WO1997009046A1 - Composes et procedes associes - Google Patents

Composes et procedes associes Download PDF

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Publication number
WO1997009046A1
WO1997009046A1 PCT/US1996/014347 US9614347W WO9709046A1 WO 1997009046 A1 WO1997009046 A1 WO 1997009046A1 US 9614347 W US9614347 W US 9614347W WO 9709046 A1 WO9709046 A1 WO 9709046A1
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Prior art keywords
chlorophenyl
compound
cgrp
phenyl
formula
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PCT/US1996/014347
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English (en)
Inventor
Robert A. Daines
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Smithkline Beecham Corporation
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Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP9511420A priority Critical patent/JPH11512396A/ja
Priority to EP96930743A priority patent/EP0851759A4/fr
Publication of WO1997009046A1 publication Critical patent/WO1997009046A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/22—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of calcitonin
    • 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

Definitions

  • This invention relates to quinine and quinidine compounds which are ligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide (hereinafter "CGRP") receptor.
  • CGRP Calcitonin Gene-Related Peptide
  • this invention relates to the treatment and prevention of disease states mediated by CGRP, including, but not limited to, headaches, especially migraines; non-insulin dependent diabetes mellitus (hereinafter "NLDDM”); cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans, by the use of CGRP receptor ligands, in particular, quinine and quinidine antagonists, thereof.
  • NLDDM non-insulin dependent diabetes mellitus
  • CGRP is a 37 amino acid polypeptide that is stored and released from nerve terminals in both the central nervous system and the peripheral nervous system.
  • CGRP has been detected in nerves innervating the heart, peripheral and cerebral blood vessels, and kidneys by immunohistochemical and radioimmunoassay methods.
  • CGRP has been shown to mediate its biological response by binding to specific cell surface receptors that have been identified in a variety of tissues.
  • Evidence from biochemical studies suggest that CGRP receptors belong to the family of G-protein coupled receptors.
  • CGRP receptors The widespread distribution of CGRP receptors on muscle, glandular, epithelial and neuronal cells is consistent with its wide range of biological actions, including peripheral and cerebral vasodilation (Brain et al., Nature, Vol. 313, pp. 54-56 (1985)); cardiac acceleration (Sigrist et al., Endocrinology, Vol. 119, pp. 381-389 (1986)); regulation of calcium metabolism (Grunditz et al., Endocrinology, Vol. 119, pp. 2313-2324 (1986)); reduction of intestinal motility (Fargeas et al., Peptides, Vol. 6, pp.
  • CGRP cardiovascular disease 2019
  • CGRP receptor mechanisms represents a novel preventative and therapeutic approach to the treatment of a broad variety of disease states that are mediated by CGRP.
  • an active CGRP receptor antagonist would be expected to be useful in the treatment of a variety of disease states that are mediated by CGRP including, but not limited to, headaches, especially migraines; NLDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans.
  • the present invention is to a method of treating CGRP mediated disease states, including, but not limited to, headaches, especially migraines;
  • NIDDM neurodegenerative disease 2019
  • cardiovascular disorders chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a quinine or quinidine compound of formula (I), or pharmaceutically active salts thereof:
  • R 1 is hydrogen, hydroxy, CO 2 R 4 or OR 4 ;
  • R 2 is phenyl, ⁇ or ⁇ naphthyl, halophenyl, dihalophenyl, CF 3 -phenyl, or optionally substituted phenoxyphenyl;
  • R 3 is hydrogen, Cl to C4 alkyl, or C2 to C4 alkene
  • R 4 is Cl to C4 alkyl; and R 5 is hydrogen or hydroxy.
  • the present invention is to a genus of novel compounds of formula (IA), or pharmaceutically active salts thereof, said compounds which are also useful in treating the above-mentioned CGRP-mediated disease states:
  • R 1 is hydroxy or CO 2 R 4 ;
  • R is phenyl, ⁇ or ⁇ naphthyl, halophenyl, dihalophenyl, CF 3 -phenyl, or optionally substituted phenoxyphenyl ;
  • R 3 is hydrogen, Cl to C4 alkyl, or C2 to C4 alkene
  • R 4 is Cl to C4 alkyl
  • R is hydrogen or hydroxy
  • the present invention is to pharmaceutical compositions comprising a compound of formula (I) or formula (IA) and a pharmaceutically acceptable carrier therefor.
  • the pharmaceutical compositions of the present invention are used for treating CGRP-mediated disease states, including, but not limited to headaches, especially migraines; NLDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans.
  • quinine or quinidine compounds of formula (I) are CGRP receptor ligands, in particular, antagonists thereof. It has also now been discovered that selective inhibition of CGRP receptor mechanisms by treatment with the receptor ligands of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to headaches, especially migraines; NIDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans.
  • alkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, and the like.
  • alkene is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethylene, propylene, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • ⁇ or ⁇ naphthyl is used herein at all occurrences to describe the point of attachment of the naphthyl moiety to the quinoline ring at position R 2 .
  • halophenyl is used herein at all occurrences to mean a phenyl moiety that is substituted by a halogen radical as defined above.
  • the halogen radical may be positioned on the phenyl moiety ortho, meta or para relative to the quinoline core to which the phenyl is attached.
  • CF 3 -phenyl is used herein at all occurrences to means a phenyl moiety that is substituted by a trifluoromethyl (-CF3) radical.
  • the trifluoromethyl radical may be positioned on the phenyl moiety ortho, meta or para relative to the quinoline core to which the phenyl is attached.
  • dihalophenyl is used herein at all occurrences to mean a phenyl moiety that is substituted by two halogen radicals as defined above.
  • one halogen radicals may be positioned on the phenyl moiety ortho, meta or para relative to the quinoline core to which the phenyl is attached. Further, the halogen radicals may be the same or different.
  • phenoxyphenyl is used herein at all occurrences to mean a moiety which is represented by the formula "phenyl-oxygen-phenyl".
  • one phenyl ring of the phenoxyphenyl moiety is attached ortho, meta or para relative to the quinoline core.
  • optionally substituted is used herein at all occurrences to mean that the moieties may or may not be substituted with one to three various functional groups including alkyl, halogen, nitro or trifluoromethyl.
  • the optional substituent(s) may be at a position ortho, meta or para relative to the quinoline core.
  • the optional substituent(s) are positioned meta or para relative to the quinoline core.
  • CGRP mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by Calcitonin Gene-Related Peptide.
  • salts include, but are not limited to, salts with organic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.
  • organic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide and nitrate
  • salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.
  • Rl is suitably hydrogen, hydroxy, CO2R 4 or OR 4 .
  • Rl is preferably hydroxy or OR 4 , more preferably, hydroxy or methoxy.
  • R*-- is suitably phenyl, ⁇ or ⁇ naphthyl, halophenyl, dihalophenyl, CF 3 -phenyl, or optionally substituted phenoxyphenyl.
  • R ⁇ is preferably halophenyl or phenoxyphenyl.
  • R3 is suitably hydrogen, C1-C4 alkyl or C2-C4 alkene.
  • R ⁇ is preferably hydrogen, methyl or C2 alkene.
  • R 4 is suitably Cl to C4 alkyl.
  • R is suitably hydrogen or hydroxy.
  • R* is preferably hydroxy.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are within the scope of the present invention.
  • the C8 and C9 positions of the compounds of formula (I) or formula (IA) may contain stereocenters.
  • the stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R).
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of formula (I) or formula (IA) ("active ingredient”) in an amount sufficient to treat headaches, especially migraines; NLDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the active ingredient may also be administered topically to a mammal in need of treatment of CGRP mediated disease states.
  • the active ingredient may be administered topically in the treatment or prophylaxis of CGRP mediated disease states, including, but not limited to headaches, especially migraines; NLDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma.
  • the amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • the topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the active ingredient may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • this invention relates to a method of treating headaches, especially migraines; NLDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CGRP receptor ligand, in particular, an antagonist as depicted in formula (I).
  • formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well- known variables.
  • the formula (I) compound is administered to a mammal in need of treatment for headaches, especially migraines; NIDDM; cardiovascular disorders; chronic inflammation; endotoxic shock; arthritis; allergic rhinitis; and asthma, in an amount sufficient to decrease symptoms associated with these disease states.
  • the route of administration may be oral or parenteral.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient.
  • the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a foimula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques.
  • a reaction is carried out in a polar aprotic solvent such as dimethylsulfoxide (“DMSO") and in the presence of a hindered amine such as triethylamine.
  • DMSO dimethylsulfoxide
  • a hindered amine such as triethylamine
  • the resulting methyl ester 6 is then hydrogenated under standard catalytic hydrogenation conditions to reduce the 10, 11 -double bond, thus providing the saturated compound 7.
  • compound 7 can be converted to the dihydrochloride salt 8 via treatment with HCl in an organic solvent such as dioxane.
  • 1- naphthylboronic acid is coupled to 9 in the presence of a suitable source of Pd°- catalyst in a alcoholic solvent such as aqueous ethanol using sodium carbonate as a base and running the reaction at a temperature such that the reaction solution is maintained at a gentle reflux.
  • a suitable source of Pd°- catalyst in a alcoholic solvent such as aqueous ethanol using sodium carbonate as a base and running the reaction at a temperature such that the reaction solution is maintained at a gentle reflux.
  • compound 10 can be converted to the dihydrochloride salt 11 via treatment with HCl in an organic solvent such as dioxane.
  • treatment of 13 in such a manner in an aprotic solvent such as chloroform provides the ar N-oxide 14.
  • the final conversion is then accomplished by treatment of the ar N-oxide in CH 2 C1 2 with tosyl chloride and triethylamine in the presence of an alcohol.
  • a phenol is used. Specifically, if 4- chlorophenol is used, phenoxy ether 15 is obtained.
  • Example 18 In particular, the procedure for the preparation of 2'-methylquinidine (on page 65) was followed, except substituting quinine ar-N-oxide for quinidine ar- N-oxide, toluene for benzene, NaOH for KOH, Na 2 SO4 for K 2 CO 3 , and using 4- chlorophenylmagnesium bromide as the Grignard reagent. Also, instead of recrystallization from methanol, the crude product was purified by flash column chromatography (silica, 5:95:0.5 and 10:90:0.5 methanol-ethyl acetate-ammonium hydroxide). MS (ES) m/e 435.2 [M+H]+.
  • Example 2 Preparation of 2'-(4-chlorophenyl)-10. 11-dihydroquinine dihydrochloride (a) 2'-(4-Chlorophenyl -10. 11-dihydroquinine: The title compound was prepared according to the experimental disclosures found in U.S. Patent No. 3,663,552, issued June 18, 1974 to Yardley et al., Example 11 (column 14, line 34), and Yardley et al., J. Med. Chem. 1971, 14, pp. 62-65.
  • Example 1(b) Following the procedure of Example 1(b), except substituting the compound of Example 4(a) (28 mg, 0.065 mmol) for 2'-(4-chlorophenyl)quinine, the title compound (28 mg, 98%) was prepared as a yellow solid.
  • Anal. (C 6H 2 9 ⁇ 2 N 2 Cl 3 • 1 H 2 O) calcd: C, 59.27; H, 5.93; N, 5.32. Found C, 59.55; H, 5.95; N, 5.01.
  • Example 6 Preparation of 2'-(4-chlorophenyl)-10. 11-dihydrocinchonidine dihydrochloride (a) 2'-(4-Chlorophenyl)-10. 11-dihydrocinchonidine: The title compound was prepared according to the experimental disclosures found in U.S. Patent No. 3,663,552, issued June 18, 1974 to Yardley et al., Example 1 l(Column 14, Line 46), and Yardley et al., J. Med. Chem. 1971, 14, pp. 62-65.
  • Example 2(b) Following the procedure of Example 2(b), except substituting the compound of Example 6(a) (63 mg, 0.16 mmol) for 2'-(4-chlorophenyl)-10, 11-dihydroquinine, the title compound (63 mg, 78%) was prepared as a light yellow solid.
  • Anal. (C 5 H 2 9ON2Cl 3 • l 3 /4 H 2 O) calcd: C, 58.72; H, 6.41; N, 5.48. Found C, 58.72; H, 6.18; N, 5.33.
  • Example 2(a) The compound of Example 2(a) (250 mg, 0.57 mmol) was dissolved in dry methylene chloride (2.7 mL) and cooled to -78 C in a dry ice/acetone bath.
  • BBr 3 (2.1 mL, 2.3 mmol, 1.1M solution in methylene chloride) was added dropwise to the stirred solution over 10 min. After stirring at -78 C for 1 h, the reaction mixture was gradually warmed to room temperature and stirred for an additional 20 h. Water was cautiously added to decompose the excess BBr 3 , and the reaction mixture was made basic (pH 11-12) with 10% NaOH.
  • Example 2(b) Following the procedure of Example 2(b), except substituting the compound of Example 8(b) for 2'-(4-chlorophenyl)-10, 11-dihydroquinine, the title compound was prepared as an amo ⁇ hous maize solid.
  • Anal. (C 2 7H 3 ⁇ O 3 N 2 Cl 3 • l 3 /s H 2 O) calcd: C, 57.63; H, 6.05; N, 4.98. Found C, 57.38; H, 5.66; N, 4.85.
  • the reaction was diluted with water and methylene chloride.
  • the organic layer was dried (Na 2 SO4), concentrated in vacuo, and purified by Chromatotron (methylene chloride and 96:4: 1 methylene chloride-methanol-formic acid).
  • the fractions containing the title compound were concentrated in vacuo, and the resulting oil was dissolved in methylene chloride and washed with aqueous sodium bicarbonate solution.
  • the organic layer was dried (Na 2 SO4) and concentrated in vacuo to afford the title compound (301 mg, 85%) as a glassy foam.
  • Example 10 Preparation of 2'-(4-chlorophenoxy)-10.
  • 11-dihydroquinine (a) 10.
  • 11-dihydroquinine 10
  • 11-Dihydroquinine ar N-oxide 51 mg, 0.15 mmol
  • CH 2 C1 2 0.5 mL
  • 4-chlorophenol 20 mg, 0.30 mmol
  • tosyl chloride 36 mg, 0.19 mmol
  • Triethylamine 0.05 mL, 0.36 mmol
  • the reaction solution was diluted with CHC1 3 and washed with 5% Na 2 CO 3 and brine and dried (Na 2 SO4).
  • test compounds were assayed for the inhibition of [ 1 5 I ] CGRP (obtained from Amersham, Chicago, LL) binding and CGRP-mediated cAMP formation in human neuroblastoma cells (SK-N-MC).
  • SK-N-MC cells were obtained from American Type Culture Collection (Rockville, MD) and grown in Minimum Essential Media (“MEM”) medium containing fetal calf serum (10%). Cells were grown in T-150 flasks or Costar multiwell plates (24 well) and maintained at 37 °C in a 90% humidified incubator with an atmosphere of 5% CO 2 and 95% air.
  • MEM Minimum Essential Media
  • SK-N-MC cells were homogenized in 5 mM Tris-HCl pH 7.4, 10 mM Na- EDTA and the homogenate was centrifuged at 48,000 g for 20 min at 4 °C. The pellet was resuspended in 20 mM Na-HEPES pH 7.4, 10 mM MgCl 2 and recentrifuged as above. The membrane pellets were resuspended in the same buffer and stored frozen at -70 °C. The protein concentration was measured by the Pierce BCA method using bovine serum albumin as the standard.
  • the [ 125 I] CGRP receptor binding assay was performed using a buffer containing 20 mM Na-HEPES pH 7.4, 10 mM MgCl , 0.05% BSA and 0.1 mg/mL bacitracin.
  • the membranes 50 ug protein/mL were incubated with various concentrations (1, 10, 30, 60 and 100 uM) of the test compounds and 40 pM [ 125 I] CGRP in a total volume of 500 uL. for 60 min at 25 °C.
  • the reaction was terminated by addition of 2 mL ice-cold 0.9% NaCl, followed by rapid filtration through Skatron Filtermates presoaked in 0.5% polyethylenimine PEI).
  • the filters were rinsed twice with 2 mL of cold 0.9% NaCl and the radioactivity counted in a gamma counter. All binding data was analyzed by computer assisted LIGAND 2 program.
  • CGRP-Mediated cAMP formation SK-N-MC cells grown in Costar multiwell plates (24 well) were washed with
  • the compounds of this invention show binding activity as CGRP receptor ligands, in particular, as antagonists thereof, and have IC50 values in the range of 0.001 to 100 ⁇ M.
  • the structure/activity relationship has not yet been established for the compounds of this invention.
  • one of ordinary skill in the art can utilize the present assays in order to determine which compounds of formula (I) are ligands of the CGRP receptor and which bind thereto with an IC50 value in the range of 0.001 to 100 ⁇ M.
  • the above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims.

Abstract

L'invention porte sur des composés de quinine et de quinidine qui sont des ligands, en particulier, des antagonistes du récepteur peptide lié au gène de la calcitonine. En outre, l'invention se rapporte au traitement et à la prévention d'états pathologiques, chez les mammifères, ayant ce peptide pour origine dont, notamment: les maux de tête, et plus particulièrement les migraines, le diabète sucré non insulino-dépendant, les troubles cardio-vasculaires, les inflammations chroniques, les chocs endotoxiques, l'arthrite, la rhinite allergique et l'asthme. Ce traitement et cette prévention impliquent l'utilisation d'antagonistes du récepteur peptide lié au gène de la calcitonine, qui sont lesdits composés de quinine et de quinidine.
PCT/US1996/014347 1995-09-05 1996-09-05 Composes et procedes associes WO1997009046A1 (fr)

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JP9511420A JPH11512396A (ja) 1995-09-05 1996-09-05 化合物および方法
EP96930743A EP0851759A4 (fr) 1995-09-05 1996-09-05 Composes et procedes associes

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EP1127074A1 (fr) * 1998-10-05 2001-08-29 The Trustees of Columbia University in the City of New York Procedes pour determiner la capacite d'un compose d'inhiber l'interaction d'un peptide avec le recepteur d'un produit final de glycation evolue (rage)
WO2003104236A1 (fr) 2002-06-01 2003-12-18 Bristol-Myers Squibb Company Antagonistes des recepteurs du peptide relie au gene de la calcitonine
WO2005065779A1 (fr) 2003-12-05 2005-07-21 Bristol-Myers Squibb Company Antagonistes du recepteur peptidique lie au gene de la calcitonine
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos
US7772244B2 (en) 2004-03-29 2010-08-10 Bristol-Myers Squibb Company Therapeutic agents for the treatment of migraine
CN1812982B (zh) * 2003-06-26 2010-10-27 默沙东公司 苯并二氮杂*cgrp受体拮抗剂
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
WO2012021291A2 (fr) * 2010-08-09 2012-02-16 University Of Maryland, Baltimore Procédés de traitement des troubles pulmonaires obstructifs en utilisant des substances sapides amères
US9115194B2 (en) 2005-11-14 2015-08-25 Labrys Biologics, Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US9328167B2 (en) 2008-03-04 2016-05-03 Labrys Biologics, Inc. Methods of treating chronic pain
US9708393B2 (en) 2011-05-20 2017-07-18 Alderbio Holdings Llc Use of anti-CGRP antibodies and antibody fragments to prevent or inhibit photophobia or light aversion in subjects in need thereof, especially migraine sufferers
US9745373B2 (en) 2011-05-20 2017-08-29 Alderbio Holdings Llc Anti-CGRP compositions and use thereof
US9855332B2 (en) 2011-05-20 2018-01-02 Alderbio Holdings Llc Use of anti-CGRP antibodies and antibody fragments to treat diarrhea in subjects with diseases or treatments that result in elevated CGRP levels
WO2018031216A1 (fr) * 2016-08-12 2018-02-15 Steven Rothman Traitement de troubles de l'excitation sexuelle grâce à l'application locale d'agents qui augmentent l'excitabilité membranaire
US9896502B2 (en) 2014-03-21 2018-02-20 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10392434B2 (en) 2016-09-23 2019-08-27 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US10556945B2 (en) 2014-03-21 2020-02-11 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10597448B2 (en) 2009-08-28 2020-03-24 Teva Pharmaceuticals International Gmbh Methods for treating visceral pain associated with interstitial cystitis by administering antagonist antibodies directed against calcitonin gene-related peptide
US11639380B2 (en) 2019-01-08 2023-05-02 H. Lundbeck A/S Acute treatment and rapid treatment of headache using anti-CGRP antibodies

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US7696192B2 (en) * 2004-09-09 2010-04-13 Merck Sharp & Dohme Corp. Tricyclic anilide spirolactam CGRP receptor antagonists
CA2579850A1 (fr) * 2004-09-13 2006-03-23 Merck & Co., Inc. Antagoniste des recepteurs cgrp spirohydantoin anilide tricyclique

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JP2002526758A (ja) * 1998-10-05 2002-08-20 ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク 或る化合物がペプチドと後生的糖化最終産物受容体（ｒａｇｅ）の相互作用を阻害することが可能かどうかを決定する方法。
EP1127074A4 (fr) * 1998-10-05 2005-04-06 Univ Columbia Procedes pour determiner la capacite d'un compose d'inhiber l'interaction d'un peptide avec le recepteur d'un produit final de glycation evolue (rage)
EP1127074A1 (fr) * 1998-10-05 2001-08-29 The Trustees of Columbia University in the City of New York Procedes pour determiner la capacite d'un compose d'inhiber l'interaction d'un peptide avec le recepteur d'un produit final de glycation evolue (rage)
WO2003104236A1 (fr) 2002-06-01 2003-12-18 Bristol-Myers Squibb Company Antagonistes des recepteurs du peptide relie au gene de la calcitonine
US7754732B2 (en) 2002-06-05 2010-07-13 Bristol-Myers Squibb Company Spirocyclic anti-migraine compounds
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7314883B2 (en) 2002-06-05 2008-01-01 Bristol-Myers Squibb Company Anti-migraine treatments
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
CN1812982B (zh) * 2003-06-26 2010-10-27 默沙东公司 苯并二氮杂*cgrp受体拮抗剂
WO2005065779A1 (fr) 2003-12-05 2005-07-21 Bristol-Myers Squibb Company Antagonistes du recepteur peptidique lie au gene de la calcitonine
US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
US7772244B2 (en) 2004-03-29 2010-08-10 Bristol-Myers Squibb Company Therapeutic agents for the treatment of migraine
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
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US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
US20150361173A1 (en) 2005-11-14 2015-12-17 Labrys Biologics, Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US9884907B2 (en) 2005-11-14 2018-02-06 Teva Pharmaceuticals International Gmbh Methods for treating headache using antagonist antibodies directed against calcitonin gene-related peptide
EP3045182B1 (fr) * 2005-11-14 2018-03-07 Teva Pharmaceuticals International GmbH Anticorps antagonistes dirigés contre le peptide relatif au gene calcitonine pour le traitement de la migraine de cluster
US9115194B2 (en) 2005-11-14 2015-08-25 Labrys Biologics, Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
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