CA2264942A1 - Compounds and methods - Google Patents

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Publication number
CA2264942A1
CA2264942A1 CA002264942A CA2264942A CA2264942A1 CA 2264942 A1 CA2264942 A1 CA 2264942A1 CA 002264942 A CA002264942 A CA 002264942A CA 2264942 A CA2264942 A CA 2264942A CA 2264942 A1 CA2264942 A1 CA 2264942A1
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Canada
Prior art keywords
dinitrobenzamide
phenyl
compound
ethylphenyl
methyl
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Abandoned
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CA002264942A
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French (fr)
Inventor
Robert A. Daines
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SmithKline Beecham Corp
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Individual
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Publication of CA2264942A1 publication Critical patent/CA2264942A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
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    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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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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    • C07C255/60—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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Abstract

This invention relates to 3,4-dinitrobenzamide 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 3,4-dinitrobenzamide CGRP receptor antagonists.

Description

WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931O D D 1QNThis invention relates to 3,4-dinitrobenzarnide compounds which areligands, in particular, antagonists, of the Calcitonin Gene-Related Peptide(hereinafter "CGRP") receptor. In addition, this invention relates to the treatmentand prevention of disease states mediated by CGRP, including, but not limited to,headaches, especially migraines; non-insulin dependent diabetes mellitus("NlDDM"); neurogenic inflammation; cardiovascular disorders; chronicinflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contactdermatitis; inflammatory skin conditions; and asthma, all in mammals, preferablyhumans, by the use of CGRP receptor ligands, in particular, 3,4-dinitrobenzarnideantagonists, thereof. CGRP is a 37 amino acid polypeptide that is stored and released from nerveterminals in both the central nervous system and the peripheral nervous system._(Goodman et al., Life Sci., Vol. 38, pp. 2169-2172 (1986)). CGRP has beendetected in nerves innervating the heart, peripheral and cerebral blood vessels, andkidneys by immunohistochernical and radioirnmunoassay methods. (Yamamoto etal., Prog. Neurobiol., Vol. 33, pp. 335-386 (1989)). CGRP has been shown tomediate its biological response by binding to specific cell surface receptors thathave been identified in a variety of tissues. Evidence from biochemical studiessuggest that CGRP receptors belong to the family of G-protein coupled receptors.The widespread distribution of CGRP receptors on muscle, glandular, epithelialand neuronal cells is consistent with its wide range of biological actions, includingpain transmission (Collin et al., 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)); 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 ofintestinal motility (Fargeas et al., Peptides, Vol. 6, pp. 1167-1171 (1985));regulation of glucose metabolism, e.g., reduction of insulin secretion and insulinsensitivity, (Hermansen et al., Peptides, Vol. 27, pp. 149-157 (1990); and Molinaet al., Diabetes, Vol. 39, pp. 260-265 (1990)); reduction of appetite and reductionof growth hormone increase (Tannenbaum et al., Endocrinology, Vol. 116, pp.2685-2687 (1985)); reduction of inflammation of the skin, for example in allergiccontact 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.WO 98/09630202530CA 02264942 1999-03-05PCT/US97/15931963-968 (1992); and Escott et al., Br. 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 discoveredthat limited and selective inhibition of CGRP receptor mechanisms represents anovel preventative and therapeutic approach to the treatment of a broad variety ofdisease states that are mediated by CGRP. In particular, the development of anactive CGRP receptor antagonist would be expected to be useful in the treatment ofa 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; andasthma, all in mammals, preferably humans ("CGRP-mediated diseases").Surprisingly, it has now been discovered that a class of non-peptidecompounds, in particular 3.4-dinitrobenzamides of formula (I) function as CGRPreceptor antagonists, and therefore, have utility in the treatment of disease stateswherein inhibition of CGRP receptor mechanisms is indicated for prevention ortherapeutic treatment thereof. NIn one aspect, the present invention is to a genus of novel compounds offormula (I), or pharmaceutically active salts thereof, said compounds which arealso useful in treating the above-mentioned CGRP-mediated disease states:N N02A2 'N02 Formula (I)wherein:R1 is hydrogen, methyl, -(CH2)n, branched (3-6 carbon) allcyl, —(CH2)nphenyl,(cI-(CH )n-N X2 \“-‘"2!-n , wherein X is CH2, oxygen or N-alkyl, or R1 is -(CH2)nNR3R4,or —(CH2)nZ, wherein Z is —CO2H, -CO2-alkyl, -CONR3R4, -N(R3)CO2R3,-N(R3)C(O)NR3R4, -oc(o)NR3R4, or -COR5, and wherein R3 and R4 areindependently hydrogen, -C1-4alkyl or -C1.4alkyiphenyl, or together with theWO 98/096301015202530CA 02264942 1999-03-05PCT/US97/1593 1nitrogen to which they are attached, form a 5-, 6-, or 7-membered heteroring,wherein the heteroxing is optionally fused to an optionally substituted phenyl ring,and R5 is methyl, trifluoromethyl, C2_5alkyl, phenyl or heteroaryl;R2 is optionally substituted aryl or heteroaryl, or R2 is A-Ar, wherein A is loweralkyl (C 1.4) or branched alkyl, wherein a branch may contain a substituted phenylring, and Ar is substituted phenyl or a substituted 5- or 6-membered heteroaryl ringwhich optionally contains one or more heteroatoms selected from N, O or S, or R2is W, wherein W is -OH, -NR3R4, -O-alkyl, an amide derived from anamino acid, N R5R7, where R5 is H, alkyl, and R7 is aryl or substituted aryl,-(CH2)n-aryl, -(CH2)n-substituted aryl, -(CI-I2)n-heteroaryl, or -(CH2)n-Z; orR1 and R2 together with the nitrogen to which they are attached form a 5- or 6-membered heteroring fused to an optionally substituted phenyl ring;mislto3; andn is 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~dinitrobenzarnide or N-phenyl-3,4—dinitrobenzamide.In another aspect, the present invention is to a method of treating CGRPmediated diseases, all in mammals, preferably humans, comprising administeringto such mammal in need thereof, an effective amount of a 3,4-dinitrobenzarnidecompound of formula (I), or a pharmaceutically active salt thereof.In yet another aspect. the present invention is to pharmaceuticalcompositions comprising a compound of formula (I), or a pharmaceutically activesalt thereof, and a pharmaceutically acceptable carrier therefor. In particular, thepharmaceutical compositions of the present invention are used for treating CGRP-mediated disease states, including. but not limited to headaches, especiallymigraines; NIDDM; neurogenic inflammation; cardiovascular disorders; chronicinflammation; pain; endotoxic shock; arthritis; allergic rhinitis; allergic contactdermatitis; inflammatory skin conditions; and asthma, all in mammals, preferablyhumans.WO 98/096301015920253035CA 02264942 1999-03-05PCT/US97/15931D D T NIt has now been discovered that 3,4-dinitrobenzamide compounds offonnula (I) are CGRP receptor ligands, in particular, antagonists thereof. It hasalso now been discovered that selective inhibition of CGRP receptor mechanismsby treatment with the receptor ligands of formula (I), or a pharmaceuticallyacceptable salt thereof, represents a novel therapeutic and preventative approach tothe treatment of a variety of CGRP-mediated disease states.The term "alkyl" is used herein at all occurrences to mean a straight orbranched chain radical of 1 to 6 carbon atoms, unless the chain length is limitedthereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, and the like. ‘The terms "halo" or "halogen" are used interchangeably herein at alloccurrences to mean radicals derived from the elements chlorine, fluorine, iodineand bromine.The term "heteroring" is used herein at all occurrences to mean a saturatedor wholly or partially unsaturated 5-. 6-, or 7-membered ring system whichcontains one or more 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.The terms "aryl" or "heteroaryl" are used herein at all occurrences to meansubstituted and unsubstituted aromatic ring(s) or ring systems which may includebi- or tri~cyclic systems and heteroaryl moieties, which may include, but are notlimited to, heteroatoms selected from O, N, or S. Representative examples include,but are not limited to, phenyl, benzyl, naphthyl, pyridyl, quinolinyl, thiazinyl, andfuranyl. VThe term "optionally substituted" is used herein at all occurrences to meanthat the moieties may or may not be substituted with one to three various functionalgroups including methoxy, hydroxy, phenoxy, trifluoromethyl, C1_4alkyl, halo,nitro, CN, C(O)OH, C(O)NR'R", wherein R’ and R" are independently hydrogen orC 1_4alkyl. It will be understood that the optional substituent(s) may be at aposition ortho, meta or para relative to the nitrogen of the amide functionality offormula (I). Preferably, the optional substituent(s) are positioned ortho relative tothe nitrogen of the amide functionality of formula (I).The term "CGRP mediated disease state" is used herein at all occurrencesto mean any disease state which is mediated (or modulated) by Calcitonin Gene-Related Peptide.WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931Suitably, pharmaceutically acceptable salts of formula (I) include, but arenot 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, pharmaceuticallyacceptable salts of compounds of formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent group comprises acarboxy moiety. Suitable pharmaceutically acceptable cations are well known tothose skilled in the art and include alkaline, alkaline earth, ammonium andquaternary ammonium cations.The compounds of the invention can exist in unsolvated as well as solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol, and the like, areequivalent to the unsolvated forms for purposes of this invention.The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically active forms.The stereocenters may be of any combination of R and S configuration, forexample, (R,R), (R,S), (S,S) or (SR). All of these compounds are within the scopeof the present invention.For the compounds of formula (I) various embodiments are as follows.R1 is suitably hydrogen, methyl, -(CH2)n, branched (3-6 carbon) alkyl,-(CH2)"—N: 1 x-(CH2)nphenyl, ‘°”a‘{v- , wherein X is CI-I2, oxygen or N-alkyl, or R1 is-(CH2)nNR3R4, or-(CH2)nZ, wherein z is —co2H, -CO2-alkyl, -CONR3R4,-N(R3)CO2R3, -N(R3)C(O)NR3R4, -OC(O)NR3R4, or -COR5 wherein R3 andR4 are independently hydrogen, C 1_4a.lkyl or C 1_4alkylphenyl, or together withthe nitrogen to which they are attached, form a 5-,6-, or 7—membered heteroring, wherein the heteroring is optionally fused to anoptionally substituted phenyl ring and R5 is methyl, trifluoromethyl, C2_5 alkyl,phenyl or heteroaryl. R1 is preferably -(CH2)nZ, wherein Z is -CO2H, -CO2-alkyl, wherein alkyl is tert-butoxy, or -CONR3R4, wherein R3 and R4 areindependently hydrogen, or C1_4alkylphenyl, C1_4alkyl, —(CH2)nNR3R4, whereinI1 is 2 or 3, and R3 and R4 are both C1_3alkyl or R3 and R4 form a 5-, 6- or 7-membered heteroring. preferably morpholino, piperidinyl, or piperazine, orwherein the heteroring is optionally fused to an optionally substituted phenyl ring,such as a benzazepine.WO 98/0963020253035CA 02264942 1999-03-05PCT/US97/15931R2 is suitably optionally substituted aryl or heteroaryl, or R2 is A—Ar,wherein A is lower alkyl (C1.4) or branched alkyl, wherein a branch may contain asubstituted phenyl ring, and Ar is substitued phenyl o_r a substituted 5- or 6-membered heteroaiyl ring which optionally contains one or more heteroatomsselected from N, O or S. R2 is preferably aryl, more preferably phenyl. Suitablesubstituents for Ar are C1_4allcyl, halo, cyano, trifluoromethyl, trifluoromethoxy,alkoxy, nitro, and aryl. Preferably, A: is substituted by C 1_4alkyl, most preferablyethyl.R1 and R2 together with the nitrogen to which they are attached suitablyform a 5- or 6—membered heteroring fused to an optionally substituted phenyl ring.Among the preferred compounds of the invention are the followingcompounds:N-(2-ethylphenyl)-N—[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenzamide;N-[2-(morpholinocarbonynethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;N -[2-(ethylarninocarbonyl)ethyl]-N -( 2-ethylphenyl)-3, 4-dinitrobenzarnide;N—[2—(diethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzarnide;N-[2-[( 1-piperidinyl)carbony1]ethyl]-N-(2-ethylphenyl)-3, 4—dinitrobenzarnide;N-[3—[(diethy1arnino)carbony1]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)—3, 4-dinitrobenzamide;N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenzamide;N-(2-ethylphenyl)-N-methyl-3, 4-dinitrobenzamide;N-(2, 6-diethyl)phenyl-N-methyl-3, 4-dinitrobenzamide;N-[3-(2, 3, 4, 5-terahydro-1H-3-benzazepin-3—yl)propyl]-N-phenyl-3, 4-dinitrobenzarnide;N-[3-(7, 8-dimethoxy-2, 3, 4, 5-terahydro-1H-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4-dinitrobenzamide;N-[3-(N'-methy1-2-pheny1ethylamino)propyl]-N-phenyl-3, 4-dinitrobenzamide;N-[3-(morpholin-4-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;N—[3-(piperidin-1-y1)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;N-[2-(N', N‘-dimethylamino)ethyl]-N-phenyl-3, 4-dinitrobenzamide;N-(3-methylbutyl)-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide; andN-methyl—N-phenyl-3, 4-dinitrobenzamide.Formulation of Pharmaceutical CommsitionsThe pharmaceutically effective compounds of this invention (and thepharmaceutically acceptable salts thereof) are administered in conventional dosageforms prepared by combining a compound of formula (1) ("active ingredient") in an6WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931amount sufficient to treat headaches, especially migraines; NIDDM; neurogenicinflammation; cardiovascular disorders; chronic inflammation; pain; endotoxicshock; arthritis; allergic rhinitis; allergic contact dermatitis; inflammatory skinconditions; and asthma, with standard pharmaceutical carriers or diluents accordingto conventional procedures well known in the art. These procedures may involvemixing, granulating and compressing or dissolving the ingredients as appropriate tothe desired preparation.The pharmaceutical carrier employed may be, for example, either a solid orliquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin,agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary ofliquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, thecarrier or diluent may include time delay material well known to the art, such asglyceryl monostearate or glyceryl distearate alone or with a wax.A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier 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 solidcarrier 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 ornonaqueous liquid suspension.The active ingredient may also be administered topically to a mammal in needof treatment or prophylaxis of CGRP mediated disease states. The amount of activeingredient required for therapeutic effect on topical administration will, of course,vary with the compound chosen, the nature and severity of the disease state beingtreated and the mammal undergoing treatment, and is ultimately at the discretion ofthe physician. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topicaladministration, the most preferred dosage being 1 mg to '100 mg, for example 5 to 25mg administered two or three times daily.By topical administration is meant non-systernic administration and includesthe application of the active ingredient externally to the epidermis, to the buccalcavity and instillation of such a compound into the ear, eye and nose, and where thecompound does not significantly enter the blood stream. By systemic administrationis meant oral, intravenous, intraperitoneal and intramuscular administration.While it is possible for an active ingredient to be administered alone as theraw chemical, it is preferable to present it as a pharmaceutical formulation. Theactive 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 much7WO 98109630101520253035CA 02264942 1999-03-05PCT/US97/15931as 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 forhuman medical use, comprise an active ingredient together with one or moreacceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The .carrier(s) must be ‘acceptable’ in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipient thereof.Formulations suitable for topical administration include liquid or serni-liquidpreparations suitable for penetration through the skin to the site of inflammation suchas liniments, lotions, creams, ointments or pastes, and drops suitable foradministration to the eye, ear or nose.Drops according to the present invention may comprise sterile aqueous or oilysolutions or suspensions and may be prepared by dissolving the active ingredient in asuitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/orany other suitable preservative, and preferably including a surface active agent. The .resulting solution may then be clarified by filtration, transferred to a-suitablecontainer 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 andtransferred to the container by an aseptic technique. Examples of bactericidal andfungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate oracetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution include glycerol, dilutedalcohol and propylene glycol.Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterile aqueous solutionoptionally containing a bactericide and may be prepared by methods similar to thosefor the preparation of drops. Lotions or liniments for application to the skin may alsoinclude 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 serni-solidformulations of the active ingredient for external application. They may be made bymixing the active ingredient ir1 finely-divided or powdered form, alone or in solutionor 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 ashard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil ofnatural origin such as almond, corn, arachis, castor or olive oil; wool fat or itsderivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as8WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931propylene glycol. The formulation may incorporate any suitable surface active agentsuch as an anionic, cationic or non-ionic surfactant such as sorbitan esters orpolyoxyethylene derivatives thereof. Suspending agents such as natural gums,cellulose derivatives or inorganic materials such as silicaceous silicas, and otheringredients_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 forsuch administration, such as an aerosol formulation or a metered dose inhaler, may beprepared by conventional techniques. The daily dosage amount of the activeingredient 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-mediateddiseases with an antagonist as depicted in formula (I). By the term "treating" ismeant either prophylactic or therapeutic therapy. Such formula (I) compound canbe administered to such mammal in a conventional dosage form prepared bycombining the formula (I) compound with a conventional pharmaceuticallyacceptable carrier or diluent according to known techniques. It will be recognizedby one of skill in the art that the form and character of the pharmaceuticallyacceptable carrier or diluent is dictated by the amount of active ingredient withwhich it is to be combined, the route of administration and other well-knownvariables. The formula (I) compound is administered to a mammal in need oftreatment for a CGRP-mediated disease state, in an amount sufficient to decreasesymptoms associated with these disease states. The route of administration may beoral or parenteral.The term parenteral as used herein includes intravenous, intramuscular,subcutaneous, intra-rectal, intravaginal or intraperitoneal administration. Thesubcutaneous and intramuscular forms of parenteral administration are generallypreferred. The daily parenteral dosage regimen will preferably be from about 30mg to about 300 mg per day of active ingredient. The daily oral dosage regimenwill preferably be from about 100 mg to about 2000 mg per day of activeingredient.It will be recognized by one of skill in the art that the optimal quantity andspacing of individual dosages of a formula (I) compound will be determined by thenature and extent of the condition being treated, the form, route and site ofadministration, and the particular mammal being treated, and that such optimumscan be determined by conventional techniques. It will also be appreciated by oneof skill in the art that the optimal course of treatment, i.e., the number of doses of9WO 98/096301015202530CA 02264942 1999-03-05PCT/US97/15931the formula (1) compound given per day for a defined number of days, can beascertained by those skilled in the art using conventional course of treatmentdetermination tests.Methods of PreparationGenerally, the compounds of the invention may be prepared by thefollowing reaction sequence:'31CI 0 R2 4 N 0R‘\ N ‘ H CHZCI,9.2 + ———>N02 tnethylamine N02Formula II NO: NO2Formula IThe reaction sequence involves the reaction of a compound of Formula II,wherein R1 and R2 are defined above, and a suitable acid chloride derived from 3,‘4-dinitrobenzoic acid. This reaction may be accomplished in any of a variety ofreaction inert solvents by mixing approximately equimolar amounts of a compoundof Formula II and the acid chloride in the presence of an amine base at or belowroom temperature. The proper choice of reaction variables is within the skill of theart. Methylene chloride is the preferred solvent. Suitable amine bases aretriethylamine, N-methylmorpholine, pyridine, and the like. In general, the reactionis allowed to proceed for about 1 hour to about 24 hours at which time the reactionis substantially complete. The completeness of a particular reaction may bemeasured by known techniques such as thin layer chromatography. The productsof the reaction are isolated and purified by standard procedures. For example, thereaction mixture may be concentrated by evaporating the solvent and the residuemay be partitioned between water and a convenient nonwater-miscible organicsolvent such as ether, ethyl acetate, and the like. The solvent may then beevaporated and the residue chromatographed, for example, on silica gel. Choice ofthe proper chromatography solvent is within the skill of the art. After, or insteadof, chromatography, the product may be recrystallized.Acid addition salts may be prepared using standard procedures. Forexample, a hydrochloride salt may be prepared by dissolving the free base in aconvenient solvent and treating this solution with a solution of hydrogen chloridedissolved in the solvent of choice. The acid addition salts may be reconverted to10WO 98/0963010152025CA 02264942 1999-03-05PCT/US97/15931the respective free base by treatment with a dilute solution of sodium hydroxide orpotassium carbonate, for example.The compounds of formula (I) are prepared by art-recognized proceduresfrom known or commercially available staxting materials. If the starting materialsare unavailable from a commercial source, their synthesis is described herein, orthey can be prepared by procedures known in the art.Specifically, compounds of formula I can be prepared according to Scheme1 (Example 8). Formation of the desired amide (3-Scheme 1) is achieved by thereaction of an amine, such as N-methylaniline (1-Scheme 1), with an acid chloridederived from 3, 4-dinitrobenzoic acid (2-Scheme 1). This is performed in an inertsolvent such as methylene chloride in the presence of an amine base such astriethylarnine at or below room temperature. If the amine (1-Scheme 1) contains abasic amino group elsewhere in the molecule, such as in Example 6, theMe5 ‘No,No,3In the event that the desired amine (1-Scheme 1) is not commerciallytriethylamine may be omitted.Scheme 1on o+No,No,2Me.N,HCH2C|2————>triethylamine1available it may be prepared according to Schemes 2 or 3. The present inventionincludes such novel amine intermediates useful in the preparation of a variety ofthe final compounds of this invention. 'Scheme 2 illustrates the case where the amine (1-Scheme 1) contains asecond amine containing group such as in Example 1.Scheme 2llCA 02264942 1999-03-05wo 98/09630 PCT/US97/15931° ° 0CIA C I 3 C I /\/[K H 4% N V021 3 NHOReagents: a) aniline, CI-IZCI2, pyridine; b) 2, 3, 4, 5-tctrahydro-1H—3~bcnzazepine hydrochloride,triethylamine. acetonitrile, cat. nBu4NI; c) I..iAlI-I4, Tl-IF. reflux.' 5 In this example, 3-chloropropionyl chloride (1-Scheme 2) is reacted withaniline in an inert solvent in the presence of an amine base such as pyridine. Thisprovides the 3-chloroamide (2-Scheme 2) which is then reacted with the 3-benzazepine compound in acetonitrile to provide amide (3-Scheme 2). This amide(3-Scheme 2) is next converted to the desired diamine (4—Scheme 2) via reduction10 using a reagent such as lithium aluminum hydride at reflux in tetrahydrofuran. Thesynthesis is then completed using (4-Scheme 2) according to Scheme 1.In the case where the desired amine is not commercially available and doesnot contain an additional amino group, as in Example 7, the amine may beprepared according to Scheme 3. In this example isovaleryl chloride (1-Scheme 3)15 is reacted with 3, 4-dimethoxyaniline in the presence of an amine base such astriethylamine 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) byreducing the amide functionality by methods previously described. The synthesisis then completed using (3-Scheme 3) according to Scheme 1.2012CA 02264942 1999-03-05WO 98/09630 PCT/U S97/ 15931ficheme 30M9 OMeO O £5/OMe / e12 2Reagents: a) 3, 4-dimethoxyaniline, CI-l2Cl2, triethylamine; b) LiAlH4. TI-IF, reflux.5 For the cases where the desired N-methyl anilines are not commerciallyavailable, they are readily prepared from the anilines via a number of methods wellknown in the art. One such method is that reported by Barluenga et al. (J. Chem.Soc. Chem. Commun., pp. 1334-1335 (1984)). Alternatively, the desired N—methyl. amides are obtained directly from the secondary amides via alkylation of the amide10 anion as illustrated in Scheme 4.ficheme 40HM NO, a' b M% No,-——-—>/ N02 / N021 2Reagents: a) KN(SiMe3)2. TI-IF; b) Methyl iodide.15In this example, the secondary amide (1-Scheme 4) is treated with a non-nucleophilic base such as potassium bis(trimethylsilyl)amide [KN(SiMe3)2] at orbelow room temperature in a solvent such as tetrahydrofuran. The reactionsolution is then treated with a suitable methylating agent such as methyl iodide.20 The resulting N-methyl amides (2-Scheme 4) are then recovered using standardisolation and purification methods. VPreparation of the compounds in which the ortho position of the phenyl ringcontains an amide functionality (e.g., 2-Scheme 5) begins with the orthocarboxylic acid 1-Scheme 5 (Example 32). Conversion of this acid to the acid25 chloride using a chlorinating agent such as thionyl chloride or oxalyl chloridefollowed by treatment with the desired primary or secondary amine (GlG2NH)produces the corresponding secondary or tertiary amide analogs (2-Scheme 5).13CA 02264942 1999-03-05wo 98/09630 PCT/US97/15931Scheme 5o oMe\N NO, 8' b O M% NO,é-——> G1\HO-2C\© No, No,G21 2Reagents: a) thionyl chloride. CHCI3; b) GIGZNH. triethylarnine, CI-12Cl2.5 Compounds containing the N-propionate side chain (e.g., Examples 103-106, 108, 110, 111, 116) were prepared as outlined in Scheme 6. Michael additionof 2-ethylaniline to tert-butyl acrylate 1-Scheme 6 provides the alkylated aniline 2-Scheme 6. This intermediate is next acylated with 3, 4-dinitrobenzoyl chloride aspreviously described to provide benzamide 3-Scheme 6 (Example 103). The tert-10 butyl ester is removed using an anhydrous acid such as trifluoroacetic acid (TFA)to give the carboxylic acid 4-Scheme 6 (Example 104). Conversion of this acid tothe acid chloride using a chlorinating agent such as thionyl chloride or oxalylchloride followed by treatment with the desired primary or secondary amine(GlG2NH) produces the corresponding secondary or tertiary amide analogs (S-15 Scheme 6). Altematively, the acid chloride can also be treated with an alcohol inplace of the amine to produce esters.§cheme 6° ° 0 o/ 3 . b‘9"°Jk/ """’ tBuO)]\/\N “'j’ tBuOJK/\N No21 Eb Et2o o '° NO ° °-—-—> HO/K/\N 2 __3'_"._. °'~NJ'\/-N N022Eb N0 ('35N022 Etfij No,520 Reagents: a) 2-Ethylaniline. acetic acid, reflux; b) 3. 4-dinitrobenzoyl chloride, triethylamine,CH2Cl2; c) trifluoroacetic acid. CH2Cl2; d) oxalyl chloride. CI-I2Cl2; e) GIGZNH.triethylamine, CH2Cl2.14WO 98/096301015202530CA 02264942 1999-03-05PCT/US97/15931An alternative method for the preparation of compounds where R1 is(CH2)nZ, is by alkylation of the desired aniline with an appropriate alkyl halidesuch as is illustrated in Scheme 7 for the preparation of Example 117. Thisprocedure is quite general and may be used to prepare a wide range of anilines ofwhich compound 3-Scheme 7 is just one example. In this particular example, 4-chlorobutyryl chloride (1-Scheme 7) is reacted with diethylamine to provide thediethylarnide 2-Scheme 7. Alkylation of 2-ethylaniline using 2-Scheme 7 as thealkylating agent then provides 3-Scheme 7. Aniline 3-Scheme 7 is then acylatedusing 3, 4-dinitrobenzoyl chloride as previously described. In the compound ofExample 118, the commercially available 3-chloropropiophenone is used in placeof the amide 2-Scheme 7 in Scheme 7.Scheme 7.. 1 Jme‘ __:__ v I/\Lcl __b___. nu”maReagents: a) diethylarnine, triethylarnine, CHZCI2, 0 °C; b) 2-ethylaniline,triethylarnine, DMF, 100 °C.EXAMPLfiExa le 1. Pre aration of N- 3- 2 3 4 5-terah dro-1H-3-benzaze in-3-I ro I -N- hen I-3 4-dinitrobenzamide h drochloridea)Aniline (1.86 g, 20 mmol) in dry methylene chloride (50 mL) was treatedwith anhydrous pyridine (l.58g, 20 mmol), cooled to 0 °C, and treated with 3-chloropropionyl chloride (2.54 g, 20 mmol) in dry methylene chloride (5 mL). Themixture was stirred for 18h, allowing the ice bath to rise to room temperature. The reaction solution was washed with 10% HCI, water, and saturated sodiumbicarbonate and dried (Na2SO4). Evaporation gave the title compound as a chalkywhite solid (3.8 g, 100%.). MS(ES) rn/e 184 [M+H]"'.b)2, 3, 4, 5-Tetrahydro-IH-3-benzazepine hydrochloride (100 mg, 0.54mmol) and 3-chloro-N-phenylpropanamide (110 mg, 0.60 mmol) were suspendedin dry acetonitrile (2.5 mL) and treated with triethylarnine (0.23 mL, 1.63 mmol)15WO 98/0963010is20253035CA 02264942 1999-03-05PCT/US97/15931and tetra-n-butylammonium iodide (20 mg, 0.05 mmol). The reaction was refluxedfor 12h. The solvent was removed in vacuo and the residue was dissolved inmethylene chloride and washed with water, 5% Na2CO3, and brine and dried(Na2SO4). The product was purified by flash column chromatography (silica, 50,75, 90% ethyl acetate in hexane) to give 75 mg (50%) of a colorless amorphoussolid. MS (ES) m/e 295.4 [M+H]‘*'.c) Amide from Example lb (70 mg, 0.24 mmol) was dissolved in drytetrahydrofuran (2.5 mL) and treated with lithium aluminum hydride (14 mg, 0.36mmol). The reaction was refluxed for 3h. The reaction mixture was cooled to 0 °Cand quenched with water (0.5 mL), 10% NaOH (0.5 mL), and water (0.5 mL). Thesolution was then stirred vigorously at room temperature for 15 min. The solutionwas diluted with ethyl acetate and dried over Na2SO4, filtered, and evaporated togive a dark colored oil. This material was dried under vacuum for 18h and thenused directly for the following step. MS (ES) m/e 281.4 [M+H]"’.d) - - 4 ' Diamine from Example lc was dissolved in methylene chloride (1.5 mL),cooled in an ice water bath, and treated with 3, 4-dinitrobenzoyl chloride (41 mg,0.18 mmol). After 30 min the cooling bath was removed and a thick solid began toform. An additional 1.5 mL of methylene chloride was added and the reaction wasstirred at room temperature for an additional 2h. Dry diethylether was added andthe solid was collected by filtration. Obtained 82 mg (67%, for two steps) of thetitle compound as an off-white powder. MS (ES) In/e 475.4 [M+H]'*', free base.Example 2: Preparation of N-| 3-(7, 8-dimethog-2, 3, 4, 5-tetrahydro-1H-3-benzaze in-3- I r0 1 -N- hen 1-3 4-dinitrobenzamide h drochlorideThis compound was prepared according to the procedure described forExample 1 substituting 7, 8-dimethoxy-2, 3, 4, 5-tetrahydro-1H-3-benzazepinehydrochloride for 2, 3, 4, 5-tetrahydro-1H-3-benzazepine hydrochloride. Rubyglass. MS (ES) m/e 535.4 [M+H]"'. phenyl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 1 substituting N-methylphenethylarnine for 2, 3, 4, 5-tetrahydro-1H-3-benzazepine hydrochloride. The title compound was purified by flash column16101520253035WO 98/09630CA 02264942 1999-03-05PCT/US97/15931chromatography (silica, 1, 2, 3% methanol in methylene chloride) to give a darkamber oil. MS (ES) m/e 463.4 [M+H]"'. dimethogphenyl )-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 1 substituting morpholine for 2, 3, 4, 5—tetrahydro-1H-3-benzazepinehydrochloride and 3-chloro-N-(3, 4-dimethoxyphenyl)propanarnide for 3-chloro-N-phenylpropanamide. Amber glass. MS (ES) m/e 475.4 [M+H]"'. dimethogphenyl [-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 1 substituting piperidine for 2, 3', 4, 5-tetrahydro-1H-3-benzazepinehydrochloride and 3-chloro-N-(3, 4-dimethoxyphenyl)propanar_nide for 3-chloro-N- _phenylpropanamide. Amber glass. MS (ES) m/e 473.4 [M+H]"‘. dinitrobenzamide hydrochlorideN, N-Dimethyl-N’-phenylethylenediamine (165 mg, 1.00 mmol) wasdissolved 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 wasremoved and the reaction was stirred for 16h at room temperature. A‘ solid beganto form after 1h. The reaction mixture was treated with diethyl ether (2 mL) andthe pale yellow solid was filtered off-, washed with diethyl ether and dried.Obtained the title compound (363 mg, 92%) as a hydrochloride salt. MS (ES) m/e359.3 [M+H]‘*', free base; 314.3 [M-NMe2]"'.Example 7: Preparation of N -1 3-methylbutyl 1-N-13, 4-dimethogphenyl 1-3, 4-dinitrobenzamide3, 4-Dimethoxyaniline (1.0 g, 6.5 mmol) was dissolved in methylenechloride and treated with triethylarnine (1.5 mL, 10.7 mmol), 4-(N, N-dimethylamino)pyridine (80 mg, 0.65 mmol), and cooled in an ice water bath. Thereaction solution was treated dropwise with isovaleryl chloride (0.88 mL, 7.2mmol). After the addition the cooling bath was removed and the reaction wasallowed to stir at room temperature for 16h. The reaction was diluted with ethylacetate and washed with water, 5% HCl, 5% Na2CO3, and brine. The organic17WO 98/096301015"20253035CA 02264942 1999-03-05PCT/US97/15931layer was dried over Na2SO4, filtered, and evaporated to give a pinkish amorphoussolid.The amide obtained above (475 mg, 2.0 mmol) was dissolved in drytetrahydrofuran (10 mL) and treated with lithium aluminum hydride (115 mg, 3.0mmol). 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). Thesolution was then stirred vigorously at room temperature for 15 min. The solutionwas diluted with ethyl acetate and dried over Na2SO4, filtered, and evaporated togive 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-dimethylamino)pyridine (25 mg, 0.2 mmol), and 3, 4-dinitrobenzoyl chloride (500 mg, 2.17 mmol). The cooling bath was removed andthe reaction was stirred at room temperature for 4h. The reaction was diluted withethyl acetate and washed with 5% HCl, 5% Na2CO3, and brine. The organic layerwas dried over Na2SO4. filtered, and evaporated. The product was purified byflash column chromatography (silica, 25, 30, 35, 40% ethyl acetate in hexane) togive a yellow oil. Crystallization from ethyl acetate and hexane gave the titlecompound as a yellow crystalline solid. MP 92 -94 °C. Total yield was 626 mg(75% for two steps).Example 8: Preparation of N-methyl-N-phenyl-3, 4-dinitrobenzamideN-Methylaniline (96.3 mg, 0.9 mmol) in dry methylene chloride (6 mL)was treated with triethylarnine (101 mg, 140 uL, 1.0 mmol) followed by a solutionof 3, 4-dinitrobenzoyl chloride (230 mg, 1.0 mmol) in methylene chloride (1.0mL). The reaction solution was placed on a shaker overnight at room temperature.The solution was stripped to dryness; the solid was triturated with ether (15 mL)and collected by filtration; the solids were rinsed with water and dried in vacuo togive the title compound as dusty shrimp colored crystals (128 mg, 47%). 1H NMR(400 MHz, CDCI3) 8 7.86 (s,1H), 7.65 (dd, 2H), 7.26-7.36(m, 3H), 7.07 (d, 2H),3.54 (s, 3H).Example 9: Preparation of N-13, 4-dimethogyphenyl)-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 3, 4-dimethoxyaniline for N-methylaniline. Orangeamorphous solid. MS (ES) m/e 346.3 [M-H]‘.1820253035WO 98/09630CA 02264942 1999-03-05PCT/US97/15931Example 10: Preparation of N-benzgl-N-phengl-3, 4-dinitrobepzamideThis compound was prepared according to the procedure described forExample 8 substituting N-benzylaniline for N-methylaniline. 1H NMR (250 MHz,CDC13) 5 7.87 (s, 1H), 7.61-7.70 (m, 2H), 7.24-7.30 (m, 8H), 6.92 (s, 2H), 5.12 (s,2H).Exam le 11: Pre arationo N-iso ro l-N- he I- 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting N-isopropylaniline for N-methylaniline. 1H NMR (250MHz, CDCl3+MeOH-d4) 5 7.72 (s, 1H), 7.58 (dd, 2H), 7.25-7.27 (m, 3H), 6.98-7.00 (m, 2H), 4.93-5.03 (m. 1H), 3.05-3.60 (m, 6H). This compound was prepared according to the procedure described -for ‘Example 8 substituting 4-aminopyridine for N-methylaniline. 1H NMR (400MHz, CDCl3+ MeOH—d4) 5 8.46 (d, 1H), 8.29-8.31 (in, 2H), 8.22-8.24 (dd, 1H), ‘7.92 (d, 1H), 7.61 (dd, 2H).Example 13: Preparation of N-(4-nitrophenxl 1-3, 4-dinitrobenzappdeThis compound was prepared according to the procedure described forExample 8 substituting 4-nitroaniline for N-methylaniline. 1H NMR (400 MHZ,CDC13+ MeOH-d4) 5 8.44 (d, 1H), 8.20-8.23 (in, 1H), 8.04-8.07 (m, 2H), 7.90 (d,1H), 7.76-7.79 (m, 2H).Example 14: Preparation of N-(3-fluoro-2-methylyphenxl-3, 4-dinitrobenzamide This compound was prepared according to the procedure described forExample 8 substituting 3-fluoro-2-methylaniline for N-methylaniline. MS (ES)m/e 318.3 [M-H1‘.Example 15: Preparation of N43, 4-dichlorozphengl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 3, 4-dichloroaniline for N-methylaniline. MS (ES) m/e354.2, 356.2 [M-H]‘.Example 16: Preparation of N-(4-phenoxyzphenxl-3, 4-dinitrobenzamideWO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931This compound was prepared according to the procedure described forExample 8 substituting 4-phenoxyaniline for N-methylaniline. MS (ES) rn/e 378,3[M-H]'.Example 17: Preparation of N-(2, 4, 6-trichlormphengl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 2, 4, 6-trichloroaniline for N-methylaniline. 1H NMR (250MHz, DMSO-d6) 5 8.60 (s, 1H), 8.25-8.50 (m, 3H), 7.99 (s, IH).Example 18: Preparation of N-(4-bgomo-2-methylzphenyl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 4-bromo-2-methylaniline for N-methylaniline. MS (ES)rn/e 378.1 [M-H]'.Example 19: Preparation of N-(2, 2-diphen1l)eth};l-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 2, 2-diphenylethylamine for N-methylaniline. MS (ES)rn/e 390.4 [M-H]'.Example 20: Preparation of N-(3-methylisoxazol-5-gl1-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 5—amino-3-methylisoxazole for N-methylaniline. MS (ES)rn/e 291.2 [M-H]'.Example 21: Preparation of N-(2, 6-diethglgphengl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 2, 6-diethylaniline for N-methylaniline. 1H NMR (400MHz, CDCI3) 5 8.44 (d, 1H), 8.23-8.25 (m, 1H), 7.98 (d, 1H), 7.69 (s,1H), 7.30-7.34 (m, 1H), 7.19 (d, 1H), 2.60 (q, 4H), 1.20 (t, 6H).Example 22. Preparation of N-g§, 6, 7, 8-tetrahgdronaphth-1-gl)-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting l-arnino-5, 6, 7, 8-tetrahydronaphthalene for N-methylaniline. 11-I NMR (250 MHz, DMSO-d6) 8 8.73 (s, 1H), 8.37-8.50 (m, 2H),7.01-7.65 (m, 3H) 3.33 (s, 2H), 2.55-2.85 (m, 6H).20WO 98/0963020253035CA 02264942 1999-03-05PCT/US97/15931Example 23: Preparation of N-14-chloro-2-nitro)phengl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 4-chloro-2-nitroaniline for N-methylaniline. 1H NMR (250MHz, DMSO—d5) 8 8.72 (d, 1H), 8.42-8.46 (in, 2H), 8.17 (d, 1H), 7.91 (dd, 1H),7.71 (d, IH). This compound was prepared according to the procedure described forExample 8 substituting indoline for N-methylaniline. 1H NMR (400 MHz,CDC13+MeOH-d4) 5 8.06 (s, 1H), 7.86-7.98 (dd, 2H), 7.17-7.19 (d, 1H), 6.80-7.16(m, 2H), 3.85-4.30 (m, 2H), 3.10 (t, 2H). 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 6-methyl-1, 2, 3, 4-tetrahydroquinoline for N-methylaniline. 1H NMR (400 MHz, CDCl3+MeOH-d4) 5 7.93 (s, 1H), 7.49-7.72(dd, 2H), 7.27 (s, 1H), 6.93 (s, 1H), 6.63 (d, 1H), 3.78-3.83 (m, 2H), 2.69-2.73 (m,2H), 2.16 (s, 11-I), 1.95-1.98 (m, 2H). 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 1 using chloroacetyl chloride, and N-methylpiperazine. MS (ES) m/e414.5 [M+H]'*'.Example 27: Preparation of N -|2-1 mog;pholin-4-1l ) |ethgl-N-( 2-methglphengl )-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 1 using ehloroacetyl chloride ortho toluidine, and morpholine. MS (ES)m/e 415.4 [M+H]+.Example 28: N, N-Diphenyl-3, 4-dinitrobenzamideA solution of diphenylamine (0.1 g, 0.59 mmol) in dry tetrahydrofuran (1.5mL) was cooled to 0 °C and treated with sodium hydride (35 mg, 0.89 mmol). The21WO 98/09630101520253035CA 02264942 1999-03-05. PCT/US97/15931resulting mixture was stirred at room temperature for 5 minutes, cooled to 0 °C.and treated with 3, 4-dinitrobenzoyl chloride (142 mg, 0.62 mmol). The resultingdirty red solution was gradually warmed to room temperature and stirred for 20 h.TLC revealed the presence of a small amount of the unreacted diphenylamine. Acatalytic amount of 4-dimethylaminopyridine (7.2 mg, 0.06 mmol) was added tothe reaction mixture and the reaction was stirred for an additional 3 h. The reactionwas diluted with methylene chloride and washed with 10% HCl, I-I20, saturatedNal-ICO3, H20, and brine. The organic layer was dried over N a2SO4, filtered, andconcentrated in vacuo to give a reddish brown oil. Trituration of the crude oil withmethanol afforded the title compound as a tan solid (66 mg, 31%). MS (ES) m/e364.1 [M+H]+.The following compounds were prepared according to Example 8 using theappropriate amines and 3, 4-dinitrobenzoyl chloride unless otherwise noted.Example 29: N-(2-Methylphenyl )-3, 4-dinitrobenzamide1H NMR(400 MHz, CDCl3+MeOH-d4) 5 8.50 (cl, 1H), 8.25 (dd, 1H), 7.95(d,.lH), 7.10 (m, 4H), 2.15 (s, 3H).Exam le 30: N-Meth l-N- 2-meth I hen l-3 4-dinitrobenzamideMS (ES) mle 316.3 [M+H]+, 339.3 [M+Na]+.Example 31: N-(2-Carboghenyl)-3, 4-dinitrobenzamideMS (ES) m/e 330.2 [M-H]‘.Exam le 32: N-Meth l- - 2-carbo hen l-3 4-dinitrobenzamideMS (ES) m/e 344.3 [M-H)‘.Example 33: N-gghenylmethyl)-3, 4-dinitrobenzamideMS (ES) m/e 300.2 [M—H]'.Example 34: N-Methyl-N-gphenylmethyl [-3, 4-dinitrobenzamideMp 112-113 °C.Example 35: N-|2-§Aminocar-bonyllphenyl |-3, 4-dinitrobenzamide1H NMR (400 MHz, DMSO-d5) 8 8.6 (m, 2H), 8.5 (m, SH). 8.0 (m, 1H),7.6 (m, 1H), 7.25 (m, 1H).2220253035WO 98/09630CA 02264942 1999-03-05PCTIUS97/15931 Example 37: N -| 2-1 Trifluoromethgl lphenxl |-3, 4-dinitrobenzamideMS (ES) m/e 254.2 [M-I-1]‘.Example 38: N-Methyl-N-| 2-gtrifluoromethgl)phen1l|-3, 4-dinitrobenzamide1H NMR (400 MHz, CDCI3) 8 7.85 (s, 1H), 7.65 (m, 5H), 7.35 (d, 1H),3.51 (s, 3H).Example 39: N-12-Fluorophenxl)-3, 4-dinitrobenzamideMS_(ES) m/e 304.3 [M-H]‘.Example 40: N -(2-Fluorophenyl Q-N-methyl-3, 4-dinitrobenzamideMS (ES) In/e 320.1 [M+H]"’.Example 41: N-|3-gAminocarbongl)phen1lI-3, 4-dinitrobengamidgMS (ES) m/c 331.2 [M+H]"'. 1H NMR (400 MHZ, CDCl3+McOI-I-d4) 5 7.72 (s, 1H), 7.55 (In, 3H), 7.4(In, 1H), 7.15 (t, 1H), 7.0 (d, 1H), 3.3 (s, 3H).Example 43: N-flrazjngl-3, 4-dinitrobenzamide1H NMR (400 MHz, DMSO-d5) 5 9.4 (s, 1H), 8.75 (s, 1H), 8.52 (m, 2H),8.45 (d, 1H), 8.35 (d, IH).Example 44: N-Mgthgl-N-pzgazingl-3, 4-dinitrobenzamideMS (ES) In/e 304.2 [M+H]"'. MS (ES) m/e 317.2 [M+H]"'.23WO 98/096301020253035CA 02264942 1999-03-05PCT/U S97/ 15931Example 47: N-(2-Cganophengl 1-3, 4-dinitrobenzamideMS (ES) m/e 311.3 [M-H]'.Example 48: N-(2-CganophenylQ-N-methyl-3, 4-dinitrobenzamide1H NMR (400 MHz, CDCI3) 5 7.8 (s, 1H), 7.75 (m, 2H), 7.65 (m, 2H),7.45 (m, 1H), 7.35 (m, 1H), 3.5 (s, 3H).Example 49: N-(2-Methozgphenxl [-3, 4-dinitrobenzamideMS (ES) m/e 316.3 [M-H]'. MS (ES) m/e 332.2 [M+H]+.Example 519: N-(2-Biphengly-3, 4-diniutrobenzamideMS (ES) m/e 362.3 [M-H)’.Example 52: N-(2-Biphengl)-N-methyl-3, 4-dinitrobenzamideMS (ES) m/e 378.1 [M+H]"'.Exam le 53: N- 4-Metho hen I -N-meth I-3 4-dinitrobenzamide1H NMR (400 MHz, CDC13+MeOH-d4) 6 7.7 (s, 1H), 7.6 (d, 1H), 7.42(dd, 1H), 6.8 (d, 2H), 6.65 (d, 2H), 4.15 (s, 3H), 3.55 (s, 3H).Example 54: N -Methyl-N-| 12-trifluoromethog lphenyll-3, 4-dinitrobenzamide1H NMR (400 MHz, CDCI3) 5 7.65 (s, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 7.2(m, 3H), 7.05 (m, 1H), 3.3 (s, 3H). 1H NMR (400 MHz, CDC13) 8 7.92 (s, 1H), 7.72 (In, 2H), 7.48 (m, 1H),7.35 (In, 3H), 3.46 (s, 3H).Example 56: N-| 2-| 1 2-Furanxlmethgl yaminocarbonyl lphenxl |-N-methyl-3, 4-dinitrobenzamideMS (ES) m/e 425.3 [M+H]+. WO 98/0963020253035CA 02264942 1999-03-05PCT/US97/15931Mp 119.5-120.5 °c.Example 58: N-|2-1_Methoxgcarbonylzphengl|-N-methyl-3, 4-dinitrobenzamideMS (ES) m/e 360.2 [M+H]‘*.Example 59: N-| 2-| (2-13, 4-Dimethogphengllethgl zaminocarbongl lphenyl |-N-methyl-3, 4-dinitrobenzamidgMS (ES) m/e 509.2 [M+H]+.Example 60: N-Methyl-N-|2-|12-phenglethylpaminocarbongllphenxll-3, 4-dinitrobenzamideMS (ES) m/e 449.3 [M+H]+. Example 61: N-Pentafluorophenyl-3, 4-dinitrobenzamideMp 161-164 °c.Example 62: N42, 6-Dimethxlphengl 1-3, 4-dinitrobenzamideMS (ES) m/e 316.3 [M+H]'*'.Example 63: N-(3-Fluorophenxl 1-3, 4-dinitrobenzamideMS (ES) m/e 304.3 [M-H]'.Example 64: N-(4-Fluorophengl)-3, 4-dinitrobenzamideMS (ES) m/e 304.3 [M-H]‘.Example 6§: N-12-Fluoro-S-methxlphengl Q-3, 4-dinitrobenzamideMS (ES) m/e 318.3 [M-H]'.Example 66: N -14-Methog-2-methglphengl [-3, 4-dinitrobenzamideMS (ES) m/e 330.3 [M-H]'.Example 67: N-(2-Iodophengll-3, 4-dinitrobenzamideMS (ES) mle 412.2 [M-H]'.Example 68: N-12-Chloro-3-methglphengl[-3, 4-dinitrobenzamideMS (ES) m/e 334.2 [M-H]'.25WO 98/09630202530CA 02264942 1999-03-05PCT/US97/15931Example 69: N-(2, 4-Dimethglphenyl)-3, 4-dinitrobenzamideMS (ES) m/e 314.4 [M-H)‘.Example 70: N-|(2-Chlorophenglpmethgl|-3, 4-dinitrobenzamideMS (ES) m/e 334.3 [M-H]'.Example 71: N-| (2-Methylphenyl {methyl |-3, 4-dinitrobenzamideMS (ES) mle 314.4 [M-H]'.Example 72: N-(3-Carboggphenyl)-3, 4-dinitrobenzamideMS (ES) m/e 330.2 [M-H]'.Example 73: N-(4-Carboxgphengl)-3, 4-dinitrobenzamideMS (ES) mle 330.3 [M-H]'.Example 74: N-52, 6-Dichlorophengl 1-3, 4-dinitrobenzamideMS (ES) m/e 354.3 [M-H]‘.Example 75: N-1 1, 3, 4-Thiadiazol-2-xl)-3, 4-dinitrobenzamideMS (ES) m/c 294.3 [M-H]'.Exam le 76: N- 1 2 4-Triazol-3- l-3 4-dinitrobenzamideMS (ES) m/e 296.2 [M+H]"'; 294.3 [M-H]'.Example 77: N-(2-Naphthgl)-3, 4-dinitrobenzamide11-I NMR(400 MHz, DMSO-d5) 8 8.75 (d, 1H), 8.51 (dd, 1H), 8.42 (m,2H), 7.82 (m, 4H), 7.48 (m, 2H).Example 78: N-(S-g zuinolinxl)-3, 4-dinitrobenzamideMp 216-218 °C (dec).Example 79: N -(3-flridingl )-3, 4-dinitrobenzamideMS (ES) mle 289.2 [M+H]+.Example 80: N-(2-ljgridingl)-3, 4-dinitrobenzamideMS (ES) m/e 289.2 [M+H]"'.2620253035WO 98/09630CA 02264942 1999-03-05PCT/US97/15931 MS (ES) m/e 363.3 [M+H]+.Example 82: N-(2-Hxdrogphenyl)-3, 4-dinitrobenzamideMS (ES) m/e 302.3 [M-H]‘.Example 83: N-1 1-Naphthgl)-3, 4-dinitrobenzamideMS (ES) In/e 336.3 [M-H]‘.Example 84: N-(Diphenxlmethgl)-3, 4-dinitrobenzamideMS (ES) In/c 376.2 [M-H]'. MS (ES) m/e 331.2 [M+H]"'.Example 87: N-(2-Ethglphenxl)-3, 4-dinitrobenzamideMS (ES) m/e 314.2 [M-H]'.Example 88: N-11-Indazolgl)-3, 4-dinitrobenzamide1H NMR (400 MHZ. CDCI3) d 8.75 (s, 1H), 8.56 (m, 2H), 8.27 (s, 1H),8.04 (d, 1H), 7.84 (d, 1H), 7.67 (t, 1H), 7.49 (t, 1H).Example 89: N4 1-Benzimidazolgl 1-3, 4-dinitrobenzamide1H NMR (400 MHz, CDC13) d 8.47 (s, 1H), 8.24 (m, 4H), 7.86 (dd, 1H),7.53 (In, 2H). 1H NMR (400 MHZ, CDCI3) d 8.34 (d, 1H), 8.18 (s, 1H), 7.95 (m, 1H),7.91 (m, 1H), 7.87 (d, 1H), 7.83 (m, 2H), 7.70 (m, 2H), 7.47 (tn, IH).Example 91: N-| 6-Methog-2-1methoggcarbonglyindol-1-gl [-3, 4-dinitrobenzamide27101520253035WO 98/09630CA 02264942 1999-03-05PCT/US97/15931This compound was prepared according to the procedure described forExample 28 substituting methyl 6-methoxy-2-indolecarboxylate fordiphenylaniline. Orange yellow solid. 1H NMR (400 MHz, CDCI3) d 8.19 (s,1H), 7.97-7.98 (m, 2H), 7.61 (d, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.03 (dd, 1H), 3.90(s, 3H), 3.63 (s, 3H). Mp 113-114 °c.Example 93: N-(2, 3, 4, 5-Tetrahydro-1H-3-benzazepin-3-yl[-3, 4-dinitrobenzamideMS (ES) m/e 342.4 [M+H]+.Example 94: Preparation of N-(2, 3, 4, 5-tetrahydro-II-L1-benzazepin-1-xl[-3,4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 2, 3, 4, 5-tetrahydro-1H-1-benzazepine for N-methylaniline. The 2, 3, 4, 5-tetrahydro-1H-l-benzazepine was prepared by themethod report by Yamamoto et al. in Tetrahedron Lett., 1983, 24, 4711-4712. MS(ES) m/e 342.4 [M+H]'*'.Example 95: Preparation of N-12-ethylphenyl1-N-methyl-3, 4-dinitrobenzamide ,A solution of the compound of Example 87 (109 mg, 0.35 mmol) in drytetrahydrofuran (1 mL) under argon was cooled to 0 °C and added (dropwise!)potassium bis(trimethylsilyl)amide (1 mL, 0.53 mmol, 0.5 M solution in toluene).After stirring at 0 °C for 5 minutes, iodomethane was added to the reaction mixtureand the reaction was gradually warmed to room temperature and stirred for 20hours. The reaction was diluted with methylene chloride and washed with H20,5% Na2CO3, and brine. The organic layer was dried over Na2SO4, filtered, andconcentrated in vacuo to give a reddish brown solid. The crude solid was purifiedby flash column chromatography (silica, 20, 30, and 40% ethyl acetate in hexane)to afford 37 mg (32%) of the title compound as a light yellow solid. MS (ES) rn/e330.2 [M+H]‘*'.Exam le 96: Pre aration of N-meth |-N- yl [carbonyl |phenyl |-3, 4-dinitrobenzamide hydrochloride28WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931The carboxylic acid prepared in Example 32 (2.0 g, 5.8 mmol) inchloroform (25 mL) was treated with thionyl chloride (5 mL) and gently refluxedfor 2 h. After cooling to room temperature the solvent and excess reagent wereevaporated to give the acid chloride that was used without further purification.Acid chloride (200 mg, 0.55 mmol) was dissolved in dry methylenechloride (10 mL) and treated with N-methyl pipcrazine (55.5 uL, 0.5 mmol). Thereaction was stirred overnight at RT. The solvent was evaporated and the resultingresidue was triturated with diethyl ether to give 99 mg of the desired product. MS(ES) m/e 428.3 [M+H]"'.Example 97: Preparation of N-| |2-|(3-methogcarbonyl [phenxl laminocarbonyl |phenyl |-N-methyl-3, 4-dinitrobenzamide APrepared according to the procedure described for Example 96 substitutingmethyl 3-aminobenzoate for N-methylpiperazine. MS (ES) m/e 477.2 [M-H]'.Example 98: Preparation of N-methyl-N-| |2-|2-15’, N’-dimethylamino lphenyl laminocarbongl lphenyl |-3, 4-dinitrobenzamidePrepared according to the procedure described for Example 96 substituting2-(N, N-dirnethylarnino)aniline for N-methylpiperazine. MS (ES) m/e 464.3[M+H]'*'. phenxlethgl |aminocarbon1l Iphengl |-§, 4-dinitrobenzamidePrepared according to the procedure described for Example 96 substitutingL-phenylalanine tert-butyl ester for N-methylpiperazine. MS (ES) m/e 547.1 [MH]‘Example 100: Epgparation pf N-||;-|2-gethogcarbongl [ethyl laminocarbongl |phen1l |-N-methyl-3, 4-dinitrobengamidgPrepared according to the procedure described for Example 96 substitutingbeta alanine ethyl ester for N-methylpiperazine. MS (ES) m/e 445.1 [M+H]"'.Example 101: Preparation of (S1-N-||2-I1-(aminocarbonyl)-Lphenylethyl |aminocarbonyl lphenyl I-N-methyl-3, 4-dinitrobenzamide29WO 981096301015'20253035CA 02264942 1999-03-05PCT/US97/15931Prepared according to the procedure described for Example 96 substitutingL-phenylalaninarnide for N-methylpiperazine. MS (ES) m/e 492.1 [M+H]+.Exam le 102: Pre aration of S -N- 2- 1-carbo -2-phenglethyl laminocarbonyl |phengl |-N-methyl-3, 4-dinitrobenzamideTert-butyl ester prepared in Example 99 (50 mg, 0.091 mmol) was treatedwith cold (0 °C) TFA (3 mL) and stirred at 0 °C for 0.5 h and then at RT for 2 h.Evaporation and trituration of the resulting residue with water gave 29 mg of thedesired compound. Mp 96-106 °C.Example 103: Preparation of N-(2-ethylphenyl)-N-|2-(tert-buto carbon I eth l -3 4-dinitrobenz mi ea) leg-butyl 3-( N-2-gthylphggyl )aminp pgoprionatgA solution of 2-ethylaniline (12. lg, 100 mmol), tert—butyl acrylate (12.8 g,100 mmol), and glacial acetic acid (2.5 mL) was gently refluxed for 24 h. Thesolvents were evaporated under reduced pressure; the viscous residue was taken upin diethyl ether (200 mL) and the resulting solution was washed in turn with diluteaqueous sodium bicarbonate solution and water and dried ( Na2SO4). Evaporationof the solvent gave a viscous syrup which was purified by flash columnchromatography (silica, 10, 15% ethyl acetate in hexane) to give 4.15 g (17%) of aviscous yellow oil. MS(ES) mle 250.3 [M+I-l]+.-bu 1 A solution of tert—butyl ester from Example 103a (498 mg, 2.0 mol), 3, 4-dinitrobenzoyl chloride (483 mg, 2.0 mmol), and triethylarnine ( 280 uL, 2.0mmol) in methylene chloride (10 mL) was stirred overnight at room temperature.The reaction mixture was washed in turn with water, dilute aqueous sodiumbicarbonate solution, dilute aqueous hydrochloric acid, and water and dried(Na2SO4). Evaporation provided 890 mg (100%) of the desired product as aviscous amber syrup. MS(ES) rn/e 466.2 [M+Na]"'.Example 104: Preparation of N-(2-carboxyethyl1-N-(2-ethylphenxl[-3, 4-dinitrobenzamideN-(2-Ethylphenyl)-N-[2-(tert-butyloxycarbonyl)ethyl]-3, 4-dinitrobenzarnide (800mg, 1.80 mmol) from Example 103 was treated at roomtemperature with a solution of trifluoroacetic acid (20 mL) and methylene chloride(20 mL). The reaction solution was stirred at room temperature for 2 h.30101520253035WO 98/09630CA 02264942 1999-03-05PCTIUS97/15931Evaporation provided a syrup that was crystallized from diethyl ether and hexaneto give 550 mg (79%) of the desired product. MS (ES) m/e 386.2 [M-H]'.Example 105: Preppration of N-|2-gethylaminocarbonyl)ethyl|-N-(2-ethylphenyl 1-3, 4-dinitrobenzamideA solution of the compound of Example 104 (150 mg, 0.387 mmol) in drymethylene chloride (15 mL) was cooled to 0 °C and treated with oxalyl chloride(3.87 mL) and a catalytic amount of N, N-dimethylforrnarnide (5 uL). Theresulting mixture was gradually warmed to room temperature and stirred for 20hours. The methylene chloride and excess oxalyl chloride were removed atreduced pressure, and the resulting golden yellow oil (acid chloride) was pump-dried for 30 minutes and used directly in the following step.A solution of the crude acid chloride (0.129 mmol) in methylene chloride(5 mL) was introduced into a cooled (0 °C) reaction mixture of ethylamine (77 uL,0.155 mmol, 2M solution in tetrahydrofuran), triethylamine (27 uL, 0.19 mmol)and 4-dimethylarninopyridine (1 mg, 0.0065 mmol). After stirring for 1 hour, thereaction was diluted with methylene chloride and washed with 10% HCI, H20, andbrine. The organic layer was dried over Na2SO4, filtered, and concentrated invacuo to give a crude oil. The crude product was purified by flash columnchromatography (silica, 1 and 5% methanol in methylene chloride) to afford 46 mg(86%) of the title compound as a viscous golden yellow oil. MS (ES) m/e 415.3[M+H]"'.Example 106: Preparation of N-|2-gdiethylaminocarbonylzethyl|-N-(2-ethylphenyl 1-3, 4-dinitrobenzamjdeThis compound was prepared according to the procedure described forExample 105 substituting diethylarnine for ethylamine. Light yellow solid. MS(ES) m/e 443.2 [M+H]+.Example 107: Preparation of N42, 6-diisopropxnphenyl-3, 4-dinitrobenzamide This compound was prepared according to the procedure described forExample 8 substituting 2, 6-diisopropylaniline for N-methylaniline. White,amorphous solid. MS (ES) m/e 370.3 [M-H]'.Example 108: Preparation of N-|2-gaminocarbonylEthyl|-N-12-ethylphenylp3, 4-dinitrobenzamide31WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931This compound was prepared according to the procedure described forExample 105 substituting ammonium hydroxide for ethylamine. Bright yellowsolid. MS (ES) m/e 387.2 [M+H]'*'.Example 109: Preparation of N-(2, 6-diethyl)phenyl-N-methyl-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 95 substituting the compound of Example 21 for the compound ofExample 87. Yellow solid. 1H NMR (400 MHz, CDCI3) d 7.75 (s, 1H), 7.60-7.67(m, 2H), 7.26-7.30 (m, 1H), 7.13 (d, 2H), 3.38 (t, 3H), 2.58-2.66 (m, 2H), 2.42-2.52 (m, 2H), 1.24 (t, 6H). ethglphengl 1-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 105 substituting piperidine for ethylarnine. Pale yellow solid. MS (ES)rn/e 455.3 [M+H]+.Example 111: Preparation of N-| 2-| gfl’-bengl-Nfimethylamino [carbonyl |gthyl |-N-1 2-ethylphenyl [-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 105 substituting N-benzyl-N-methylamine for ethylarnine. Goldenyellow oil. MS (ES) m/e 491.2 [M+H]"'. dinitrobenzamidgThis compound was prepared according to the procedure described forExample 95 substituting the compound of Example 107 for the compound ofExample 87. Light yellow solid. MS (ES) rn/e 386.4 [M+H]"’.Example 113: Preparation of N-(2-n-butylphenyl)-3, 4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 8 substituting 2-n-butylaniline for N-methylaniline. Off-white solid. MS(ES) rn/e 342.3 [M-H]'.Example 114: Preparation of N-(2-isopropylphenyl)-3, 4-dinitrobenzamide32WO 98/09630101520253035CA 02264942 1999-03-05PCT/US97/15931This compound was prepared according to the procedure described forExample 8 substituting 2-isopropylaniline for N-methylaniline. Off-white solid.MS (ES) m/e 328.1 [M-H)‘.Example 115: Preparation of N-(2-butylphenyl1-N-methyl-3, 4-djnitrobenzamideThis compound was prepared according to the procedure described forExample 95 substituting the compound of Example 113 for the compound ofExample 87. Golden brown oil. 1H NMR (400 MHz, CDCI3) d 7.80 (s, 1H),7.61-7.68 (m, 2H), 7.16-7.29 (m, 3H), 7.08 (d, 1H), 3.44 (t, 3H), 2.49-2.60 (m,1H), 2.35-2.45 (m, 1H), 1.48-1.67 (m, 2H), 1.36-1.45 (m, 2H), 0.95 (t, 3H).Example 116: Preparation of N-|2-gmogholinocarbonyllethyl|-N-(2-ethylphenyl [-3, 4-dinitrobeggamide 1This compound was prepared according to the procedure described forExample 105 substituting morpholine for ethylamine. Pale amber glass. MS (ES)In/e 457.3 [M+H]+.Example 117. Preparatiop of N-|§-|gdiethylaminogcarbonyl|propyl|-N-(2-ethylphenyl 1-3, 4-dinitrobenzamidga) 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) and4-chlorobutyryl chloride (1.7 mL, 15 mmol). The resulting mixture was graduallywarmed to room temperature and stirred for 20 h. The reaction was diluted withmethylene chloride and washed with 10% HCI, water, and brine. The organic layerwas dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crudeoil was pump-dried overnight and used directly in the following step.A solution of 2-ethylaniline (250 mg, 2.06 mmol) in N, N-dimethylforrnamide (6 ml.) was treated with the crude chloride prepared above(550 mg, 3.1 mmol), triethylarnine (0.48 mL, 3.4 mmol), and tetra-n-butylarnmonium 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 withwater, 10% HCI, water, and brine. The organic layer was dried over Na2SO4,filtered, and concentrated in vacuo. The resulting crude oil was purified by flashcolumn chromatography (silica, 20: 10:70 and 30: 10:60 ethyl acetate-methylenechloride-hexane) to afford the title compound (215 mg, 40%) as a viscous light33WO 98/0963020253035CA 02264942 1999-03-05PCT/US97/15931brown oil. 1H NMR (400 MHz, CDCI3) d 7.11 (t, 1H), 7.06 (d, 1H), 6.69 (t, 1H),6.61 (d, 1H), 4.10 (bs, 1H), 3.40 (tn, 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-— ithl --2-dini n 'A solution of the compound of Example 117(a) (211 mg, 0.807 mmol) inmethylene 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). Theresulting mixture was gradually warmed to room temperature and stirred for 20 h.The reaction was diluted with methylene chloride and washed with 10% HCI,water, and brine. The organic layer was dried over Na2SO4, filtered, andconcentrated in vacuo. The resulting crude oil was purified by flash columnchromatography (silica, 30: 10:60, 40: 10:50, and 50:10:40 ethyl acetate-methylenechloride-hexane) to afford the title compound (242 mg, 66%) as a golden yellowoil. MS (ES) rn/e 457.1 [M+H]"’.Example 118. Preparation of N-13-oxo-3-phenylpropyl1-N-(2-ethylphengll-3,4-dinitrobenzamideThis compound was prepared according to the procedure described forExample 117 substituting 3-chloropropiophenone as the alkylating agent. MS (ES)In/e 917.1 [2M+Na]+, 1364 [3M+Na]"'.BIQLQGIQAL DATAEffect of Qommunds on the QQRP ReceptorThe test compounds were assayed for the inhibition of [1251 ] CGRP(obtained from Amersham, Chicago, IL) binding and CGRP-activated adenylatecyclase activity.SK-N-MC cells were obtained from American Type Culture Collection(Rockville, MD) and grown in Minimum Essential Media ("MEM") mediumcontaining fetal calf serum (10%). Cells were grown in T—l50 flasks or Costarmultiwell plates (24 well) and maintained at 37 °C in a 90% humidified incubatorwith an atmosphere of 5% CO2 and 95% air.Im =SK-N-MC cells were homogenized in 5 mM Tris-HCI pH 7.4, 10 mM Na-EDTA and the homogenate was centrifuged at 48,000 g for 20 min at 4 °C. Thepellet was resuspended in 20 mM Na-HEPES pH 7.4, 10 mM MgCl2 and34WO 98/096301015202530.35CA 02264942 1999-03-05PCT/US97/15931recentrifuged as above. The membrane pellets were resuspended in the samebuffer and stored frozen at -70 °C. The protein concentration was measured by thePierce BCA method using bovine serum albumin as the standard.The [1251] CGRP receptor binding assay was performed using a buffercontaining 20 mM Na-HEPES pH 7.4, 10 mM MgCl2, 0.05% BSA and 0.1 mg/mLbacitracin. The membranes (50 ug protein/mL) were incubated with variousconcentrations (1, 10, 30, 60 and 100 uM) of the test compounds and 40 pM [1251]CGRP in a total volume of 500 uL. for 60 min at 25 °C. The reaction wasterminated by addition of 2 mL ice-cold 0.9% NaCl, followed by rapid filtrationthrough Skatron Filtermates presoaked in 0.5% polyethylenimine PEI). The filterswere rinsed twice with 2 mL of cold 0.9% NaCl and the radioactivity counted in agamma counter. All binding data was analyzed by computer assisted LIGAND 2program. =Adenylate cyclase activity was measured in triplicate as the rate ofconversion of ot[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 ug] were incubated in triplicate in buffer containing 50mM Tris-HCI (pH 7.4), 10 nM MgCl2, 1.2 mM ATP, 1.0 uCi ot[31P]ATP, 0.1 mMCAMP, 2.8 nM phosphoenolpyruvate and 5.2 ttg/ml myokinase in a final volume of100 pl for 20 min at 30°C. The reactions were stopped with 1 ml solutioncontaining cAMP, ATP and 22000 cpm of [3H] cAMP. [32P]cAMP was separatedusing sequential chromatography (Dowex and alumina columns) (Salmon et al.,Ana..Biochem. Vol. 58, pp. 541-548 (1974)). Adenylate cyclase activities weredetermined in the absence (basal) or presence of 2.5 nM of hCGRPoL with variousconcentrations (0.1 p.M to 30 LIM ) of compound.The compounds of this invention show CGRP receptor antagonist activityhaving IC50 values in the range of 0.001 to 100 uM. The full structure/activityrelationship 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 thepresent assays in order to determine which compounds of formula (I) are ligands ofthe CGRP receptor and which bind thereto with an IC50 value in the range of0.001 to 100 uM.All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated by reference as if35CA 02264942 1999-03-05wo 98/09630 PCT/US97/15931each individual publication were specifically and individually indicated to beincorporated by reference herein as though fully set forth.The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodiments5 specifically disclosed herein are within the scope of the following claims. Withoutfurther elaboration it is believed that one skilled in the art can, given the precedingdescription, utilize the present invention to its fullest extent. Therefore anyexamples are to be construed as merely illustrative and not a limitation on thescope of the present invention in any way. The embodiments of the invention in10 which an exclusive property or privilege is claimed are defined as follows.36

Claims (6)

What is claimed is:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:

R1 is hydrogen, methyl, -(CH2)n, branched (3-6 carbon) alkyl, -(CH2)nphenyl, , wherein X is CH2, oxygen or N-alkyl, or R1 is (CH2)n NR3R4, or (CH2)n Z, wherein Z is CO2H, CO2-alkyl, CONR3R4, -N(R3)CO2R3, -N(R3)C(O)NR3R4, -OC(O)NR3R4, or COR5, and wherein R3 and R4 are independently hydrogen, C1-4alkyl or C1-4alkylphenyl, 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. C2-6alkyl, phenyl or heteroaryl;

R2 is optionally substituted aryl or heteroaryl, or R2 is A-Ar, wherein A is lower alkyl (C1-4) or branched alkyl, wherein a branch may contain a substituted phenyl ring, and Ar is substituted phenyl or a substituted 5- or 6-membered heteroaryl ring which optionally contains one or more heteroatoms selected from N, O or S, or R2 is , wherein W is OH, NR3R4, O-alkyl, an amide derived from an amino acid, NR6R7, where R6 is H, alkyl, and R7 is aryl or substituted aryl, (CH2)n-aryl, (CH2)n-substituted aryl, (CH2)n-heteroaryl, or (CH2)n -Z; or R1 and R2 together with the nitrogen to which they are attached form a 5- or 6- membered heteroring fused to an optionally substituted phenyl ring;

m is 1 to 3; and n is 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-dinitrobenzamide or N-phenyl-3,4-dinitrobenzamide.
2. The compound as claimed in claim 1 selected from:
N-(2-ethylphenyl)-N-[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenzamide;
N-[2-(morpholinocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-(ethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-(diethylaminocarbony)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-[(1-piperidinyl)carbonyl]ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenzamide;
N-(2-ethylphenyl)-N-methyl-3, 4-dinitrobenzamide;
N-(2,6-diethyl)phenyl-N-methyl-3, 4-dinitrobenzamide;
N-[3-(2, 3, 4, 5-terahydro-1H-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(7, 8-dimethoxy-2, 3, 4, 5-terahydro-1H-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(N'-methyl-2-phenylethylamino)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(morpholin-4-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;
N-[3-(piperidin-1-yl)propyl]-N-(3. 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;
N-[2-(N',N'-dimethylamino)ethyl]-N-phenyl-3, 4-dinitrobenzamide;
N-(3-methylbutyl)-N-(3,4-dimethoxyphenyl)-3,4-dinitrobenzamide; and N-methyl-N-phenyl-3, 4-dinitrobenzamide.
3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmceutically acceptable carrier.
4. A method of treating a CGRP-mediate 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:

wherein:

R1 is hydrogen, methyl, -(CH2)n, branched (3-6 carbon) alkyl, -(CH2)n phenyl, , wherein X is CH2, oxygen or N-alkyl, or R1 is (CH2)n NR3R4, or (CH2)n Z, wherein Z is CO2H, CO2-alkyl, CONR3R4, -N(R3)CO2R3, -N(R3)C(O)NR3R4, -OC(O)NR3R4,or COR5, and wherein R3 and R4 are independently hydrogen, C1-4alkyl or C1-4alkylphenyl, 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, C2-6alkyl, phenyl or heteroaryl;

R2 is optionally substituted aryl or heteroaryl, or R2 is A-Ar, wherein A is lower alkyl (C1-4) or branched alkyl, wherein a branch may contain a subtituted phenylring, and Ar is substituted phenyl or a substituted 5- or 6-membered heteroaryl ring which optionally contains one or more heteroatoms selected from N, O or S, or R2 is , wherein W is OH, NR3R4, O-alkyl, an amide derived from an amino acid, NR6R7, where R6 is H, alkyl, and R7 is aryl or substituted aryl, (CH2)n-aryl, (CH2)n-substituted aryl, (CH2)n-heteroaryl, or (CH2)n -Z; or R1 and R2 together with the nitrogen to which they are attached form a 5- or 6- membered heteroring fused to an optionally substituted phenyl ring;
m is 1 to 3; and n is 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-dinitrobenzamide or N-phenyl-3,4-dinitrobenxamide.
5. The method as claimed in claim 4 wherein the compound of formula (I) is a compound selected from:

N-(2-ethylphenyl)-N-[2-(tert-butoxycarbonyl)ethyl]-3, 4-dinitrobenzamide;
N-[2-(morpholinocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-(ethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-(diethylaminocarbonyl)ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[2-[(1-piperidinyl)carbonyl]ethyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-[3-[(diethylamino)carbonyl]propyl]-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-(3-oxo-3-phenylpropyl)-N-(2-ethylphenyl)-3, 4-dinitrobenzamide;
N-Methyl-N-(2-methylphenyl)-3, 4-dinitrobenzamide;
N-(2-ethylphenyl)-N-methyl-3, 4-dinitrobenzamide;
N-(2,6-diethyl)phenyl-N-methyl-3, 4-dinitrobenzamide;
N-[3-(2, 3, 4, 5-terahydro-1H-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(7, 8-dimethoxy-2, 3, 4, 5-terahydro-1H-3-benzazepin-3-yl)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(N'-methyl-2-phenylethylamino)propyl]-N-phenyl-3, 4-dinitrobenzamide;
N-[3-(morpholin-4-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;
N-[3-(piperidin-1-yl)propyl]-N-(3, 4-dimethoxyphenyl)-3, 4-dinitrobenzamide;
N-[2-(N', N'-dimethylamino)ethyl]-N-phenyl-3, 4-dinitrobenzamide;
N-(3-methylbutyl)-N-(3,4-dimethoxyphenyl)-3,4-dinitrobenzamide; and N-methyl-N-phenyl-3, 4-dinitrobenzamide.
6. A process for preparing a compound defined in claim 1 having the structure of formula (I) which comprises reacting a suitable acid chloride compound derived from 3, 4-dinitrobenzoic acid, with a compound of formula (II) wherein R1 and R2 are defined in claim 1, in the presence of an amine base.
CA002264942A 1996-09-09 1997-09-09 Compounds and methods Abandoned CA2264942A1 (en)

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US2569096P 1996-09-09 1996-09-09
US60/025,690 1996-09-09
US4801297P 1997-05-29 1997-05-29
US60/048,012 1997-05-29
PCT/US1997/015931 WO1998009630A1 (en) 1996-09-09 1997-09-09 Compounds and methods

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