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WO1998009630A1 - Composes et methodes - Google Patents

Composes et methodes Download PDF

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Publication number
WO1998009630A1
WO1998009630A1 PCT/US1997/015931 US9715931W WO9809630A1 WO 1998009630 A1 WO1998009630 A1 WO 1998009630A1 US 9715931 W US9715931 W US 9715931W WO 9809630 A1 WO9809630 A1 WO 9809630A1
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WIPO (PCT)
Prior art keywords
dinitrobenzamide
dinitrobenz
amide
methyl
phenyl
Prior art date
Application number
PCT/US1997/015931
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English (en)
Inventor
Robert A. Daines
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP97940951A priority Critical patent/EP0934068A1/fr
Priority to JP51299498A priority patent/JP2002511836A/ja
Priority to AU42616/97A priority patent/AU4261697A/en
Priority to CA002264942A priority patent/CA2264942A1/fr
Publication of WO1998009630A1 publication Critical patent/WO1998009630A1/fr

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    • A—HUMAN NECESSITIES
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to 3,4-dinitrobenzamide 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 migr ⁇ nes; non-insulin dependent diabetes mellitus (“NIDDM”); neurogenic inflammation; cardiov.ascular disorders; chronic infl.ammation; p.ain; endotoxic shock; .arthritis; .allergic rhinitis; .allergic contact dermatitis; inflammatory skin conditions; .and asthma, all in mammals, preferably humans, by the use of CGRP receptor lig ⁇ ds, in particular, 3,4-dinitrobenzamide antagonists, thereof.
  • NIDDM non-insulin dependent diabetes mellitus
  • NIDDM non-insulin
  • CGRP is a 37 amino acid polypeptide that is stored and released from nerve terminals in both the central nervous system .and the peripher ⁇ d nervous system. (Goodman et al., Life Sci., Vol. 38, pp. 2169-2172 (1986)). CGRP has been detected in nerves innervating the he.art, peripheral and cerebral blood vessels, and kidneys by immunohistochemic and radioimmunoassay methods. (Y ⁇ unamoto 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.
  • CGRP receptors belong to the family of G-protein coupled receptors.
  • the widespread distribution of CGRP receptors on muscle, glandular, epitheli ⁇ and neuronal cells is consistent with its wide range of biological actions, including pain transmission (Collin et ⁇ d., Pain, Vol. 54, p. 20 (1993); .and J. Neurosci., Vol. 16, No. 7, pp.2342-2351 (1996)); peripheral and cerebral vasodilation (Brain et al., Nature, Vol. 313, pp. 54-56 (1985)); car.di.ac acceleration (Sigrist et al., Endocrinology, Vol. 119, pp.
  • 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; infljunmatory skin conditions; .and asthma, all in mainmals, preferably humans ("CGRP-mediated diseases").
  • no ⁇ -peptide compounds in particular 3,4-dinitrobenzamides 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.
  • 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 dise.ase states:
  • R 1 is hydrogen, methyl, -(CH2) n . branched (3-6 carbon) al yl, -(CH2)nphenyl,
  • X is CH , oxygen or N-alkyl, or R 1 is -(CH 2 ) n NR 3 R 4 , or -(CH2) n Z.
  • Z is -CO2H, -CO 2 -alkyl, -CONR 3 R 4 , -N(R 3 )CO 2 R 3 , -N(R 3 )C(O)NR 3 R 4 , -OC(O)NR 3 R 4 , or -COR5, and wherein R 3 and R 4 are independently hydrogen, -C ⁇ _4a.
  • lkyl or -C ⁇ _4alkylphenyl or together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring, wherein the heteroring is optionally fused to an optionally substituted phenyl ring, and R5 is methyl, trifluoromethyl, C 2 _ ,alkyl, phenyl or heteroaryl;
  • R2 is optionally substituted .aryl or heteroaryl, or R 2 is A-Ar, wherein A is lower alkyl (C ⁇ ) or branched alkyl, wherein a branch may cont.ain a substituted phenyl ring, and Ar is substituted phenyl or a substituted 5- or 6-membered hetero.aryl ring which option ly contains one or more heteroatoms selected from N, O or S, or R 2
  • W is -OH, -NR 3 R 4 , -O-alkyl, an amide derived from an amino acid, NR ⁇ R 7 , where R > is H, alkyl, and R? is aryl or substituted aryl, -(CH2) n -aryl, -(CH 2 ) n -subsututed aryl, -(CH2) n -heteroaryl, or -(CH 2 ) n -Z; or
  • Rl and R 2 together with the nitrogen to which they are attached form a 5- or 6- membered heteroring fused to an option ly substituted phenyl ring;
  • n 1 to 3;
  • n 1 to 6, provided that the compound is not N-3-(2,3,4,5-tetrahydro-7,8- dimethoxy- 1 -H-3-benzazepine-3-yl)propyl]-N-(3 ,4-dimethoxyphenyl)-3 ,4- dinitrobenz.amide or N-phenyl-3,4-dinitrobenzarnide.
  • 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 3,4-dinitrobenz.amide compound of formula (I), or a pharmaceutically active salt thereof.
  • the present invention is to ph.armaceutic.al compositions comprising a compound of formula (I), or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier therefor.
  • 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.
  • 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.
  • 3,4-dinitrobenz ⁇ imide 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.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine .and bromine.
  • heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, thiazole, immidazole, thiadiazole or triazole.
  • aryl or “hetero-aryl” 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, and furanyl.
  • optional substituent(s) may be at a position ortho, meta or para relative to the nitrogen of the amide functionality of formula (I).
  • 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 or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfon
  • 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.
  • 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 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.
  • various embodiments are as follows.
  • Rl is suitably hydrogen, methyl, -(CH2) n > branched (3-6 carbon) alkyl,
  • R 5 is methyl, trifluoromethyl, C2-6 alkyl, phenyl or heteroaryl.
  • Rl is preferably -(CH2) n Z, wherein Z is -CO2H, -CO2- alkyl, wherein alkyl is tert-butoxy, or -CONR 3 R 4 , wherein R 3 .and R 4 are independently hydrogen, or Cj ⁇ alkylphenyl, C ⁇ _4alkyl, -(CH2) n NR 3 R 4 , wherein n is 2 or 3, and R 3 and R 4 are both C1.3al.kyl or R 3 and R 4 form a 5-, 6- or 7- membered heteroring, preferably morpholino, piperidinyl, or piperazine, or wherein the heteroring is option ly fused to an optionally substituted phenyl ring, such as a benzazepine.
  • R 2 is suitably optionally substituted aryl or heteroaryl, or R 2 is A-Ar, wherein A is lower alkyl (C ⁇ _4) or branched alkyl, wherein a branch may contain a substituted phenyl ring, and Ar is substitued phenyl or a substituted 5- or 6- membered hetero.aryl ring which optionally contains one or more heteroatoms selected from N, O or S.
  • R 2 is preferably aryl, more preferably phenyl.
  • Suitable substituents for Ar are C ⁇ al yl, halo, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, nitro, and aryl.
  • Ar is substituted by Cj ⁇ alkyl, most preferably ethyl.
  • Rl .and R 2 together with the nitrogen to which they are attached suitably form a 5- or 6-membered heteroring fused to an optionally substituted phenyl ring.
  • Rl .and R 2 together with the nitrogen to which they are attached suitably form a 5- or 6-membered heteroring fused to an optionally substituted phenyl ring.
  • compositions 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 sl ⁇ n 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 monoste.arate 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 physici ⁇ .
  • 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 exte ⁇ udly to the epidermis, to the buccal cavity .and instillation of such a compound into the e.ar, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • 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 infl-a mation 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.
  • bactericid.al 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 option-ally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the slcin 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 a . re semi-solid formulations of the active ingredient for extem ⁇ 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, com, 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 d ly 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).
  • te ⁇ n treating or prophylactic therapy.
  • fo ⁇ nula (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 ph.armaceutic.ally 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 dise.ase st es.
  • the route of administration may be oral or parenteral.
  • the term p.arenteral 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. Methods of Preparation Generally, the compounds of the invention may be prepared by the following reaction sequence:
  • the reaction sequence involves the reaction of a compound of Formula ⁇ , wherein R* and R 2 are defined above, and a suitable acid chloride derived from 3, 4-dinitrobenzoic acid.
  • This reaction may be accomplished in any of a variety of reaction inert solvents by mixing approximately equimolar .amounts of a compound of Formula ⁇ and the acid chloride in the presence of an amine base at or below room temperature.
  • Methylene chloride is the preferred solvent.
  • Suitable amine bases are triethylamine, N-methylmorpholine, pyridine, and the like. In general, the reaction is allowed to proceed for about 1 hour to about 24 hours at which time the reaction is substantially complete.
  • the completeness of a particul.ar reaction may be me.asured by known techniques such as thin layer chromatography.
  • 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 recryst-allized.
  • Acid addition salts may be prepared using standard procedures. For example, a hydrochloride salt may be prep-ared 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.
  • compounds of formula I can be prepared according to Scheme 1 (Example 8).
  • Formation of the desired amide (3-Scheme 1) is achieved by the reaction of an amine, such as N-methyl.aniline (1 -Scheme 1), with an acid chloride derived from 3, 4-dinitrobenzoic acid (2-Scheme 1). This is performed in an inert solvent such as methylene chloride in the presence of an amine base such as triethyl-amine at or below room temperature. If the amine (1 -Scheme 1) cont.ains a basic amino group elsewhere in the molecule, such as in Example 6, the triethylamine may be omitted.
  • Scheme 2 illustrates the case where the .amine (1 -Scheme 1) contains a second amine containing group such as in Example 1.
  • Reagents a) aniline, CH2CI2, pyri ine; b) 2, 3, 4, 5-tetr.ahydro-lH-3-benz.azepine hydrochloride, triethylamine, acetonitrile, cat. nBu4Nl; c) UAIH4, THF, reflux.
  • 3-chloropropionyl chloride (1 -Scheme 2) is reacted with aniline in an inert solvent in the presence of an amine base such as pyridine.
  • This provides the 3-chloroamide (2-Scheme 2) which is then reacted with the 3- benz.azepine compound in acetonitrile to provide amide (3-Scheme 2).
  • Tliis amide (3-Scheme 2) is next converted to the desired di-amine (4-Scheme 2) via reduction using a reagent such as lithium .aluminum hydride at reflux in tetrahydrofuran.
  • the synthesis is then completed using (4-Scheme 2) according to Scheme 1.
  • the amine may be prepared according to Scheme 3.
  • isovaleryl chloride (1 -Scheme 3) is reacted with 3, 4-dimethoxy .aniline in the presence of an amine base such as triethyl-amine in an inert solvent such as methylene choride.
  • This provides amide (2-Scheme 3) which is then converted into the required amine (3-Scheme 3) by reducing the amide functionality by methods previously described.
  • the synthesis is then completed using (3-Scheme 3) .according to Scheme 1.
  • Reagents a) 3, 4-dimethoxyaniline, CH2CI2, triethylamine; b) L1AIH4, THF, reflux.
  • desired N-methyl .anilines are not commercially available, they are readily prepared from the anilines via a number of methods well known in the art. One such method is that reported by Barluenga et al. (J. Chem. Soc. Chem. Commun., pp. 1334-1335 (1984)).
  • the desired N-methyl amides are obt.ained directly from the second.ary amides via alkylation of the amide anion as illustrated in Scheme 4.
  • Reagents a) KN(SiMe 3 ) 2 , THF; b) Methyl iodide.
  • the secondary amide (1 -Scheme 4) is treated with a non- nucleophilic base such as potassium bis(trimethylsilyl)amide [KN(SiM ⁇ 3)2] at or below room temperature in a solvent such as tetrahydrofuran.
  • a non- nucleophilic base such as potassium bis(trimethylsilyl)amide [KN(SiM ⁇ 3)2]
  • KN(SiM ⁇ 3)2 potassium bis(trimethylsilyl)amide
  • a suitable methylating agent such as methyl iodide.
  • the resulting N-methyl amides (2-Scheme 4) are then recovered using standard isolation and purification methods.
  • Reagents a) thionyl chloride, CHCI 3 ; b) G1G2NH, triethylamine, CH 2 Cl2.
  • Reagents a) 2-Ethylaniline, .acetic acid, reflux; b) 3, 4-dinitrobenzoyl chloride, triethy unine, CH 2 Cl2; c) trifluoroacetic acid, CH2CI2; d) oxalyl chloride, CH 2 Cl2; e) G1G2NH, triethylamine, CH2CI2.
  • R 1 is (CH2)n z » is °y alkylation of the desired aniline with an appropriate alkyl halide
  • This procedure is quite general and may be used to prepare a wide range of anilines of which compound 3-Scheme 7 is just one example.
  • 4- chlorobutyryl chloride (1-Scheme 7) is reacted with diethylamine to provide the diethylamide 2-Scheme 7.
  • Alkylation of 2-ethylaniline using 2-Scheme 7 as the alkylating agent then provides 3-Scheme 7.
  • Aniline 3-Scheme 7 is then acylated using 3, 4-dinitrobenzoyl chloride as previously described.
  • the commercially available 3-chloropropiophenone is used in place of the amide 2-Scheme 7 in Scheme 7.
  • Reagents a) diethylamine, triethylamine, CH2CI2, 0 °C; b) 2-e-th ⁇ yloaniline, triethylamine, DMF, 100 °C.
  • Example 1 substituting N-methylphenethylamine for 2, 3, 4, 5-tetrahydro-lH-3- benz.azepine hydrochloride.
  • the title compound was purified by flash column chromatography (silica, 1, 2, 3% methanol in methylene chloride) to give a dark amber oil.
  • MS (ES) m/e 463.4 [M+H]+.
  • Example 6 Preparation of N-f2-(N'. N'-dirnethylamino)ethyl1-N-phenyl-3.4- dinitrobenzamide hydrochloride N, N-Dimethyl-N'-phenylethylenedi.amine (165 mg, 1.00 mmol) was dissolved in dry methylene chloride, cooled to 0 °C, and treated with 3, 4- dinitrobenzoyl chloride (230 mg, 1.0 mmol). After 10 min the cooling bath was removed and the reaction was stirred for 16h at room temperature. A solid beg.an to form after lh. The reaction mixture was treated with diethyl ether (2 mL) and the pale yellow solid was filtered off, washed with diethyl ether and dried.
  • the amide obtained above (475 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (10 mL) and treated with lithium aluminum hydride (115 mg, 3.0 mmol). The reaction was refluxed for 3.5h. The reaction mixture was cooled to 0 °C and quenched with water (1 mL), 10% NaOH (1 mL), .and water (1 mL). The solution w.as then stirred vigorously at room temperature for 15 min. The solution was diluted with ethyl .acetate and dried over Na2SO4, filtered, and evaporated to give a dark colored oil.
  • the amine obtained above was dissolved in dry methylene chloride (5 mL), cooled in an ice water bath, and treated sequentially with triethylamine (0.61 mL, 4.37 mmol), 4-(N, N-dimethyl.amino)pyridine (25 mg, 0.2 mmol), and 3, 4- dinitrobenzoyl chloride (500 mg, 2.17 mmol).
  • the cooling bath was removed and the reaction was stirred at room temperature for 4h.
  • the reaction was diluted with ethyl acetate and washed with 5% HCl, 5% Na2CO3, and brine.
  • the organic layer was dried over Na2SO4, filtered, and evaporated.
  • N-Methyl.aniline (96.3 mg, 0.9 mmol) in dry methylene chloride (6 mL) was treated with triethylamine (101 mg, 140 uL, 1.0 mmol) followed by a solution of 3, 4-dinitrobenzoyl chloride (230 mg, 1.0 mmol) in methylene chloride ( 1.0 mL).
  • the reaction solution was placed on a shaker overnight at room temperature. The solution was stripped to dryness; the solid WJIS triturated with ether (15 mL) and collected by filtration; the solids were rinsed with water and dried in vacuo to give the title compound as dusty shrimp colored cryst s (128 mg, 47%).
  • *H NMR 400 MHz, CDC1 3 ) ⁇ 7.86 (s,lH), 7.65 (dd, 2H), 7.26-7.36(m, 3H), 7.07 (d, 2H), 3.54 (s, 3H).
  • Example 8 substituting 4-nitroaniline for N-methylaniline. ⁇ H NMR (400 MHz, CDCI3+ MeOH-d4) ⁇ 8.44 (d, IH), 8.20-8.23 (m, IH), 8.04-8.07 (m, 2H), 7.90 (d, IH), 7.76-7.79 (m, 2H).
  • Example 16 Preparation of N-(4-phenoxy)phenyl-3.4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 4-phenoxyaniline for N-methylaniline. MS (ES) m/e 378.3 [M-H]".
  • Example 8 substituting indoline for N-methylaniline. *H NMR (400 MHz, CDCl 3 +MeOH-d4) ⁇ 8.06 (s, IH), 7.86-7.98 (dd, 2H), 7.17-7.19 (d, IH), 6.80-7.16 (m, 2H), 3.85-4.30 (m, 2H), 3.10 (t, 2H).
  • Example 48 N-(2-Cvanophenyl)-N-methyl-3., 4-dinitrobenzamide l NMR (400 MHz, CDCI3) ⁇ 7.8 (s, IH), 7.75 (m, 2H), 7.65 (m, 2H),
  • Example 85 N-[4-(N*. N , -Dimethylamino)phenvn-3. 4-dinitrobenzamide MS (ES) m/e 331.2 [M+H] + .
  • Example 91 N-r6-Methoxy-2-(methoxycarbonvnindol-l-vn-3.4- dinitrobenzamide This compound was prepared according to the procedure described for Example 28 substituting methyl 6-methoxy-2-indolecarboxylate for diphenylaniline. Orange yellow solid. *H NMR (400 MHz, CDCI3) d 8.19 (s, IH), 7.97-7.98 ( , 2H), 7.61 (d, IH), 7.53 (s, IH), 7.44 (s, IH), 7.03 (dd, IH), 3.90 (s, 3H), 3.63 (s, 3H).
  • This compound was prepared according to the procedure described for Example 8 substituting 2, 3, 4, 5-tetrahydro-lH-l-benz.azepine for N- methyl-aniline.
  • the 2, 3, 4, 5-tetr.ahydro-lH-l-benzazepine was prepared by the metiiod report by Yamamoto et al. in Tetrahedron Lett., 1983, 24, 471 1-4712. MS (ES) m/e 342.4 [M+H]+.
  • Example 96 Preparation of N-methyl-N-[2-f(4-methylpiperazin-l- yl)carbonvnphenyll-3. 4-dinitrobenzamide hydrochloride
  • the carboxylic acid prepared in Example 32 (2.0 g, 5.8 mmol) in chloroform (25 mL) was treated with thionyl chloride (5 mL) and gently refluxed for 2 h. After cooling to room temperature the solvent and excess reagent were evaporated to give the acid chloride that was used without further purification.
  • Acid chloride 200 mg, 0.55 mmol
  • MS (ES) m/e 428.3 [M+H]+.
  • Example 99 Preparation of (Sl-N-methyl-N-rr2-ri-(tert-buto. vcarbonvn-2- phenylethv ⁇ aminocarbonvPphenyll-3.4-dinitrooenzam.de Prep-ared according to the procedure described for Example 96 substituting
  • Example 101 Preparation of (S)-N-r[2-fl -(aminocarbon yl)-2- phenylethyllaminocarbonyllphenyll-N-methyl-3. 4-dinitrobenzamide Prep.ared according to the procedure described for Example 96 substituting L-phenylalaninamide for N-methylpiperazine. MS (ES) m/e 492.1 [M+H]+.
  • Example 105 Preparation of N-[2-(ethylaminocarbonyl)ethvn-N-(2- ethvIphenvO-3.4-dinitrobenzam.de
  • Example 108 Preparation of N-[2-(aminocarbonyl)ethyll-N-(2-ethylphenyl)- 3. 4-dinitrobenzamide This compound was prepared according to die procedure described for Example 105 substituting ammonium hydroxide for ethyl-amine. Bright yellow solid. MS (ES) m/e 387.2 [M+H]+.
  • Example 110 Preparation of N-r2-[(l-piperidinyl arbonvnethyll-N-f2. ethylphenyl)-3. 4-dinitrobenzamide This compound was prepared according to die procedure described for
  • Example 111 Preparation of N ⁇ 2- ⁇ (N , -benz ⁇
  • Example 114 Preparation of N-(2-isopropylphenyl)-3., 4-dinitrobenzamide This compound was prepared according to the procedure described for Example 8 substituting 2-isopropylamiline for N-methyl.aniline. Off-white solid. MS (ES) m/e 328.1 [M-H] ' .
  • Example 116 Preparation of N-r2-(morpholinocarbonyl ethyl1-N-(2- ethy
  • SK-N-MC cells were obtained from American Type Culture Collection
  • MEM Minimum Essential Media
  • SK-N-MC cells were homogenized in 5 mM Tris-HCl pH 7.4, 10 mM Na-
  • 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 MgCl2 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 MgCh, 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 die 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 die rate of conversion of ⁇ [ 32 P]ATP to [ 32 P]c.AMP as previously described (Aiyer et al., Endocrinology, Vol. 129, pp 965-969 (1991)).
  • Human neuroblastoma cell (SK-N- MC ) membranes [40-60 ⁇ g] were incubated in triplicate in buffer cont ning 50 mM Tris-HCl (pH 7.4), 10 nM MgCl 2 , 1.2 mM ATP, 1.0 ⁇ Ci ⁇ [ 32 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 reactions were stopped witii 1 ml solution containing cAMP, ATP and 22000 cpm of [ 3 H] cAMP.
  • [ 32 P]cAMP was separated using sequential chromatography (Dowex and alumina columns) (Salmon et al., An ⁇ ..Biochem. Vol. 58, pp. 541-548 (1974)). Adenylate cyclase activities were determined in the absence (basal) or presence of 2.5 nM of hCGRP ⁇ with various concentrations (0.1 ⁇ M to 30 ⁇ M ) of compound.
  • the compounds of this invention show CGRP receptor antagonist activity having IC50 values in die range of 0.001 to 100 ⁇ M. The full structure/activity relationship has not yet been established for die compounds of this invention.

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Abstract

Cette invention concerne des composés 3,4-dinitrobenzamide, lesquels sont des ligands, notamment des antagonistes, du récepteur du peptide lié au gène de la Calcitonine ('CGRP'). De plus, cette invention concerne le traitement et la prévention d'états pathologiques induits par CGRP, y compris, de façon non limitative les maux de tête, notamment les migraines; le diabète sucré non insulino-dépendant, l'inflammation neurogène, les troubles cardio-vasculaires, l'inflammation chronique, la douleur, le choc endotoxique, l'arthrite, les rhinites allergiques, l'eczéma de contact allergique, les états cutanés inflammatoires ainsi que l'asthme, tous chez des mammifères, par l'utilisation d'antagonistes 3,4-dinitrobenzamide du récepteur du CGRP.
PCT/US1997/015931 1996-09-09 1997-09-09 Composes et methodes WO1998009630A1 (fr)

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EP97940951A EP0934068A1 (fr) 1996-09-09 1997-09-09 Composes et methodes
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AU42616/97A AU4261697A (en) 1996-09-09 1997-09-09 Compounds and methods
CA002264942A CA2264942A1 (fr) 1996-09-09 1997-09-09 Composes et methodes

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WO2001032648A1 (fr) * 1999-10-29 2001-05-10 Boehringer Ingelheim Pharma Kg Nouveaux cyclopropanes utilises comme antagonistes de cgrp, medicaments contenant lesdits composes et procedes permettant de les preparer
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
WO2003104236A1 (fr) 2002-06-01 2003-12-18 Bristol-Myers Squibb Company Antagonistes des recepteurs du peptide relie au gene de la calcitonine
US6780883B2 (en) * 1998-11-05 2004-08-24 Warner-Lambert Company Amide inhibitors of microsomal triglyceride transfer protein
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
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
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
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WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos
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US9328167B2 (en) 2008-03-04 2016-05-03 Labrys Biologics, Inc. Methods of treating chronic pain
US9452973B2 (en) 2012-05-04 2016-09-27 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Modulators of the relaxin receptor 1
US9585940B2 (en) 2002-08-12 2017-03-07 Birkir Sveinsson Use of CGRP antagonist compounds for treatment of psoriasis
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
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
US11433119B2 (en) 2016-11-18 2022-09-06 Nepsone Ehf Methods of treating inflammatory skin disorders
US11639380B2 (en) 2019-01-08 2023-05-02 H. Lundbeck A/S Acute treatment and rapid treatment of headache using anti-CGRP antibodies
US12122821B2 (en) 2013-07-03 2024-10-22 H. Lundbeck A/S Regulation of glucose metabolism using anti-CGRP antibodies

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US6780883B2 (en) * 1998-11-05 2004-08-24 Warner-Lambert Company Amide inhibitors of microsomal triglyceride transfer protein
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7285565B2 (en) 1999-09-17 2007-10-23 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7407963B2 (en) 1999-10-29 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Cyclopropane CGRP antagonists, medicaments containing these compounds, and method for the production thereof
WO2001032648A1 (fr) * 1999-10-29 2001-05-10 Boehringer Ingelheim Pharma Kg Nouveaux cyclopropanes utilises comme antagonistes de cgrp, medicaments contenant lesdits composes et procedes permettant de les preparer
US9108922B2 (en) 2000-02-29 2015-08-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
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US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
US7314883B2 (en) 2002-06-05 2008-01-01 Bristol-Myers Squibb Company Anti-migraine treatments
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US9585940B2 (en) 2002-08-12 2017-03-07 Birkir Sveinsson Use of CGRP antagonist compounds for treatment of psoriasis
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US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
US7544803B2 (en) * 2004-01-23 2009-06-09 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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US7544680B2 (en) 2004-11-03 2009-06-09 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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