NZ280544A - 2-(acylaminomethyl)benzylamine derivatives, 2-(aminomethyl)arylalkylamine derivatives and medicaments - Google Patents

Description

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Initials N.Z. PATENT OFHCF, 2 8 NOV 1995 NEW ZEALAND RECEIVED DIVIDED OUT OF APPLICATION No.: 264710 Date: U October 1994 PATENTS ACT, 1953 COMPLETE SPECIFICATION ARYL-FUSBD AND HETARYL—FUSED-2,4-DIAZEPIKE AMD 2,4-DIAZOCINE ANTIARRHYTHMIC AGENTS I /We, STERLING WINTHROP INC., a corporation organised under the laws o£ the State of Delaware, United States of America of 90 Park Avenue, New York, State of New York 10016, united States of America hereby declare the invention for which I / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by page la) 280544 D.N. 2510B la- ARYT.—FUSED AND HF.TARYI.-FHSED-? . 4-DTAZEPINF. AND 2. 4-DIAZOCINF. ANTIARRHYTHMIC AGENTS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel 4,5-dihydro-lH-2,4-aryl fused diazepines, and benzodiazocines to related diamines and aminoamides, to processes for preparing them and to methods and compositions for treating cardiac arrhythmias in mammals utilizing said 10 4,5-dihydro-lH-2,4-benzodiazepines, and diazocines.

Information Disclosure Statement U.S. Patent 3,696,093 to Rodriguez et al. discloses a single 3,4-disubstituted benzodiazepine: 3,4-dimethyl-4,5-dihydro-lH-2, 4-benzodiazepine hydrochloride.

Also disclosed are 4,5-dihydro-lH-2,4-benzodiazepines monosubstituted in the 3 position with benzyl, dimethyl-aminoethyl, amino, 1-piperidinylmethyl, and phenyl. The compounds are said to be useful as cardiovascular agents, 20 for example, in the treatment or management of the various forms of hypertension or of congestive heart failure. The patent does not disclose antiarrhythmic properties for the genus, and the single example of a disubstituted benzodiazepine was found to be inactive as an 25 antiarrhythmic when tested in the protocol used to evaluate the compounds of the present invention. 28054 D.N. 2510A Japanese application 59/013766 (CA 101:23612m) discloses a series of 1,2,4-trisubstituted-tetrahydrobenzo-diazepines of general structure wherein is lower alkyl or phenethyl (opt. substd. with lower alkoxy). The compounds are said to be analgesics.

Elslager et al [jl. Het. Chem. jj., 609-613 (1968) ] describe the synthesis of a series of tetrahydrothiazolo-[3,2-b][2,4] benzodiazepines. The authors state that 10 "None of the compounds possessed appreciable biological activity." As intermediates in the synthesis, they disclose •in /_N. / INII H O y- NH —*NH SCH, NH N .N 1,2,4,5-tetrahydro-3H-2, 4-benzodiazepine-3-thione and 2,5,dihydro-3-(methylthio)-1H-2,4-benzodiazepine hydroiodide.

U.S. Patent 4,840,948 to Lang et al. discloses a series of 1-(hydroxystyryl)-5H-2,3—benzodiazepines of 20 general formula: 28054 D.N. 2510A - 3 -R1 wherein R stands for a hydrogen or halogen atom, or a Ci_4 alkoxy group, R1 represents a hydrogen atom or a Ci_4 alkyl group, R^ and R^ are identical and denote a Ci_4 alkyl group, 'or combined they denote a methylene group. The compounds are said to be positive inotropes and 10 therefore useful as cardiotonics. 280544 D.N. 2510A The reader's attention is also directed to our New Zealand Patent Specification No. 239407 which in a product aspect relates to compounds of the formula XXXVI: XXXVI wherein A is a ring chosen from the group consisting of phenyl, thienyl, furanyl, naphthyl, pyridinyl, cyclohexyl and phenyl having one or two substituents chosen from the group consisting of amino, lower-alkyl, lower-alkoxy, halogen, nitro, and lower-alkylsulfonamido; R1 is hydrogen, lower-alkyl, benzyl, naphthyl, thienyl, pyridinyl, phenyl, or phenyl having one or two substituents chosen from the group consisting of lower-alkyl and lower-alkoxy; R2 is hydrogen; lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or R2 is -CH2CH2R7 where R7 is lower-alkoxy; benzyl; di-(lower-alkyl)amino, pyrrclidino; piperidino; morpholino; phenyl; or phenyl substituted with amino, nitro or lower-alkyl sulfonamido; R3 is Yp-(CH2)m-Xn-R8 wherein CH3 I 2.5 Y is -NH-, -0-, -S-, or -CH-; p is zero or one; 280544 D.N. 2510A m is an integer from zero to seven; OH NH? O I I II X is -S-, -0-, -S02~, -CH-, —CH-, —C—, O COOlower-alkvl ch3 II I I A -C-0-, -CHC-0-, —CH=CH-, -0=0-, -C=C-, or ' \ ; 0 CH3 n is zero or one; and 5 R8 is hydrogen;lower-alkyl; phenyl; furanyl; thienyl; pyridinyl; phenyl having one or two substituents chosen from the group consisting of halogen, lower-alkyl, nitro, hydroxy, lower-alkoxy, lower-alkylcarbonylami.no, lower-alkylsulfonamido 10 dilower-alkylaminosulfonyl, and amino; or when n is zero and m is other than zero, R8 is additionally halogen; benzyl(lower-alkyl)- amino; di-(lower-alkyl)amino; or a 5- or 6- membered heterocycle containing one or two nitrogens, 15 said heterocycle being unsubstituted or substituted with one lower-alkyl group; or X and R8 taken together are cyclohexylidine; R* is hydrogen; lower-alkyl; allyl; lower-alkoxy-lower-alkyl; acetyl; lower-alkoxycarbonyl-lower-alkyl; lower-20 alkoxy carbonyl; or a-hydroxy-lower-alkyl; and R5 is hydrogen; lower-alkyl; naphthyl; thienyl; pyridinyl; benzyl; phenyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl,lower-25 alkoxy, halogen, hydroxyl, amino, di-(lower- alkyl) amino, lower-alkylsulfonamido and lower acylamino; with the proviso that the total number of carbon atoms in R-*-plus R2 plus R4 plus r5 must be five or greater. 30 The compounds of formula XXXVI are useful as antiarrhythmic agents.

U.N. Z5 JLUA 6 - 280544 Lower-alkyl as used herein describes linear, branched, or cyclic saturated carbon chains of eight or fewer carbon atoms; lower-alkoxy as used herein describes linear or branched alkyloxy substituents containing eight or fewer carbon atoms; halogen describes bromine, chlorine or fluorine.

In the text that follows, the substituents R are defined when initially presented and maintain that definition whenever they occur subsequently.

The reader's attention is also directed to our New Zealand Patent Specification No. 248974 and EP 475527 which, in a product aspect, relate to compounds of the formula II wherein R1 is hydrogen, lower-alkyl, benzyl, naphthyl, thienyl, pyridinyl, phenyl, or phenyl having one or two substituents chosen from the group consisting of lower-alkyl and lower-alkoxy; R4a is hydrogen or lower-alkyl; R$b is hydrogen; lower-alkyl; phenyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy, and halogen; naphthyl; thienyl; pyridinyl; or benzyl; r6 is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, halogen, nitro and lower-alkylsulfonamido; or R^ is a fused benzene ring; R15 is hydrogen or, when R^ is phenyl, may additionally be lower-alkyl; Rl6 is (CH2)m-(Xa)n-R8a; m is an integer from zero to seven; Xa is -S-, -SO2-, -0-, or -CH=CH-; II 7 - n is zero or one; R8a is hydrogen; lower-alkyl; phenyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl; lower-alkoxy, and halogen; and q is one or two.

The compounds of formula II are useful as antiarrhythmic agents.

The reader's attention is further directed to our New Zealand Patent Specification No. 264710 which in a product aspect, relates to compounds of formula XXX wherein R2b is hydrogen; lower-alkyl; benzyl; phenyl; or phenyl substituted with halogen, lower-alkyl or lower-alkoxy; R3 is Yp-(CH2)m~^n—wherein RSd R4a XXX Y is -NH-, —O—, -S-, or -CH-; p is zero or one; X is -S-, -O-, OH NHo O I i II -S02-, -CH-, —CH-, -C-, 0 COOlower-alkyl II I —C-0—, -CHC-O-, -CH=CH- alkyl ch3 CH=CH-, -C~C~, -C-C-, or 1 "A"; II o ch3 I m is an integer from zero to seven; n i.«. zero or one; and R® is hydrogen; lower-alkyl; phenyl; furanyl, thienyl, pyridinyl, or phenyl having one or two substituents chosen from the group consisting of (followed by page 7A) 280544 D.N. 2510A - 7A - halogen, lower-alkyl, nitro, hydroxy, lower-alkoxy, lower-alkylcarbonylami.no, lower-alkylsulfonamido, dilower-alkylaminosulfonyl, and amino; or when n is zero and m is other than zero, R8 is additionally halogen; benzyl(lower alkyl)-amino; di-(lower-alkyl)amino; or a 5- or 6-membered heterocycle containing one or two nitrogens, said heterocycle being unsubstituted or substituted with one lower-alkyl group; or X and R8 taken together are cyclohexylidine; R4a is hydrogen or lower-alkyl; R5d is lower-alkyl; phenyl; naphthyl; thienyl; pyridinyl; benzyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy and halogen; R6a is hydrogen, lower-alkyl, lower-alkoxy or halogen.

The compounds of formula XXX are useful as antiarrhythmic agents.

SUMMARY OF THE INVENTION In a product aspect, the present invention relates to compounds of formula III 28 0 5 4 D.N. 2510A NHC-(CH2)n-R10 II O III wherein Rla is hydrogen, lower-alkyl or phenyl; R5a is hydrogen; phenyl; phenyl having one or two substituents chosen from the group consisting 5 of halogen, lower-alkyl and lower-alkoxy; naphthyl; thienyl; pyridinyl; or benzyl; R*> is one or two substituents chosen from the group consisting of hydrogen, lower-alkyl, lower-alkoxy and halogen; or R*> is a fused benzene ring; R^ is hydrogen, lower-alkyl, benzyl, phenethyl or [di- (lower-alkyl)amino]lower-alkyl; rIO is hydrogen; lower-alkyl; phenyl; phenyl substituted with halogen, lower-alkyl, lower- alkylsulfonamido or lower-alkoxy; phenoxy; phenoxy substituted with halogen, lower- alkyl or lower-alkoxy; benzyl; or R1® is a 5- or 6-membered heterocycle containing one or two nitrogens; and n is zero or one.

The compounds of formula III are all useful as intermediates in the synthesis of compounds of formula I (see below) and are useful as antiarrhythmic agents as 20 well.

In a further product aspect, the invention relates to compounds of formula XXI'VII 280544 D.N. 2510A 9 - Rla NHR2a NH2 XXXVII wherein A is a ring chosen from the group consisting of phenyl, thienyl, furanyl, naphthyl, pyridinyl and phenyl having one or two substituents chosen independently from the group consisting of amino, lower-alkyl, lower-alkoxy, halogen, nitro and lower-alkylsulfonamido; Rla is hydrogen, lower-alkyl or phenyl; R2a is lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or R2a is -CH2CH2R7 where R7 is lower-alkoxy, phenyl, benzyl, di(lower-alkyl)amino, pyrrolidino, piperidino, or morpnolino; and R5a is hydrogen; naphthyl; thienyl; pyridinyl or benzyl; phenyl; or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl and lower-alkoxy; and at least one of R^a and R->a is phenyl, benzyl, naphthyl, thienyl, or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl and lower-alkoxy.

The compounds of formula XXXVII are useful as interroediates in the synthesis of compounds of formula XXXVI and are useful as antiarrhythymic agents as well.

In a further product aspect, the invention relates to compounds of formula XXXII (followed by page 9A) 280544 - 9A - XXXII wherein R2b is hydrogen; lower-alkyl; benzyl; phenyl; phenethyl; di(lower-alkyl)aminoalkyl; or phenyl substituted with halogen, lower-alkyl, or lower-alkoxy; R5d is lower-alkyl; phenyl; naphthyl; thienyl; pyridinyl; benzyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy, and halogen; R6a is hydrogen, lower-alkyl, lower-alkoxy, or halogen.

The compounds are useful as intermediates in the synthesis of compounds of formula XXX.

In a process aspect, the invention of NZ 239407 relates to processes for the production of benzodiazepines of formula 2805^ D.N. 2510A R 5b wherein R3a is (Ya)p-(CH2)m-(Xa)n-R® wherein CH3 Ya is —0-, -S- or -CH-; and Xa is -S-, -S02-, -O- or -CH=CH-; by the condensation of diamines of formula VId VId with iminoethers of formula R^c (OR12) NH, wherein R12 is methyl or ethyl, with orthoesters of formula R3ac(OR12)3 or with esters of formula R^acoOR12.

In a further process aspect the invention of NZ 239407 relates a process for producing a compound of formula V 28 05^ D.N. 2510A ,3a V which comprises reacting a compound of formula XXVII or XXVIII with a trialkylaluminum. d1 XXVII XXVIII In a further process aspect, the invention of NZ 239407 relates to a process for preparing a compound of formula la 3i la wherein R^b is lower-alkyl, allyl, lower-alkoxylower-alkyl, acetyl, lower-alkoxycarbonyl, or a- hydroxyloweraJkyl; and R5c is phenyl; phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy and halogen; 28054* D.N. 2510A naphthyl; thienyl; or pyridinyl; which comprises reacting a compound of formula Va Va with a strong base and then with a suitable electrophile. 5 In a further process aspect, the invention of NZ 239407 relates to a process for preparing a compound of formula VII VII wherein OH NH2 O . I I il Xb is -S—, -SO2-, -0-, -CH=CH-, -CH-, -CH-, or -C-; 1° R4c is lower-alkyl, allyl, or lower-alkoxylower- alkyl; R14 is hydrogen or methyl, which comprises reacting a compound of formula Vila 28054 D.N. 2510A Rib Vila with a strong base followed by reaction with an electrophile chosen from the group consisting of R8COOR12, R8CHNR12, R8CHO, R8SSR8 and R8 (Xa) n (CH2) m-lZ wherein Z is a 5 group subject to nucleophilic displacement.

In a process aspect, the present invention relates to a process for preparing a compound of formula Via which comprises reacting a compound of formula VIII or IX "O VIII or , R2 280 51 D.N. 2510A IX with an excess of diborane. in a further process aspect, the present Invention relates to a process for preparing a compound of formula VIb R1 ^—S. / NHR2 HOC VIb which comprises reaction a compound of formula X or XI 28 0 5 4 or XI D.N. 2510A with an excess of diborane.

Also described but not claimed is a process for preparing a compound of formula IVa >6a NHR^ NH, ,5b IVa which comprises reducing a compound of formula Villa 2805 D.N. 2510A - 16 sequentially with an aluminum hydride, hydrogen in the presence of a noble-metal catalyst and hydrogen in the presence of a nickel catalyst.

In a process aspect, the inventions of NZ 248974 and EP 475527 relate to a process for preparing a compound of formula Ha <CH2)( Ila which comprises reacting a diamine of formula Vic Vic 28054 D.N. 2510A with an (o-haloorthoester or co-haloiminoether of formula ZCH2(CH2)qCH2C(OR12)3 or ZCH2(CH2)qCH2C(OR12)NH .

In a further process aspect, the Inventions of NZ 248974 and EP 475527 relate to a process for preparing a compound of formula Ila (CH2) Ila which comprises reacting a compound of formula XII (Bzl=benzyl) R1 XII with a CO-chloroester of formula CICH2 (CH2) qCH2COOR12, 10 followed by cyclization of the resulting co-chloroalkyl-amide, hydrogenolysis of the benzylamine, and closure of the diazepine ring.

Other aspects of the invention comprise methods of using the benzodiazepines of the invention for the 15 treatment of cardiac arrhythmia in patients and compositions for the treatment of cardiac arrhythmia containing those compounds. The benzenemethanamines and the 5-aminoamides of the invention are useful both as 2805 D.N. 2510A intermediates and in their own right in methods and compositions for the treatment of arrhythmia.

DF.TAILED DESCRIPTION INCLUSIVE OF PRF.FF.RRF.D EMBODIMENTS A general synthesis of compounds of the invention sharing general formula XXXVI may be outlined as shown in Scheme A. 2805 - 19 -Scheme A D.N. 2510A ^.COOH 0^.

R RA /■""N .R2 NH2NH-R GL >— * 3 12 R COOR R3C(OR12) 3 1. 2.

BuLi R42 or R3C (=NH) OR12 0 x 1. 2.

[RXLi] B2H6 [NaBH4] NHR^ NH N y~' R5 R* This is more particularly illustrated in Scheme B wherein A is phenyl or substituted phenyl: 2805 D.N. 2 510A - Scheme B A suitably substituted Y~oxo_acid of formula XIII is reacted with a suitably substituted hydrazine to form a 280541 D.N. 2510A - 21 ■' that R1 be other than hydrogen, the phthalazinone is reacted with a slight excess of a suitable alkyl or aryllithium compound in an inert solvent, preferably THF, at -78° to 0°C, preferably about -65°C, and the resulting adduct is reduced as described below without isolation.

In the case where R1 is hydrogen, the phthalazinone (VIII) is reduced directly to the diamine (VI) with 3.5 to 9.0 equivalents of diborane in an inert solvent, preferably THF, at 20° to 100°, preferably 67°C. A catalytic amount of sodium borohydride and some diglyme may be added.

The diamine (VI) may be condensed in one of three ways to produce the benzodiazepine (I,r4=H): (1) the free base of the diamine in acetic acid is treated with five to seven equivalents of the appropriate orthoester r3c(OR12)3 15 at 0-50°C, preferably 25°C, or the diacid salt of the diamine, preferably the dihydrochloride salt, in an inert solvent is treated with five to seven equivalents of an appropriate orthoester plus one to two equivalents of a weak base, preferably sodium or potassium acetate; (2) a 20 diacid salt of the diamine (VI), preferably the dihydrochlcride salt, in an inert solvent, preferably methanol, is treated with two to three equivalents of the appropriate iminoether hydrochloride and about two equivalents of a weak base, preferably sodium acetate, at 25 0 to 60°C, preferably 25°C, or the free base of the diamine (VI) in an inert solvent, preferably methanol, is treated with two to three equivalents of the appropriate iminoether hydrochloride and two to three equivalents of a weak acid, preferably acetic acid, at 0°to 60°C, preferably 30 25°C, or (3) a diamine or a diacid salt of the diamine, preferably the dihydrochloride salt, in an inert solvent, preferably toluene, is treated with slightly more than two equivalents of trimethylaluminum at -30°to +110°C, followed 280544 D.N. 2510A by treatment with 1 to 1.5 equivalents of a lower-alkyl ester of the appropriate acid (R3COOR12).

In the case where it is desired that R4 be other than hydrogen, the diazepine (I, R4=H)may be reacted with a 5 strong base such as butyllithium and the resulting anion reacted with an appropriate electrophile.

It will, of course, be appreciated that all of the reactions described for the compounds of formula XXXVI wherein A is a phenyl ring are equally applicable to the 10 compounds wherein A is other than phenyl. The starting materials are likewise commercially available or known in the art.

Compounds of formula XXXV, which may also be visualized as analogs of the compounds of formula I having an 15 alkylene substituent R2 cyclized into the methine to which R1 is attached, may be synthesizetd in a similar fashion using butyllithium and an alkylene dihalide followed by reductive debenzylation when R2c is benzyl: Compounds of formula V, a subset of benzodiazepines of formula I, may be prepared by the ring closure of aminoamides. A monosalt of the aminoamide XXVII or XXVIII, preferably the monohydrochloride in an inert solvent, preferably toluene, is treated with a slight 25 excess, preferably about 1.1 equivalents, of 28054 D.N. 2 510A trimethylalurainum at 0° to 150°, preferably about 110° to produce a benzodiazepine of formula V: Aminoamides of formula XXVII may be obtained as described 5 in Examples 177-184 by incomplete cyclization or, as described in General Method U, by hydrolytic cleavage of benzodiazepines. Aminoamides XXVII or XXVIII or mixtures of the two may also be obtained by procedures well known in the art for condensing acids of formula R^acOOH with 10 amines of formula VId D.N. 2510A R1 R5b VId In the case of compounds of formula I where p (in R3) is one and Y*5 is -NH-, -S-, or -0-, the compounds may be made by an alternate route from the diamine VI shown in Scheme C: 2805 - 25 -Scheme C D.N. 2510A R1 XXIX H(YV<CH2)mXn-R8 u 280544 D.N. 2510A - 26 " The diamine (VI) is reacted with carbonyl diimidazole (CDI) in an inert solvent, preferably chloroform, at ambient temperature to produce a benzodiazepin-3-one, which is treated with a large excess, preferably about 13 equivalents, of phosphorus oxychloride and preferably about 0.25 equivalents of phosphorus pentoxide to produce a 3-chlorobenzodiazepine (XIV). The 3-chlorobenzodiaze-pine is then reacted, usually without isolation, with the appropriate nucleophile, R®Xn (CH2) m^*3) to produce the benzodiazepines of structure Vb.

Alternatively the diamine VI is reacted with preferably about one equivalent of carbon disulfide in an inert solvent, preferably 2-propanol, at 0°to 100°C, preferably at about 20° to 85°C and the resulting carbamodithioic acid is treated with a catalytic amount of an acid, preferably hydrochloric acid, in an inert solvent, preferably ethanol, at 0 to 100°C> preferably at about 78°C, to produce a tetrahydrobenzodiazepine-3-thione. The thione is oxidized with slightly more than three equivalents of 30% hydrogen peroxide according to the procedure of Maryanoff et al. [J[. Org. Chem. £1, 1882 (1986)] to produce the sulfonic acid XXIX. The sulfonate may then be displaced by an appropriate nucleophile, as before, optionally in an inert solvent at 0°-100°C.

Example 153 illustrates an alternative, lower-yield conversion of the thione to the compounds of formula Vb.

In the case where all of R2, R4 and R^ are other than hydrogen, the subgenus of compounds of formula VII wherein R3 is attached to the benzodiazepine ring through a carbon (i.e. p in R3 is zero and R3 is -CH2(CH2)m-lxnR® or P one and Y is 280544 D.N. 2510A CH3 I -CH-) may be made alternately Vila nBuLi R^X^ntCHzJm-iZ R2a n' r" j) CH-tCHaJ^fXhjnR6 VII by treatment of a compound of formula Vila wherein R14 is hydrogen or methyl in an inert solvent, preferably THF, at -78° to +25°, with a slight excess, preferably about 10 to %, of a strong base, preferably n-butyllithium followed by a slight excess, preferably 10-50%, of an appropriate electrophile. The electrophile can be of the form R8-(Xa)n-(CH2>m-l-z wherein Z is a group that is readily displaced by an anion, such as a halogen, sulfide, sulfonate, ester, etc. or in the case where m minus one is zero it can take the form of an aldehyde, ketone or imine so that addition of the anion to the electrophile followed by quenching 280544 D.N. 2510A with a proton source results in the overall addition of the elements of Vila to the electrophile.

In cases where is attached to the benzodiazepine via a heteroatom-methylene link (XV), that is r3 is of the 5 form -CH2(Xc)nR8 wherein Xc is -S-, -O- or -SO2- (i.e. in formula XXXVI, X is -S-, -0- or -SO2-, p is zero, m is one and n is one when R8 is lower-alkyl, phenyl or substituted phenyl; n is zero when R8 is amino or an N- attached heterocycle) the compounds may conveniently be synthesized 10 from the corresponding chloromethyl species (XVI).

R8 (Xc) nH 1' XV The 3-chloromethyl-2,4-benzodiazepine (XVI) in an inert solvent, preferably chloroform when the heteroatom is nitrogen and methanol or acetonitrile when the heteroatom 15 is sulfur, is treated with one to three equivalents of the 280544 D.N. 2510A R8 (Xc) nH species at 0° to 100°C, preferably at 25° to 65°C. The chloromethyl benzodiazepine XII can be synthesized directly from the diamine VI by condensation with ethyl 2-chloroethanimidate or in the case where all of R2, R4 and R5 are other than hydrogen, the chloromethyl benzodiazepine (XVI) may be synthesized from the corresponding 3-methyl-benzodiazepine by anion formation as described in the foregoing paragraph and quenching with about 1.1 equivalents of hexachloroethane.

Compounds of formula Ila and XVII may be synthesized by the routes shown in Schemes D and E. Scheme D produces mixtures from which the isomers can be separated by chromatography; Scheme E produces a single isomer selectively.

Scheme D R5b XVII 280544 D.N. 2510A - 30 " A diamine of formula Vic as its dihydrochloride is treated with about two equivalents of an appropriate co-haloiminoether salt, preferably the (D-chloroiminoether hydrochloride, and about two equivalents of a weak base, 5 preferably sodium acetate, in an inert solvent, preferably methanol. The resulting mixture of isomers is separated, usually by chromatography on silica gel, although in some cases separation may be achieved by simple crystallization. It will be noted that the compounds of 10 structure XVII can be represented by formula Ila wherein the substituents R1 and R5b are interchanged. 28054 D.N. 2510A Scheme E nh2 12 c ZCH2(CH2)qCH2COOR 0 II NHBzl MB»A1 r6 xviii ^^J^NHCCH2 (CH2) qCH2Z •NHBzl ,5b XIX base h2 XXI Me3Al T Uy^iCH2)q n/^s"%(ch2) q XX Ila A disalt, preferably a dihydrochloride, of a monobenzyldiamine of formula XVIII is treated with 1 to 1.5 equivalents of an co-activated methyl or ethyl ester of formula ZCH2 (ch2) qCH2COOR12 and about two equivalents of 28054 D.N. 2 510 A trimethylaluminum in an inert solvent, preferably toluene, at 0 to 60°, preferably about 55°. The resulting amide (XIX) is treated with about a 3-fold excess of a hindered strong base, preferably potassium t-butoxide, in an inert 5 solvent, preferably THF, at 0-60°, preferably about 25°, to produce a pyrrolidinone (XX, q=l) or a piperidinone (XX, q=2). The N-benzyl is removed, preferably by hydrogenolysis in the presence of a palladium metal catalyst. The aminoamide XXI as its salt, preferably the 10 hydrochloride, is treated with a slight excess of trimethylaluminum in an inert solvent, preferably toluene, at 50 to 150°. preferably 110°, to provide a tricyclic benzodiazepine of formula Ila.

If it is desired that R4a or R15 in formula II be 15 other than hydrogen, the compounds of formula Ila may be alkylated in a similar fashion to that described for the benzodiazepines of formula I, using a strong base such as butyllithium and an electrophile such as R4aZ or R15Z. Similarly, if it is desired that R16 be other than 20 hydrogen, the appropriately substituted tricycles may be alkylated as before, using a strong base such as butyllithium and an electrophile, R16Z. The sequence of alkylations will depend on the nature of the substituents R1 and R5. For example, when R1 is aryl and R5 is other 25 than aryl, the alkylation will occur first for R15 and then for R16 (via lid and lie); when R5 is aryl and R1 is other than aryl, the alkylation will occur first for R4a and then for R16 (via lib and lie): 280544 D.N. 2510A K'-OC M (CHj) -ex y R15^ BuLi R"Z u N N <CH2>«» nd He Compounds of formula III may be synthesized from the corresponding compounds of formula I by hydrolysis in the • presence of 1 to 5 equivalents of aqueous base, preferably potassium hydroxide, in a cosolvent, preferably methanol, at 0 to 70°, preferably 25 to 30°.

Compounds of formula IV may be prepared by the reduction and cleavage of phthalazinones and phthalazines as shown in Scheme F. 28054 D.N. 2510A Scheme F OH , R ,N —«r - *€%y . R2 XXIII XXV A phthalazinone of formula VIII is reacted with 3.5 to 9.0 equivalents of diborane in an inert solvent, preferably THF, at 20° to 100°, preferably about 67°, to produce diamines of the formula VId wherein R1 is hydrogen. A catalytic amount of sodium borohydride in diglyme may be added. If it is desired that R1 be other than hydrogen, phthalazines of formulas XXII, XXIII and XXV may be 28 0 5 4 4 D.N. 2510A reduced in like fashion. The phthalazines XXII and XXIII may be obtained from the corresponding phthalzinones by reaction with a suitable alkyllithium or aryllithium in an inert solvent, preferably THF, at -78° to 0°, preferably 5 about -65°. The resulting phthalazine may exist as the hydroxyphthalazine XXII or may spontaneously eliminate the elements of water to form the phthalazinium species XXIII. The phthalazines of formula XXV may be synthesized by the condensation of the appropriate hydrazine with a y-10 haloketone, preferably a Y-bromoketone.

In the case wherein in formula VIII R2 is hydrogen, the simple reduction with diborane described above is so slow as to be of less practical use than a three-step reduction: 28054 d.n. 2 510a - 36 Scheme G Villa 1. LAH R' 6a 2. H2 Pd/C RaNi NH I NH >5b h2 xxvi ■-OCT R IVa Sb The phthalazinone Villa is treated with about two equivalents of an aluminum hydride reducing agent, preferably lithium aluminum hydride, in an inert solvent, preferably at 20° to 120°, preferably about 65°. The resulting dihydro-phthalazine is reacted with hydrogen in an inert solvent, preferably a lower alkanol, most preferably ethanol, in the presence of a palladium catalyst at 20° to 60°, preferably 40°-50°, preferably at about 3 atmospheres pressure. The resulting tetra-hydrophthalazine (XXVI) is reacted with hydrogen in an inert solvent, preferably methanol, in the presence of a 28054 D.N. 2510A Raney nickel catalyst at 20° to 80°, preferably about 65°, preferably at about 3 atmospheres pressure.

The 1,4,5,6-tetrahydro-2, 4-benzodiazocines of formula XXX may be synthesized in an analogous fashion to the 5 benzodiazepines of formula I by the condensation of the appropriate diamines XXXII with orthoesters, iminoesters or esters plus trialkylaluminum reagents. The desired diamines are obtained, as before, by diborane reduction of the corresponding 2,3-benzodias.epin-4-ones XXXIII, which 10 are available by reaction of cotoacids XXXIV with hydrazines. The ketoacids are obtained by Grignard reaction of indenones followed by oxidation with chromium trioxide according to the procedure of de Paulis et al. [al. Med. Chem. 24f 1021-1026 (1981) ] . The sequence is 15 shown in Scheme H. 28054 D.N. 2510A - 38 -Scheme H > 6d R5dMgZ N— R2b.

R2bNHNH2 r Ga.

XXXIII bh3 IDC N—^ y-ra o5d NHR NH2 2b R3COOR12 Cr03 COOH R3C (OR) 312 or R3C (—NH) OR12 "*^R6a XXXII >2b N N R 5d XXX (R4a=H) BuLi (lower-alkyl) z XXX 28054 D.N. 2510A It will be noted that many of the compounds of the invention are asymmetric at C-l of the benzodiazepine or benzodiazocine. In some cases there may be an advantage to using one or the other enantiomer for the treatment of 5 arrhythmia. Single enantiomers may be synthesized from chiral starting materials or the racemates may be resolved by methods well known in the art, such as chromatography on chiral media or recrystallization of diastereomeric salts.

The compounds of the invention are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use, and in practice the use of the salt form 15 inherently amounts to the use of the base form. The acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts, that is, salts whose anions are relatively innocuous to the animal 20 organism in medicinal doses of the salts so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. In practicing the present invention, it is convenient to form the hydrochloride, fumarate, toluenesulfonate, hydrogen 25 sulfate, methanesulfonate, or maleate salts. However, other appropriate medicinally acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid-addition salts of the basic compounds are prepared either by dissolving 30 the free base in aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and an acid in an organic solvent, in which case the salt separates directly, is precipitated with a second organic solvent, 28054 D.N. 2510A - ao - or can be obtained by concentration of the solution. Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention. All acid-5 addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product, as, for example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in 10 preparing a medicinally acceptable salt by ion exchange procedures.

The structures of the compounds of the invention were established by the mode of synthesis, by elemental analysis, and by infrared, nuclear magnetic resonance, and 15 mass spectroscopy. The course of the reactions and the identity and homogeneity of the products were assessed by thin layer chromatography (TLC) and high-pressure liquid chromatography (HPLC). The starting materials are either commercially available or may be prepared by procedures 20 well known in the art.

In the following procedures, melting points are given in degrees C and are uncorrected.

In the examples which follow, Me is methyl, Et is ethyl, Ph is phenyl, Bzl is benzyl, iPr is isopropyl, tBu 25 is t-butyl, OAc is acetyl, THF is tetrahydrofuran, hex is hexane, IPA is isopropylamine, DMF is dimethylformamide, and TMS is trimethylsilyl. t Example R2 No. ~o: R3 .TAg^S A NHR2 +R3C (OR12) 3 R* R5 R2 R C(NH)OR or . R3COOR12 R6 12 K»-S- Method Yield Melting Salt Recrystalllzed % Range From Me Ph Ph 63 114-115 free base hexane Me Me IPr Me Et Et Ph 6 Ph 27 177-178 maleate B 26 213-215 HC1 71 232-234 HC1 IteCN UeCN I EtOAc/ether Bzl Et Ph H C 37 222-224 HC1 EtOH/MeCN/ether JH20 Me "O" OMe -CH2C1 Et Ph Ue -95 129-131 free base tBuOMe/hexane 59 207-209 HC1 EtOH/tBuOMe O Z N) cn M O > l\3 LTJ 4N * • • # TABLE A Example No.

R2 +R3C (OR12) 3 R'{ J R5 R3 r5 R3C (NH) OR12 or R3C00R12 r6 R®£ Method Yield Melting % Range Salt Recrystalllzcd From Me Et Ph 40 198-200 HC1 WeCN/tBuOMe 8A 163-165 m&leate acetone 8B 8C 98-100 free base IPrOAc 201-202 i fumarate acetone M I 8D 178-179 toluene-sulfonate iPrOH 8E Me Me nPr Ph Ph 172-174 methane-sulfonate 49 218-221 HC1 EtOAc 7,8-diOMe A 48 148-150 maleate EtOAc/MeCN MeCN/tBuOUe O z Cn M O > f>o LTl :amp No. 11 12 13 14 16 17 18 * # TABLE A R2 +r3c (or12) a r3c (nh) or12 R6xjv nH2 R3 Rs R5 or r3coor12 R6 *•£- Hethod Yield Melting % Range Salt Recrystallized From Me nBu Ph 46 212-214 HC1 UeCN/tBuOMe CH2CH2OMe Et Ph 44 186-189 HC1 iPrOH/tBuOUe Me CH2CH2-cCgH11 pj, 80 146 HC1 MeCN/ether *-W Me •(CH2>4CB3 Ph 27 197-198 HC1 acetone/ether H -CH2CH2Ph Ph 90 148-149 free base CH2Cl2/hexane Me Et Ph 6-F 50* 152-154 maleate MeOH/ether Me Et Ph 7-F 53 * 185-187 maleate MeOH/ether D Z Me Et Ph 8-f 69 158-161 maleate MeOII/ether •over two steps ro en o > ♦ + m # TABLE A —nhr2 +r3c (or12) 3 r3c(nh)0r12 R# vA^NH, R5 or r3coor12 ■*- R«-H- Example No.

R2 R3 R5 R6 Method Yield Melting % Range Salt Recrystallized From 19 Ue Et 48 145-148 EtOII Me iPr Ph B 60 79-80 Et3N/pentane 21 Me Bzl Ph B 79 236-237 HC1 UeCN 22 iPr PI1CH2CH2 Ph E 73 150-153 maleate acetone/ether 23 iPr Me Ph 56 165-166 maleate acetone/ether 71 130-132 free base EtOAc/hexane 24 iPr nBu Ph E 78 108-109 maleate hemihydrate acetone/ether or MeCN/tBuOMe O z ro Me PhCH2CH2 Ph D F 50 62 118-123 132-133 HC1 11C1 MeCN/ether MeCN ro H* o > LTI m • TABLE A Example No. 26 R2 Ph r9-£ R3 Ue nhr2 +r3c(or12)3 nh2 R5 Me R3C (NH)OR12 or r3c00r12 R6 Method 27 28 29 31 32 Ph Me Me Ue -o Me Ue Et Me Ph Ue Ue Et Me 0 P 0 $ OMe Me Ph >,9 R2 /H3 R5 Yield Melting % Range Salt Recrystallized From . 89-92 I1C1 EtOH/tBuOUe 2 207-208 HC1 MeCN/tBuOMe 53 185-187 maleate EtOH/tBuOMe 4> ui 48 146-148 free base MeCN 26 235-237 HC1 UeCN/tBuOMe 60 241-243 HC1 UeCN/tBuOMe 40 149-151 free base florisil EtOAc/IPA Chromatog. a z ro Ui t-» o > ro m • Rs Example r^ r3 j{5 No. 33 Me Et Ph 34 Me -(CH2)7CH3 Ph Ue CH2CH2 Ph 37 Ue Et jj^j 38 Me -CH2O-0O> Ph 39 Ue -CH20 -O-Cl Ph 40 Ue -CH20^=^-0Ue Ph TABLE A +R3C(0R")3 R3C (NH) OR12 or R3COOR12 R6 Method Yield Melting % Range Salt Recrystallized From 9-!ie 49-53 free base •*H20 florisil EtOAc/IPA Chromatog. 28 159-161 HC1 tteCH/ether a* 53 131-133 HC1 MeOH/ether 58 133-135 maleate MeCN/tBuOUe 33 196-198 HC1 14 166-168 HC1 iH20 17 225-226 HC1 EtOII/ether EtOH/ether EtOH/ether D Z tv> en o > ro am * • TABLE A r«JL T r3c :jh) or12 ^5#5Nr-NH2 or I. R3C00R12 R5 Example R2 R3 R5 R6 No. 41 Ue Et C^L.NH2 H CI 42 Ue -CH2OPh Ph H 43 Ue -\C.H2)3Pb Ph H 44 CH2CH20Ue Ph Ph H 45 Cll2CH2NEt2 Me Ph H 46 CH2CH2NEt2 H Ph H /~\ 47 CH2C«2-N^ 0 H Ph H Method Yield Melting % Range Salt Recrystallized From 23 249-251 fumarate EtOH/ether 74 153-155 HC1 EtOH/ether E 79 101-106 fumarate EtOH/ether 70 170-172 maleate -si 24 154-156 2 maleate 18 145-147 2 maleate 27 175-177 2 maleate UeCN MeCN acetone tBuOWe EtOH o z N) tn t-1 o ro lti No, 48 49 50 51 52 53 54 55 TABLE A —'nhr2 +r3c (or12) j Rs R3C(NH)OR12 or R3COOR12 32 R3 R5 R6 Method Yield Melting % Range Salt Recrystallized !?rom /—\ CIloCHoN O V—/ Me Ph 167-1*9 2 maleate MeCW/tBuOMe Me Ph 7 149-151 2 maleate EtOH CH2CH2NEt2 Et Ph 224-227 2 HC1 MeCN/tBuOMe Me ■<3 Ph 29 113-115 free base iPrOH Me CH2CH2Ph Bzl 47 139-141 fumarate EtOH CH2<] CH2CH2Ph Ph 45 173-187 HC1 acetone/ether C"2<] ch2<] Et He Ph Ph E 87 189-191 HC1 acetone/ether E 70 226-234 HC1 acetone/ether TAWfB A -or1 R5 NHR2 NH2 +R3C(0R")3 R3C(NH)0R12_ or R3COOR12 Example No.

R2 R3 R5 R® Method 56 CU2CH2Ph Et Ph 57 CH2CH2Ph Me Ph 58 Me CH2CH2-Q-C1 Ph 59 Me CH2S02Ph Ph 60 Me ch2cf 2Ph hQ-och3 61 He CH«CHPh trans Ph 62 Me Ph 6 63 He CH2CII2Ph R"4r- Yleld Melting Salt % Range Recrystallized From 90 225-228 HC1 acetone 95 233-235 HC1 acetone/ether 48 185-187 fumarate iPrOH/ether o 47 255-257 HC1 MeOH/ether 204-206 HC1 MeOH/ether 67 245-250 HC1 31 202-203 HC1 CHCl3/ether 134(d) free base IPrOII/hexanc MeCN/EtOH O Z ro en i-1 o > ro Ul tamp No. 210 211 212 213 214 215 216 217 TABLE A R2 "-CC^, R3 R5 +R3C(ORl2)3 R3C(NH)OR1J or R3COOR12 R6 Method Yield Melting Salt % Range Recrystallized From Bzl Me Ph H E 74 126-127 free bjise 148-149 HC1 EtOAC/hexane MeOH/HeOtBu Ue Me Me Me Ue Me CH»CH-^ CH-CH-C3 Clt2CH2-^) CH2CH2 CH«CH-/^0 CH-CH-^S Ph Ph Ph Ph Ph Ph 28 237-239 fumarate MeOH/EtOH/ether F 22 234-236 fumarate MeOH/EtOH/ether 67 184-185 fumarate EtOH/ether 48 176-177 fumarate EtOH/ether 22 212-213 fumarate EtOH/ether 42 246-247 fumarate MeOH/EtOH/ether Me CH2CH2Ph (CH2)3CH3 152-154 HC1 MeOH/ether TABLE A Example No. 218 219 220 221 222 223 224 225 R2 Me Me Me Bzl Me Bzl Vv,., +R3C (OR12) 3 R3C (NH) OR12 or R3COOR12 R#ir N r3 R5 R6 Method Yield Melting Salt % Range Recrystallized From C112CH2-£s Ph ch2ch2-0> Ph CH»CH-(0>C1 Ph CH2CH2Ph Ph CH2CH2Ph 1-naphthyl CK-CH-Ph Ph Me CH-CH-(O>0Me Ph Me CH»CH Ph H H F D F 64 179-180 fumarate MeOH/EtOH/ether 32 169-171 fumarate MeOH/EtOH/ether 32 219-222 fumarate MeOH/EtOH/ether 13 137-138 fumarate EtOH/EtOAC 6 268-270 HCl-iH20 HeOH/THF/ether 39 197-199 HC1 28 207-208 fumarate TlIF/ether EtOH 230-232 fumarate MeOH/EtOH/ether •h2o I l/l a z w en O > /S5 cn Kxample No.

R2 NHR NH, TABLE A +R3C (OR12) 3 P.3Cl NH)OR12 or R3C00R12 R3 R5 R6 Method Yield Melting Salt % Range Recrystallized From 226 227 228 229 230 CII3 Me C-C(CH3)Ph* Ph Me CH2CH2Ph cyclohexyl Me CH2CH2-^C^-C1 -<0>C1 Me CH2CH2-^^-OMe -^Q^OUe o 14 207-209 fumarate S3 215-216 fumarate MeOH/ether MeOH/ether CH= Ph F 39 155-157 fumarate MeOH/ether F 66 154-156 fumarate MeOH/EtOH/ether F 34 217-218 fumarate MeOH/ether <_n fo 231 232 Me Me C-C-Ph Ph CH-C Ph ♦mixture of isomers F 5 223-225 HC1-H20 EtOH/ether •iEtOH F 18 243-245 2HC1• MeOH/THF/ether /4 H20 O z NJ cn M o > ro cn TABLE A Example No.

R2 r3 +R3C (OR12) 3 R3C (NH) OR12 or R3C00R12 R5 R6 Method 233 234 lie Ctt-CM-^^-Cl -Qci -©•01 CH-CH-Ph 235 236 237 238 239 Ph Me Me Me Me ch2ch2ph V ■O Ph CH2CH2yo) MeO Me Ph Ph Ph -^O^OMe H H H H F f Yield Melting % Range Salt Recrystallized From 54 233-234 fumarate MeOH/ether 64 229-231 fumarate MeOH/ether 207-209 HCliH20 THF/ether 86 205-207 fumarate MeOH/ether •4/5 H20 Ul w 47 137-139 free base HeOIl 37 110-112 free base MeOtBu/hexane 98 196-198 fumarate MeOH/UeCN/ether O Z N) en i-1 o > ro CO ui ,xainp No. 240 241 242 243 244 245 246 247 XMLS.A R2 He Me Ue lie Me Me Me -a; NHR2 +R3C(OR12)3 R3 R5 MeO CH2CH2^CN Me CH-CH N02 CH2CH2^0^ CH3 -(0)-N02 Ph Ph Ph Ph CH2CH2-^0)-N02 Ph CH2CH2-^^-Cl CH2CII2 ^o) Ph N02 R3C (NH) OR12 or R3COOR12 R6 -**- R«r n Method Yield Melting Salt % Range Recrystallized From 16 204-205 fumarate MeOH/ether 45 241-243 2 HC1 MeOH/MeCN/THF 54 209-210 fumarate EtOH/ether F 52 235-237 2HC1JH20 MeOH/ether 34 145-150 fumarate MeOH/ether 91 123-125 HC1•jEtOH EtOH/ether 71 191-193 fumarate MeOH/MeCN/ether 66 234-236 HC1 MeOH/ether TABLE A Example No. 248 269 R2 Me R'4 I R3 R5 Ph CH2CH2Ph Me C!I2CH2-^^-S02NEt2 Ph 276 CH2CH2-^5)-N02 Et Ph +R3C(OR12)3 R3C(NH)0R12 or RJCOOR12 R6 Method Yield Melting % Range Salt Recrystallized From 8-no2 88 241-242 54 171-173 64 222-224 HCl HC1 HCl MeOH/ether EtOH/ether MeCN/THF Ln O Z to cn i-1 o > ro IMI£ Example No.

A 200 CCI cis 201 <xl 202 00 203 00 X^NHCH, of ^—'\^-nh2 Ph R3 Method CH2CH2Ph CH2CH2Ph CH2CH3 CH=CH -o Yield % 32 67 61 204 <X CH2S02Ph 55 I A Melting Range Salt 190-192 fumarate Recrystal-lized from THF/MeCN 180-181 fumarate EtOH/ether 191-192 fumarate EtOH/ether CTl 184-185 132-135 fumarate fumarate MeOH/MeCN (after chromatography on Sj02 with 4:49:3 hexane/ tBuOMe/IPA) EtOH/ether ro a z to cn o > Ln NHCH, Example Yield No. r3 Method % 205 CH2CH2Ph F 35 206 CH=CHPh F 17 TABLE K Melting Recrystal- Range Salt lized from 255-256 HCl-1/2 H20 MeOH/ether amorphous HCl*1/2 H20 EtOAc 280544 D.N. 2S10A - 58 * General Method A The appropriate diamine and five to seven equivalents of the corresponding triethylorthoester were stirred at room temperature while 0.4-0.5 mL of acetic acid per mmol 5 of diamine were added in one portion. The mixture was stirred at reflux for 2-12 hours or stirred at room temperature for 2-72 hours. The reaction was diluted with ethyl acetate, washed with 2N sodium hydroxide and extracted into three portions of 2N HCl. The HCl extracts 10 were combined/ washed twice with ether, made basic with excess 35% sodium hydroxide and extracted into three portions of ether. The ether extracts were combined, dried over magnesium sulfate and the solvent removed in vacuo. The free base or the salt was recrystallized as 15 shown in Table A.

General Method B The diamine was added to two equivalents of potassium acetate or a catalytic amount of potassium acetate in 0.8-1.2 mL of acetic acid per mmol of diamine. The mixture 20 was stirred at room temperature and from two to five equivalents of the appropriate triethylorthoester were added. The reaction was stirred at room temperature for 18-72 hours and stripped in vacuo. The product was worked up as described for General Method A. 280544 D.N. 2510A - 59 " GenerfO. Method C The dihydrochloride of the diamine was dissolved in 1-3 mL of acetic acid per mmol of diamine and about 2.0 to 2.5 equivalents of sodium acetate were added. The mixture 5 was stirred for about ten minutes at room temperature, and three to five equivalents of the appropriate triethylorthoester were added. The mixture was stirred at room temperature for 2-48 hours and stripped in vacuo. The reaction was worked up as described in General Method A.

General Method D The diamine dihydrochloride and two to three equivalents of the appropriate methoxyimine hydrochloride were dissolved in 2-6 mL of methanol per mmol of diamine. The mixture was stirred, and two equivalents of sodium 15 acetate were added. After 2-18 hours the solvent was removed in vacuo and the product worked up as described in General Method E.

General Method E 20 The diamine dihydrochloride, 1.3-3.0 equivalents of the appropriate trimethyl- or triethylorthoester and 1.0-1.8 equivalents of sodium acetate were combined in about 3 to 6 mL of isopropyl acetate per mmol of of the diamine. The mixture was refluxed for 3-18 hours. The reaction was 25 cooled, washed with two portions of 2N sodium hydroxide and dried over sodium sulfate. The solvent was removed in vacuo and either the salt or the free base was purified from the residue as shown in Table A. 28054 D.N. 2510A General Method F To the diamine dihydrochloride, slurried in about 3 mL of toluene per mmol of diamine, was added dropwise at 0° under nitrogen 2.1 equivalents of 2M trimethylaluminum in 5 toluene. The reaction was allowed to come to room temperature and stirred for 2 hours, then 1.25 to 1.50 equivalents of the appropriate methyl or ethyl ester were added. The reaction was refluxed 2 hours, cooled and quenched by the sequential addition of ice, methanol, 10 dichloromethane and 2N NaOH. The aluminum salts were filtered off, the layers separated, washed with more dichloromethane, dried over sodium sulfate, stripped and crystallized as shown in Table A. Occasionally flash chromatography on silica gel with MeOtBu, optionally 15 containing up to 2% isopropylamine, was necessary before crystallization.

Kftnpral Method G The free base of the diamine, three equivalents of acetic acid and three equivalents of either the 20 appropriate triethylorthoester or the hydrochloride of the appropriate ethoxyimine in 2-4 mL of methanol per mmol of diamine were stirred at room temperature for 18 hours. The solvent was removed in. vacuo and the product treated as described in General Method A.

TABLE B Example R2 R3 Method Yield No. %_ 64 Ue Et C 92 65 Me Me C 27 66 Me H C 32 67 Me nPr C 62 68 Bzl Et C 49 69 Bzl H H 52 70 Bzl nPr I 20 249 Me CH2CH2Ph E 78 Uelting Salt Recrystallized Range From 205-207 HCl MeOH/ether 261-264 • HCl MeOH/ether 244-245 HCl MeOH/ether 223-226 . HCl MeOH/ether 209-210 HCl EtOAc/HCl in ether 149-151 H20 211-212 HCl EtOAc/ether amorphous HCl*3/5 H20 ether 280 5 44 D.N. 2510A flpnaral Method H The diamine dihydrochloride, 2.2 equivalents of sodium acetate and 1.5 equivalents of triethylorthoester were combined in 1.2 mL of isopropyl acetate per mmol of* 5 diamine and refluxed for four days. The solvent was removed in vacuo, the residue taken up in dichloromethane, the dichloromethane was washed two times with 2N sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and the product chromatographed on 10 silica gel eluting with 49:49:2 ethyl acetate/dichloromethane/ diethylamine. The hydrochloride of the purified free base was formed by dissolving the free base in ethyl acetate and adding HCl in ether.

General Method I 15 The diamine dihydrochloride, 2.1 equivalents of sodium acetate, 3 equivalents of trimethylorthoester, and 5 equivalents of acetic acid were stirred together for seven days at room temperature. The workup was the same as that described for General Method H.

TABLE C Nucleophile Example Nucleophile No.

• R3 Method Yield* % 71 EtSH -CH2SEt 59 PhS02Na O ii -CH2S-Ph 6 31 72 Me2NH -CH2NMe2 41 73 PhSH -CH2SPh 12 74 (jm ch2-N3 43 75 BzlNHCH3 ch2n' Bzl Me 23 ♦yield calculated over two steps from the diamine.

Me N h* N Ph ileltlng Salt Recrystallized Range From 267-269 HCl EtOH/ether 246-248 HCl MeOH/ether I 184-186 fumarate EtOH/ether w 1 196-197 fumarate MeOH/ether 194-196 fumarate EtOH/ether 102-104 fumarate EtOH/ether ro o z 2 U1 O > TABLE C ,Me Nucleophile ^-C^CJ Ph Example Nucleophile R3 Method Yield* No. % / \ r~\ „ 76 UN, N-Ue CH2-N K-Me K 52 \ I * \_/ / \ f—\ 77 HN 0 CH2N 0 K 28 78 Et2NU CH2NEt2 K 24 79 CH30-Q>-SH CH2S-£^OCH3 J 16 80 CH3-^^-S02Na CH2S02 -^~^-CH3 K 30 81 Cl-^^S02Ha CH2S02-^)-Cl k 10 Melting Range Salt Recrystallized From 233-235 2 fumarate MeOH/ether 206-208 fumar&te MeOH/ether 133-135 1.5 fumarate 0.25 EtOH EtOH/ether 208-210 HCl MeCH/ether 247-249 HCl EtOH/MeCN 214-217 HCl MeOH/lleCN 280 5 44 D.N. 2510A General Method J The 3-chloromethylbenzodiazepine was dissolved in three mL of acetonitrile per mmol of benzodiazepine and added to 1.0-1.7 equivalents of the thiol plus 2.3 5 equivalents of milled potassium carbonate in three mL of acetonitrile per n.mol of benzodiazepine. The reaction was stirred at room temperature for 18 hours and filtered. The acetonitrile was removed In vacuo and the product worked up as described in General Method A.

General Method K The 3-chloromethylbenzod .azepine and three equivalents of the appropriate amine or sodium sulfinate were combined in 1-5 mL of solvent per mmol of benzodiazepine and refluxed for 3-5 hours. The reactions 15 with amines were run in chloroform; the reactions with sulfinate were run in methanol. The product was worked up as described in General Method A.

• • Example R^ r3 No. fl2 N TABLE D l)nBuLi /V-rS ,n 2) Electrophile ptr "h R4 Electrophile Method Yield % 82 Mo Et -CH2COOEt BrCH2COOEt 22 pH 83 Ue Et -CHCH2CH3 CH3CH2CHO 21 84 Ue Et -COOEt CICOOEt 57 85 Ue Et 9 -CUe CH3COCI 22 86 Me Et -CH2CH»CH2 BrCH2CH-CH2 87 Me Et iPr il'rl 88 Me Et Et 89 CH2-<3 Ue Ue 90 Me Ph Et EtI Uel EtI L L 45 56 80 Uelting Range Salt Recrystallized From 166-167 fumarate EtOII/ether 155(d) fumarate EtOH/ether 162(d) fumarate EtOH 184-185 fumarate EtOH 180-187 fumarate EtOH/ether 208-210 fumarate iPrOH 234-235 fumarate EtOH 107-108 free base ether/hexane 126-127 free base tBuOMe/hexane table d 1)nBuLi 2) Electrophile Example R2 r3 r4 Electrophile Method Yield No. % 91 Me Et n-Pr nPrl L 50 92 iPr Me Me Mel L 93 93 iPr Me Et EtI L 79 94 Me Ph Me Mel L 40 95 Me Et Me Mel L 66 96 Me Me Me Mel L 61 97 Me Me CH20Me ClCI^OMe L 17 N /H3 N r4 Melting Salt Recrystallized Range From a* -J 199-202 fumarate EtOH/ether 150-151 maleate acetone/ether 103-104 free base hexane 158-159 maleate acetone/ether unrecorded free base hexane 130-132 free base hexane/CH2Cl2 244-246 fumarate EtOH 228-230 fumarate trtt. iPrOH 115-116 free base hexane g Z 155-156 free base EtOAc/hexane fo cn H O > ro Example No.

R2 ( )~Rl TABLE E 1)nBuLi R3 2) Electrophile R4 Electrophile R14 Method 98 99 100 101 102 103 103A 10313 me Me Me Me Me Me -CH2C1 CH2NMe2 Hj -CH2C00Et n Me C2CI6 Me CICOOEt -ClKCOOEt )2 Me CICOOEt II Me C2Cl6/Me2iJH H /^H Me C2C16/HN^J H N -CH2CH2-{~)-Cl Me ClCH2-^hCl H L L L N h1 Ph R' Yield Melting % Range Salt Recrystallized From 18 118-120 free base CH2Cl2/hex 51* 89-90 free base Chromatog 9:1 hex/Et2NH 17* 144-145 free base CH2Cl2/hex 12* 100-102 free base CH2Cl2/hex 00 17* 146-147 free base CH2Cl2/hex 48* 149-151 maleate acetone hemihydrate 78 143-147 HCl (+)isomer H2? 66 . 143-146 HCL (-)isomer II20 *Over two steps D Z N) y o > ro Ln Example No.

R2 R3 .R1 N TABLE E l)nBuLi Ph' R4 2) Electrophile Electrophile R14 Method 104 iPr -CH2CH2Ph 105 Cll2-<] CII2CH2-^-Cl 106 iPr -Ph lie BzlBr Me ClCIt2-^~^-Cl Et BzlBr H 107 Me iPr Me Uel Ue 108 109 110 111* 1124 Me Me Me Me Me CH2NEt2 CH2N a -CH2C0Ph 9h3 -CHCH2Ph 9"3 -CIIC»2Ph Me C2Cl6/Et2NH H Ue C2C16/h/ 0 h N \ / Ue PhCOOUe Ue Me BzlBr OzlBr Ue Ue ♦diastereomeric pair N /)~F Yield Melting % Range Salt Recrystallized From 86 173-175 maleate acetone/ether 70 189-191 HCl MeCN/.icetone/ ether 88 160-162 maleate acetone/ether 40 223-225 fumarate EtOH <T-vO 65 200-206 2HC1 MeCN/ether 137-140 LH2S04 ' MeOH/acetone 18 160-161 free base EtOAc/hex 6 168-169 maleate 177-180 maleato MeCN/ether McCN D Z ro cn o > ro c_n I h"' TABLE E 1)nBuLi R3 2) Electrophile R4 Electrophile R14 Method hh2 CH2CHPh OH OH CH2CH-Ph Me PhCH-NTMS H -CH2CH-^~\l Me O-CH0 Me PhCHO CH2CH2^^0Ue Me ClCH^^OMe H CH2SEt Me EtSSEt CH2SPh Me PhSSPh Ph Yield Melting X Range Salt Recrystallized From 80 222-256 2HC1 MeOH/ether 45* 189-190 fumarate EtOH/ether 44* 169-171 maleate EtOH/ether •vi o 84* 171-172 maleate acetone/ether 1 69* 235-236 hcl AI2O3 Chromatog then ether 27* 240-250 *over two steps HCl Si02 EtOAc/MeOH/IPA then ether U z ro en (-* o > ro <_n TABLE E 1)nSuLi 2) Electrophile Example n2 R3 R4 Electrophile R14 Method No. 119 Me CH2CH2Ph Me BzlBr H 120 Me CH2C^~^OMe Me MeO-^~VcNMe H OMe -J* Ph' N /H3 'r4 Yield Melting Salt Recrystallized % Range From 82 168-169 maleate MeCN/ether 50 144-146 maleate acetone/ether a *z NJ cn i-" o > ro oo o 280544 D.N. 2510A General Method L The benzodiazepine in 3-7 mL of THF per mmol of benzodiazepine was stirred at -78°C to -42°C while 1.1 equivalent of N-butyllithium was added under nitrogen. 5 The solution was stirred for one hour at -78°C, 1.1-1.3 equivalents of the appropriate electrophile were added, and the reaction was allowed to come to room temperature. The reaction was poured into IN HCl, washed with ether, made basic, and extracted into ether. The combined ether 10 layers were dried over potassium carbonate, filtered and the solvent removed in vacuo. The free base was recrystallized or a salt was prepared as shown in Table D.

Example 265 1-(4-Chlorophenyl)-3-[2-(4-chlorophenyl)ethyl]-4,5-15 dihydro-1,4-dimethyl-lH-2,4-benzodiazepine (Formula la: R1, R6 »= H; R2a, R4b = Me; R3a = CH2CH2 -^O^-Cl; r5c = According to General Method L, 14.5 g of l-(4-chlorophenyl)-3-[2-(4-chlorophenyl)ethyl]-4,5-dihydro-l,4-20 dimethyl-lH-2,4-benzodiazepine as its fumarate salt was prepared from 17.3 g of the compound of Example 228 and 7.6 g of methyl iodide. The salt was recrystallized from EtOH/ether, mp 173-175.

General Method M 25 The procedure described under General Method L was followed except that two equivalents of N-butyllithium and two equivalents of aldehyde were used. 28 0 5 4 4 D.N. 2510A General Method N The benzodiazepine in 3-7 mL of THF per minol of benzodiazepine was stirred at -78°C while 1.1 equivalents of butyllithium was added under nitrogen. The solution 5 was stirred for one hour at -78°C, 1.1-1.3 equivalents of hexachloroethane were added, and the reaction was stirred for one-half hour at -78°C. The reaction was poured into IN HCl, washed three times with ether, made basic with 35% sodium hydroxide, extracted into ether, dried over 10 potassium carbonate, filtered and strapped. The resulting brown oil was filtered through silica with ethyl acetate, stripped and taken directly to the next step. The 3-chloromethyl benzodiazepine was either dissolved in chloroform and treated with 3-5 equivalents of the 15 appropriate amine or it was dissolved directly in a large excess of the amine. The solution was refluxed from 1-20 hours. The solvent was removed and the product was crystallized as shown in Table E.

General Method 0 The procedure was substantially similar to General Method L except that inverse addition of the lithium salt of the benzodiazepine was made to 1.5 equivalents of the chloroester.

General Method P The procedure was substantially similar to General Method L except that lithium diisopropylamide, generated from butyllithium and diisopropylamine, was used as the base and the reaction was run at 0°. 280544 D.N. 2510A General Method Q The procedure was substantially similar to General Method L except that the reaction was quenched after stirring one hour at -55° by adding a slight excess of acetic acid in THF.

General Method R The benzodiazepine-3-one was dissolved in 13-14 equivalents of phosphorus oxychloride and one-quarter equivalent of phosphorus pentoxide was added. The mixture 10 was stirred at room temperature under nitrogen briefly, then heated at 90°C for 18 hours. The solution was stripped in vacuo, and the residue treated with 4-9 equivalents of the appropriate amine and stirred for two hours at room temperature. The excess amine was stripped 15 in vacuor and the residue was crystallized as shown in Table F.

TABLE F Example No.

R3 Method Yield % Melting Range / \ 121 -NO R 20 245-246 \_/ 122 N(Me)2 R 33 124-125 -o 123 -N 7 R 53 159-161 Ph Salt Recrystallized From HCf CIl2Cl2/hexane not rex; from column 9:1 EtOAc Et2N 2-butanone free base so3h Example Starting R2 No. Material R5 R6 Method 124 VIII CH2CH2N r\ \ / Ph 125 VIII Ph tie 126A 126B IX VIII Ue We 127 VIII o OMe lie 128 VIII Me Ph 7,8-diOMe S 129 VIII CH2CH20Me Ph 130 VIII Me Co v^/^nhr1 Yield % Melting Range Salt Recrystallized From 100 oil 88 71-72 free base ether/hexane 48 1 70 245-247 2I1C1 MeOH/ether ^ 100 oil oil 42 252-254 2 11C1 72 244-246 2HC1-1H20 EtOII/ether O *Z ro U1 o > oi n* Example Starting R2 No. Material or r*-£ IX R5 Method 131 Vlll iPr Ph 132 133 VIII VIII tie lie Ph 6 134 135 VIII VIII Bzl Ue Ph CI nh2 h s T 136 VIII Me 1J7 ix Ue Ph 6-F -eg NHR* NH, Yield Melting % Range Salt Recrystallized From 94 264-266 2UC1 UeOII/ether 94 163-168 HCl EtOH/ether 48 201-203 2HC1 MeOH/EtOH —j 70 83 >360 275-276 2HC1 2HC1 UeOII/ether UeOH/ether 57 free base 100 free base 89 oil free base a z fO cn >-* o > ro oi n'-S- Example Starting No. Material -R* or R*-iL IX R5 Method 138 IX Me Ph 7-F 139 140 141 IX IX IX Me Me Me Ph Ph Ph 8-F 6- 8,9 fused 9-Me 142 VIII CH2CH2NEt2 Ph 143 HI 145 146 VIII VIII VIII VIII Et Ph Me ch2-0 Me -o Ph o II II T T -cc NHR* NHj Rs Yield Melting Salt Recrystallized % Range From 92 oil free base 61 oil free base 56 oil free base -4 3D 29-61 oil free base 89 oil free base 91 241-243 2HCl-iH20 MeOH/THF 61 259-261 2HC1 90 amorphous 2IIC1 72 EtOH/ether ether O 2 w cn i-1 o > R' IX Example Starting No. Material R5 table g j or *4 R6 Method 147 VIII CH2CH2Ph Ph 148 207 VIII VIII Me Bzl H Me cyclohexyl H T S 245 277 VIII Ue Ph VIII CH2CH2-(c^-N02 Ph N02 Yield Melting Salt Recrystallized % Range From 96 156-160 2HC1 MeOH/THF/ether 87 267 2HC1 MeOH/ether 98 275-277 2HC1 MeOH/ether , 24 80-81 free base MeOtBu/hexane ^ I 82 amorphous 2HCl UeOH/ether a z M cn O > l\3 CJ1 28054 D.N. 2510A Genftrfll Method S The appropriate phthalazine or phthalazinone was treated with 4-8 equivalents of diborane in THF and the mixture was refluxed for 2-5 days under nitrogen. Usually 5 the 4-8 equivalents of diborane were added in two or three portions over the course of the reaction. The reaction was allowed to cool to room temperature and excess aqueous or alcoholic hydrochloric acid was added carefully under nitrogen. The reaction was refluxed, the THF was removed 10 in. vacuo and the residue was made basic with 35% aqueous sodium hydroxide. The product was extracted into ethyl acetate, dried over sodium sulfate, concentrated in vacuof and either purified as the hydrochloride salt as shown in Table G or, more commonly, used without further 15 purification as the free base. In Table G, the Roman numeral IX indicates that the starting material was the corresponding phthalazine; the Roman numeral VIII indicates that the starting material was the corresponding phthalazinone.

General Method T The procedure was substantially similar to General Method S except that 0.1-0.5 equivalent of sodium borohydride and 0.7 to 1.5 mL of diglyme per mmol of phthalazinone were added.

Example. 149 4,5-Dihydro-3-ethyl-4-methyl-l-phenylmethyl-lH-2,4- benzodiazepine (Formula I: R1, R4, R6 - H; R2 - Me; R3 = Et; R5 = Bzl) A solution of 12.5 g (50 mmol) of 2-[(l-amino-2-30 phenyl)-ethyl]-N-methylbenzenemethanamine in 150 mL of isopropyl acetate was treated with 4.1 g (50 mmol) of sodium acetate and 30 mL (150 mmol) of 28054 D.N. 2510A triethylorthopropionate and 5 mL (87 mmol) of acetic acid. The mixture was refluxed for three hours and poured into 1.5 L of ice water containing 200 mL of 2N sodium hydroxide. The product was extracted into ethyl acetate, 5 dried over sodium sulfate and stripped. The residue was recrystallized from isopropyl alcohol/ether to yield 7.5 g of the free base. The free base in ethanol was treated with 4.6 g of cyclohexane sulfamic acid and the solvent removed in vacuo. The residue was recrystallized from 10 isopropyl alcohol/ether to provide 5.8 g of product as the cyclohexane sulfamic acid salt, mp 137-138.

Example 15Q 4,5-Dihydro 3-ethyl-l-phenyl-lH-2, 4-benzodiazepine 15 (Formula I: R1, R2, R4, R6 - H; R3 - Et; R5 - Ph) A mixture of 1.36 g (3.6 mmol) of 4-banzyl-4,5-dihydro-3-ethyl-l-phenyl-lH-2,4-benzodiazepine, 136 mg of 10% palladium on carbon, and 257 mg (4.0 mmol) of ammonium formate in 50 mL of methanol was refluxed under nitrogen 20 for three hours. Four more 230-mg portions of ammonium acetate were added every two hours during reflux until TLC on silica gel with 5% diethylamine in ethyl acetate showed a complete conversion. The reaction was cooled, filtered and stripped. The residue was distributed between aqueous 25 sodium hydroxide and ether. The ether extract was dried over sodium sulfate, treated with decolorizing carbon, filtered and stripped. The residue was taken up in 60:40 ethyl acetate/ether and acidified with dilute ethereal HCl. The resulting precipitate was filtered off and 30 recrystallized from isopropanol/ether to yield 0.61 g (61%) of the hydrochloride salt of the product, mp 203-204. 28054 D.N. 2510A - 82 -Example 151 4, 5-Dihydn'o--4-methyl-l-phenyl-lH-2, 4-benzodiazepin-3-amine monohydrochloride (Formula I: R1, R4, R6 - H; R2 - Me; R3 = NH2; R5 - Ph) A solution of 15 g (66 mmol) of 2-[(methylamino)- methyl] -a-phenylbenzenemethanamine in 85 mL of methanol was treated with 7.2 g (68 mmol) of cyanogen bromide at room temperature. The solution was stirred at room temperature for 18 hours and stripped. The residue was 10 dissolved in ethanol and the ethanol stripped off. The residue was recrystallized from methanol/isopropyl acetate to yield 4.55 g of the free base, mp 156-159. The mother liquors vere dissolved in ethanol, treated with a slight excess of ethanolic HCl and recrystallized from ethanol to 1* yield 1.3 g of the hydrochloride salt, mp 259-261.

Example 1.53 1, 2, 4, 5-Tetrahydro-4-methyl-l-phenyl-3H-2, 4-benzodiazepin-3-thione To a suspension of 15 g (50 mmol) of 2-20 I (methylamino)-methyl]-a-phenylbenzenemethanamine dihydrochoride in 100 mL of isopropyl alcohol was added 10 g (100 itrool) of potassium acetate followed by 3.3 mL (55 mmol) of carbon disulfide in 35 mL of isopropyl alcohol. The suspension was stirred at room temperature for one and 25 one-half hours and then refluxed for 30 minutes. The reaction "was chilled in ice and the internal salt of the carbamodithioic acid, contaminated with two equivalents of of potassium chloride, was filtered off. The carbamodithioic acid was suspended in 125 mL of 95% 30 ethanol, and 1.3 mL of of 12N hydrochloric acid was added. The suspension was refluxed for three days, cooled, and 15.3 g (114%) of the crude benzodiazepin-3-thione was filtered off. A 6-g portion of the crude product was 280544 D.N. 2510A recrystallized from 2-ethoxy ethanol to yield 2.0 g (38%) of product, mp 208-209.

Example 153 3- [ [2- (Diethylamino) ethyl]amino] -4, 5-dihydro-4-rnethyl-l-phenyl-lH-2,4-benzodiazepine [Formula I: R1, R4, R6 - H; R2 = Me; R3 -NH (CH2) 2N(C2H5)2] A slurry of 11.7 g (44 mmol) of 4-methyl 1-phenyl-1,2,4,5-tetrahydro-3H-2,4-benzodiazepin-3-thione of 10 Example 152 in 146 mL ethanol was treated with 4.2 mL (67 mmol) of iodomethane in 30 mL ethanol added dropwise at 50°. The reaction was stirred at ambient temperature for 18 hours and 13.48 g (75%) of 4-methyl~l-phenyl-3-methylthio-4,5-dihydro-lH-2,4-benzo-diazepine was 15 collected, mp 201-205, as the hydriodide salt.

A solution of 22.7 g (55 mmol) of the 3-methylthio-benzodiazepine in 285 mL of methanol was refluxed with 7.8 mL (55 mmol) of N,N-diethylethylenediamiue for 18 hours. The reaction was filtered hot to remove a small amount of 20 insoluble impurity, cooled, stripped, and distributed between methylene chloride and aqueous sodium hydroxide. The organic extracts were dried over magnesium sulfate and stripped. The residue was recrystallized with great difficulty as the fumarate salt from isopropanol. After 25 multiple recrystallizations 1.5 g of the product was obtained as the difumarate hemihydrate, mp 160-162. 280544 D.N. 2510A 4,5-Dihydro-4-methyl-l-phenyl-lH-2, 4-benzodiazepin-3- sulfonic acid (Formula I: R1, R4, R6 = H; R2 - Me; R3 = SO3H; R5 » Ph) 5 Twenty-nine grams (108 mmol) of 1,2,4,5-tetrahydro-4- methyl-l-phenyl-3H-2,4-benzodiazepin~3-thione of Example 152 was treated with 2.4 g of sodium chloride, 420 mg of sodium molybdate dihydrate and 35 mL of 30% hydrogen peroxide in 50 mL of water and 10 mL of t-butanol 10 according to the procedure of Maryanoff et al., J.O.C. 51, 1882 (1986). The reaction remained a suspension at all times, and after heating at 70-80° for two hours, the product was filtered off from the chilled suspension to yield 30.6 g (90%) of the sulfonic acid requiring no 15 further purification, mp 188-190.

Example 155 4,5-Dihydro-4-methyl-l-phenyl-3(1-pyrrolidino)-1H-2,4- benzodiazepine (Formula I: R1, R4, R6 = H; R2 = Me; R3 = C4H3N; R5 - Ph) 20 A mixture of 4.75 g (15 mmol) of the sulfonic acid of Example 154 and 20 mL of pyrrolidine was refluxed for 18 hours. The pyrrolidine was stripped off and the residue was chromatographed on 340 g of silica gel, eluting with 95:5 ethyl acetate/diethylamine to yield 3.12 g of residue 25 which was recrystallized from 40 mL of hexane to yield 2.14 g (47%) of product, mp 118-119. 28054 D.N. 2510A Example 156 3-[(4,5-Dihydro-4-methyl-l-phenyl-lH-2,4-benzodiazepin-3-yl)thio]-N,N-diethylpropaneamine (Formula I: R1, R4, R6 - H; R2 - Me; R3 -5 S (CH2)3N(C2H5)2/R5 - Ph) A solution of of 12 g (45 mmol) of 1,2,4,5-tetrahydro-4-methyl-l-phenyl-3H-2,4-benzodiazepin-3-thione of Example 152 in 100 mL of DMF was treated with 1.24 g (50 mmol) of sodium hydride at 70° and 7.5 g (50 mmol) of 10 3-diethylaminopropyl chloride was added dropwise at 70°.

The reaction was stirred at 70° for five hours and then at room temperature for two days. The reaction was poured into 250 mL of ice water and extracted twice into ethyl acetate. The product was extracted into 150 mL of 2N HCl, 15 washed with ethyl acetate, made basic, and extracted back into ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, stripped, and the residue was dissolved in acetone. Two equivalents of maleic acid in 40 mL of acetone was added, followed by a small amount of 20 ether. The resulting precipitate was recrystallized from acetone/ether to provide 13.2 g of product as the dimaleate salt, mp 95-97.

Example 157 4,5-Dihydro-4-methyl-3-methylthio-l-phenyl-lH-2,4- benzodiazepine (Formula I: R1, R4, R6 = H; R2 = Me; R3 = SMe; R5 = Ph) A solution of 8 g (30 mmol) of the thione of Example 152 and 2.7 mL (44 mmol) of methyl iodide in 100 mL of 30 ethanol was refluxed two hour?, cooled, and the hydriodide of the product filtered off. The salt was partitioned between methylene chloride and aqueous sodium bicarbonate, the organic layer dried over magnesium sulfate, and stripped. The residue was dissolved in ethanol and 2.7 g 280544 D.N. 25I0A of methanesulfonic acid was added followed by ether. The resulting precipitate was filtered off and recrystallized from ethanol to yield 5.2 g of product as the methane-sulfonate salt, mp 195-196.

Example 158 1,2,4,5-Tetrahydro-4-methyl-l-phenyl-3H-2,4-benzodiazepin-3-one A solution of 32.8 g (145 mmol) of 2-[(methylamino)-methyl]-a-phenylbenzenemethanamine in 215 mL of chloroform was treated with 25.9 g (159 mmol) of carbonyldiimidazole. The reaction was stirred at room temperature for 19 hours, washed four times with water, dried over sodium sulfate and stripped in vacuo. The gummy residue was triturated in and recrystallized from ethyl acetate to yield 26 g 15 (71%) of product, mp 198-199.

Example 159 -Butyl-4,5-dihydro-3-ethyl-4-methyl-l-phenyl-lH- 2,4-benzodiazepine (Formula I: R3- =* nBu; R2 = Me; R3 = Et; R4 and R® = H, R5 =Ph) A suspension of 14.16 g (60 mmol) of 2-methyl-4-pheny1-1(2H)-phthalazinone in 340 mL of THF was cooled to -65° under nitrogen and treated with 24.8 mL (62 mmol) of 2.5N n-butyllithium in hexane. The mixture was stirred 25 for 20 minutes at -65°, and 240 mL (240 mmol) of IN borane- THF complex was added. The solution was allowed come to room temperature and 340 mg (9 mmol) of sodium borohydride were added. The reaction was refluxed for 20 hours, another 340 mg of sodium borohydride was added, the 30 reaction refluxed another 24 hours. The reaction was cooled and quenched with 100 mL of methanol. Eighty milliliters of 3.5N HCl in methanol was added, the 28054 D.N. 2510A - «7 - reaction was refluxed two hours and 19.9 g (93%) of the dihydrochloride of 2-[1-(methylamino)pentyl]-a-phenyl- benzenemethanamine was isolated by filtration. The benzene-methanamine was treated with 5 triethylorthopropionate and sodium acetate in isopropyl acetate according to General Method E to yield 9.48 g of the free base of the product, mp 102-114 after recrystallization from methyl t-butyl ether/hexane. Seven grams of the free base was coverted to the hydrochloride 10 salt and recrystallized from acetone ether to yield 5.08 g of product as the monohydrochloride salt, mp 209-211.

Example 160 4,5-Dihydro-l, 5-diphenyl-3-ethyl-4-methyl-lH-2, 4- benzodiazepine (Formula I: R1, R5 «* Ph; R2 - Me; R3 - Et; R4, R6 = H) The procedure of Example 159 was used, substituting phenyllithium for butyllithium. The intermediate 2-[ (methylamino) phenylmethyl] -a-phenylbenzenemethanamine was crystallized as the dihydrochloride salt containing 0.6 20 moles water of hydration, mp 202-216. It was cycylized with triethyl-orthopropionate as in Example 158 to yield 32% of the product as the hydrochloride salt, mp 275-276, from acetone/ether. 4-5-Dihydro-l-(4-hydroxyphenyl)-4-methyl-3-<"'-phenylethyl) -1H-2, 4-benzodiazepine (lormula I: R1, R4, R6 = H; R2 = Me; R3 - CH2CH2PH; R5 = -(o^rOH) 30 A solution of 6.78 g (17 mmol) of the methoxy compound of example 60 in 70 mL of methylene chloride was treated with 32 mL of 1M boron tribromide in methylene chloride (32 mmol) at 0° under nitrogen for 2 hours. The 28054 D.N. 2510A reaction was poured into 2N aqueous HCl, stirred 1 hour, filtered free of boron salts and extracted into methylene chloride with a trace of methanol after making basic with Na2C03. The organic layer was dried, stripped and the 5 residue taken up in methanol. Methanolic HCl was added and the salt crystallized by the addtion of ether. The hydrochloride was recrystallized from methanol, mp 245-247,. yield 90%.

Example 267 4,5-Dihydro-3-[2-(4-hydroxyphenyl)ethyl]-4-methyl- l-phenyl-lH-2, 4-benzodiazepine (Formula I: R1, R4, R6 = H; R2 = Me, R3 - CH2CH2-^O^-0H; R5 = Ph) By a process analogous to that of Example 2£6, 1.14 g 15 of 4,5-dihydro-3-[2-(4-hydroxyphenyl)ethyl]-4-methyl-l-phenyl-lH-2,4-benzodiazepine was obtained as the hydrochloride salt from 2.47g (6.1 mmol) of the methoxy compound of Example 35, mp 160-162 from methanol/ether.

Example 268 4,5-Dihydro-l-(4-hydroxyphenyl)-3-[2-(4-hydroxyphenyl)- ethyl]-4-methyl-lH-2,4-benzodiazepine (Formula I: R1, R4, R6 - H; R2 - Me; R3 - CH2CH2-^O^-0H'* r5 = -^O^-0H By a process analogous to thi of Example 266, 1.80 g 25 of 4,5-dihydro-l-(4-hydroxyphenyl)-J-[2-(4-hydroxyphenyl)-ethyl]-4-methyl-lH-2,4-benzodiazepine was obtained from 4.5 g (8.7 mmol) of the dimethoxy compound of example 229 using 3.5 equivalents of boron tribromide. The free base was insoluble in methylene chloride. The hydrochloride 30 hemihydrate was obtained by recrystallization from MeCN/MeOH, mp 266-228. 28054 D.N. 2510A - 89 -Example 161 1,2,3,5-Tetrahydro-lO-phenylpyrrolo[1,2-b][2,4] benzodiazepine (Formula II: R1 - Ph; q = 1; R4a, R5b, R6 = H) 5 A. A mixture of 18.95 g (66.5 mmol) of 2-(aminomethyl)-a-phenylbenzenemethanamine dihydrochloride, 24.74 g (133 mmol) of ethyl 4-chlorobutanimidate hydrochloride, and 10.91 g (133 mmol) of sodium acetate was reacted in methanol according to General Method D. The residue after 10 extraction and stripping was chromatographed on 4 00 g of silica gel, eluting with a gradient from 5-6% isopropylamine in methyl t-butyl ether. The two products resulting from cyclization toward and away from the phenyl substituent were isolated. The first to emerge was the 15 isomer resulting from cyclization away from the phenyl group, i.e. the compound of Example 162 (see below). The second to emerge was the compound resulting from cyclization towards the phenyl group. It eluted primarily between 500 and 625 mL and yielded 5.8 g of residue on 20 stripping. The residue was converted to the fumarate salt with 3.48 of fumaric acid in 60 mL of ethanol and recrystallized twice from ethanol/ether to yield 5.65 g of pure product as the fumarate salt, mp 205-207.

B. The free base of the product was dissolved in a 25 minimum of hot acetonitrile and one equivalent of D-a- bromocamphorsulfonic acid was added. The diastereomeric salt with the (-) enantiomer of the diazepine crystallized out. The free base of the single enantiomer was regenerated and the fumarate salt again formed; mp 145-30 14 7°; [a]d25 (c=l, MeOH) -230°.

C. The free base of the mother liquors from part B was treated as before with one equivalent of L-a-bromocamphorsulfonic acid to obtain the fumarate salt of the ( + ) enantiomer, mp 145-147; [a]<i25 (C=l; MeOH) +249°. 28054 D.N. 2510A -Methyl-10-phenyl-l,2,3, 5-tetrahydro-10H- pyrrolo[1,2-b][2,4]benzodiazepine (Formula IIi.R1 - Ph; R4a, R5bf R6=H; R15=Me) 5 Following General Method L, 2.1 g (8 mmol) of 10- phenyl-1,2,3,5-tetrahydropyrrole[1,2-b)[2,4]benzodiazepine of Example 161 was reacted with 1.37 g (9.6 mmol) of methyl iodide to produce 10-methyl-10-phenyl-l,2,3,5-tetrahydro-lOH-pyrrolo[1,2-b][2,4]benzodiazepine, obtained 10 by chromatography on silica gel with 3% isopropylamine in MeOtBu and recrystallization of the fumarate salt from ethanol-etber, mp 198-200, yield 1.37 g (62%).

Example 162 1,2,3,5-Tetrahydro-5-phenylpyrrolo[1,2-b][2,4] 15 benzodiazepine (Formula II: Rla, R4a, R6 ** H; q = 1; R5 « Ph) In the synthesis described in Example 161, the earlier fractions, which eluted between 125 and 250 mL in the isopropylamine/t-butylmethyl ether chromatography, 20 were combined and stripped to yield 7.9 grams of residue which was converted to the fumarate salt with 4.6 grams of fumaric acid in 120 mL of ethanol. The fumarate was recrystallized from ethanol/ether to yield 8.9 g of the fumarate salt, mp 217-218. The fumarate salt was 25 reconverted to the free base with 2N aqueous sodium hydroxide and the free base recrystallized from methylene chloride/hexane to yield 5.58 g of pure product as the free base, mp 152-153. 280544 D.N. 2510A - "91 - Example 163 1,2,3,5-Tetrahydro-5-methyl-5-phenylpyrrolo[1,2-b][2,4] benzodiazepine (Formula II: Rla, R6 = H; q - 1; R4a = Me; r5 = Ph) 5 A solution of 2.10 g (8 mmol) of the benzodiazepine of Example 162 in 32 mL of THF was treated with 3.5 mL of 2.5N n-butyllithium in hexane and 1.31 g of methyl iodide according to General Method L. The residue was recrystallized from acetone to yield 0.9 g of product, mp 10 166-168, as the free base. A further 1.07 g were obtained by chromatography of the mother liquors using the same system as Example 161. The combined residues were treated with one equivalent of maleic acid in acetone and \ recrystallized from acetone/ether to provide 2.24 g of 15 E product as the maleate salt, mp 209-210.

Example 164 l,2,3,4-Tetrahydro-ll-phenyl-6H-pyrido[1,2-b][2,4] benzodiazepine (Formula II: Rla « Ph, q = 2; R4a, R5, R6 - H) 20 By a procedure analogous to that of Example 161, using ethyl 5-chloropentanimidate hydrochloride in place of ethyl 4-chlorobutanimidate hydrochloride, 17.1 g (60 mmol) of 2-(aminomethyl)-a-phenylbenzenemethanamine was converted to a mixture of two isomers resulting from 25 cyclization towards and away from the phenyl group. The mixture was separated as before using isopropylamine in methyl t-butyl ether. Once again the slower fraction was the isomer resulting from cyclization towards the phenyl group. The residue from chromatography, which weighed 6.6 30 9f was converted to the hydrochloride salt and recrystallized from methanol/ether to give 2.95 g of the hydrochloride salt of the product, mp 310-311. 28054 D.N. 2510A - 92 -Example 165 1,2,3/ 4-Tetrahydro-6-phenyl-6H-pyrido[ 1, 2-b] [2,4] benzodiazepine (Formula II: Rla, R4a, R6 = H; q = 2; R"5 « Ph) 5 The chromatography as in Example 161 of the reaction mixture from Example 164 yielded 10.35 g of impure benzodiazepine. It was converted to the HCl salt, recrystallized from methanol/ether, and the free base was liberated with aqueous sodium hydroxide and recrystallized 10 from methylene chloride/hexane to provide 4.6 g of free base, mp 113-114. The free base was reconverted to the HCl salt and recrystallized from methanol/ether to provide 3.0 g of product as the monohydrochloride, mp 296-297.

Example 166 1, 2, 3, 4-Tetrahydro-6-methyl-6-phenylpyrido [1,2--b] [2,4] benzodiazepine (Formula II: Rlaf R6 » H; q = 2; R4a - Me; P.5 = Ph) By a process analogous to Example 163, 2.9 g of benzodiazepine of Example 165 was converted to 2.75 grams 20 of the maleate salt of the product. The maleate salt was recrystallized twice from methanol/ether to yield 2.42 grams of product, mp 190-192.

Example 281 10a-Phenyl-4-(2-phenylethyl)-5-phenylethyl-l,2,3,10-a-25 tetrahydro-6H-pyrrolo[2,1-a][2,4]benzodiazepinium chloride (Formula XXXIV: R2c - Bzl; R3a = CH2CH2PH; R5c = Ph) A solution of 16.4 g (39 mmol) of 4,5-dihydro-l-phenyl-3-(2-phenylethyl)-4-phenylmethyl-lH-2,4-benzodiazepine of Example 221 in 100 mL of THF was stirred 30 at -78° under nitrogen and 17.3 mL (43 mmol) of 2.5 N butyllithium in hexane was added. The mixture was stirred 280544 D.N. 2510A 1 hour and 4.9 mL (49 mmol) of l-bromo-3-chloropropane was added. The reaction was stirred 1 hour at -7 8°, 1 hour at -4 5° and 18 hours at room temperature, then poured into saturated brine and extracted into about 300 mL of 6:1:1 5 . ether-ethyl acetate-dichloromethane. The organic layer was dried over sodium sulfate and stripped. The residue was recrystallized from methanol-acetone-ether to yield 2.99 g of product as the monohydrate, mp 190-192.

Example 282 4-Methyl-10a-phenyl-5-phenylmet*iyl-l, 2, 3, lOa-tetrahydro-6H-pyrrolo[2,1-a][2,4]benzodiazepinium bromide (Formula XXXIV: R2c - Bzl; R3a = Me; R5c = Ph Following the procedure of Example 281, 5.7 g of 4-methyl-10a-phenyl-5-phenylmethyl-l,2,3,10a-tetrahydro-6H-15 pyrrolo\2,1-a][2,4]benzodiazepinium bromide was obtained from 12g (37 mmol) of 4,5-dihydro-3-methyl-l-phenyl-4-phenylrnethyl-lH-2,a-benzodiazepine of Example 210. It was recrystallized fj:om methanol-ether, mp 24 9-250°.

Example 283 10a-Phenyl-4-(2-phenylethyl)-1,2,3,10a-tetrahydro-6H- pyrrolo[2,1-a][2,4]benzodiazepine (Formula XXXV: R3a = CH2CH2PH, R5c «= Ph) A solution of 5.0 g (10 mmol) of the 5-benzyldiazepinium chloride of Example 281 in 130 mL of 25 methanol was reduced with 3.3 g (50 mmol) of ammonium formate and 1.25 g of 10% Pd on carbon at reflux for 1 hour. The product was recrystallized from ether-hexane as the free base, mp 134-136, yield 3.23g (87%). Some of the free base was converted to the hydrochloride salt and 30 recrystallized from THF-EtOAc-ether with a few drops of methanol, mp 195-197. 280544 D.N. 2510A 94 - Example 284 4-Methyl-lOa-phenyl-l, 2,3,10a-tetrahydro-6H-pyrrolo[2,1-a] [2,4]benzodiazepine (Formula XXXV: R3® = Me; R5c - Ph) 5 Following the procedure of Example 283, 3 g (7.5 mmol) of the 5-benzyl benzazepinium compound of Example 282 was reduced to provide 1.80 g of 4-methyl-10a-phenyl-1,2,3,10a-tetrahydro-6H-pyrrolo[2,1-a][2,4]benzodiazepine hydrochloride, mp 231-235, from methanol-THF-ether. io Example 285 -Methyl-10-phenyl-3-phenylmethyl-l,2, 3,5-tetrahydro-l0H-pyrrolo[1,2-b][2,4]benzodiazepine (Formula II: R1 - Ph, R4a - R5b - R6 - H; R15 - Me; R16 - Bzl; q - 1) Following General Method L, 5 g (18 mmol) of 10- methyl-l-phenyl-1, 2,3, 5-tetrahydro-10H-pyrrolo[l,2-b] [2,4]benzodiazepine of Example 280 was reacted with 3.72 g of benzyl bromide to provide 1.96 g of the fumarate salt of 10-methyl-10-phenyl-3-phenylmethyl-l,2, 3,5-tetrahydro-20 10H-pyrrolo[l,2-b][2/4]benzodiazepine, mp 125-150, (mixture of diastersomers) from ethanol-ether. In this case the reaction was worked up by pouring into water made slightly basic with NaOH and extracting into methylene chloride, then flash chromatographing on silica gel with 25 MeOtBu-methylene chloride then MeOtBu.

Example 286 3,10-Dimethyl-l-phenyl-l,2,3,5-tetrahydro-l0H-pyrrolo [1,2-b][2,4]benzodiazepine (Formula II: Ri = Ph, R4a = R5b = R6 = H; 30 R15 = R16 = Me; q = 1) By a procedure analogous to that of Example 285, the benzodiazepine of Example 280 was reacted with methyl 280544 D.N. 2510A iodide to provide 1.58 g of the fumarate salt of 3,10-dimethyi-l-phenyl-1,2,3/5-tetrahydro-10H-pyrrolo[1,2-b] [2,4]benzodiazepine, mp 210-211, from ethanol-etn®r. The chromatography was with 0.5% isopropylamine in MeOtBu.

Resolution of enantiomera Example 167 (R)-(+)-4,5-Dihydro-4-methy1-1—phenyl-3-(2-phenylethyl)- 1H-2,4-benzodiazepine To a 1 L Erlenmeyer flask was added 100 mL of methanol, 200 mL of water and 49.8 g (0.133 mol) of the racemic hydrochloride salt of Example 25. The solution was stirred for ten minutes, then 200 mL of t-butylmethyl ether (TBME) added to the homogeneous solution followed by 220 mL (0.66 mol, 5.0 eq) of 3N sodium hydroxide. The mixture was stirred for 10 minutes. The layers were separated and the aqueous layer extracted with 100 mL of saturated sodium chloride. The organic layer was dried over magnesium sulfate* filtered and the solvent removed under reduced pressure vt 30°C to give a quantitative yield of free base. The viscous golden-brown oil was placed on a vacuum pump at 0.5 mmHg for 1 hour.

The free base was dissolved into 40 mL of methanol with slight warming. The solution was transferred to a 500 mL 3 neck flask equipped with mechanical stirrer and condenser. The transfer was completed by rinsing with an additional 20 mL of methanol. The methanol solution was warmed to 45°C with an external temperature-controlled water bath.

To a 250 mL beaker was added 40.4 g (0.113 mol, 0.85 eq) of D-0,0'-dibenzoyltartaric acid and 40 mL of methanol. (Slight warming may be necessary to get chiral acid into solution.) The methanol solution of the chiral acid was added slowly with constant stirring to the 280544 D.N. 2510A - 96 " solution of free base. The resulting mixture became a very light green color. An additional 20 mL of methanol was used for rinsing to complete the transfer. After stirring 5 minutes, the solution was seeded. The product 5 began to precipitate immediately. The solution was stirred overnight at 45°C. The granular, white precipitate was collected on a Buchner funnel, washed 3 x 25 mL with cold methanol (5°C) and dried overnight at 60°C under reduced pressure.

The dried dibenzoyltartrate salt weighed 40.9 g (88%) after correcting for the quantity of seed crystal; (cc]d25 = +192. (c=l, methanol); mp 143-145°C dec.

The hydrochloride salt may be made by the following procedure: The free base from 100 g (0.143 mol) of dibenzoyltartrate salt was prepared as above. The free base was dissolved into 300 mL of ethyl acetate. The solution was transferred to a 2-liter 3-neck flask equipped with mechanical stirrer, condenser and additional 20 funnel. The transfer was completed by rinsing with an additional 300 mL of ethyl acetate. The ethyl acetate solution was warmed to 45°C with a temperature-controlled water bath.

To the warmed ethyl acetate solution of the free base 25 was slowly added 69 mL of a 2.3N hydrogen chloride/ethyl acetate solution. The addition of the acid was completed over a 0.5 h period, followed by stirring at 45°C for 1 hour. The ethyl acetate suspension of.the resulting hydrochloride salt was refluxed for 1 hour to eliminate 30 the excess hydrogen chloride present in the solvent and cooled to ambient temperature. The flocculent white' precipitate was collected on a Buchner funnel and washed 3 x 150 mL with ethyl acetate. The product was dried overnight at 80°C under reduced pressure. 28054 D.N. 2510A The dried hydrochloride salt weighed 50.9 g, [cx)d25 13 +234° (c»l, methanol); mp 197-199°C.

Rxamplft 168 (S)-(-)-4,5-Dihydro-4-methyl-l-phenyl-3- (2-phenylethyl)-5 1H-2,4-benzodiazepine The mother liquors from cyrstallization in Example 167 were stripped and the free base liberated as before using tBuOMe and aqueous NaOH. The free base was dissolved in 100 mL of methanol, treated with 34.3 g of 10 dibenzoyl-L-tartaric acid and seeded. There was obtained 37.2 g of the diastereomeric salt of the (-) isomer, mp 160-170, [a]D25 -198° (C-1, MeOH) . The free base was generated as above, and the HCl salt was formed and recrystallized from acetonitrile/ether, mp 198-199, 15 [a]D25 - -24$i° (C-1, CHCI3) .

Example 169 (+)-4,5-Dihydro-l-pbenyl-l,3,4-trimethyl-lH-2,4- benzodiazepine By a process analogous to that of Example 167 20 involving multiple recrystallizations, 1.4 g of (+)-4,5- dihydro-l-phenyl-1,3,4-trimethyl-lH-2,4-benzodiazepine was obtained from 8.9 g (33.7 mmol) of the racemic product of Example 96 and 12.7 g (33.7 mmol) of dibenzoyl-L-tartaric acid hydrate. The free base was obtained, without 25 recrystallization, by stripping the tBuOMe, mp 115-116, [a]D25 - +101° (C-1, MeOH). 280544 D.N. 2510A Example 17Q (-)-4,5-Dihydro-l-phenyl-l, 3, 4-trimethyl-lH-2, 4- benzodiazepine By a process analogous to that of Example 168, 1.9 g of (-)-4,5-dihydro-l-phenyl-l,3,4-trimethyl-lH-2,4-benzodiazep-ine was obtained from the mother liquors of Example 169, mp 116-117, la]D25 - -93° (C-1, MeOH).

Example 171 (R)-(+)-4,5-Dihydro-3-ethyl-4-methyl-l-phenyl-lH-2,4- benzodiazepine By a process analogous to that of Example 167, 7.5 g of R-(+)-4,5-dihydro-3-ethyl-4-methyl-l-phenyl-lH-2,4-benzodiazepine was obtained from 92 g of the free base of the racemic product of Example 8, after repeated crystallization. The hydrochloride salt was obtained from ethanol/ether, mp 244-247, [a]D25 - +347° (C-1, CHCI3).

The d-10-camphorsulfonic acid salt was obtained from acetonitrile, mp 215-218, [a]D25 - + 203° (C-1, MeOH), (a]D25 - +242° (C-1, CHCI3).

Example 172 (S-) (-) -4,5-Dihydro-3-'jthyl-4-methyl-l-phenyl-lH-2, 4- benzodiazepine By a process analogous to that of Example 168, 15 g of the levo enantiomer was obtained from the mother liquors of Example 171. The product was crystallized as the hydrochloride from ethanol/ether, mp 247-249, s -343° (C-1, CHCI3). 280544 D.N. 2510A - 99" Example 173 (S) - (-) 4,5-Dihydro-3-ethyl-4-methyl-l-phenyl-1H-2,4-benzodiazepine The following procedure describes an alternate synthesis of the compound of Example 172: Two qranis (6.3 mmol) of the monohydrochloride of (S)-N-t[[2-(methylamino)methyl]phenyl]phenylmethyl]propanamide (Example 181) was stirred in 15 mL of toluene under nitrogen arid 3.45 mL of 2M trimethy.l aluminum in toluene was added at 0°. The mixture was stirred two hours at room temperature, then 1.5 hours at reflux. The reaction was coolod and quenched with 0.31 mL of water followed by 0.93 mL of 30% aqueous NaOH. Methylene chloride, a small amount of methanol and some sodium sulfate were added, the mixture was filtered, stripped and the residue recrystallized from MeOH/ether as the hydrochloride, mp 247-248.

Example 174 2-[ [ (1,l-Dimethylethyl)amino]methyl]-a-phenylbenzenemethanamine (Formula IV: Rla, R6 = H, R2a - tBu; R5a - Ph) A solution of 15.9 g (90 mmol) of N-t-butylbenzamide in 390 mL of HF was cooled to -15° under nitrogen and 77 mL (193 mmol) of ?.5N n-butyllithium in hexane was added. The mixture was stirred at -5 ± 3° for one hour and 17.5 g (99 mmol) of the trimethylsilylimine of benzaldehyde [prepared according to the procedure of Hart et al., il. Org. Chem. 48r 289-294 (1983)] was added over ten minutes at -10°. The reaction was stirred at 0° for one hour, then 5° for 45 minutes. It was poured into 400 mL of ice water containing 225 mL of 2N HCl and washed twice with ether. The aqueous layer was made basic with sodium hydroxide and extracted into ether. The ether extracts were dried over 280544 D.N. 2510A sodium sulfate and stripped to yield 25.4 g of 2-[(amino)(phenyl)methyl]-N-(1,1-dimethyl-ethyl)benzamide.

The entire portion of aminoamide in 50 mL of THF was combined with 450 mL (4 50 mmol) of IN borane-THF complex 5 and the mixture stirred at reflux for 18 hours. The reaction was cooled, 225 mL of methanol was added, and the solution was refluxed for one hour. It was recooled and 200 mL of half-saturated methanolic HCl was added. The solution was again refluxed for one hour, evaporated in 10 vacuo and the residue recrystallized from chloroform/ether to yield 21.3 g (70%) of product as the dihydrochloride, mp 222-231.

Example 175 2-(Aminomethyl)-N-methyl-a-phenylbenzenemethanamine 15 (Formula IV: Rla - Ph; R2a - Me; R5a, R6 - H) Seventy-five grams (0.36 mole) of 2-benzoylbenzaldehyde was dissolved in 70 mL of THF and 18.5 g (0.39 moles) of methylhydrazine was added over 30 minutes at 0°. Th'3 suspension became a homogeneous solution which was allowed to stand for four days. A • first portion comprising 8.5 g of product was obtained by addition of hexme and filtration. A second portion of 27.5 g of product was obtained by chromatography on silica gel with 85:15 methylene chloride/ethyl acetate. The mp 25 of the hydrazone after recrystallization from methylene chloride-hexane was 164-165.

A solution of 44.5 g of the methylhydrazone in 80 mL of THF was treated with 374 mL of 1 M borane-THF and stirred at reflux. After 24 hours and 72 hours, 30 additional 187 mL portions of 1 M borane were added.

After six days the reaction was worked up as described in Example 164 and the dihydrochloride recrystallized from methanol ether, mp 224-226. 280544 D.N. 2510A 2-(Aminomethyl)-a-phenyl-N-(phenylmethyl)benzene- methanamine (Formula IV: Rla - Ph; R2a = Bzl; R5a, R5 = H) 5 Sixty-two grams (0 30 mole) of 2-benzoylbenzaldehyde in 140 mL of THF was treated with 81.5 g (0.59 mole) of potassium carbonate and 64 g (0.32 mole) of benzylhydrazine dihydrochloride. The mixture was stirred 30 minutes at 0° and 40 mL of methylene dichloride was added. The mixture was stirred at room temperature for one day, filtered and stripped in vacuo to provide 131 g of 2-benzyl-l-phenyl phthalazinium chloride.

The crude phthalazinium chloride in 175 mL of THF was treated with 1.325 L of 1 M borane-THF at reflux under 15 nitrogen. After 24 hours the reaction was worked up as described in Example 175 and the dihydrochloride salt was formed by precipitation from ether with ethereal HCl to provide 36.8 g of dihydrochloride of the product, mp 175-178.

Example 27 0 N-Methyl-a'-phenyl-2,3-thiophenedimethanamine (Formula XXXI: Rla - H; R2b = Me; RSa - Ph Following the procedure of General Method T, 19 g of N-methyl-a'-phenyl-2,3-thiophenedimethanamine was prepared 25 from 32.6 g (0.135 mol) of br7-dihydro-6-methyl-7-oxo-4-phenylthieno[2,3-d]pyridazine. The product was recrystallized as its dihydrochloride from ethanol-water, mp 290-292. 28054 D.N. 2510A - 102 -Example 279 2-(Amino)phenylmethyl-N-methylbenzeneethanamine (Formula XXXII: R2b - Me, RSd - Ph, R6a - H) By General Method T, 25.8 g (0.103 mol) of 4,5-dihydro-3-methyl-l-phenyl-2, 3-benzodiazepin-<!-one was reduced to yield 18.6 g of 2-(amino)phenylmethyl-N-methylbenzeneethanamine as its dihydrochloride salt, mp 257-258 from methanol-ether.

TABLE K Exjmplc No. all B5a Source 177 178 179 180 He He He Me CH2CH2Ph Ph CHjCHjPh -(>1 CH20-(>C1 Ph Ph General Method U benzodiazepine from Ex. 25 alunlna chromatography of Ex. 63 hexane/CH2CH2 80:20 silica gel chrooatography of Ex. 76 MeOtBu/hexane/lPrNH2 85>10>5 alllca gel chromatography of Ex. 39 toluene/hexane/lPrNHj 50:49■1 181 He Et Ph General Hethod 0 benzodiazepine of Ex. 8 182 He Ph Ph silica gel chrooatography of Ex. 1 0.751 lPrStt2 in tBuOMe 183 ll'r He Ph from recrystallization ln EtOAc/hexane of Ex. 23 184 CU2CH2NEt2 Et Ph silica gel chromatography of Ex. 50 CHCl3/Et3N 96.4 Yield Melting Salt/Solvate Recrystallization X Range From 96 110-123 HCl CH2CH2/ether (amorphous) 274-275 ' HCl EtOH/ether 12 134-136 1.5 fuaarate MeOH/ether u> 26 178-179 HCl EtOH/ether 89 206-208 HCl MeOH/ether 8 132-133 free base CH2Cl2/tBuOMe/ hexane 4 116-117 free b«6C EtOAc/hcxanc 2 viscous free base liquid O •z to ui o > ro Ol TABLE H Example No.

R9 ill r5« Source Yield Melting Salt/Solvate Recrystallization t Range Fron 208 209 Ph ChjCl^Ph Me silica gel chromatography of Ex. 235 34 137-138 free base MeOtBu/hexane MeOcBu/hexane It1 Me CU2CII2-/0VMHSO2CU3 Phe crystallized froa free base of Ex. 34 224-228 —' in toluene HCl EtOH/ether O -p- 273 NHBzl NHCO(CH2)2CH3 silica gel chrooatography at Ex. 70 C82C12/EtOAc/dlethylaaine (49.50.1) 116-119 HCl a z ro cn 1—» o > 28054 D.N. 2510A Examples 177-18,4,208.20,9. 273.

Aminoamides of formula III Rla III were obtained as by-products of the synthesis of the 5 corresponding benzodiazepines and were usually isolated via chromatography on silica gel using basic elution solvents. They were also obtained by hydrolysis of the corresponding benzodiazepines as described in General Method U. Examples are given in Table H General Method U A solution of the appropriate benzodiazepine in 3 to 5 mL of methanol per millimole of diazepine was stirred at room temperature for 1 to 4 days with 3 to 5 equivalents of potassium hydroxide in 1 to 2 mL of water per millimole 15 of diazepine. Aqueous sodium chloride was added and the aminoamide was extracted into ether. The ether layer was dried over MgSO^ filtered, stripped and the residue was treated as shown in Table H. It is anticipated that any species described in Tables A through E could be converted 20 to the corresponding aminoamide by this procedure.

• • TftBLE L Reduction of NO2 to NH2 in compound of formula: ,ch3 b /~(CH2)BXn Position Example No.

Rs X n Of N02 —>NH2 m Hathod Yield i Melting Ranqe Salt Recrystallized fron 250 Ph CH-CH 1 c 0 V 58 234-237 2HC1 MeOH/ether 251 Ph 0 •1 0 V 81 314-315 2 HCl HeOH/echer 252 Ph 0 a 2 V 77 209-211 2HC1 MeOH/ether 1—* 253 Ph 0 b 2 H 92 215-228 2HC1 HeOH/ether O O* 254 -Q-ci 0 d 2 W 80 290-291 2NC1 MeOH/ether t 255 Ph 0 d 2 H 86 173-175 HCl.1/4 EtOH EtOH/ethe: 256 Ph CH-CH 1 d 0 V 212-21S* 2HC1 HeCn/ethcr *4.1 trans/cls O Z ro cn H* o > ro 01 280544 D.N. 2510A - 107 " General Method V The appropriate nitro compound, as its salt, usually the fumarate salt, was dissolved in about 10 mL of dry methanol per millimole of nitro compound and 0.1 to 0.15 g 5 of 10% Pd on carbon was added per millimole of nitro compound- The reaction was stirred at 18-24° and 7.5 to 8.0 equivalents of ammonium formate was added. After 1-2 hours the reaction was filtered, stripped, distributed between methylene chloride and 2N NaOH, separated, dried 10 and stripped. The residue was crystallized as shown in Table L.

General Method W The appropriate nitro compound, as its hydrochloride salt or the free base plus one equivalent of methanolic 15 HCl, was dissolved in about 20 mL of methanol or ethanol per millimole of nitro compound and about 0.05 to 0.1 g of 10% Pd on carbon was added per millimole of nitro compound. The mixture was hydrogenated at 3.5 to 1.4 atm on a Parr shaker. When the calculated amount of hydrogen 20 had been consumed, the reaction was filtered, excess ethereal HCl was added, and the solution was stripped. The residue was crystallized as shown in Table L.

Example 274 4-[2-(4,5-Dihydro-3-ethyl-lH-2, 4-benzodiazepin-4-yl) 25 ethyl]benzeneamine (Formula I: R1, R4, R6 » H; R2 = CH2CH2 R3 - Et; P5 = Ph By General Method W, 4.50 g (10.3 mmol) of 4,5-dihydro-3-ethyl-4-[2-(4-nitrophenyl)ethyl]-1H-2,4-30 benzodiazepine hydrochloride of Example 27 6 was reduced to 3.33 g of 4[2-(4,5-dihydro-3-ethyl-lH-2,4-benzodiazepin-4- 28054 D.N. 2510A yl)ethyl]benzeneamine as its monohydrochloride, mp 14 9-151 from EtOH-ether.

NO. 257 258 259 260 261 262 263 261 TABLE M Acylation and Sulfonylation of Amines of Formula: R5 m X n Position of nh2 Product Method Yield % Melting Ranee Salt Recrystallized from Ph 0 CH-CH 1 d nhs02cu3 X 82 274-276 HCl EtOH/ether Ph 0 ch-cfl 1 c nhso2ch3 X 60 297-298 HCl MeOH/ether Ph 0 CH-CH 1 d NHCOCH3 X 62 174-190 HC1.2H20 EtOH/H20 Ph 0 0 d NHSOjCHJ X 53 283-284 HCl MeOH/ether Ph 0 0 d NHCOCH3 X 76 >300 HCl MeOH/ether Ph 2 0 d NHS02CH3 X 87 153-159 HCl.EtOH EtOH/ether Ph 2 0 a nhso2ch3 x 75 170-182 HCl MeCN/ether D-ci 2 0 d NHSOjCHJ X 93 168-112 HCl MeOH/ether 28054 D.N. 2510A General,Method X A solution of the appropriate amine as its dihydrochloride and from 3 equivalents of pyridine to 30 equivalents of pyridine were stirred at 0° in about 10 mL of methylene chloride per millimole of amine under a nitrogen atmosphere while 1.1 to 1.5 equivalents of methanesulfonyl chloride or acetyl chloride was added dropwise. The reaction was stirred at 0° for 1-2 hours and one volume of saturated aqueou3 Na2C03 was added. In a few 10 cases where TLC showed incomplete reaction, an additional 1 to 3 equivalents of chloride was added before the Na2CC>3 solution. The layers were separated and the organic layer was stripped. The residue was flash chromatographed, if necessary, on silica gel eluting with 15 MeOH/MeOtBu/isopropylamine 49:49:2. The product was recrystallized as shown in Table M.

Example 275 N-[4-[2-(4,5-Dihydro-3-ethyl-lH-2,4-benzodiazepin-4-yl) ethyl]phenyl]methanesulfonamide 20 (Formula I : R1, R4, R6 - H; R2 - CH2CH2 -^Qy-NHS02CH3; R3 «= Et; R5 - Ph) By General Method X, 3.25 g of 4-[2-(4,5-dihydro-3-ethyl-lH-2,4-benzodiazepin-4~yl)ethyl]benzeneamine of Example 274 was converted to 3.49 g of N—[4-[2- (4,5-25 dihydro-3-ethyl-lH-2,4-benzodiazepin-4-yl)ethyl]phenyl]- methanesulfonamide, mp 129-142 as the free base from EtOH-ether-methylene chloride. 280544 D.M. 2510A - Ill - Starting Materials The phthalazinones, which are the starting materials for the synthesis of diamines described in Table G, are generally available by methods known in the literature. 5 They are most commonly synthesized by condensation of the corresponding y-ketoacids with the appropriate hydrazine.

For example, Example 185 2-Methyl-4-phenyl-l(2H)-phthalazinone 10 A 100 gallon stainless steel unit was charged with 40.0 kg of 2-benzoylbenzoic acid and 87.5 kg of toluene. Methylhydrazine was added over about 45 minutes with the internal temperature rising to 34°.

The resulting thin slurry was warmed at reflux (95-15 118°) for 4 1/2 hours while collecting about 7.5 L of water.

The reaction mixture was cooled slowly with initial precipitation evident at 88°. The resulting slurry was cooled to 0 to -5° before collecting the beige colored crystals. the cake was washed with 2 x '20 L of cold toluene and dried in vacuo at 45-50° overnight to afford 38.0 kg (91.0% yield) 2-methyl-4-phenyl-l(2H)-phthalazinone, mp 166-168.

Example 271 6,7-Dihydro-6-methyl-7-oxo-4-phenylthieno[2, 3-d] pyridazine A solution of 31.2 g (0.134 mol) of 3-benzoyl-2-thiophenecarboxylic acid in 400 mL of ethanol was treated 30 with 9.3 (0.2 mol) of methylhydrazine at room temperature for 18 hours, refluxed 3 hours, cooled and 30.7 g of the product filtered off, mp 174-175. 280544 D.N. 2510A The 3-benzoyl-2-thiophene carboxylic acid was obtained from 3-bromothiophene by the method of MacDowell and Ballas [j;. Org. Chem. £2., 3717 (1977) .] In thy cases where the appropriate alkylhydrazine for 5 the condensation to the phthalazinone is not readily available, the y-ketoacid is condensed with hydrazine and the resulting 2-unsubstituted 1-phthalazinone is alkylated. For example/ Example 166 4-Phenyl-2-(2-phenylethyl)-1(2H)-phthalazinone Eighty-five grams (0.38 moles) of 4-phenyl-l(2H)-phthalazinone was added to 18.4 g (0.47 moles) of sodium hydride in 1L of DMSO in four portions. The mixture was stirred for two hours at room temperature until evolution 15 of hydrogen had ceased, and 95.5 g (0.52 moles) of 2- bromoethylbenzene was added. The mixture was stirred 1.5 hours at room temperature, 1 L of 2N NaOH was added and the slurry was poured into 1 L of water. The product was filtered off and dried to yield 118 g (95%) of 4-phenyl-2-20 (2-phenylethyl)-1(2H)—phthalazinone, mp 135-138.

Example 278 2-[2-(4-Nitrophenyl)ethyl]-4-phenyl-l(2H)-phthalazinone (Formula VIII: R2 » CH2CH2-^O^-N02, R5 =» Ph, R6 » H) By a procedure analogous to that of Example 186, 11.8 g of 2-[2-(4-nitrophenyl)ethyl]-4-phenyl-l(2H)-phthalazinone was prepared from 10.0 g (45 mmol) of 4-phenyl-1(2H)-phthalazinone and 11.6 g (50 mmol) of 4-nitrophenethyl bromide. The product was recrystallized 30 from EtOAc-ether-hexane, mp 152-155°. 28054 D.N. 2510A Synthesis of Esters of the formula RaCH-CH-COOEt and R8CH2CH2COOEt wherein R®is heteroaryl 5 In those cases where the appropriate propanoate and propenoate esters were not commercially available, the propenoate was synthesized by condensation of ethyl acetate with the appropriate aldehyde in the presence of rue equivalent of sodium metal. .The unsaturated esters 10 were reduced with a large excess of .i.agnesium metal in methanol to provide the propanoates.

Miscellaneous syntheses of diamines, phthalazines, and precursors are shown below: Example 131 4-Benzyl-2-methyl-l(2H)-phthalazinone A solution of 30 g of potassium hydroxide and 31.3 g (140 mmol) of benzylidenephthalide in 100 mL of water was heated to homogeneity and poured into a solution of 40 mL of H2SO4 in 250 mL of water. After cooling, the resulting solid was collected and dissolved in aqueous sodium bicarbonate. 2N HCl was added until the first signs of precipitation, the aqueous solution was washed four times with chloroform and then acidified with excess 2N HCl. A white precipitate of 20.3 g of 2-(l-oxo-2-phenyl-25 ethyl)benzoic acid was filtered off and dried, mp 74-75, after recrystallization from ethanol water. This Y~ ketoacid was treated with methylhydrazine according to the method of Example 185 to yield 17.3 g of the phthalazinone product, mp 14 4-14 6. 280544 D.N. 2510A Example 188 2-Methyl-4-thienyl-l(2H)-phthalazinone A solution of 74.1 g (0.5 mole) of phthalic anhydride in 300 mL of nitrobenzene was treated with 147 g (1.1' I mole) of aluminum chloride. The solution was stirred for two hours and 42.1 g (0.5 mole) of thiophene was added dropwise over 80 minutes at 40-45°. The reaction was stirred at 50-55° for two hours and then let sit at room temperature overnight. The reaction was poured into 2.8 L l0 of cold water, stirred, separated, and the nitrobenzene was removed from the nitrobenzene layer by steam distillation. The residue was recrystallized from toluene to provide 31.1 g (27%) of 2-thienoylbenzoic acid, mp 141-143. The thienoylbenzoic acid was treated with 15 methylhydrazine as described in Example 185 to provide 24.4 g (75%) of the phthalazinone product, mp 143-144, after recrystallization from ethyl acetate.

Example 18 9 -Fluoro-3,4-dihydro-3-methyl-l-phenylphthalazine 20 To a solution of 20 g (0.14 mole) of 2-fluoro-6- chloro-toluene in 125 mL of THF was added 6.9 g (0.28 mole) of magnesium turnings. The mixture was refluxed while 12 mL of 1,2-dibromoethane in 50 mL of benzene was added dropwise over three hours. The reaction was 25 refluxed a further hour and 15 mL of benzonitrile was added. The reaction was refluxed a further two hours, cooled and quenched with 50 mL of water added dropwise. The mixture was extracted into ethyl acetate, dried over sodium sulfate and stripped. The residue was dissolved in 30 50 mL of ethanol, 25 mL of IN HCl was added, and the mixture was refluxed for three hours. The ethanol was stripped, the product was extracted into ethyl acetate, the ethyl acetate dried over sodium sulfate and stripped. 28054 D.N. 2510A - 115 " The residue of 3-fluoro-2-methyl-benzophenone was chromatographed on silica gel with 20% ether in hexane.

A solution of 1.69 g (7.89 nunol) of the benzophenone in 40 mL of carbon tetrachloride was treated with 100 mg 5 of benzoyl peroxide and 1.5 g (8.43 mmol) of N- bromosuccinimide. The reaction was stirred at room temperature for two hovirs and then refluxed an additional four hours during which a second portion of 50 mg of benzoyl peroxide and 400 mg of N-bromosuccinimide were 10 added. The reaction was cooled, a small amount of impurity filtered off, and the filtrate concentrated In vacuo to provide 2.5 g of 2-bromomethyl-3-fluorobenzophenone, presumably containing trapped carbon tetrachloride.

The residue of <*-!.>romr nethylketone was dissolved in 40 mL of chloroform and i i tcture of 1.5 mL of triethylamine and one equivalent of methylhydrazine was added dropwise. The reaction was stirred one hour, washed with 20 mL of aqueous sodium bicarbonate and filtered 20 directly through silica gel eluting with 25% ethyl acetate in hexane. Concentration An vacuo gave 1.86 g (98%) of product which was reduced immediately as shown in Table G.

Example 190 2-Benzoyl-5-fluorobenzoic acid 25 Following the procedure of Example 189, 4.0 g (21.2 mmol) of 2-bromo-5~fluoro toluene was treated with 2.4 mL (23.5 mmol) of benzonitrile. The imine resulting from the conden3< ior . not hydrolyzed. Instead 28.6 g (0.13 mole) of 4-'- o-2-methyl-benzophenoneimine in 200 mL of 30 water and ".00 ml. of pyridine was refluxed for eight hours and treated with four portions of potassium permanganate a ou.: .wo-hour intervals. The portions were 53 g, 28 g, ZL> g, and 1C g. The roaction was coolad, filtered 280544 D.N. 2510A - L16 - through diatomaceous earth and concentrated An vacuo. The residue was distributed between aqueous acetic acid and ethyl acetate, the ethyl acetate was dried over magnesium sulfate, and the ethyl acetate was removed An vacuo to provide 16.2 g (51%) of a yellow gum which was used as is.

Example 191 2-Benzoyl-4-fluorobenzoic acid The procedure of Example 190 was used to provide 14.2 g (53%) of product from 21.3 g of 2-bromo-4-fluorotoluene.

Example 192 3,4-dihydro-3-methyl-l-phenylbenzo[f]phthalazine A solution of 10 g (45 mmol) of l-bromo-2-methyl-naphthalene in 75 mL of THF was refluxed with 1.2 g (50 mmol) of magnesium turnings for three hours. The reaction was cooled on ice and 4.8 mL (43 mmol) of benzaldehyde was added. The ice was removed, the reaction was stirred 45 minutes and quenched with 5 mL of IN HCl followed by 50 mL of water. The reaction was extracted into ethyl acetate, dried over sodium sulfate and flash chromatographed through silica gel with 5-10% ethyl acetate in hexane to provide 8.4 g (75%) of 2-methyl-a-phenyl-l-naphtha-lenemethanol as a pale yellow gum.

A solution of 10.0 g (40 mmol) of the secondary alcohol in dichloromethane was treated with 12.4 g (58 mmol) of pyridine chlorochromate, refluxed briefly, and stirred at room temperature for one hour. The reaction was diluted with 150 mL of ether and filtered through florisil. Concentration of the filtrate in vacuo afforded 7.92 g (80%) of l-benzoyl-2-methylnaphthalene as a bright orange gum which slowly crystallized on standing.

By the procedure described in Example 189, 4.4 g (18 mmol) of the benzoylnaphthalene was converted to 1.73 g of 280544 D.N. 2510A the phthalazine product, which was reduced immediately as shown in Table G. 3,4-Dihydro-3,8-dimethyl-l-phenylphthalazine 5 By a procedure exactly analagous to that of Example 192, the phthalazine was synthesized from 2-bromo-m-xylene.

Example 194 2-Aminomethyl-a-phenylbenzenemethanamine To a slurry of 3.8 g (100 mmol) of lithium aluminium hydride in 120 mL of THF was added 11.1 g (50 mmol) of 4-pheny1-1(2H)phthalazinone. The mixture was refluxed one hour, cooled, diluted with 100 mL of ether and sequentially treated with 3.8 mL of water, 3.8 mL of 15% 15 aqueous sodium hydroxide and 11.4 mL of water. The mixture was stirred for 30 minutes and the granular precipitate filtered off. The filtrate was diluted with a little toluene, dried over sodium sulfate and stripped to provide 14.1 g of an oil which was dissolved in 180 mL of 20 ethanol and hydrogenated at 50 psi in the presence of 20 mL of ethanolic HCl and 1.5g of 10% palladium on carbon. After 24 hours a precipi-tate had formed. The reaction was filtered, the precipitate was slurried in 250 mL of hot methanol and filtered again. The combined filtrates 25 were stripped to about 100 mL and diluted with ether. On cooling, 7.3 g of 1,2,3,4-tetrahydro-l-phenylphthalazine as the monohydrochloride salt was filtered off. It was recrystallized from methanol/ether to provide 6.93 g (56%) of product, mp 251-253.

The tetrahydrophthalazine was redissolved in 200 mL of methanol by warming and hydrogenated at 50 psi at 66° for 20 hours in the presence of 3.5 g of Raney nickel 28054 D.N. 2510A - Uft " catalyst. The catalyst was filtered off and the filtrate stripped. The residue was recrystallized from methanol/ether to provide 99% yield of the diamine dihydrochloride salt, mp 270-273.

Example 195 2-(4-Methoxybenzoyl)benzoic acid A mixture of 57 g (0.4 mole) of phthalic anhydride and 43 mL (0.4 mole) of anisole in 400 mL of benzene was treated with 105 g (0.8 mole) of aluminum chloride at 5°. 10 The reaction was kept for five days at 5°, poured into 600 mL of 2N aqueous HCl and ice and filtered. The residue was triturated in aqueous sodium carbonate and filtered repeatedly until the solid no longer contained product. The sodium carbonate extracts were combined, washed with 15 ether, and acidified with 2N aqueous HCl. The product was extracted into ether, dried over sodium sulfate and stripped. It was recrystallized from toluene to provide 80% yield of product, mp 145-147.

Example 196 2-(2-Methoxyethyl)-4-phenyl-l(2H)-phthalazinone Eighty-five grams (0.38 mole) of 2-benzoylbenzoic acid and 28.6 g (0.38 mole) of hydroxyethylhydrazine were reacted according to the procedure of Example 185. The resulting hydroxyethyl-phthalazinone was suspended in 300 25 mL of DMF and 200 mL THF and 12.3 g of 60% sodium hydride in oil was added in portions over 40 minutes under nitrogen. The reaction was stirred an additional 45 minutes at room temperature and the evolution of hydrogen ceased. Thirty-one milliliters of methyl iodide was added 30 over 1.5 hours and the reaction was stirred at gentle reflux for 16 hours. It was poured into water and extracted into ether. The ether layers were dried over 28054 D.N. 2510A ~ HQ " sodium sulfate and stripped. The residue was chromatographed on silica with 5% ethylamine in ethyl acetate to provide 39 g (47%) of product, mp 115-118 after recrystallization from cyclohexane.

Example 197 2-Benzoyl-4,5-dimethoxybenzoic acid Five hundred milliliters of 37% formalin solution was saturated with hydrogen chloride gas at 15-20°C and 70 g (0.38 mole) of veratric acid was added in one portion. 10 The mixture was heated at 60-70° for seven hours and allowed to sit at room temperature for 14 hours. The solution was concentrated in vacuo,, dissolved in about 300 mL of water, cooled and made basic with ammonium hydroxide. The resulting solid was collected by 15 filtration and dried to provide a 65% yield of dimethoxyphthalide.

One hundred eight grams (0.56 mole) of the phthalide was oxidized with 258 grams (1.64 moles) of potassium permanganate according to the procedure of Example 190. 20 Eighty-one grams of the dimethoxyphthalic acid was converted to 72 g of the corresponding dimethoxyphthalic anhydride by heating briefly in 200 mL of acetic anhydride.

Thirty grams (0.14 mole) of 4,5-dimethoxyphthalic 25 anhydride was suspended in 300 mL of THF and 87 mL (0.17 mole) of phenylmagnesium chloride in THF was added over two hours. The reaction was stirred at room temperature for 14 hours, refluxed for two hours, cooled and poured into saturated ammonium chloride. The mixture was made 30 acidic with 6N HCl, extracted into chloroform, dried over magnesium sulfate, concentrated to provide 30 g of 2-benzoyl-4,5-dimetnoxybenzoic acid. 28054 D.N. 2510A 120- Example 272 Methyl 4- (Diethylaminosulfonyl)benzenepropanoate To 14.5 g of N/N-diethyl-4-bromobenzenesulfonamide (50 mmol) (prepared by reaction of 4-bromobenzenesulfonyl 5 chloride with diethylamine) was added 13.8 g of tetrabutylammonium chloride (50 mmol), 10.3 g of NaHC03 (124 mmol), 266 mg of palladium (II) acetate (1.07 mmol) and 100 mL of DMF in the order given. To this suspension was added 8.8 ml of methyl aerylate (98 mmol) and the 10 reaction was stirred 1 hour at 80°. The reaction was cooled, 500 mL of water and 900 mL of ether were added, the layers were separated and the ether layer was filtered to remove Pd (0) and combined with 2 further ether washes of the aqueous phase. The combined ether solutions were 15 dried over MgS<>4, filtered, stripped and recrystallized from methanol/ether to yield 9.4 g of methyl 4-(diethylaminosulfonyl) benzene-2-propenoate. Six grams of the propenoate was reduced in ethanol at 3.5 atm over 10% Pd on carbon in a Parr Shaker to produce 5.9 g of product 20 as a yellow oil. It was used in that form in Example 2 69.

By a procedure analogous to that of Example 41, it is contemplated that 1-[4-(diethylamino)phenyl]-3-ethyl-4-methyl-lH-2,4-benzodiazepine can be synthesized from 2—[4— (diethylamino)benzoyl]benzoic acid (see U.S. Pat. 4,106,174), methylhydrazine, and triethylorthopropionate.

Example 198 1[4-(Diethylamino)phenyl]-3-ethyl-4-methyl-lH-2,4- benzodiazepine (Formula I: R1, R4, R6 = H; R2 = Me; R3 = Et; D.N. 2510A 121 Example 199 3-Methyl-l-[2-[(1-oxopropyl)amino]phenyl]-4-(3- phenylpropyl) -1H-2,4-benzodiazepine (Formula I: R1, R4, R6 =. H; R2 = nBu; R3 = Me; By a procedure analogous to that of Example 41, it is contemplated that 1-(2-aminophenyl)-4-butyl-3-methyl-lH-2, 4-benzodiazepine can be synthesized from 2-(2-aminobenzoyl)-benzoic acid, hydrazine, bromobenzenepropane and triethyl-orthoacetate. It is further contemplated that this product may be acylated by treatment with propionic anhydride at room temperature to produce 3-methyl-1-[2-[(1-oxopropyl)amino]-phenyl]-4-(3-phenylpropyl)-1H-2,4-benzodiazepine.

R5 = NHCOPr 280544 D.N. 2510A Iminoethers (alkoxyimines) R3COR12 -HCl I NH The ethoxy and methoxy imines used for condensation 5 with the diamines were obtained from the corresponding nitriles by methods well known in the art. In general, the nitrile was dissolved in ether, 1.1 equivalents of alkanol was added, 1.1 equivalents of dry HCl gas was bubbled in, and the mixture was held at 5° for 24-48 hours; the hydrochloride salt of the iminoether was recovered by simple filtration.

The trialkylorthoesters were obtained by treating the corresponding iminoether with the appropriate alkanol under conditions known in the art.

The compounds of this invention having formulas XXXVI, XXX, III and XXXVII have antiarrhythmic activity as shown by the results of standard pharmacological tests carried out on representative examples as described below.

Antiarrhythmic activity was demonstrated by a 20 procedure, which is a modification of standard programmed electrophysiological techniques utilized in large animals and in clinical studies in humans. Male Duncan-Hartley guinea pigs (600-800 grams) were anesthetized with sodium pentobarbital (30 mg/kg, i.p.) and artificially ventilated 25 with a Harvard small-animal respirator. A left thoracotomy was performed and a fluid-filled catheter and transducer (Millar Micro-tip, Model 4F, Millar Inst. Inc., Houston, Texas) were inserted through the anterior wall of the left ventricle to monitor left ventricular pressure 30 (LVP). The first derivative of the LVP (dP/dt) was 28054 D.N. 2510A - 123 " obtained from a Grass differentiator (Model 7P20B) and used as an index of contractile function. A lead II EKG along with LVP and dP/dt were continuously recorded or. a Grass polygraph (Model 7B). Rate pressure product (RPP), 5 an index of cardiac work, was calculated using peak systolic LVP and heart rate (HR).

Effective refractory periods (ERP) were evaluated during left ventricular pacing. Grass subcutaneous electrodes were implanted as bipolar ventricular 10 electrodes to deliver stimuli from a Bloom DTU-2 stimulator (Bloom Electronics, Inc., Reading, Pennsylvania) and stimulus isolation unit. Hearts were stimulated at the slowest frequency allowing consistent pacing (SI, 240-300 bpm) using 2 ms pulses at twice 15 diastolic threshold. Threshold was determined by increasing the stimulation voltage until a 1:1 capture of the ventricular response with the stimulus was observed. A train of 8 normal pulses was delivered followed by a premature (S2) pulse. The interval between the last SI 20 and the premature S2 pulse was reduced in 10-ms increments until a ventricular response was not initiated. The longest S1-S2 interval that failed to produce a ventricular response was defined as the ERP. Pacing stimuli and the EKG were displayed at a sampling frequency 25 of 92 Hz on an Apple lie microcomputer using a two-channel 8-bit A/D converter (R.C. Electronics, Compu-Scope APL-D2, Santa Barbara, California).

Baseline hemodynamic function was evaluated followed by ventricular pacing to determine ERP. Pacing was 30 discontinued prior to drug administration and resumed at set intervals during the protocol to evaluate ERP. Test compounds were administered (1 mL/kg) via the left ventricular catheter over a 15-second interval for doses less than 10 mg/kg. Higher doses (>10 mg/kg) were slowly 28054 D.N. 25lOA - 124 " infused over a 1-minute interval. Doses were cumulatively increased every 15 minutes until a maximally tolerated dose which reduced dP/dt by 50% was noted. Ten minutes after each dose, hemodynamics and ERP were reevaluated. 5 Data were analyzed using an analysis of variance for repeated measures of raw data and are expressed as means. An effective dose to increase ERP by a minimum of 20 msecs (ED2o)r which was consistently a statistically significant increase, was derived for each animal from a linear 10 regression of the data and expressed as a mean for the treated population. Biological significance was established at a probability of error less than 0.05. The results are presented in Table N. 280544 D.N. 25lOA ED20 ED20 EXAMPLE (mg/kg) EXAMPLE (mq/kq) 1 0.31 48 2.20 2 1.17 49 1.36 4 0.20 50 0.50 1.0-1.2 51 0.52 7 0.72-0.91 52 0.18 8 0.4-2.5 53 0.15 8B 0.32-0.42 54 0.23 8C 0.31 55 0.25 8D 0.16 56 0.09 8E 0.93 57 0.14 9 0.50 58 0.10 0.44 59 0.02-0.1 11 0.14-0.39 60 0.13 12 0.08 61 0.05 13 0.14 62 1.4-1.74 14 0.13 63 0.20 16 0.53 64 0.39-1.2 17 0.52-1.29 65 0.48-0.95 18 0.25-0.44 66 0.40 19 0.57 67 0.2-0.4 0.40 68 NE* 21 0.35 69 0.54 22 0.23 70 0.71 23 0.21 72 0.57 24 0.15 74 0.43 0.04-0.2 75 0.41 2 6 1.97 7 6 0.42 27 0.99 77 0.25 28 0.65 78 0.15 29 0.43 80 0.04 0.28 81 0.41 31 4.40 82 0.29 32 0.28 84 0.39 34 0.17 85 0.93 0.11 86 0.28 37 1.27 87 NE* 39 0.22 88 0.08 40 0.10 89 0.08 41 0.35 90 0.47 42 0.34 91 0.35 43 0.17 92 0.22 44 0.24 93 0.28 45 0.60 94 0.56 46 0.60 95 0.16-0.66 47 0.41 96 0.76-0.83 28054 D.N. 2510A - 126 -TABLE N EXAMPLE ED20 (mcr/kq) EXAMPLE ED20 (mq/kq) 97 2.49 165 0.19 98 0.42 166 0.36 99 0.80 167 0.01-0.05 100 0.57 168 0.02-0.15 101 0.32 169 0.17 102 0.04-0.18 170 NE* 103 0.18 171 0.03-1.0 104 0.27-1.87 176 0.81 105 0.26 177 2.63 106 0.30 179 1.66 107 0.4-0.81 180 0.18 108 0.16 181 0.84-5.7 109 2.40 182 1.14 112 0.38-2.32 183 .50 113 0.27 184 1.14 114 0.53 200 0.20 115 0.14 201 0.06 116 0.10 202 0.70 117 0.30 203 0.08 118 0 .15 204 0 .003 119 0.34 205 0.10 120 0.88 6 0.07 121 0.29-0.60 9 0.16 122 0.08 210 0.80 123 0.34 211 0.04 125 29.9 212 0.05 129 2.12 213 0.20 130 0.66 214 0.10 131 0.50 215 0.03 133 NE* 216 0.06 134 1.00 217 0.10 143 1.40 218 170.00 149 0.23 219 0.40 150 1.10-1.18 220 0.40 151 1.70 223 0.20 153 0.70 224 0.40 155 0.18 225 0. 60 156 2.00 226 0.10 157 1.7-3.2 227 0.20 159 4 .39 228 0.50 160 NE* 229 0.07 161 0 .38-1.94 230 0.20 162 0.80 232 0.02 163 0.15 235 0.20 164 0.12-0.45 236 0.40 28054 D.N. 2510A - 127 -TABLE N ED20 ED20 EXAMPLE (:nq/kcr) EXAMPLE (mq/kq) 237 0.20 262 0.07 238 0.30 263 0.16 239 0 .08 266 0.20 240 0 .20 267 0.10 241 0 .04 268 0.50 243 0 .07 273 434.00 244 0 .28 280 0. 65 249 0.05 281 0.20 250 0.10 282 .00 251 0 .11 283 0.10 257 1.00 284 1.10 259 0.17 285 0.10 260 0.19 286 0. 55 261 0.17 The compounds of the invention can be prepared for use by conventional pharmaceutical procedures: that is, by dissolving or suspending them or their pharmaceutical^ acceptable salts in a pharmaceutically acceptable vehicle, 5 e.g., water, aqueous alcohol, glycol, oil solution or oil-water emulsion, for parenteral or oral administration; or by incorporating them in unit dosage form as capsules or tablets for oral administration either alone or in combination with conventional adjuvants or excipients, 10 e.g., calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like.

The percentage of active component in the composition and method for treating or preventing arrhythmia can be varied so that a suitable dosage is obtained. The dosage 15 administered to a particular patient is variable depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the 280544 D.N. 2510A - 128 " size and condition of the patient, the potency of the active component, and the patient's response thereto. An effective dosage amount of active component can thus be determined by the clinician considering all criteria and utilizing his best judgement on the patient's behalf.

HS08Z

Claims (25)

1. WHAT WE CLAIM IS: !• A compound of formula D.N. 2510A if — ) NHR9 _plO NHC- <CH2)n-R II wherein Rla is hydrogen, lower-alkyl or phenyl; R5a is hydrogen; phenyl; phenyl having one or 5 two substituents chosen from the group consisting of halogen, lower-alkyl and lower-alkoxy; naphthyl; thienyl; pyridinyl; or benzyl; r6 is one or two substituents chosen from the 10 group consisting of hydrogen, lower-alkyl, lower-alkoxy and halogen; or is a fused benzene ring; R9 is hydrogen, lower-alkyl, benzyl, phenethyl or [di (lower-alkyl)amino]lower-alkyl; 15 r10 is hydrogen; lower-alkyl; phenyl; phenyl substituted with halogen, lower-alkyl, lower-alkylsulfonamido, or lower-alkoxy; phenoxy; phenoxy substituted with halogen, lower-alkyl or lower-alkoxy; benzyl; or r1® is 20 a 5- or 6-membered heterocycle containing one or two nitrogens; and n is zero, one or two.
2. 2. A compound according to claim l wherein one of Rla and R^a is phenyl, the other of r1® and R^a is hydrogen and R® is hydrogen.
3. 3- A compound according to claim 1 wherein R*a is hydrogen, is phenyl, R^ is lower-alkyl, and r1® is 280544 D.N. 2 51OA - 130 phenoxy or phenoxy substituted with halogen, lower-alkyl, or lower-alkoxy.
4. 4. A compound of the formula therein A is a ring chosen from the group consisting of phenyl, thienyl, furanyl, naphthyl, pyridinyl and phenyl having one or two substituents chosen independently from the group consisting of amino, lower-alkyl, lower-alkoxy, halogen, nitro and lower-alkylsulfonamido; Rla is hydrogen, lower-alkyl or phenyl; R2a is lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or R2a -CH2CH2R^ where R^ is lower-alkoxy, phenyl, benzyl, di(lower-alkyl)amino, pyrrolidino, piperidino, or morpholino; and R5a is hydrogen; naphthyl; thienyl; pyridinyl or benzyl; phenyl; or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl and lower-alkoxy; and at least one of Rla and R^a is phenyl, benzyl, naphthyl, thienyl, or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl and lower-alkoxy. Ru R5* 28054 D.N. 2 51OA - 131
5. 5. A compound according to claim 4 having the formula NHR2a wherein R6 is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, amino, halogen, nitro and lower-alkylsulfonamido, or R6 is a fused benzene ring.
6. A compound according to claim 5 wherein Rla and R6 are hydrogen, R2a is lower-alkyl and R5a is phenyl or phenyl having one or two substituents chosen from the group consisting of halogen, lower-alkyl and lower-alkoxy.
7. 7. 2- [ (Methylamino) methyl ] -tt-pheny lbonzenemethanamine according to claim 6.
8. 8. A compound according to claim 5 wherein R^a is phenyl, R^a and R*> are hydrogen, and R2a is lower-alkyl or benzyl.
9. 9. 2- (Aminomethyl) -N-methyl-a-phenylbenzenemethanamine according to claim 8.
10. 10. a compound according to claim 4 having the formula NHR2a D.N. 2510A 132
11. 11. A compound according to claim 10 wherein Rla is hydrogen, R2a is lower-alkyl and RSa is phenyl or phenyl having one or two substituents chosen from the group consisting of halogen,, lower-alkyl and lower-alkoxy.
12. 12. N-Methyl-a'-phenyl-2,3-thiophenedimethanamine according to claim Ilia.
13. A compound of formula wherein R2b is hydrogen; lower-alkyl; benzyl; phenyl; phenethyl; di(lower-alkyl)aminoalkyl; or phenyl substituted with halogen, lower-alkyl, or lower-alkoxy; RSd is lower-alkyl; phenyl; naphthyl; thienyl; pyridinyl; benzyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy, and halogen; R®a is hydrogen, lower-alkyl, lower-alkoxy, or halogen.
14. 14. 2-( Amino) phenylmethyl-N-methylbenzeneethanamine according to claim 13. R5d 280544 D.N. 2510A 133
15. 15. A process for preparing a compound of formula ~NHR2 NH2 wherein R2 is hydrogen; lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or R2 is -CH2CH2R^ where R^ is lower-alkoxy, benzyl, 10 di-(lower-alkyl)amino, pyrrolidino, piperidinor morpholino, phenyl, or phenyl substituted with amino, nitro or lower-alkylsulfonanddo; r5 is hydrogen; lower-alkyl; naphthyl; thienyl; pyridinyl; benzyl; phenyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxyl, amino, di-(lower-alkyl) amino, lower-alkylsulfonamido and lower acylamino; is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, halogen; nitro and lower-alkylsulfonamido or R6 is a fused benzene ring; ich comprises reacting a compound of formula VIII O R5 VIII wherein R2, R5 and R6 are is defined above, 280544 D.N. 2510A - 134 - or formula wherein r2, r5 an<j r6 are as defined above with an excess of diborane.
16. 16. a process for preparing a compound of formula wherein R1 is hydrogen, lower-alkyl, benzyl, naphthyl, thienyl, pyridinyl, phenyl, or phenyl 5 having one or two substituents chosen from the group consisting of lower-alkyl and lowe r-alkoxy; R2 is hydrogen; lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-10 alkyl or lower-alkoxy; or R2 is -CH20H2R^ where R^ is lower-alkoxy, benzyl, di-(lower-alkyl)amino, pyrrolidino, piperidino, morpholino, phenyl, or phenyl substituted with amino, nitro or lower-alkylsulfonamido; 15 R6 is one or two substituents chosen independently 28054 D.N. 2510A - 135 - from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, halogen; nitro and lower-alkylsulfonamido or R.6 is a fused benzene ring; which comprises reacting a compound of formula or with an excess of diborane.
17. 17. A process for preparing a compound formula R5b wherein is hydrogen; lower-alkyl; naphthyl; thienyl; pyridinyl; benzyl; phenyl; or phenyl 5 having one or two substituents chosen from the group consisting of lower-alkyl,lower-alkoxy, and halogen; 28 0 5 4 4 D.N. 2 510A - 136 - R6a is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, and halogen;; which comprises reducing a compound of formula 0 R5b sequentially with an aluminum hydride, hydrogen in the presence of a noble-metal catalyst and hydrogen in the presence of a nickel catalyst.
18. 18. A composition for the treatment of cardiac arrhythmia comprising an antiarrhythmically effective amount of a compound according to any one of claims 1 to 14.
19. 19. The use of a compound as claimed in any one of claims 1 to 14 in the preparation of a medicament suitable for use in the treatment of cardiac arrhythmia.
20. 20. A compound as defined in claim 1 substantially as herein described with reference to any example thereof.
21. 21. A compound as defined in claim 4 substantially as herein described with reference to any example thereof.
22. 22. A compound as defined in claim 13 substantially as herein described with reference to any example thereof.
23. 23. A process as claimed in any one of claims 15 to 17 substantially as herein described with reference tpr,.ai example thereof. 28 0 5 4 4 - 137 -
24. 24. A composition suitable for use in the treatment of cardiac arrhythmia as claimed in claim 18 substantially as herein described with reference to any example thereof.
25. 25. The use as claimed in claim 19 substantially as herein described with reference to any example thereof. t>v rht ^Utoonstid agents A. J Park & Son END OF CLAIMS