WO1998056779A1 - 4-sulfinyl benzamides as calcitonin gene-related peptide receptor antagonists - Google Patents

4-sulfinyl benzamides as calcitonin gene-related peptide receptor antagonists Download PDF

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WO1998056779A1
WO1998056779A1 PCT/US1998/012304 US9812304W WO9856779A1 WO 1998056779 A1 WO1998056779 A1 WO 1998056779A1 US 9812304 W US9812304 W US 9812304W WO 9856779 A1 WO9856779 A1 WO 9856779A1
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methyl
methylphenyl
nitrobenzamide
sulfinyl
formula
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PCT/US1998/012304
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French (fr)
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Robert A. Daines
Pamela A. Chambers
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical

Definitions

  • This invention relates to 4-sulfinyl benzamide 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 (“NIDDM”); neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans, by the use of CGRP receptor ligands, in particular, 4-sulfinyl benzamide antagonists, thereof.
  • NIDDM 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 pain transmission (Collin et al., Pain, Vol. 54, p. 20 (1993); and J. NeuroscL, Vol. 16, No. 7, pp. 2342-2351 (1996)); peripheral and cerebral vasodilation (Brain et al., Nature, Vol. 313, pp. 54-56 (1985)); cardiac acceleration (Sigrist et al.,
  • CGRP cardiovascular disease 2019
  • CGRP-mediated diseases all in mammals, preferably humans
  • the present invention is to a genus of novel compounds of formula (I), or pharmaceutically active salts thereof, said compounds which are also useful in treating the above-mentioned CGRP-mediated disease states:
  • Q is NO2 or NH2
  • Y is hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano;
  • Ri is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl;
  • R 2 is H, methyl, C 2 _4 alkyl, CH2-A-CONR3R , CH2-A-CO R 5 , CH -A-COR 5 , CH 2 -A-SO 2 NR3R4 ; CH 2 -A-N(R 3 )SO R 5 , CH2-A-N(R3)COR 5 , CH2-A-N(R3)C ⁇ 2R 6 , CH2-A-N(R 3 )C(O)NR 3 R 4 , CH2-A-N(R3)C(O)NR3SO 2 R 5 . or CH 2 -A-OC(O)NR 3 R4 ;
  • A is (CH2) n where n is 0-6, or C6H4;
  • R3 and R4 independently are H, C ⁇ g alkyl, or C 1.4 alkylphenyl, or R3 and R , together with the nitrogen to which they are attached, form a 5-, 6-, or
  • 7-membered heteroring such as piperidine, piperazine, or morpholine
  • R5 is methyl, trifluoromethyl, C2-6 alkyl (including branched alkyls), phenyl, or heteroaryl;
  • R6 is tert-butyl, CH2-phenyl, or CH2-pyridinyl; m is 0, 1 or 2; and
  • Ar is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
  • the present invention is to a method of treating CGRP mediated diseases, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a 4-sulfinyl benzamide compound of formula (I), or a pharmaceutically active salt thereof.
  • the present invention is to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically active salt thereof, 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; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans.
  • 4-sulfinyl benzamide 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 CGRP-mediated disease states.
  • 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.
  • alkoxy 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, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, 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.
  • heteroatoms are used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-, 6-, or 7-membered ring system which contains one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, and the like.
  • aryl or “heteroaryl” are used herein at all occurrences to mean substituted and unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and heteroaryl moieties, which may include, but are not limited to, heteroatoms selected from O, N, or S.
  • Representative examples include, but are not limited to, phenyl, benzyl, naphthyl, pyridyl, quinolinyl, thiazinyl, furanyl, imidazolidine, pyrazolidine, thiazole, immidazole, thiadiazole, triazole, benzothiazole, and the like.
  • 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.
  • pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic 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.
  • inorganic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide and nitrate
  • an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- tolu
  • pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic (particularly when oxidation of the sulfide results in a racemic mixture of sulfoxides) and optically active forms.
  • the stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention. Also within the scope of this invention are the corresponding sulfides of the examples cited herein which may serve as prodrug forms of the active sulfoxides.
  • Q is suitably NO2 or NH2.
  • Q is preferably NO2.
  • Y is suitably hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano.
  • Ri is suitably phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
  • R is preferably substituted phenyl.
  • substituted means that the phenyl or heteroaryl moiety is substituted with one or more, up to three, of the following functional groups, C ⁇ . ⁇ alkyl, halo, alkoxy, CF3, CN, or NO2.
  • the phenyl or heteroaryl moiety is substituted by C1.4 alkyl.
  • the phenyl or heteroaryl moiety is substituted by Cj_4 alkyl, in the ortho position.
  • R 2 is suitably H, methyl, C2-4 alkyl, CH 2 -A-CONR 3 R4, CH 2 -A-CO 2 R 5 , CH2-A-COR 5 , CH 2 -A-SO 2 NR3R4, CH2-A-N(R3)S ⁇ 2R 5 , CH2-A-N(R3)COR 5 , CH 2 -A-N(R 3 )CO 2 R 6 , CH 2 -A-N(R3)C(O)NR3R4. CH2-A-N(R3)C(O)NR 3 SO R 5 , or CH 2 -A-OC(O)NR3R4.
  • A is suitably (CH2) n where n is 0-6, or CgH4.
  • A is (CH2) n , wherein n is 2-4.
  • R3 and R independently are suitably H, C ⁇ 6 alkyl, or C 1.4 alkylphenyl, or R3 and R4, together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring such as piperidine, piperazine, or morpholine.
  • R5 is suitably methyl, trifluoromethyl, C2-6 alkyl (including branched alkyls), phenyl, or heteroaryl.
  • R6 is suitably tert-butyl, CH2-phenyl, or CH2-pyridinyl.
  • R ⁇ is tert-butyl or CH2 ⁇ phenyl.
  • Variable m is suitably 0, 1, or 2, preferably m is 1.
  • Ar is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
  • Ar is heteroaryl.
  • substituted means that the phenyl or heteroaryl moiety is substituted with one or more, up to three, of the following functional groups, ⁇ . alkyl, halo, alkoxy, carboxymethyl, CF3, CN, NO2, amino, or phenyl. It will be understood that the optional substituent(s) may be in an ortho, meta or para position on the phenyl or heteroaryl ring.
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient”) in an amount sufficient to treat headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; 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 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 or prophylaxis of CGRP mediated disease states.
  • 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.
  • topical formulations of the present invention 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. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • 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 CGRP-mediated diseases with an antagonist as depicted in formula (I).
  • treating is meant either prophylactic or therapeutic therapy.
  • Such 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 a CGRP-mediated disease state, 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.
  • the optimal quantity and spacing of individual dosages of a formula (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. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • This reaction may be accomplished in any of a variety of reaction inert solvents by mixing approximately equimolar amounts of a compound of Formula II and the aryl thiol in the presence of a base at or below room temperature.
  • DMF is the preferred solvent.
  • Suitable bases are potassium carbonate, DBU, and the like.
  • the reaction is allowed to proceed for about 2 hours to about 24 hours at which time the reaction is substantially complete. The completeness of a particular reaction may be measured by known techniques such as thin layer chromatography. The reaction mixture is then treated with sodium bicarbonate. The products of the reaction are isolated and purified by standard procedures.
  • the reaction mixture may be concentrated by evaporating the solvent and the residue may be partitioned between water and a convenient nonwater-miscible organic solvent such as ether, ethyl acetate, and the like.
  • the solvent may then be evaporated and the residue chromatographed, for example, on silica gel.
  • Choice of the proper chromatography solvent is within the skill of the art.
  • the product may be recrystallized.
  • Acid addition salts may be prepared using standard procedures. For example, a hydrochloride salt may be prepared by dissolving the free base in a convenient solvent and treating this solution with a solution of hydrogen chloride dissolved in the solvent of choice. The acid addition salts may be reconverted to the respective free base by treatment with a dilute solution of sodium hydroxide or potassium carbonate, for example.
  • the compounds of formula (I) are prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • Scheme 2 illustrates the preparation of the compound described in Example 1 (i.e., 8-Scheme 2).
  • Commercially available 4-fluoro-3-nitrobenzoic acid (4- Scheme 2) is converted to the acid chloride 5-Scheme 2 using a suitable agent such as, but not limited to, oxalyl chloride or thionyl chloride.
  • a suitable agent such as, but not limited to, oxalyl chloride or thionyl chloride.
  • this reaction may be carried out using methylene chloride as a solvent with the addition of a catalytic amount of dimethylformamide.
  • This acid chloride is next coupled to the desired aniline portion via standard acylation conditions (e.g., triethylamine, methylene chloride, 0 °C).
  • the acid 4-Scheme 2 may be directly coupled to the aniline using standard peptide coupling reagents (e.g., DCC or BOP, HOBT, N-methylmorpholine). Using these methods, the desired benzamide 6-Scheme 2 may be obtained.
  • N-methyl-o- toluidine is used to illustrate the process. Reaction of 6-Scheme 2 with an aryl thiol (aryl mercaptan) such as 2, 5-dichlorothiophenol in the presence of a base such as powdered potassium carbonate in an aprotic solvent such as dimethylformamide, produces the sulfide-containing benzamide 7-Scheme 2.
  • Conversion of the sulfide 7-Scheme 2 to the sulfoxide 8-Scheme 2 is then accomplished by treatment with a suitable oxidizing agent.
  • a suitable oxidizing agent in this example, 3-chloroperoxybenzoic acid (mCPBA) was used, however, other agents well known in the art could have been employed.
  • Reagents (a) oxalyl chloride, CH2CI2, cat. DMF, rt.; (b) N-methyl-o-toluidine, triethylamine, CH2CI2, 0 °C; (c) 2, 5-dichlorothiophenol, K2CO3, DMF, rt.; (d) mCPBA, CH 2 C1 2 , 0 °C.
  • Scheme 3 illustrates the case in which a 3, 4-dinitrobenzamide (i.e., wherein X of formula (II) is NO2) is utilized as a starting material (Example 31).
  • Acid chloride 9-Scheme 3 may be prepared using methods outlined above. Acylation as previously described using 9-Scheme 3 and an aniline provides the 3, 4-dinitrobenzamide 10-Scheme 3.
  • Conversion of 10-Scheme 3 to the desired sulfide is performed as described in Scheme 2 (aryl thiol, K2CO3, DMF).
  • 2-mercaptothiazole was employed as the aryl thiol to produce the sulfide 11-Scheme 3.
  • Oxidation as before (mCPBA) yields the target sulfoxide 12-Scheme 3.
  • Reagents a) 15, triethylamine, CH2CI2, 0 °C; b) 2-mercaptothiazole, K2CO3, DMF, rt.; c) mCPBA, CH 2 C1 2 , 0 °C.
  • Example 3 The racemic compound of Example 3 (50 mg) was separated into the title enantiomeric forms by preparative LC using Daicel Chiralcel® OD; 25 cm x 21.2 mm; ethanol, 100%; 8.0 mL/min; UV detection at 254 nm yielding the (+) sulfoxide enantiomer (19.9 mg) [ ⁇ ] ⁇ j +10.9° (c 0.9, CHCI3); HPLC tR 10.27 min (Daicel Chiralcel® OD; 25 cm x 4.6 mm; ethanohhexane, 60:40, 1.0 mL/min; UV detection at 215 nm)and the (-) sulfoxide enantiomer (18.1 mg) [ ⁇ ] > -11.6 (c 0.80, CHCI3); HPLC t R 20.25 min (Daicel Chiralcel® OD; 25 cm x 4.6 mm; ethanohhexane, 60:40, 1.0 mL/min
  • Example 15 Preparation of ( ⁇ )-methyl 2-IT4-rrmethyl-(2- methylphenyl ) amino1carbonyll-3-nitrophenvnsulfinyllbenzoate Prepared according to Example 1 by substituting methyl thiosalicylate for 2, 5-dichlorothiophenol. MS(ES) m/e 453.3 [M+H]+ 475.2 [M+Na]+.
  • Example 22 Preparation of ( ⁇ )-4-r(3-methoxyphenyl)sulf ⁇ nyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide Prepared according to Example 1 by substituting 3-methoxythiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 425.0 [M+H]+.
  • Example 29 Preparation of (+)-N-methvI-N-(2-methylphenyl)-4-r(5-methyl-l. 3, 4-thiadiazol-2-yl)sulfinyll-3-nitrobenzamide Prepared according to Example 1 by substituting 2-mercapto-5- methylthiadiazole for 2, 5-dichlorothiophenol. MS(ES) m e 417.2 [M+H]+.
  • Example 32 Preparation of ( ⁇ )-3-amino-4-IY2-chlorophenyl)sulfinyll-N- methyl-N-(2-methylphenyl benzamide
  • test compounds were assayed for the inhibition of [ 125 I ] CGRP (obtained from Amersham, Chicago, DM) binding and CGRP-activated adenylate cyclase activity.
  • 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 MgCt ⁇ 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 2 , 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.
  • Adenylate cyclase activity was measured in triplicate as the rate of conversion of oc[ 32 P]ATP to [ 32 P]cAMP as previously described (Aiyer et al.,
  • Human neuroblastoma cell ( SK- N-MC ) membranes [40-60 ⁇ g] were incubated in triplicate in buffer containing 50 mM Tris-HCl (pH 7.4), 10 nM MgCl 2 , 1.2 mM ATP, 1.0 ⁇ Ci ⁇ [ 3 P]ATP, 0.1 mM cAMP, 2.8 nM phosphoenolpyruvate and 5.2 ⁇ g/ml myokinase in a final volume of 100 ⁇ l for 20 min at 30°C.
  • the compounds of this invention show CGRP receptor antagonist activity having IC50 values in the range of 0.001 to 100 ⁇ M.
  • the full 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.

Abstract

This invention relates to 4-sulfinyl benzamide compounds which are ligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide ('CGRP') receptor. In addition, 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; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, by the use of 4-sulfinyl benzamide CGRP receptor antagonists.

Description

4-SULFLNYL BENZAMIDES AS CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION This invention relates to 4-sulfinyl benzamide compounds which are ligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide (hereinafter "CGRP") receptor. In addition, 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 ("NIDDM"); neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans, by the use of CGRP receptor ligands, in particular, 4-sulfinyl benzamide antagonists, thereof.
BACKGROUND OF THE INVENTION
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. (Goodman et al., Life Sci., Vol. 38, pp. 2169-2172 (1986)). CGRP has been detected in nerves innervating the heart, peripheral and cerebral blood vessels, and kidneys by immunohistochemical and radioimmunoassay methods. (Yamamoto et al., Prog. Neurobiol., Vol. 33, pp. 335-386 (1989)). 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. The widespread distribution of CGRP receptors on muscle, glandular, epithelial and neuronal cells is consistent with its wide range of biological actions, including pain transmission (Collin et al., Pain, Vol. 54, p. 20 (1993); and J. NeuroscL, Vol. 16, No. 7, pp. 2342-2351 (1996)); 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. 1167-1171 (1985)); regulation of glucose metabolism, e.g., reduction of insulin secretion and insulin sensitivity, (Hermansen et al., Peptides, Vol. 27, pp. 149-157 (1990); and Molina et al., Diabetes, Vol. 39, pp. 260-265 (1990)); reduction of appetite and reduction of growth hormone increase (Tannenbaum et al., Endocrinology, Vol. 116, pp. 2685-2687 (1985)); reduction of inflammation of the skin, for example in allergic contact dermatitis (Gutwald et al., J. Invest. Derm., Vol. 96, pp. 695-698 (1991)) and other inflammatory skin conditions (Buckley et al., Neuroscience, Vol. 48, pp. 963-968 (1992); and Escott et al., Rr. J. Pharmacol, Vol. 110, pp. 772-776 (1993)).
Since CGRP has a number of effects on the cardiovascular, central nervous, gastrointestinal, respiratory, and endocrine systems, it has now been discovered that limited and selective inhibition of 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. In particular, the development of 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; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans ("CGRP-mediated diseases"). Surprisingly, it has now been discovered that a class of non-peptide compounds, in particular 4-sulfinyl benzamides of formula (I) function as CGRP receptor antagonists, and therefore, have utility in the treatment of disease states wherein inhibition of CGRP receptor mechanisms is indicated for prevention or therapeutic treatment thereof.
SUMMARY OF THE INVENTION
In one aspect, the present invention is to a genus of novel compounds of formula (I), or pharmaceutically active salts thereof, said compounds which are also useful in treating the above-mentioned CGRP-mediated disease states:
Figure imgf000004_0001
Formula (I) wherein:
Q is NO2 or NH2;
Y is hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano;
Ri is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl; R2 is H, methyl, C2_4 alkyl, CH2-A-CONR3R , CH2-A-CO R5, CH -A-COR5, CH2-A-SO2NR3R4; CH2-A-N(R3)SO R5, CH2-A-N(R3)COR5, CH2-A-N(R3)Cθ2R6, CH2-A-N(R3)C(O)NR3R4, CH2-A-N(R3)C(O)NR3SO2R5. or CH2-A-OC(O)NR3R4; A is (CH2)n where n is 0-6, or C6H4;
R3 and R4 independently are H, Cμg alkyl, or C 1.4 alkylphenyl, or R3 and R , together with the nitrogen to which they are attached, form a 5-, 6-, or
7-membered heteroring such as piperidine, piperazine, or morpholine;
R5 is methyl, trifluoromethyl, C2-6 alkyl (including branched alkyls), phenyl, or heteroaryl;
R6 is tert-butyl, CH2-phenyl, or CH2-pyridinyl; m is 0, 1 or 2; and
Ar is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
In another aspect, the present invention is to a method of treating CGRP mediated diseases, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a 4-sulfinyl benzamide compound of formula (I), or a pharmaceutically active salt thereof.
In yet another aspect, the present invention is to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier therefor. In particular, the pharmaceutical compositions of the present invention are used for treating CGRP- mediated disease states, including, but not limited to headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; and asthma, all in mammals, preferably humans.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that 4-sulfinyl benzamide 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 CGRP-mediated disease states. The term "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.
The term "alkoxy" 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, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine. The term "heteroring" is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-, 6-, or 7-membered ring system which contains one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, and the like. The terms "aryl" or "heteroaryl" are used herein at all occurrences to mean substituted and unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and heteroaryl moieties, which may include, but are not limited to, heteroatoms selected from O, N, or S. Representative examples include, but are not limited to, phenyl, benzyl, naphthyl, pyridyl, quinolinyl, thiazinyl, furanyl, imidazolidine, pyrazolidine, thiazole, immidazole, thiadiazole, triazole, benzothiazole, and the like.
The term "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. Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic 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. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic (particularly when oxidation of the sulfide results in a racemic mixture of sulfoxides) and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention. Also within the scope of this invention are the corresponding sulfides of the examples cited herein which may serve as prodrug forms of the active sulfoxides.
For the compounds of formula (I) various embodiments are as follows.
Q is suitably NO2 or NH2. Q is preferably NO2.
Y is suitably hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano.
Ri is suitably phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl. R is preferably substituted phenyl. As used herein for Ri , the term "substituted" means that the phenyl or heteroaryl moiety is substituted with one or more, up to three, of the following functional groups, C\.^ alkyl, halo, alkoxy, CF3, CN, or NO2. Preferably, the phenyl or heteroaryl moiety is substituted by C1.4 alkyl. Most preferably, the phenyl or heteroaryl moiety is substituted by Cj_4 alkyl, in the ortho position.
R2 is suitably H, methyl, C2-4 alkyl, CH2-A-CONR3R4, CH2-A-CO2R5, CH2-A-COR5, CH2-A-SO2NR3R4, CH2-A-N(R3)Sθ2R5, CH2-A-N(R3)COR5, CH2-A-N(R3)CO2R6, CH2-A-N(R3)C(O)NR3R4. CH2-A-N(R3)C(O)NR3SO R5, or CH2-A-OC(O)NR3R4. A is suitably (CH2)n where n is 0-6, or CgH4. Preferably, A is (CH2)n, wherein n is 2-4.
R3 and R independently are suitably H, Cμ6 alkyl, or C 1.4 alkylphenyl, or R3 and R4, together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring such as piperidine, piperazine, or morpholine. R5 is suitably methyl, trifluoromethyl, C2-6 alkyl (including branched alkyls), phenyl, or heteroaryl.
R6 is suitably tert-butyl, CH2-phenyl, or CH2-pyridinyl. Preferably, R^ is tert-butyl or CH2~phenyl.
Variable m is suitably 0, 1, or 2, preferably m is 1. Ar is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
Preferably, Ar is heteroaryl. As used herein for Ar, the term "substituted" means that the phenyl or heteroaryl moiety is substituted with one or more, up to three, of the following functional groups, \. alkyl, halo, alkoxy, carboxymethyl, CF3, CN, NO2, amino, or phenyl. It will be understood that the optional substituent(s) may be in an ortho, meta or para position on the phenyl or heteroaryl ring.
Among the preferred compounds of the invention are the following compounds:
(±)-4-[(2-chlorophenyl)sulfιnyl]-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide;
(+)-4-[(2-chlorophenyl)sulfιnyl]-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide; (-)-4-[(2-chlorophenyl)sulfιnyl]-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide;
(±)-4-[(4-chlorophenyl)sulfιnyl]-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide;
(±)-N-methyl-N-(2-methylphenyl)-4-[(l-oxido-2-pyridinyl)sulfιnyl]-3- nitrobenzamide;
(±)-N-methyl-N-(2-methylphenyl)-3-nitro-4-(2- thiazolylsulfιnyl)benzamide;
(±)-N-methyl-N-(2-methylphenyl)-4-[(5-methyl- 1, 3, 4-thiadiazol-2- yl)sulfιnyl]-3-nitrobenzamide; and N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3-nitro-4-(2- thiazolylsulfinyl)benzamide.
Formulation of Pharmaceutical Compositions
The pharmaceutically effective compounds of this invention (and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") in an amount sufficient to treat headaches, especially migraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronic inflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skin conditions; 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. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, 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.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, 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. 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 or prophylaxis of CGRP mediated disease states. 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.
By topical administration is meant 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. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
While it is possible for an active ingredient to 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. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of 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. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. 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. 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. By "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. In one aspect, this invention relates to a method of treating CGRP-mediated diseases with an antagonist as depicted in formula (I). By the term "treating" is meant either prophylactic or therapeutic therapy. Such 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 a CGRP-mediated disease state, in an amount sufficient to decrease symptoms associated with these disease states. The route of administration may be oral or parenteral.
The term 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 formula (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. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
Methods of Preparation
Generally, the compounds of the invention may be prepared by the following reaction sequence: Scheme 1
idation
Figure imgf000012_0001
Figure imgf000012_0002
Formula I
Scheme 1 illustrates a process in which a 3-nitrobenzamide of formula (II)
(1-Scheme 1), containing a suitable leaving group X which is a halogen, preferably, fluorine, or a nitro group, is treated with an aryl thiol in the presence of a base. This process produces the sulfide of formula (III) (2-Scheme 1) which is then converted to the desired sulfoxide of formula (I) (3-Scheme 1) by using an appropriate oxidizing agent. R* and R2 are as defined above. Specific examples of this process are given in Schemes 2 and 3.
This reaction may be accomplished in any of a variety of reaction inert solvents by mixing approximately equimolar amounts of a compound of Formula II and the aryl thiol in the presence of a base at or below room temperature. The proper choice of reaction variables is within the skill of the art. DMF is the preferred solvent. Suitable bases are potassium carbonate, DBU, and the like. In general, the reaction is allowed to proceed for about 2 hours to about 24 hours at which time the reaction is substantially complete. The completeness of a particular reaction may be measured by known techniques such as thin layer chromatography. The reaction mixture is then treated with sodium bicarbonate. The products of the reaction are isolated and purified by standard procedures. For example, the reaction mixture may be concentrated by evaporating the solvent and the residue may be partitioned between water and a convenient nonwater-miscible organic solvent such as ether, ethyl acetate, and the like. The solvent may then be evaporated and the residue chromatographed, for example, on silica gel. Choice of the proper chromatography solvent is within the skill of the art. After, or instead of, chromatography, the product may be recrystallized. Acid addition salts may be prepared using standard procedures. For example, a hydrochloride salt may be prepared by dissolving the free base in a convenient solvent and treating this solution with a solution of hydrogen chloride dissolved in the solvent of choice. The acid addition salts may be reconverted to the respective free base by treatment with a dilute solution of sodium hydroxide or potassium carbonate, for example.
The compounds of formula (I) are prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
Scheme 2 illustrates the preparation of the compound described in Example 1 (i.e., 8-Scheme 2). Commercially available 4-fluoro-3-nitrobenzoic acid (4- Scheme 2) is converted to the acid chloride 5-Scheme 2 using a suitable agent such as, but not limited to, oxalyl chloride or thionyl chloride. In the case of oxalyl chloride, this reaction may be carried out using methylene chloride as a solvent with the addition of a catalytic amount of dimethylformamide. This acid chloride is next coupled to the desired aniline portion via standard acylation conditions (e.g., triethylamine, methylene chloride, 0 °C). Alternatively, the acid 4-Scheme 2 may be directly coupled to the aniline using standard peptide coupling reagents (e.g., DCC or BOP, HOBT, N-methylmorpholine). Using these methods, the desired benzamide 6-Scheme 2 may be obtained. In this example, N-methyl-o- toluidine is used to illustrate the process. Reaction of 6-Scheme 2 with an aryl thiol (aryl mercaptan) such as 2, 5-dichlorothiophenol in the presence of a base such as powdered potassium carbonate in an aprotic solvent such as dimethylformamide, produces the sulfide-containing benzamide 7-Scheme 2. Conversion of the sulfide 7-Scheme 2 to the sulfoxide 8-Scheme 2 is then accomplished by treatment with a suitable oxidizing agent. In this example, 3-chloroperoxybenzoic acid (mCPBA) was used, however, other agents well known in the art could have been employed.
Scheme 2
Figure imgf000014_0001
Reagents: (a) oxalyl chloride, CH2CI2, cat. DMF, rt.; (b) N-methyl-o-toluidine, triethylamine, CH2CI2, 0 °C; (c) 2, 5-dichlorothiophenol, K2CO3, DMF, rt.; (d) mCPBA, CH2C12, 0 °C.
Scheme 3 illustrates the case in which a 3, 4-dinitrobenzamide (i.e., wherein X of formula (II) is NO2) is utilized as a starting material (Example 31). Acid chloride 9-Scheme 3 may be prepared using methods outlined above. Acylation as previously described using 9-Scheme 3 and an aniline provides the 3, 4-dinitrobenzamide 10-Scheme 3. Conversion of 10-Scheme 3 to the desired sulfide is performed as described in Scheme 2 (aryl thiol, K2CO3, DMF). In this example 2-mercaptothiazole was employed as the aryl thiol to produce the sulfide 11-Scheme 3. Oxidation as before (mCPBA) yields the target sulfoxide 12-Scheme 3.
Scheme 3
Figure imgf000015_0001
Reagents: a) 15, triethylamine, CH2CI2, 0 °C; b) 2-mercaptothiazole, K2CO3, DMF, rt.; c) mCPBA, CH2C12, 0 °C.
Preparation of the aniline 15-Scheme 4 used in the preparation of Example 31 (Scheme 3) is shown in Scheme 4. This procedure is quite general and may be used to prepare a wide range of anilines of which compound 15-Scheme 4 is just one example. In this particular example, 4-chlorobutyryl chloride (13-Scheme 4) is reacted with diethylamine to provide the diethylamide 14-Scheme 4. Alkylation of 2-ethylaniline using 14-Scheme 4 as the alkylating agent then provides 15-Scheme 4. Aniline 15-Scheme 4 is then used as illustrated in Scheme 3.
Scheme 4
Figure imgf000015_0002
Reagents: a) diethylamine, triethylamine, CH2CI2, 0 °C; b) 2-ethylaniline, triethylamine, DMF, 100 °C. EXAMPLES
Example 1. Preparation of (±)-4-.(2, 5-dichlorophenyl)sulfinyll-N-methyl-N- (2-methylphenyl)-3-nitrobenzamide a) 4-Fluoro-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide
To a stirred solution of 4-fluoro-3-nitrobenzoic acid (3.70 g, 20.0 mmol) in methylene chloride (50 mL) at 0° C was added oxalyl chloride (4.0 mL, 46.0 mmol), followed by dimethylformamide (luL). The reaction was stirred at ambient temperature for 1.5 h. The reaction solution was evaporated to dryness_under reduced pressure. The crude acid chloride was redissolved in methylene.chloride (40 mL) and added at 0°C to a stirred solution of N-methyl-o-toluidine (2.24 mL, 20.0 mL) and triethylamine (2.78 mL, 20.0 mL) in methylene chloride (20 mL). The reaction was stirred at ambient temperature for lh. After standing_for 18h, the reaction was treated with saturated sodium bicarbonate (60mL). The_organic layer was washed with brine, dried (MgSO4), and evaporated to yield a tan oil.
Crystallization from diethyl ether gave the title compound as a light beige solid (4.56g, 79%). MS(ES) m/e 289.1 [M+H]+. b) (±)-4-r(2. 5-Dichlorophenyl)thiol-N-methyl-N-C2-methylphenyl)-3- nitrobenzamide To a stirred solution of the compound of Example 1(a) (72mg, 0.25 mmol) in dimethylformamide (1.5 mL) was added 2, 5-dichlorothiophenol (49.2 mg, 0.275 mmol) and anhydrous powdered potassium carbonate (38.0 mg, 0.275 mmol). The reaction was stirred at ambient temperature. After 18 h, the reaction was treated with saturated sodium bicarbonate. The organic layer was washed with brine, dried (MgSO4) and evaporated to afford a yellow solid. MS(ES) m/e 447.1 [M+H]+, 469.1 [M+Na]+. c) (±)-4-IY2, 5-Dichlorophenyl)sulfιnyll-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide
To a stirred solution of the compound of Example 1 (b) ( 111.5 mg, 0.25 mmol) in methylene chloride (5 mL) at 0° C, was added 50% m- chloroperoxybenzoic acid (88.6 mg, 0.258 mmol). After 40 min, the reaction was treated with saturated sodium bicarbonate. The organic layer was washed with brine, dried (MgSO4) and evaporated to afford a yellow oil. Flash chromatography (silica gel, 2: 1 hexane:ethyl acetate) gave a pale yellow oil. Crystallization from diethyl ether yielded the title compound (59.4 mg, 51%). MS(ES) m/e 463.2 [M+H]+, 485.0 [M+Na]+; mp 168-171°C. The following compounds were purified either by flash column chromatography (silica gel, hexane/ethyl acetate), or by crystallization (ethyl acetate or diethyl ether).
Example 2. Preparation of (+)-N-methyl-N-(2-methylphenyl)-3-nitro-4- ( henylsul-lnyl benzamide
Prepared according to Example 1 by substituting thiophenol for 2, 5- dichlorothiophenol. MS(ES) m/e 395.2 [M+H]+, 417.2 [M+Na]+.
Example 3. Preparation of (+)-4-[Y2-chlorophenyl)sulfinyl1-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-chlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m e 429.1 [M+H]+, 451.1 [M+Na]+.
Example 4 and 5. Preparation of (+)-4-r(2-chlorophenyl)sulfinyll-N-methyl- N-(2-methylphenyl)-3-nitrobenzamide and (-)-4-r(2-chlorophenyl)sulfinyll-N- methyl-N-(2-methylphenyl)-3-nitrobenzamide
The racemic compound of Example 3 (50 mg) was separated into the title enantiomeric forms by preparative LC using Daicel Chiralcel® OD; 25 cm x 21.2 mm; ethanol, 100%; 8.0 mL/min; UV detection at 254 nm yielding the (+) sulfoxide enantiomer (19.9 mg) [α]τj +10.9° (c 0.9, CHCI3); HPLC tR 10.27 min (Daicel Chiralcel® OD; 25 cm x 4.6 mm; ethanohhexane, 60:40, 1.0 mL/min; UV detection at 215 nm)and the (-) sulfoxide enantiomer (18.1 mg) [α] > -11.6 (c 0.80, CHCI3); HPLC tR 20.25 min (Daicel Chiralcel® OD; 25 cm x 4.6 mm; ethanohhexane, 60:40, 1.0 mL/min; UV detection at 215 nm).
Example 6. Preparation of (±)-4-r(3-chlorophenyl)sulfinyll-N-methyl-N-(2- methylphenvD-3-nitrobenzamide
Prepared according to Example 1 by substituting 3-chlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m e 429.1 [M+H]+, 451.1 [M+Na]+.
Example 7. Preparation of (±)-4-fY4-chIorophenyl)sulfinvπ-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 4-chlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 429.1 [M+H]+, 451.1 [M+Na]+. Example 8. Preparation of (±)-4-IY2. 4-dichlorophenyl)sulfinyll-N-methyl-N- (2-methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2, 4-dichlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 463.2 [M+H]+, 485.0 [M+Na]+.
Example 9. Preparation of (± -4-IY3. 4-dichlorophenyl)sulfinyl .-N-methyl-N- (2-methylphenvD-3-nitrobenzamide
Prepared according to Example 1 by substituting 3, 4-dichlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m e 463.0 [M+H]+, 484.9 [M+Na]+.
Example 10. Preparation of (+)-4-r(2-bromophenyl)sulfιnyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-bromothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 472.8 [M+H]+.
Example 11. Preparation of (±)-4-F(4-fluorophenyl)suIfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 4-fluorothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 413.0 [M+H]+.
Example 12. Preparation of (±)-4-.(2-isopropylphenvI)suIfinvπ-N-methyl-N- (2-methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-isopropylthiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 437.2 [M+H]+.
Example 13. Preparation of (±)-4-r(2-methylphenyl)sulfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-methylthiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 406.9 [M-H]~, 431.3 [M+Na]+.
Example 14. Preparation of (+)-4-r(2-methoxyphenyl)sulfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-methoxythiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 425.2 [M+H]+, 447.3 [M+Na]+.
Example 15. Preparation of (±)-methyl 2-IT4-rrmethyl-(2- methylphenyl)amino1carbonyll-3-nitrophenvnsulfinyllbenzoate Prepared according to Example 1 by substituting methyl thiosalicylate for 2, 5-dichlorothiophenol. MS(ES) m/e 453.3 [M+H]+ 475.2 [M+Na]+.
Example 16. Preparation of (±)-4-r(4-bromophenyl)sulfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 4-bromothiophenol for 2, 5-dichlorothiophenol. MS(ES) m e 473.0 [M+H]+.
Example 17. Preparation of (±)-N-methyl-N-(2-methylphenyl)-3-nitro-4-(2- pyrimidinylsulfinvObenzamide
Prepared according to Example 1 by substituting 2-mercaptopyrimidine for 2, 5-dichlorothiophenol. MS(ES) m/e 397.2 [M+H]+, 419.2 [M+Na]+.
Example 18. Preparation of (±)-N-methyl-N-(2-methylphenyl)-4-r(4-methyl-2- pyrimidinyl)sulfinyl1-3-nitrobenzamide
Prepared according to Example 1 by substituting 4-methyl-2- mercaptopyrimidine for 2, 5-dichlorothiophenol. MS(ES) m/e 411.1 [M+H]+, 433.0 [M+Na]+.
Example 19. Preparation of f+)-N-methyl-N-(2-methylphenvn-4-[Yl-methyI-2- imidazolyl)sulfinvn-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-mercapto-l- methylimidazole for 2, 5-dichlorothiophenol. MS(ES) m/e 399.3 [M+H]+.
Example 20. Preparation of (±)-4-r(2-aminophenyl)sulfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-aminothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 410.3 [M+H]+.
Example 21. Preparation of (+)-4-r(3-aminophenyl)sulfinvπ-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 3-aminothiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 410.1 [M+H]+.
Example 22. Preparation of (±)-4-r(3-methoxyphenyl)sulfιnyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide Prepared according to Example 1 by substituting 3-methoxythiophenol for 2, 5-dichlorothiophenol. MS(ES) m/e 425.0 [M+H]+.
Example 23. Preparation of (±)-N-methyl-N-(2-methylphenyl)-4-fYl-oxido-2- pyridinyl)sulfinvn-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-mercaptopyridine-N- oxide for 2, 5-dichlorothiophenol. MS(ES) m e 412.1 [M+H]+, 434.1 [M+Na]+.
Example 24. Preparation of (±)-4-r(4-aminophenyl)sulfinyll-N-methyl-N-(2- methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting 4-aminothiophenol for 2, 5-dichlorothioρhenol. MS(ES) m/e 410.1 [M+H]+.
Example 25. Preparation of (+)-4-r(5-amino-lH-l. 2. 4,-triazol-3-vI sulfinyl- N-methyl-N-(2-methylphenyl)-3-nitrobenzamide
Prepared according to Example 1 by substituting by 3-amino-5-mercapto-l, 2, 4-triazole for 2, 5-dichlorothiophenol. MS(ES) m e 401.1 [M+H]+, 399.1 [M-H]-.
Example 26. Preparation of (±)-N-methyl-N-(2-methylphenyl)-4-fY4-phenyl-2- thiazolyl)sulfinyll-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-mercapto-4- phenylthiazole for 2, 5-dichlorothiophenol. MS(ES) m e 478.0 [M+H]+.
Example 27. Preparation of (±)-N-methyl-N-(2-methyIphenyI)-3-nitro-4-(2- thiazoIylsulfinvDbenzamide
Prepared according to Example 1 by substituting 2-mercaptothiazole for 2, 5-dichlorothiophenol. MS (ES) m/e 402.1 [M+H]+
Example 28. Preparation of (±)-N-methvI-N-(2-methvIphenyl)-4-r(2- naphthyl)sulfinvn-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-mercaptonaphthalene for 2, 5-dichlorothiophenol. MS (ES) m/e 445.1 [M+H]+.
Example 29. Preparation of (+)-N-methvI-N-(2-methylphenyl)-4-r(5-methyl-l. 3, 4-thiadiazol-2-yl)sulfinyll-3-nitrobenzamide Prepared according to Example 1 by substituting 2-mercapto-5- methylthiadiazole for 2, 5-dichlorothiophenol. MS(ES) m e 417.2 [M+H]+.
Example 30. Preparation of (±)-N-(2-n-butylphenvD-4-.(4- chlorophenyl)sulfinyll-3-nitrobenzamide
Prepared according to Example 1 by substituting 2-n-butylaniline for N- methyl-o-toluidine and 4-chlorothiophenol for 2, 5-dichlorothiophenol. MS(ES) 457.0 [M+H]+.
Example 31. Preparation of N-r3-r(diethylamino)carbonyllpropyll-N-(2- ethylphenyl)-3-nitro-4-(2-thiazolylsulfinyl benzamide a) N-r3-r(Diethylamino)carbonyllpropyl]-2-ethylaniline
A solution of diethylamine (1.4 mL, 13.7 mmol) in methylene chloride (20mL) was cooled to 0 °C and treated with triethylamine (2.1 mL, 15 mmol) and 4-chlorobutyryl chloride (1.7 mL, 15 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was diluted with methylene chloride and washed with 10% HC1, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude oil was pump-dried overnight and used directly in the following step. A solution of 2-ethylaniline (250 mg, 2.06 mmol) in N, N- dimethylformamide (6 mL) was treated with the crude chloride prepared above (550 mg, 3.1 mmol), triethylamine (0.48 mL, 3.4 mmol), and tetra-n- butylammonium iodide (74 mg, 0.2 mmol). The resulting mixture was stirred at 90 °C for 20 hours. The reaction was diluted with ethyl acetate and washed with water, 10% HC1, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (silica, 20:10:70 and 30:10:60 ethyl acetate-methylene chloride-hexane) to afford the title compound (215 mg, 40%) as a viscous light brown oil. H NMR (400 MHz, CDCI3) 67.11 (t, IH), 7.06 (d, IH), 6.69 (t, IH), 6.61 (d, IH), 4.10 (bs, IH), 3.40 (m, 2H), 3.30 (m, 2H), 3.21 (t, 2H), 2.62-2.40 (m, 4H), 2.13-2.02 (m, 2H), 1.25 (t, 3H), 1.08-1.24 (m, 6H). b) N-r3-r(Diethylamino)carbonyllpropyn-N-(2-ethylphenyl)-3. 4- dinitrobenzamide
A solution of the compound of Example 31(a) (211 mg, 0.807 mmol) in methylene chloride (2.2 mL) was cooled to 0 °C and treated with triethylamine
(0.12 mL, 0.85 mmol) and 3, 4-dinitrobenzoyl chloride (195 mg, 0.85 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was diluted with methylene chloride and washed with 10% HC1, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (silica, 30:10:60, 40:10:50, and 50:10:40 ethyl acetate-methylene chloride-hexane) to afford the title compound (242 mg, 66%) as a golden yellow oil. MS (ES) m/e 457.1 [M+H]+. c) N-r3r(Diethylamino carbonyllpropyn-N-(2-ethylphenyl)-3-nitro-4-(2- thiazolvIthio)benzamide
A solution of the compound of Example 31 (b) (50.5 mg, 0.11 mmol) in acetonitrile (1 mL) was treated with 2-mercaptothiazole (19 mg, 0.165 mmol) and potassium carbonate (23 mg, 0.165 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction was diluted with methylene chloride and washed with 10% HC1, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (50 mg, 86%) as a viscous golden yellow oil. MS (ES) m/e 527.2 [M+H]+. d) N-r3-r(Diethylamino)carbonyllpropyll-N-(2-ethylphenyl)-3-nitro-4-(2- thiazolylsulfinvPbenzamide
A solution of the compound of Example 31 (c) (39 mg, 0.074 mmol) in methylene chloride (1.5 mL) was cooled to 0 °C and treated with 3- chloroperoxybenzoic acid (26.4 mg, 0.076 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 1 h. The reaction was diluted with methylene chloride and washed with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (silica, 1% and 3% methanol in methylene chloride) to afford the title compound (32 mg, 81%) as a viscous light golden yellow oil. MS (ES) m e 543.1 [M+H]+.
Example 32. Preparation of (±)-3-amino-4-IY2-chlorophenyl)sulfinyll-N- methyl-N-(2-methylphenyl benzamide A mixture of 4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3- nitrobenzamide (21 mg, 0.049 mmol), obtained as described in Example 3, and anhydrous stannous chloride (48 mg, 0.253 mmol) in absolute ethanol was heated at 65-70° under argon for 30 minutes. The reaction was cooled to room temperature, basified to pH 8 with saturated sodium bicarbonate, diluted with water (3 mL) and extracted with ethyl acetate (x3). The combined organic extract was washed with saturated brine, evaporated to dryness in vacuo and pumped to constant weight to give the title compound (16 mg, 83%). Mp 147-150°C; MS(ES) m/e 399 [M+H]+.
BIOLOGICAL DATA Effect of Compounds on the CGRP Receptor
The test compounds were assayed for the inhibition of [125I ] CGRP (obtained from Amersham, Chicago, DM) binding and CGRP-activated adenylate cyclase activity.
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% CO2 and 95% air.
r125Il CGRP Bindine assay:
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 MgCtø 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 [125I] CGRP receptor binding assay was performed using a buffer containing 20 mM Na-HEPES pH 7.4, 10 mM MgCl2, 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 [125I] 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.
Adenylate cyclase activity:
Adenylate cyclase activity was measured in triplicate as the rate of conversion of oc[32P]ATP to [32P]cAMP as previously described (Aiyer et al.,
Endocrinology, Vol. 129, pp. 965-969 (1991)). Human neuroblastoma cell ( SK- N-MC ) membranes [40-60 μg] were incubated in triplicate in buffer containing 50 mM Tris-HCl (pH 7.4), 10 nM MgCl2, 1.2 mM ATP, 1.0 μCi α[3 P]ATP, 0.1 mM cAMP, 2.8 nM phosphoenolpyruvate and 5.2 μg/ml myokinase in a final volume of 100 μl for 20 min at 30°C. The reactions were stopped with 1 ml solution containing cAMP, ATP and 22000 cpm of [3H] cAMP. [32P]cAMP was separated using sequential chromatography (Dowex and alumina columns) (Salmon et al., Ana. Biochem. Vol. 58, pp. 541-548 (1974)). Adenylate cyclase activities were determined in the absence (basal) or presence of 2.5 nM of hCGRPα with various concentrations (0.1 μM to 30 μM ) of compound.
The compounds of this invention show CGRP receptor antagonist activity having IC50 values in the range of 0.001 to 100 μM. The full structure/activity relationship has not yet been established for the compounds of this invention. However, given the disclosure herein, 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 μM.
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. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000025_0001
Formula (I) wherein:
Q is NO2 or NH2;
Y is hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano;
Ri is phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
R2 is H, methyl, C2-4 alkyl, CH2-A-CONR R4, CH -A-CO2R5, CH2-A-COR5,
CH2-A-SO2NR3R4, CH2-A-N(R3)S╬╕2R5, CH2-A-N(R3)COR5,
CH2-A-N(R3)CO2R6, CH2-A-N(R3)C(O)NR3R4,
CH2-A-N(R3)C(O)NR3SO R5, or CH2-A-OC(O)NR R4; A is (CH2)n where n is 0-6, or CgH4; R and R4 independently are H, C g alkyl, or C 1.4 alkylphenyl, or R3 and R4, together with the nitrogen to which they are attached, form a 5-, 6-, or
7-membered heteroring; R5 is methyl, trifluoromethyl, C2-6 alkyl, phenyl, heteroaryl; R6 is tert-butyl, CH2-phenyl, CH2-ρyridinyl; m is 0, 1 or 2; and Ar is phenyl, substituted phenyl, heteroaryl, substituted heteroaryl.
2. The compound as claimed in claim 1 selected from: (┬▒)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide; (+)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide; (-)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide; (+)-4-[(4-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide; (┬▒)-N-methyl-N-(2-methylphenyl)-4-[(l-oxido-2-pyridinyl)sulfinyl]-3- nitrobenzamide; (┬▒)-N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulf╬╣nyl)benzamide; (┬▒)-N-methyl-N-(2-methylphenyl)-4-[(5-methyl- 1, 3, 4-thiadiazol-2-yl)sulfinyl]-3- nitrobenzamide; and
N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3-nitro-4-(2- thiazolylsulf╬╣nyl)benzamide.
3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.
4. A method of treating a CGRP-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000026_0001
Formula (I) wherein:
Q is NO2 or NH2;
Y is hydrogen, halo, CF3, alkyl, alkoxy, NO2, cyano;
Ri is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl;
R2 is H, methyl, C2_4 alkyl, CH2-A-CONR3R4, CH2-A-CO2R5, CH2-A-COR5, CH2-A-S╬╕2NR3R4, CH -A-N(R3)SO2R5, CH2-A-N(R3)COR5, CH2-A-N(R3)CO2R6, CH2-A-N(R3)C(O)NR3R4) CH2-A-N(R3)C(O)NR3S╬╕2R5, or CH2-A-OC(O)NR3R4;
A is (CH2)n where n is 0-6, or CgH4;
R3 and R4 independently are H, C 6 alkyl, or C 1.4 alkylphenyl, or R3 and R , together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring such as piperidine, piperazine, or morpholine;
R5 is methyl, trifluoromethyl, C2-6 alkyl, phenyl, or heteroaryl;
R6 is tert-butyl, CH2-phenyl, or CH2-pyridinyl; m is 0, 1 or 2; and
Ar is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl.
5. The method as claimed in claim 3 wherein the compound of formula (I) is a compound selected from: (┬▒)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide;
(+)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide;
(-)-4-[(2-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide;
(┬▒)-4-[(4-chlorophenyl)sulfinyl]-N-methyl-N-(2-methylphenyl)-3-nitrobenzamide;
(┬▒)-N-methyl-N-(2-methylphenyl)-4-[(l-oxido-2-pyridinyl)sulfinyl]-3- nitrobenzamide;
(┬▒)-N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)benzamide;
(┬▒)-N-methyl-N-(2-methylphenyl)-4-[(5-methyl- 1, 3, 4-thiadiazol-2-yl)sulfinyl]-3- nitrobenzamide; and
N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3-nitro-4-(2- thiazolylsulfinyl)benzamide.
6. A process for preparing a compound defined in claim 1 having the structure of formula (I)
Figure imgf000027_0001
which comprises the steps of:
(a) reacting a suitable aryl thiol compound with a compound of formula (II)
Figure imgf000027_0002
Formula (II)
wherein, X is a suitable leaving group selected from halogen and NO2, and R1, R2 and Y are defined in claim 1, in the presence of a base to provide a compound of formula (HI)
Figure imgf000028_0001
Formula (HI) and
(b) oxidizing the compound of formula (HI) with an appropriate oxidizing agent to provide a compound of formula (I).
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