle's salts and L-glutamine (Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen).
• Membrane Preparation Crude membranes were prepared from SK-N-MC cells expressing CGRP receptors. The cells were rinsed twice with phosphate-buffered saline (155 mM NaCl, 3.3 mM Na 2 HP0 4 , 1.1 mM KHYDROGENP0 4 , pH 7.4), 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 (16 x 100 mm) and homogenized using a polytron. Homogenates were centrifuged at 32,000 x g for 30 min.
• phosphate-buffered saline 155 mM NaCl, 3.3 mM Na 2 HP0 4 , 1.1 mM KHYDROGENP0 4 , pH 7.4
• hypotonic lysis buffer consisting of 10 mM Tris (pH 7.4) and
• the pellets were resuspended in cold hypotonic lysis buffer with 0.1% mammalian protease inhibitor cocktail (Sigma) and assayed for protein concentration.
• the SK-N-MC homogenate was aliquoted and stored at - 80 °C. Radioligand Binding Assay .
• the compounds of invention 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 2 , 0.005% Triton X-100) and transferred (volume 50 ⁇ ) into 96 well assay plates.
• [ 125 I]-CGRP (GE Healthcare or Perkin-Elmer) was diluted to 72 pM in assay buffer and a volume of 50 ⁇ was added to each well.
• SK-N-MC membranes were thawed, diluted in assay buffer with fresh 0.1% mammalian protease inhibitor cocktail (Sigma), and re-homogenized.
• SK-N-MC homogenate (7 ⁇ g/well) was added in a volume of 100 ⁇ . The assay plates were then incubated at room temperature for 2 h.
• the compounds of Formula I inhibit the CGRP receptor. As such, they are useful for treating conditions or disorders associated with aberrant CGRP levels or where modulating CGRP levels may have therapeutic benefit.
• another aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula I with a pharmaceutically acceptable adjuvant, carrier, or diluent.
• compositions 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.
• compositions 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 formulation 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 of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg, and 1000 mg. Liquid compositions are generally in a unit dosage range of 1-100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
• the invention encompasses all conventional modes of administration including oral, parenteral, intranasal, sublingual, and transdermal methods.
• the daily dose will be 0.01-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement.
• 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 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 pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001, 15(10),745-53; Williamson, D. J. Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J.
• Serum levels of CGRP are elevated during migraine (Goadsby P. J. et al. Ann. Neurol. 1990, 28, 183-7) and treatment with antimigraine drugs returns CGRP levels to normal coincident with alleviation of headache (Gallai V. et al. Cephalalgia 1995, 15, 384-90).
• Migraineurs exhibit elevated basal CGRP levels compared to controls (Ashina M. et al, Pain 2000, 86(1- 2), 133-8).
• Intravenous CGRP infusion produces lasting headache in migraineurs (Lassen L.H. et al. Cephalalgia. 2002, 22(1), 54-61).
• CGRP-receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5-HT1B/1D agonists, "triptans" (e.g., sumatriptan).
• Another aspect of the invention is a method of inhibiting the CGRP receptor comprising contacting the CGRP receptor with a compound of formula I or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a method for treating conditions associated with aberrant levels of CGRP comprising the administration of a therapeutically effective amount of a compound of formula I to a patient.
• Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of conditions related to aberrant levels of CGRP.
• Another aspect of the invention is a method of treating migraine or headache.
• Another aspect of the invention relates to a method of treating inflammation (particularly neurogenic inflammation), pain, thermal injury, circulatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid/ cranial hemorrhage, tumor growth, flushing associated with menopause and other conditions the treatment of which can be effected by the antagonism of the CGRP receptor by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
• Another aspect of the invention relates to methods selected from the group consisting of (a) immune regulation in gut mucosa (b) protective effect against cardiac anaphylactic injury (c) stimulating or preventing interleukin-lb(IL-lb)- stimulation of bone resorption (d) modulating expression of NK1 receptors in spinal neurons and (e) airway inflammatory diseases and chronic obstructive pulmonary disease including asthma.
• a) immune regulation in gut mucosa (b) protective effect against cardiac anaphylactic injury (c) stimulating or preventing interleukin-lb(IL-lb)- stimulation of bone resorption (d) modulating expression of NK1 receptors in spinal neurons and (e) airway inflammatory diseases and chronic obstructive pulmonary disease including asthma.
• Another aspect of this invention relates to a method of treatment using combinations of Formula I compounds with one or more agents selected from the group consisting of COX-2 inhibitors, NSAIDS, aspirin, acetaminophen, triptans, ergotamine and caffeine for the treatment of migraine.
• Migraine “headache,” and related terms are as understood by medical practitioners. Migraine encompasses all classes of migraine including common, classic, cluster, fulgurating, hemiplegic, opthalmoplegic, and opthomalmic.
• “Therapeutically effective” means there is a meaningful patient benefit as understood by medical practitioners. "Patient” means a person who may benefit from treatment as determined by medical practitioners.
• NaHMDS sodium bis(trimethylsilyl)amide
• DMFE N,N- dimethylformamide
• MeOH for methanol
• NBS N-bromosuccinimide
• THF trifluoroacetic acid
• LAH lithium aluminum hydride
• BOC BOC
• DMSO dimethylsulfoxide
• H for hours
• Rt room temperature or retention time (context will dictate); "min” for minutes;
• EtOAc for ethyl acetate; "THF” for
• the products were purified by Prep HPLC using the column YMC S5 ODS (30 x 100 mm) at a flow rate of 40.0 mL/min and gradient time of 8.0 min. starting from solvent composition of 40% methanol- 60% water-0.1% TFA and ending with solvent composition 95% methanol-5% water-0.1% TFA.
• the products were analyzed by a HPLC instrument using an XTERA column (3.0 x 50 mm S7) starting from solvent A (10% methanol - 90% water - 0.1% trifluoroacetic acid (TFA)) and reaching solvent B (10% water - 90% methanol - 0.1% TFA) over a gradient time of 2 min.
• the flow rate is 5 mL/min. and retention time (Rf) of product was measured at 220 nm wavelength.
• TBAF 0.752 mL, 0.752 mmol
• LCMS indicated complete conversion of major component while the minor one did not change.
• Tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Sodium sulfate, and concentrated to give a tan oil.
• Tetrahydrofuran was removed in vacuo and the residue was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a colorless oil. Purification by FCC up to 70% ethyl acetate/hexane afforded the desired product (648mg, 87% for 2 steps) as a colorless oil.
• Triphenylphosphine (1.475 g, 5.62 mmol) was added. After stirring under nitrogen for 5min, (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9- tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.007 g, 2.250 mmol) was added in one portion to the gray suspension. The resulting reddish suspension was stirred at room temperature. The solids gradually dissolved to give a tan solution. After 5h, LCMS indicated complete conversion.
• Tetrahydrofuran was removed in vacuo and the remaining red oil was directly purified by ISCO (240g silica column) up to 60% ethyl acetate/hexane. Pure ethyl acetate eluted the non polar component and the product was eluted by 10% methanol (with 2.0M NH 4 OH) in Methylene chloride. The product fractions were combined and re-purified by FCC up to 50% Ethyl acetate/hexane to afford the desired product as a colorless oil (869mg, 83%).
• Epoxide 1. In an oven-dried 250 mL round-bottom flask was dissolved 5(S)-9- hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (3.16 g, 17.83 mmol) in Methylene chloride (50 mL) to give a tan solution. After cooling to 0°C, TIPS-OTf (4.84 mL, 17.83 mmol) and triethylamine (4.97 mL, 35.7 mmol) were added via syringe, and the mixture was stirred at 0°C for lh. LCMS indicated complete conversion.
• Triethylamine (6.04 mL, 43.4 mmol) was added via syringe at -50°C and the reaction mixture was gradually warmed up to -20°C for 30 min. TLC showed complete conversion. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 50% ethyl acetate/hexane afforded the desired product as a light yellow oil (2.08g, 72%).
• TBAF (4.80 mL, 4.80 mmol) was added, and the mixture was stirred at 50°C overnight for 16h. LCMS indicated good conversion with some SM left. Another 0.2 equiv of TBAF was added and the reaction continued at 50°C for 2h.
• Tetrahydrofuran was removed and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product as a white solid (458mg,
• 6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-6,9-diol (458 mg, 1.572 mmol) (azeotroped with dry benzene) in tetrahydrofuran (8 mL) to give a light orange solution.
• Lithium borohydride (0.283 g, 13.01 mmol) was added to a cyclopentyl methyl ether (15 mL) solution of (6S,9R)-6-(3,5-difluorophenyl)-9-(triisopropylsilyloxy)- 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1.4496 g, 3.25 mmol) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 6 h at room temperature. The reaction was quenched by adding methanol and continued to stir for 0.5 h.
• Triphenylphosphine (636 mg, 2.423 mmol) was added in one portion. After stirring under nitrogen for 5min, (5S,6S,9R)-6-(3,5-difluorophenyl)-9-(triisopropylsilyloxy)- 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (493 mg, 1.101 mmol) dissolved in 1 mL tetrahydrofuran (1 mL rinse) was added via canuula to the gray suspension. The resulting grayish suspension was stirred at room temperature. After 5h, LCMS indicated little conversion. The reaction was continued at 40°C overnight for 16h. LCMS showed complete conversion.
• Osmium tetroxide (0.021 mL, 1.710 ⁇ ) (2.5 wt-% solution in 2-methyl- 2-propanol) was added (the tan color instantly changed to very light yellow). The mixture was stirred at room temperature, lh: ⁇ 5% conversion. 0.021mL Os0 4 was added. 22h: 1/3 conversion. Another 0.021 mL Os0 4 solution was added. 28 h (50 h total). Sodium bisulfite (1.2g) was added and stirring continued for 30 min. Acetone was removed in vacuo and the residue was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried and concentrated to an off-white solid.
• FCC (a few drops of methanol helped to completely dissolve the solids in methylene chloride) up to 10% methanol/methylene chloride afforded two products: a less polar, likely the desired trans product (61mg, 49%) and a more polar cis product (47.1mg, 38%) as white solids.
• Triethylamine (0.038 mL, 0.28 mmol) was added under nitrogen and the mixture was cooled to -20°C.
• Trichloromethyl chloroformate (0.012 mL, 0.100 mmol) was added dropwise. The mixture was gradually warmed up with stirring to 10°C for lh, during which time the solution became slightly yellow. The reaction was concentrated to dryness under vacuum.

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