PH26547A - 2-substituted-O-heteroaryl benzeneethanamines pharmaceutical composition containing and compound and method of use thereof - Google Patents

Description

! } } ,

This application is a divisional application of S.N. 37886 filed December 5, 1988.

This invention relates to 4,5-dihydro-h-hete- roaryl-3H-1,3-benzodiazepines. More particularly, this invention relates to 4,5-dihydro-lU-heteroaryl- 3H-1,3-benzodiazepines of the formula I:

R rt y (xX), = (1 : . Ar wherein Ar is a radical selected from the group consisting . . i . = : (Y)_, | -(1) (0, (OA 1 jl [<0 0 | _Foy, [ en, _ | ’ _q 1] ’

boo ' 3 iG r® Rr? !

A N N

Je oo, To,

My (0 (1D, oO = wherein a is hydrogen, loweralkyl or loweralkanoyl, , Y is selected from the group consisting of halogen, hydroxyl, loweralkyl, loweralkoxy, and trifluorome- thyl n is an integer having a value from § to 3 in- - clusive, p is an integer having a value of # or 1, and q is an integer having a value from # to 4 in- clusive; X is selected from the group consisting of halogen, hydroxyl, nitro, loweralkjl, lovweralkoxy, and trifluoromethyl; m is an integer having a value ) - from # to 2 inclusive; R is selocted from the group } . consisting of hydrogen, joweralkyl , aryl, aralkyl, ecycloalkylloweralkyl, loweralkenyl, and loweralkynyly and R* is selected from the group consisting of hydro- gen, loweralkyl, and aralkyl wherein for each value of m, n.P, or q each X or Y may be the same or differents the optical antipodes; geometrical isomers; or pharma- ceutically acceptable acid addition salts thereof which are useful as antidepressants.

Cs.

Preferred l,5-dihydro-4-hetercaryl-3H-1,3~ benzodiazepines of this invention are compounds of the formula lag

R

) Ar wherein AT is selected from the group consisting ef 7 ~ 4 =D, | -(1) . rx Cy (n, wherein Y loweralkyl, most preferably methyl, n is an integer having a value of # or 1, and R is selected from the group consisting of hydrogen, loweralkyl, . aralkyl, and aryli the optical antipodes, geometrical isomers; or pharmaceutically acceptable acid addition salts thereof.

Subgeneric to the L,5-dihydro-k-heteroaryl-3H- - bh a

. . “143- benzodiazepines of this invention are Formula '

I compounds wherein ’ (a) Ar is

SE wherein Y and n are as previously described; © (b) Ar is - R$ Ce 0D... Y (0 (Mg my. wherein ¥ and q are as previously describedy (¢) Ar is i : 2 [0m or | I _ wherein R?, Y and n are as previously describedy

(d) Ar is s { -(Y l ) m, oI or 0] |] wherein Y and p are as previously deacribeds (e) Ar is ’ 2

R

} R° 7 ~~

Jn. er (D4 > I pr] wherein RZ, Y and p are previously described; : (£f) Ar is x . oo -(1), or | -(1) wherein Y and n are as previously described; (g) Ar is r® loo

Teo, wherein R?, Y and p are as previously describeds

(nh) R is hydrogen, loweralkyl, aryl, aralkyl, loweralkenyl or loweralkynyls (i) R is hydrogen, loweralkyl, aryl or aral- : kyls » R' is hydrogen; : (kx) pr} is loweralkyl, or aralkyl (1) RZ ie hydrogen or loweralkyl; (m) n is zero or 1j (n) m is zero or 13 (0) 7p is zero} (p) q is zero or 13 ’ (aq) X is loweralkylj (r) X is hydfoxyl or loweralkoxy; (s) X is hadogen or trifluoromethyls (¢) X is nitro; } (vu) Y is hydroxyl or loweralkoxys - (v) Y is loweralkyls

N (w) Y is halogen or trifluoromethyl; and (x) Y is loweralkyl or chlorine.

In another embodiment this invention relates to compounds of the formula II - , ’ 23 rt wd " (11)

CH ,C8 -N- rR

Ar wherein Ar is selected from the group consisting 2 of RS R = ~

Fo, 1 bog IL om, my } ’ NN (0, | ky,

Ss —(Y Y) 1 | Y {

Tl 2 ( r ’ ¢ 23 ’ 5

R r2 R® i -(1 Y AY : | ¢ )p, ( Si ’ )p, (Y) CC

Y) (Y) ' » — 9 and

N — ] wherein rR? is hydrogen, loweralkyl or loweralkanoyl,

Y ie selected from the group consisting of halogen, hydroxyl, loweralkyl, loweralkoxy and trifluormethyl, n is an integer having a value from # to 3 inclusive, p is an integer having a value of # or 1, and q is an ee . oe : , jnteger having a value from § to 4 inclusive; K is” selected from the group consisting of halogen, hy- droxyl, nitro, loweralkyl, loweralkoxy, and trifluoro- methyl; m is an integer having a value from @# to 3 inclusive; rt js selected from the group consisting of hydrogen, loweralkyl, and aralkyl; R is hydroxys loweralkoXy, amino, loweralkylamino, diloweralkylamino, or rOc(®) r wherein rt and g® are independently hydro- gen or loweralkyl; and rR is hydrogen, loweralkyl or (0) Rr wherein Rr’ is hydrogen or loweralkyl, wherein for each value of my, ny DP OF Qo each X or Y may be the same of different; the geometrical isomers, opti- cal antipedes Or pharmaceutically acceptable acid ad- dition salts thereof. ;

The Formula II compounds of this invention, are useful as anticonvulsants. Additionally, peveral of _ these Formula II compounds have utility as intermediates in the synthesis of the h-heteroaryl-1,3-benzodiazepines of this invention. Subgeneric to the ¥ ormula II com- pounds of this invention are those compounds wherein (as) R: is hydrogeny’ : (bb) gt ims loweralkylj (ce) gl is aralkyl; (ad) R> is amino fy / ) (ee) R’ #8 loweralkylamino; (ff) R is diloweralkylamino} (gg) R is nrbco)r? wherein gt and r® are independently hydrogen or loweralkyls (hh) R> is hydroxyj (11) R? is loweralkoxys (33) R’ is hydrogen; (kk) Rr’ 8 -C(O)R’ wherein R? is hydrogen or loweralkyls (11) R° is loweralkyl; : (mm) Ar is selected from the group consisting of ~ (ND, or | LT), wherein n is an integer having a value of # or 1 and

Y is loweralkyl, most preferably methyl. (nn) Ar is (Y)

N— ’ = or wherein n is an integer having a value of # or 1 and TL

Y is loweralkyl, most preferably methyl. (e0) Ar is

~~ -(1) or -(1) wherein n is an integer having a value of § or 1 and Y is loweralkyl, most preferably methyl.

A clase of preferred 2-substituted -ac -(hete- roaryl)-benzeethanamines of this invention is rep- ’ resented by the formula III §:4 \ 2 NHCH (x) (111) n . wherein X is halogen , preferably bromine or chlorine, m is zero or 1, and Ar is - | hl or [ J

H.C .

H,C 3

As used throughout the specification and append- ed claims, the term "loweralkyl" shall mean a straight or branched chain hydrocarbon group containing no un- saturation and having from 1 to 5 carbon atoms such as methyl, ethyl, l-propyl, 2-propyl, l-butyl, l-pentyl, 2-pentyl. : The term "cycloalkyl" shall mean a saturated hy-

drocarbon group possessing at least one carbocyc- lic ring and having from 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, cycloheptyl.

The term "loweralkoxy'" shall mean a monovalent substituent which consists of a loweralkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen, such as methoxy, ethoxy, lsopropskxy, -t-butoxy, pentoxy. The term "aryl" shall mean phenyl or phenyl substituted with one or more chloro, bromo, fluoroy loweralkyl, methoxy, hydroxy, or trifluoromethyl groups. The term "aralkyl" refers to a radical formed by attachement of a lower- ) alkyl function having up to 4 carbon atoms, inclusives to an aryl moiety. The term "alkanoyl" shall means the residue pf an alkyl carboxylic acid (alkanoic acid) having from 1 to 5 carbon atoms formed by the removal ' ~ of the hydroxy group of the carboxylic acid moiety. . Examples of alkanoyl groups include formyl, acetyl, propiohyl, butyryl, pentanoyl. The term "loweralkenyl" ' shall mean a saturated hydrocarbon group of 1 to 5 car- bon atoms having one or more carbon-carbon double bonds, © and the term "alkynyl" shall mean a hydrocarbon group of 1 to 5 carbon atoms having one or more carbon-carbon triple bonds.

As shown by Reaction Scheme A, Formula II compounds wherein Rr is amino, Ro is hydrogen and rt is loweralkyl or aralkyl are produced by reacting a

N-(2-me thyphenyl)-2,2-dime thylpropanamide 1, via the corresponding dilithium adduct 2, with a hetero- : aryl carboxaldehyde imine 3 to produce a heteroaryl- substituted intermediate Kk, hydrolysis of which yields the corresponding diamine 3. Ts . N-(2-me thyphenyl)-2,2-dimethylpropanamide 1 can be synthesized by the reaction of o-toluene and trime- oo thylacetyl chloride as described in U.S. Patent No. bh, : 374,067 to Lee at al., assigned to Hoechst-Roussel

Pharmaceuticals, Inc. The reaction of primary alipha- tic or aromatic amines with heteroaryl carboxaldehydes t : to yield heteroaryl carboxaldehyde imines is well known in the art and is analogous to the reaction of : aromatic aldehydes and primary amines described, for : example, in G. Rilgetag and A. Martini, Preparative oo Organic Chemistry, John Wiley & Sons, Inc., New York, 1972, pp. 504-L09.

Production of the neteroaryl-substituted inter- ’ mediate 4 is conveniently accomplished by first treat- ing N-(2-methylphenyl)-2,2-dimethylpropanamide 1 with an organélithium compound (e.g. tert-butyllithium, sec-butyllithium, n-butyllithium, and the like; n-butyl-

. + ’ lithium being preferred) and thereafter converting the regultant dilithium adduct 2 to the heteroaryl- substituted intermediate h by reaction with the heteroacryl carboxaldehyde imine 3. In general, the reaction is conducted in the presence of an inert organic solvent without isolation of the intermediate dilithium adduct. Among the suitable solvents for } the reaction there may be mentioned ethereal solvents, . hydrocarbone, and the like, and mixtures thereof. Rep- resentative of such solvents are diethyl ether, dio- xane, 1,2-dimethoxyethane, teterahydrofuran, hexane,. cyclohexane, benzene, toluene, xylene, and the like.

Tetrahydrofuran, toluene, and mixtures thereof with hexane (commonly present as a solvent for the organo- lithium compound) are preferred. The reaction is or- © dinarily conducted at temperatures of from about -70%¢ : . to about 30°C, with temperatures of about -10°C to about 0°C being preferred. Typically, the amount of organé- lithium compound reacted is up to about 10% in excess - of the 2 molar equivalents required for the reaction. : Owing to the reactivity of the organolithium compound, it is recommended that the reaction be conducted under anhydrous conditions.

Hydrolysis of the heteroaryl substituted interme- diate i to the corresponding diamine 5 is convend#ntly

ET oo accomplished in the presence of an aqueous solvent by an appropriate mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, 6N-hydro- chloric acid being preferred) under reflux condi- tions. Desirably the hydrolysis is conducted under an inert atmosphere to avoid undesirable side re- actions,

As further illustrated in Research Scheme A, ¥ormula II compounds wherein R> ie amino or-NHC(0) RY, and R° is -C(0)R’ can be produced by treating a di- amine 5 with a suitable alkanoic acid anhydride. (e.g, formic acid anhydride, acetic acid anhydride, propionic acid anhydride, butyric acid anhydride, pentanoic acid anhydride) like). The acylation is generally conducted at temperatures of from about Cf 030°C to about 20%, preferably from about 0° to . about 10%, in the presence of a suitable inert or- . | ganic solvent. Suitable solvents include non-nucleo- . philic amines such as, for example, pyridine, lutidine, collidine, trimethyl amine. Pyridine is preferred, : | Reduction of the resultant carbonyl derivatives

Ja and 5b affords Formula II compounds 6a and 6b where- in rR’ is amino or loweralkylamino, and rR’ is hydrogen ‘ or loweralkyl. Reduction may be accomplished by any of several methods which are well known in the art, For example, treatment of formyl substituted derivatives

Sa and 5b with a boron tetrahydrofuran 5a and 5b with a tetrahydrofuran complex followed by hydrolysis with a mineral acid (e.g. concentrated hydrochloric acid).

Treatment of a formyl substituted derivative 5b with formaldehyde and succinimide followed by reduct- jon of the resultant dioxo-pyrrolidinyl substi tuted compounds 6c, affords a derivative 6d wherein rR’ is Co

Co me thylamino, Hydrolysis of 6d with mineral acid or reduction provides compounds 6e where R? is hydrogen . or loweralkyl. .

Diazotization of derivative 5b with nitrous acid and quenching into aqueous copper sulfate solution af- fords Formula III compounds 6f wherein Rt is loweralkyl and rR? is hydrogen or loweralkyl. Hydrolysis of car- bonyl derivatives 6f with a mineral acid affords For- mula III compounds 6q wherein R’ is hydrogen.

It should be noted that, if desired, substitution of the phenyl ring of the Formula II compounds of this invention can be effected subsequent to formation of the diamine 5. For example, treatment of a phenyl- unsubstituted diamine 5 with a halosuccinimide (e.g.

N-bromosuccinimide or N-chlorosuccinimide) prabides the compound with one or more halide substituents, X-.

T

Alternatively, as shown in Reaction Scheme B, ¥ormula II compounds wherein rR and Rr are hydro- : gen and R? is amino may be prepared by converting a heteroaryl-substituted 2-(2-nitrophenyl) aceto- 6 phenone 7 to an oxime 8, acylating the oxime 8 ! with an alkanoic acid anhydride, and reducing the resultant oxime akkanoate 9 to a diamine 10. ’ The synthesis of heteroaryl-substituted 2-(2- nitrophenyl)acetophenones 7 is known in the art and is analogous to the synthesis of phenyl-substi- tuted »-(2-nitrophenyl) acetophenones described in greater detail in U.8. Patent No. 4,459,231 incorpo- rated herein by reference. ' Oxime conversion may be accomplished by any of several - I 15 methods known in the art.

A preferred method involves refluxing the 5 (2-ni trophenyl)acetophenons 7 in a mix- ture of ethyl alcohol, aqueous sodium acetate and hy- : h | droxylsmine to provide corresponding oxime 8. Alkanoic Co . . acid anhydrides suitable for acylation of the oxime 8 include formic acid anbydride, acetic acid anhydride, butric acid anhydride, pentanoic acid anhydride, acid ! anhydride is preferred.

The acylation is generally conducted at a temperature of from about 0°C to about 100°¢, preferably from about 0°C to about 25°C, in the presence of pyridine.

Reduction of the oxime aklanoate

9 may be accomplished by any of several methods known in the art, among which treatment with a boron-tetrahydrofuran complex followed by hydro- lysis is preferred. | ~ As shown in reaction Scheme C, Formula II di- ‘ amines 5 can be cyclised by reaction with a compound : of the formula: .

Cxtax1?

Callan 100-R : 10 CxPoxi1® wherein R is hydrogen, loweralkyl, ralkyl or aryl, and x is 1 or 2, (e.g. trimethyl orthoformate, tri- methyl orthoacetate, triethyl orthoacetate, trimethyl orthoacetate, triethyl orthoisoproprionate, trimethyl orthodsobutyrate, trimethyl orthobenzoate, and the like) to provide Formula I 4,5-dihydro-l-hetercaryl-3H-1,3= benzodiazepine 12 wherein R is hydrogen, loweralkyl, aralkyl or aryl. The cyclization is generally conducted in the presence of an appropriate acid catalyst (e.g. alkanoic or alkanoic acids such as, for example, Bla- cial acetic acid, ethanolic hydrochloric acid, metha- nolic hydrochloric acid, and the likeg glaciel acetic acid being preferred, at a temperature of from about

25°C to the reflux temperature of the reaction ) medium. Aternatively, the cyclization may be conducted in the presence of acetonitrile at a temperature of about 80°C in the presence of an acid catalyst.

The *ormula I compounds of this invention are useful as antidepressants by virtue of their ability to elicit an antidepressant response in mammals.

Antidepressants activity is demonstrated in the tet- rabenzene induced ptosis assay in mice/International

Journal of NeuropharmacolOgy, 8, 73 (1969)7, a standard assay for antidepressant activity.

The intraperitoneal (i.p) dosages at which the following compounds effect a 50% inhibition from the ptosis of tetrabenzine-induced depression in mice (EDg() are? - 19 = b

Table 1

Anti-Depressant Activity

Compound EDcy (mg/kg, i. pe) ,5-Dihydro-2-ethyl-3-methyl 4-( 2-thienyl)-3H-1,3-benzodia- zepine hydrochloride L,7 4,5-Dihydro-2-ethyl-3-methyl- -(3-thienyl)-3H,1,3-benzodia~ zepine hydrochloride | 8.7 4,5-Dihydro-2-etyl-3-methyl- . : 3-(3-methyl-2-thienyl)-3H-1,3- benzodiazepine hydrochloride monohydrate 5.3 4,5-Dinhydro-2-ethyl-3-methyl . 43(4-pyridinyl-3H-1,3-benzodia- zepine hemihydrate 6.8 4,5-Dihydro-2,3-dimethyl-i-(2- . methyl-4- thienyl)-3H-1,3- ; benzodiazipine hydrochloride 12.2

Doxepin (standard) 3.8 : a Dosage levels which the h-heteroaryl-1,3- benzodiazepine of this invention achive an anti- depressant response is subject to variation depend- oo ing upon the particular compound employed. In gene-

. » ral, antidepressant response may be elicited at effective oral, parenteral, or intravenous doses ranging from about O.1 to about 50 .mg/kg of body weight per day. ‘1b jg to be understood, however, . 5 that for any particular subject, specific dosage : regimens should be adjusted according to the in- dividual need and the professionai judgement of the person administering or supervising the administra-

N tion of the aforesaid compound. : . +10 @t is to be further understood that the do sages set forth herein are exemplary only and they do not, to . any extent, limit the scope or practice of the in- ; vention. Cea ead ee skip ee . ; Te formula II compounds of this invention are useful as anticonvulsants due to their anticonvul=- sant activity in mammals. Anticonvulsant activity ~- is measured in the male mouse uaing the suppamaximal oo electroshock (SES) assay described in Arch. Int. - pharmacodyn, 92t 97-107, 1952.

Intraperitoneal doses of representative compound of the invention and their ability to protect from the effect of SES is shown below in Tabld 2. EDg, “yalues, j.e., the doses at which , within 95% con- - fidence intervals, 50% of the animals are protected are calculated by computerized probit analysis.

i . h

Table 2

Anticonvulsant

Activity Compound Ed; (mg/kg, i.p.) 2-Amino-N-methyl-alpha-(3-methyl- ’ 2-thienyl)benzenethanamine 4.6 2-Amino-N-methyl-alpha-(2-thienyl) } benzeneethanamine dihydrochloride - hemihydrate 30,4 . : 3 2-Amino-5-bromo-N-methyl-alpha=- 2-Amino-5-bromo~-N-me thyl-alpha- (3-methyl-2-thienyl)benzeneethanamine 9,2 ‘ } Tr *

Diphenylhydantoin (standard) 3.9 ny ve

Anticonvulsant activity is achieved when the compounds of this jnvention are administered to a . 15 subject requiring such treatment at an effective oral, parental or intravenous dose of from 1 to 50 mg/kg of body weight per day. It is to be un- derstood, however, that for any particular subject, specific dosage regimens should be adjusted accod- ing to the individual need and the professional judgement of the person administering or supervising the administration of the compounds of the invention.

It is to be further dnderstood that the dosages set forth herein are examples only and that they do not, to any extent, 1imit the scope of the prac- tice of the invention.

The compounds of this invention, while effect- ive themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for the purposes of stability, con- venience or crystalization, increased solubility.

Preferred pharmaceutically acceptable addition salts jnclude salts of mineral acids, for example, hydro- chloric acid, sulfuric acid, nitric acid, salts of monobasic carboxylic acids such as, for example, ace- tic acid, propionic acid, salts of dibasic carboxy- 1ic acids such as, for example, maleic acid, fumaric acid, and salts of tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid.

Effective quantities of the compounds of this oo invention may be administered orally, for example, . with an inert diluent or with an edible carrier. They : 20 may be enclosed in gelatin capsules or compressed in- to tablets. For the purpose of oral therapeutic ad- ministration, the aforesaid compounds may be incorpo- rated with excipients and used in the form of tablets, troches, capsules , elixirs,suspensions, BYrups, wafers, chewing gums and the 1ike. These preparation should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between Ly to about 70% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and prepara- tions according to the present invention are prepared go that an oral dosage unit form contains between 1.0 and 300 milligrams of the active compound. . 10 The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum traga- oo } canth or gelatin; an excipient such as starch or lac- tose, a disintegrating agent such as alginic acid,

Primogel ® cornstarch, a lubricant such as mag- nesium stearate; a giidant such as colloidal silicén dioxide; and a sweetening agent such as surrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. when the dosage unit form is a capsule, it may con- tain, in addition to materials of the preceeding type, : a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating - 2k 9

: agents. A syrup may contain, in addition to the } active compounds, sucrose as a sweetening agent , and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various © compositions should be pharmaceutically pure and : nontoxic in the amounts used.

For the purposes of parenteral therapeutic administration, the active compounds of this invent- jon may be jncorporated into a solution of suspen- ‘sion. These preparations should contain at least 0.1% of active compound, but may be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compo- sitions and preparations according to the present in- vention are prepared so that a parenteral dosage unit

Co i contains between 0.5 to 100 milligrans of active com- pound. C

The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycole, glycerine, propylene glycol or other synthetic solvents; antibacterial agents . such as benzylalcohol or methyl parabensj antioxi~ dants such as ascorbic acid or sodium bisulfitey chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agente for the adjustment of tonicity such as so- dium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or mul- tiple dose vials mdde of glass or plastic.

Compounds of the invention include: ,5-dihydro-k-(2-thienyl)-3H-1,3-benzodiazepine; ,5-dihydro-2-me thyl-l-(3-thienyl)-38-1,3-benzodiazepine; 4,5-dihydro-2-cyclopropylme thyl-3-methyl-4-(3-thienyl)=- 2H-1,3-benzodiazepine; ,5-dihydro-3-benzyl-2-me thyl-h-(2-thienyl)=3H-1,3= benzodiazepine; 4,5-dihydro-2-(4-fluorophenyl)-3-me thyl-l-(4-pyridin) -2H1,3-benzodiazepine; . 4, 5-dihydro-2,3-dime thyl-4-(4-pyrazolyl)-3i-1,3- benzodiazepine; 4, 5-dihydro-2-(1-propyl)-3-methyl-b-(4-pyrazolyl)-3H- 1,3-benzodiazepine; l4,5-dihydro-2-e thyl-3-methyl-h(2-pyrrolyl)-3H-1,3- benzodiazepines 4 ,5-dihydro-2,3-dime thyl-8-hydroxy-4-(3-fluoro-2- . thienyl)=-3H=- 1,3-benzodiazepine. " oe »-amino-N-me thyl-c; -( h-me thyl-2-thienyl)benzeneethanamine;

>_amino-N-methyl- -( 4-methyl-3-thienyl)benzene- ethaaamine; 5-amino-5-fluoro-N-me thyl-of -(3-me thyl-2-theinyl)- bengeneethanamines s.amino-5-iodo-N-methyl-c( -(3-me thyl-2-thienyl) benzeneethanamine; 2-amino-N-methyl-5-trifluoromethyl-o «(3-methyl-2- thienyl)-benzeneathanamine; >-amino-5-me thoxy-N-me thyl-ol -( 3-me thyl-2-thienyl)- benzenee thanamine ; 2-amino-5-methyl-N-methyl -¢ ~(3-methyl-2-thienyl) benzeneethanamines 5 aminoli-f1uoro-N-me thyl-o -( 3-me thyl~2-thienyl) " benzeneethanaminej . - 5 amino-lb-chloro-N-me thyl-c -( 3-me thyl-2-thieryl) . benzeneethanamine; - >-amino-l-bromoiN-methyl-& -(3-methyl-2-thienyl) . benzeneethanamines 2-amino-l-1odo-N-me thyl-c.~(3-me thyl-2-thienyl) . * 20 benzeneethanamines + amino-Nome thyl-ct ~( 3-me thyl-2-thienyl) -b-triflvoro- oo methylbenzeneethanamines 2-amino-k-me thoxy-N-methyl-c -( 3-methyl-2-thienyl) benzeneethanamine; 2-amino-l-methyl-N-methyl-c -(3-methyl-2-thienyl)

benzeneethanamine; >-amino-N-methyl-of.-( 1-me thyl-2-pyrrolyl)benzene- ethanamine} 2-amino-N- methyl-of -(1-methyl-3-pyrrolyl)benzene- ethanamine; 2-amino-o. -(li-pyrazolyl) -N-me thylbenzeneethanamine; 2-amino-N-methyl-cof -(2-thiazolyl)benzenee thanamines 2-amino-N-methyl-o.-(4-thiazolyl) benzeneethanamine; h 2-amino-N-methyl-oc -(5-thiazolyl)bengzeneethanamines ami 00-Nne thyl.-(2-me thyl-h-thiazolyl) benzene ethanamine; oo 2-amino-N-methyl-of -(5-methyl-2-thiazolyl)benzene- ethanamine; 2-amino-N-methyl-( -(2-methyl-5-thiazolyl)benzene- ethanamine} 2-amino-of -(3-pyrazolyl)-N-methylbenzeneethanaminey 2-amino-«. -(2-chloro-4-thiazolyl)~N-methylbenzene- 2-amino-ot -(5-chloro-2-thiazolyl)-N-methylbenzene- ethanamine; }

L-amino-of —=(2-chloro-4-thiazolyl)-N-methylbenzene- ethanamines 2-amino-N-methyl-o -(l4-pyrazolyl)benzeneethanamine; } 2-amino-N-methyl-o -(3-pyrazolyl)benzeneethanamine; ' : 2=-amino-o _(2-imidazolyl)-N-methylbenzenee thanamine;

N-formyl-2-hydroxy-N-methyl-o —(3-me thyl-2-thienyl}

benzenee thanamine; 2-hydroxy-N-me thyl-o(3-methyl-2-thienyl)benzene- ethanamine;} 2-me thoxy-N-methyl-c -(3-methyl-2-thienyl)benzene- ethanamines

N,N-dime thyl-2-me thylamino-c ( 3-me thyl-2-theinyl)- benzeneethanamines 4,5-dihydro-4-(2-thienyl)-3H1,3-benzodiazepine; by, 5-dihydro-3-methyl-k-( 2-thienyl)-3H-1,3-benzodia- h 10 zepine; 4,5-dihydro-2-methyl-4-(2-thienyl)-3h-1,3-bénzodia- zepine; 4, 5-dihydro-2-ethyl-7-fluoro-3-me thyl-4-(3-me thyl-2- thienyl)-3H-1,3-benzodiazepine; n-chloro-lig5-dihydro-2-ethyl-3-methyl-4-( 3-_methyl-2- thienyl)-3H-1,3-benzodiazepine; 7-bromo-l,5-dihydro-2-ethyl-3-methyl=h-(3-methyl-2- ~ thienyl)-3H-1,3-benzodiazepine; b,5-dihydro-2-ethyl-3-methyl-4-(3-methyl)-2-thienyl) o-trifluoromethyl-3H-1,3-benzodiazepine; oC 4 ,5-dihydro-3,7-dime thyl-2-ethyl-4-(3-me thyl-2-thienyl) 34-1, 3-benzodiazepine; ,5-dihydro-2-ethyl-7-me thoxy-k-(3-me thyl-2-thienyl)- 3H-1,3-benzodiazepine; ’ ,5-dihydro-2-ethyl-8-me thoxy-l-(3-methyl-2-thienyl)~

Cag -

-3H-1,3-benzodiazepine; 8-chloro-4,5-dihydro-2-ethyl-3-methyl-b~(3-methyl- 2-thienyl)-3H-1,3-benzodiazepine; 4,5-dihydro-2-ethyl-3-methyl-4-(1l-methyl-2-pyrrolyl)- 3H-1,3- benzodiazepiney 4,5-dihydro-2-ethyl-3-methyl-4-(1l-methyl-3-pyrrolyl)- 3H-1,3- benzodiazepine; : b,5-dihydro-2-ethyl-3-methyl-4-(2-thiazolyl)-3H-1,3- benzodiazepine; : 4,5-dihydro-2-ethyl-3-methyl-4-(4-thiazolyl)-3H, 1,3- benzodiazepine; : 4,5-dihydro~2-ethyl-3-methyl-h-(5-thiazolyl)-3H,1,3- benzodiazelrine; 2-cyclopropyl-4,5-dihydro-3-methyl-4-(3-methyl-2- thienyl)-3H-1,3-benzodiazepine; ‘3-benzyl-l,5-dihydro-2-ethyl-l4-(2-thienyl)-3H,1,3~ benzodiazepine; 4,5-dihydro-2-( k-fluorophenyl)-3-methyl-l-(4-pyridi- nyl)-3H,1l,3-benzodiazepine; '4,5-dihydro-2~ethyl-3-methyl-4-(b-pryrazolyl)-3H,1,3~- benzodiazepine; 4,5-dihydro-2-ethyl-3 -methyl-4-(3-pyrazolyl)-3gml,3- benzodiazepine; and }

I,5-dihydro-2-ethy-4(2-imidazolyl)3-me thyl-3H-1,3-ben- zodiazepine.- 30 -

EXAMPLES

. The following examples are for illustrative purposes only and are not to be construed as limiting the in- vention. All percentages are by volume, unless other- wise noted.

EXAMPLE 1

N-/2-/Z-Methylamino-2-(2-thienyl)ethyl/phenyl/-2,2- _. dimethylpropanamide

A stirred, chiled (-10°C) solution of 19.3 g of

N-/Ta- methyl) phenyl7-2,2-dime thylpropanamide in 150 ml of tetrahydrofuran was treated over 43 min with "140 ml of a 1.6M solution of nebutillithium in hexane, while maintaining the temperature at or below 0%. : Stirring for 2.3 hours with cooling afforded a sus- pension. The stirred, cooled (-6°C) suspension was ~ treated over 13 min with a solution of 15.02 g of N- (2-thienylmethylene)methaneamine in 20 ml of toluene.

The reaction mixture was stirred with cooling (1%) for 1.5 hours, quenched byhthe addition of 120 ml of water and concentrated. The consentrate was extracted with dichloromethane (2 x 200 ml), and the combined extract was dried over anhydrous sodium sulfate, fil- tered, and evaporated to an oil. Preliminary purifica- tion of the oil was achieved by preparative high pres- sure liquid chromatography (hereinafter WEPLGM) separa-

tions utilizing a Water's Model 500A High Pressure

Liquid Chromatograph (silica gel; eluting with 10% methanol in ethyl acetate). The appropriate frac- tions from each separation were combined and con- centrated to an oil. The purification procedure was repeated utilizing 5% methanol in ethyl acetate as the eluent to yield 11.71 g of M-/2-/2-methyl- amino-2-(2-thienyl)ethyl7phenyl/-2,2-dine thylpropanamine as a solid, mp 78.5-82°.

ANALYSIS: -.

Calculated for C, gH, N08: 68.32%C .7.64%H 8.85%N

Found: 67.96%C 7.69%H 8.74%N

EXAMPLE 2 2-amino-N-methyl-oC~(2-thienyl)benzeneethanamine dihydrochloride hemihydrate

A stirred suspension of 11.28 g of N-/2-/2-methyl amino-2-92-thienyl)ethyl/phenyl/-2,2-dimethylpropan~ amide in 100 ml of BN hydrochloric acid was refluxed under nitrogen for 8 hours. The mixture was cooled, decanted over crushed ice and water (2@0 m), basified by the addition of 50% sodium hydroxide soluticn, and extracted with dichloromethane (3 x 150 ml). The com- bined extract was dried ober anhydrous sodium,

basified wbth 10% sodium hydroxide solution, and 4 extracted with dichloromethane (2 x 50 ml). The : combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which crystallised under refrigeration. The crystalline product was purified by HPLC (Water's

Associates Prep LC/ System 500A; silica gel, sample applied in dichloromethane; 2% triethylamine in me- thanol as the eluent). Concentration of the appro-= priate fractions yielded an 0il which crystallized on trituration with hexane. The compound was iso- lated, washed with hexane, and dried in vacuo at room temperature to afford 2.05 g of 4,5-dihydro-2g3-di- ne thyl-li-(2-thienyl)%30-1,3-henzodiazepine, mp 106- 108.5%.

ANALYSIS: )

B Calculated for Cy 5H, No5* 70.28%C 6.29%H 10.93%N oo 70.61%C 6.30%H 10.91%N

EXAMPLE 4

A Lo 4,5-] _pinydro-3-methyl-2=(1-methethyl)-h=(2-thienyl)= 3H-1,3-benzodiazepine hydrochloride

A stirred solution of 3,45 g of 2-amino ~N-methyl~- o -(2-thienyl) benzeneamine and 13.34kg of trimethyl orthoisobutyrate was treated rapidly with 3.8 ml of sulfate, filtered, and concentrated to an oil. The oil.was purified by means of HFLC on a Water's Model 500A High Pressure Liquid Chromatograph (silica gel) “. utilizing methanol as the eluent. Concentration of the appropriate fractions yielded 5.96 g of 2-amino~N-methyl- ot -(2-thienyl) benzeneethanamine. A sample of the pro- duct (2 g) in methanol (5 ml) was treated with ether- eal hydrogen chloride and a solid was precipitated by further dilution with anhydrous ether. Recrystallizat- jon from absolute ethanol gave 2.12 g of 2-amino-N-methyl- - -k -(2-thienyl)benzeneethanamine dihydrochloride hemihy- drate, mp 210-215°C (dec.).

ANALYSIS:

Co . Jalculated for Cy 4ff, gN,8"2HC170.5H,08

Co 4o.68%c 6.00%H 8.91an”

Found: | 49.32%C 5.94%H 8.87%N

EXAMPLE 3 l,5-Dihydro-2, 3-dimethy-h-(2-thienyl)-3i-1,-benzodia- - pine

A stirred solution of 3.06 g of 2-amino-N-methyl- 0--(2-thienyl)benzeneethanamine (prepared as described “ in example 2) and 12.72 g of triethyl orthoacetate was treated rapidly with 5 ml of glacial acetic acid, The resulting solution was refluxed for 8 hours and allowed ‘to stand at room temperature overnight. The solution was concentrated on a rotary evaporator and the residual syrup was dissolved in 50 ml of 10% hydrochloric acid. } The solution was washed with diethyl ether (2 x 30 ml), ’ - 32a = glacial acetic acid. The reaction mixture was re- fluxed for 8 hours and cooled to room temperature overnight. The mixture was concentrated on a rota- } ry evaporator at 70%. After standing overnight under refrigeration, the residue was dissolved in 60 ml of 10% hydrochloric acid solution and extracted with diethyl ether (2 x 50 ml). The aqueous phase was basified oo with 10% sodium hydroxide solution and extracted with dichloromethane (2 x 75 ml). The combined organie phase was dried over anhydrous sodium sulfate, fil- tered, and concentrated to an oil. The oil was pu- rified by HPLC (Water's Associates Prep LC/System 500; silica gel; sample applied in dichloromethane; methanol as eluent). Concentration of the appro- | priate fractions yielded 1.08 g of 4,5-dihydro-3- methyl-2-(1-methylethyl)-4-(a-thienyl)-3H-1,3-benzo~ diazepine as an oil,

The oil was dissolved in methanol (2 ml) and the solution was treated with a slight excess of ethereal hydrogen chloride, followed by dilution with 4oml of anhydrous diethyl ether. Upon dilution, separate oil and ether phases formed. The oil phase was separated and triturated with three spccessive portions of diethyl ether to afford a semisolid which was recrystallized from propionitrile to yield 0.54 g of crystalline solid.

' .

Work-up of propionitrile mother liquor addorded } an additional 0.24 g of crystals. The final pro- pionitrile mother liquor and combined ethereal phases were concentrated to an oil which was re- crystallized from propionitrile to yield an addi- tional 0.11 g of crystals. The three crops of crystals were mixed together to yield 0.89 of 4,5- dihydro-3-methyl-2-(1l-methylethyl)-k-(2-thienyl) -3H,1,3-benzodiazepine hydrochloride, mp 202-205.5°C.

ANALYSIS: oo Caloulated for Cy H, N,§'HCL: 63.63%C 6.60%H 8.73%N 3 63.43%C ~~ 6.62&H 8.72%N

EXAMPLE 5 4,5-Dihydro=-3-methyl-2-(1-propyl)-4-(2-thienyl)-3H- 1,3-benzodiazepine hydrochloride

A stirred solution of 3.36 g of 2-amino-N-methyl- ~(2-thienyl) benzenee thanamine (prepared as described jin Example 2) and 12.89 g of trimethyl orthobutyrate was treated rapidly with 3.5 ml of glacial acetic acid. ‘

The resulting solution was refluxed for 8 hours, cool- } : . ed, and concentrated on a rotary evaporator at 70°C. The residue was prtitioned between 10% hydrochloric acid solution and diethyl ether. After extraction of the | ’ aqueous phase with a second portion of fiethyl ether,

the solution was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2 x 100 ml).

The combined organic phase was dried over an- hydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by HPLC (Water's

Associates Prep LC/System 500, silica gel; and alut- ed with methanol followed by 2% triethylamine in me- thanol). Concentration of the appropriate fractions yielded 2.85 g of 4,5-dihydro-3-methyl-2-(1-propyl)- 4-(2~-thienyl)3H-1,3~benzodiazepine as an oil.

The oil was dissolved in diethyl ether and treated with ethereal hydrogen chloride. The resulting preci- pitate was triturated with diethyl ether until solidi- fication was complete, isolated by vacuum filtration, and dried in vacuo at 40°C. Recrystallization from acetonitrile yielded 2.21 g of 4,5-dihydro-2-methyl-2- (1-propyl)-l-(2-thienyl)-3H-1,3-benzodiazepine hydro- ©. chloride, mp 222-223, 5°C.

ABALYSISs ; . calculated for Cy Hl pol 8 HCL: . 63.63%C 6.60%8 8.73%N 63.49%C 6.60%H 8.75%N

EXAMPLE _6

N=/3-/3-(Methyl amino) -2-(3-thienyl)ethyl/phenyl/=2,2- dimethylpropanamide ]

To a chilled, solution (-50°C) of 19.13 g of 2,2-dime thyl-N-/{2-me thyl) phenyl/grppanamide in 200 v ml of tetrahydrofuran was added, dropwise over 1.5 hours, 88 ml of a 2.5 M solution of n-butyllithoum in hexane. Upon completion of the addition, the re- sultent solution was stirred for 2 hours with cool- . 10 ing. A solution of 15.0 g of 3-thiophene-carboxal- : - dehyde methylimine in 30 ml of toluene, vas then add- “ed, dropwise over 15 minutes, to the cooled solution.

Upon completion of the. 3-thiphens-carboxaldehyde methyl- - imine addition, the reaction mixture was stirred for : minutes at 0°C, quenched by the addition of 300 ml Co : | of water, concentrated, and extracted with dichloro- oo - methane. The combined extract wes dried over anhy- drous magnesium sulfate, filtered, and concentrated : to an oil. HPLC of the oil (Water's fssociates Prep. 20 1c/ ystem 500; silica gel; methanol as the eluent) atforded a semipurified product which was subsequently chromatographed under otherwise identical conditions - utilizing ethyl acetate, followed by methanol as eluents. “Yoncentration of the appropriate fractions and trituration oo - 37 - :

with hexane yielded 18.0 g of N-/2-/2-(methylamino) -2-(3-thienyl)ethyl/-phenyl/-2,2-dimethylpropan-~ amide, mp 81-84°C.

ANALYSIS: : 5 Calculated for C,gH, N08: 68.32%C 7.6lH 8.85%N © Found: 68.25%C 7.75%N 8.71%N

EXAMPLE 7 2-Amino-N-Methyl-of -(3-thienyl)benzenethanamine

A solution of 11.0 g of N-/2-/2- (methylamine) -2-(3-thienyl)ethyl/phenyl/-2,2-dimethylpropanamide in 150 ml of 6N hydrochloric acid was refluxed for 8 hours. The solution was then decanted into an ice- water mixture (S500 ml) and basified with 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloroemthane, dried over anhydrous magnesium sulfate and concentrated to an oil.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System $00, silica gel, methanol eluent). Concentration of the appropriate fractions yielded 3.21 g of 2-amino-N-methyl- of (3- thienyl)benzeneethanamine as an oil.

ANALYSIS:

Calculated for Cy 5H) gN St 67.20%C 6.94%H 12.06%N oo Found: 67.17%C 6.93%H 11.84%N

EXAMPLE 8 4,5-Dihydro-2,3-dimethyl-k-(3-thienyl)-3H-1,3~ benzo- diazepine

A solution of 6.50 g of 2-amino-N-me thyl- oC ~(3- thienyl) benzeneethanamine and 15.5 ml of triethyl- orthoacetate was treated with glacial acetic acid (9 ml). After refluxing for eight hours, the volatile ‘ components were removed at 20°C on a rotary evapora- tor. The residual oil was decanted into an ice-water mixture and basified with 10% sodium hydroxide solu- tion. The aqueous mixture was extracted with dichloro- methane and the organic phase was dried over anhydrous magnesium sulfate and concentrated to an oil. : Purification was accomplished by preparative HPLC (Water's Associates Prep LC/System 500, silica gel, elution with 2% triethylamine in methanol). Concen- tration of the appropriate fractions afforded a solid which was triturated with hexane and dried in vacuo at 50°C to yield 3.79 g of 4,5-dihydro-2,3-dimethyl- li_(3-thienyl)-3H-1,3-benzodiazepine; mp 113-117°C.

ANALYSIS:

Calculated for Cy JH) RyS: 70.27KC 6.20%H 10.93%N

Found: 69.88%C 6.30%H 10.82%N -

EXAMPLE 9 : §,5-Dihydro-2-ethyl-3-methyl-4-(2-thienyl)-3H-1,3- benzodiazepine hydrochloride

A stirred solution of 2.47 g of 2-amino-N-methyl- «. -(2-thienyl)benzenethanamine and 11.21 g of trie- thyl orthopropionate was treated rapidly with glacial acetic acid (4 ml). The golution was refluxed for 5 hours, allowed to stand overnight at room temperature, and concentrated on a rotary evaporator. A solution of the residual oil and 10% hydrochloric acid (50 ml) was extracted with ether (2 x 50 ml), basified with 10% sodium hydroxide solution and extracted with dich- loromethane (2 x 50 mi). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil.

Purification was accomplished by preparative HPLC ("ater's Associates Prep LC/System 500, silica gel, sample applied in dichloromethane, and eluted with 2% triethylamine in methanol), Concentration of the ap- propriate frections yielded ,5-dihydro-2-ethyl-3-me- thyl-4(2-thienyl)-3H, 1,3-benzodiazepine as an oil.

The oil was solubilized in 30 ml of anhydrous diethyl ether and treated with excess ethereal hydrogen chlo- ride to precipitate the corresponding hydrochloride . 25 salt. The precipitate was washed with ether, isolated - LO -

by vacuum filtration, washed again with ether and dried in vacuo at 40°C over sodium hydroxide pel- lets to give 1.86 g of 4,5-dihydro-2-ethyl-3- methyl-4~(2-thienyl)-3H-1,3-benzodiazepine hydro- chloride, mp 216-219°C.

ANALYSIS: “alculated for C, gH, gN,S "HCL: 62.6C 6.2u6H 9.13%N

Found: 62.24%C 6.2u%H 9.02%N

EXAMPLE 10 4,5-Dihydro=3-methyl-2-(1-propyl)-=(3-thienyl)- =3H-1,3-benzodiazepine

A solution of 4.80 g of 2-amino-N-methyl-oc (3-thienyl)benzeneethanamine and 18.35 ml of tri- methyl orthobutyrate was treated with 6.90 ml of : glacial acetic acid. After refluxing for 8 hours, to the volatile components were removed on a rotary evaporator. The residual oil was acidified with 10% hydrochloric acid solution, and extracted with diethyl ether (2 x 100 ml). The .aqueous layer was basified with 10% sodium hydroxide solution, and extracted with dichloromethane (3 x 100 ml).

The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to an oil. } : - hh -

oo . Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500A, si- lica gel, elution with 2% triethylamine in me tha- nol). Concentration of the appropriate fractions yielded an oil which solidified under refrigeration.

Trituration of the solid with hexane afforded gra- no nular crystals which wkere collected, washed with hexanes, and dried in vacuo to yield 4.08 g of 4, 5-dihydro -3-methyl-2-(1l-prop§l)-4-(3-theinyl)-3H- 1,3-benzodiazepine, mp. b4.5-5-46,5°C,

ANALYSIS:

Calculated for Cyl pol ,8¢ 71,78%C 7.09%H 9.85%N

Found: h 71.65%C 6.9UFH 9.92%N

EXAMPLE 11 4,5 Dihydro-3-methyl-2-(1-methylethyl)-4-(3-thienyl)- 3H-1,3-benzodiazepine hydrochloride monohydrate

A solution of 4.78 g of 2-amino-N-methyl-ol (3-thienyl)benzeneethanamine and 16.77 g of tri- methyl orthoisobutyrate was treated with glacial acetic acid (6.87 ml). After refluxing for 8 hra., the volatile components were removed on a rotary evapo- . rator. The residual oil was acidified with 10% hy- drochloric acid aqueous solution and extracted with

. a

J ' diethyl ether (2 x 100 ml). The aqueous solution was basified with 10% sodium hydroxide aqueous so- lution to a pH of 12, and extracted with dichloro- mate (3 x 100 ml).: The combined dichloromate la- yers were washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated to an oil.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/Syetem 500A; sili- ca gel; elution with 2% triethylaminegethanol). Con- centrations of the appropriate fractions yielded 4,5- dihydro-3-methyl-2-(l-methylethyl)-4-(thienyl)-3H-1,3- benzodiapepine., The oil was converted to the corres- ponding hydrochloride salt whibh was triturdted with =~ Ra : ether to yield 2.90 g of 4, 5~-dihydro=3-methyl-2-(1- methylethyl)-L-(3-thienyl)-3H-1,3-benzodiazepine hydrochloride monohydrate, mp. 119-122%.

ANALYSIS: - C . . : ] . alculated for Cy7H20N 8 HCl H,0t 60.24%C 6.84%H 8.27%N

Found: 60.20%C 6.59%H 8.31%N

ERAMPLE 12 4,5-Dihydro-3-methyl-2-phenyl-4-(3-ghienyl)-3H-1,3- benzodiazepine hydrochloride Co

A solution of 6.50 g of 2-amino-N-methyl- o-

(3-thienyl)benzeneethanamine and 14.5 ml of tri- methyl orthobenzoate was treated with glacial acetic acid (9 ml). After refluxing for eight hours, the volatile components were removed at 70°¢C on a rotary evaporator. The residual oil was decanted into an ice-water mixture and basi- fied with 10% sodium hydroxide solution. The aqueous mixture was extracted with dichloromathane and the organic phase was dried over anhydrous mag- nesium sulfate, filtered, and concentrated to an oil.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500A, sili- ca gel, eluted withsethanol). Concentration of the appropriate fractions yielded I, 5-dihydro-3-methyl-2- phenyl-l-(2-thienyl)-3H-1,3-benzodiazepine as an oil.

The oil was dissolved in methanol and treated dropwise with ethereal hydrogen chloride to precipitate the : i corresponding hydrochloride salt. Tye salt was col~- ) © lected by vacuum filtration, washed with ether, and dried overnight under vacuum to yield L,49 g of 4,5-

Co dihydro-3-methyl-2-phenyl-k-(3-thienyl)-3H-1,3-benzo- : diazepine hydrochloride, mp 266-269°C.

ANALYSIS:

Calculated for C,H, gh ,S “HCL: 67.68%C S5.4L0%H 7.90%R - hy oo

- —~

Found: 67.26%C S.46%H 7.78%N

EXAMPLE 13 4,5-Dihydro-2-ethyl-3-methyl-h-(3-thienyl)-3H-1,3- benzodiazepine hydrochloride

A solution of 6.00 g of 2-amino-N-methyl- o- (3- thienyl) benzeneethanamine and 10 ml of triethyl orthopropionate, was treated with 8 ml of glacial acetic acid, After refluxing for eight Bours, the volatile components were removed at 20° on a rotary evaporator. The residual oil was decanted into an jce-water mixture and basified with 10% sodium hydro- xide solution. The aqueous mixture was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentra- ted to provide lk, 5-dihydro-2-ethyls3- me thyl-b-(3- | - .

LL thienyl)-3H-1,3-benzodiazepine as an oil. = “a

Purification was accomplished by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing with 2% triethylamine in methanol as the eluent).

Concentration of the appropriate fractions yielded an 0il which was dissolved in methanol and treated drop - wise with ethereal hydrogen chloride. The resultant : precipitate was washed with ether and dried in vacuo to yield 3.89 g of 4,5-dihydro-2-ethyl-3-methyl-4-(3- i ous -

thienyl)-3H,1,3- benzodiazepine hydrochlorde, mp 242- 244°¢,

ANALYSIS:

Calculated for C,H, gN,S.HCI: 62.63%C 6.2U%H 9.13%N

Found: 62.71%C 6.26%H 9.06%N

EXAMPLE 1h ; N-/2-/Z-(Methylamino)-2~( 3-methyl-2-thienyl) ethyl] 2,2-dimethylpropanamide

A chilled solution (06°C) of 76.0 g of 2,2-dime- thyl-N-/{2-methyl) phenyl/ propanamide in 600 ml of tetrahydrofuran was treated dropwise over 1.25 hours with 344 ml of a 2.5 M solution of n-butyllithium in hexanes. After the addition was complete, the re- sultant solution was stirred for 2 hours with cool- ing and then was treated dropwise over 20 minutes, with a solution of 6.0 g of 3-methyl-2-thiophene- carboxaldehyde methylimine in 30 ml of toluene. After the addition was complete, the mixture was stirred for an additional 20 minutes. The reaction was quenched by the rapid addition of water. After concentration to remove the organic solvents, the residual oil- water mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous magne- sium sulfate, filtered, and concentrated to an oil. - Le -

Purification was accomplished by preparative

HPLC (Water's Agsociates Prep LC/System 500, silica gel, eluted with ethyl acetate). Concentra- tion of the appropriate fractions afforded an oil which was further purified by preparative HPLC to yield 70 g of N-/2-/2- (methylamine) -2-( 3-me thy1-2.% : thienyl)ethyl/pheny1/ 2y2-dimethylpropanamide as an oil,

Cl ANALYSIS:

Calculated for CioHogN,08: 69.05%C 7.93%m 8.u48xN

Found: 68.80%C 7.80%H 8.13%N

EXAMPLE 15 2-"mino-tipme thyl- ct -(3-ne thyl-2- thienyl) benzene tha- mine TTT

A solution of 35. 0 g of N-/2-/2-(methylamino)- 2-( 3-methyl-2-thienyl)ethyl/phenyl7-2,2-dime thyl- . propanamide in $00 ml of 6N hydrochloric acid was refluxed for 8 hours. The solution was then decant- ¢d into an ice-water mixture and basified with 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane (2L), dried over an- hydrous magnesium sulfate and concentrated to an oil.

Purification was accomplished by preparative Cs

HPLC (Water's Associates Prep LC/System 5004, silica gel, eluted with methanol). Concentration of the appropriate fractions yielded 6.42 g of 2-amino-N- me thyl-of ( 3-me thyl-2-thienyl)-benzeneethanamine as an oil,

ANALYSIS:

Calculated for CyB, gN,8¢ 68.25%C 7.36%H 11.37%N

Found: 68.35%C 7.26%H 11.35%N

EXAMPLE 16 45=Dihydro-2,3-dimethyl-b-( 3-methyl-2-thienyl)=-3H-1,3-benzodia-~ C zepine hydrochloride monohydrate

A solution of 4.42 g of 2-amino-N-methyl-ol- (3-methyl-2-thienyl) benzeneethanamine and 10 ml of triethyl orthoacetate was tested with glacial acetic acid (8 ml). After refluxing for eight hours, the volatile components were removed at 70°¢C on a rota- ’ oo 15 ry evaporator. The residual oil was decanted into an ice-water mixture and basified with 10% sodium hydroxide solution. The agueous mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to an oil. purification was accomplished by preparative

HELC (Water's Associates Prep LC/System 500, Silica gel, eluted with 2% triethylamine in me thanol). Con- centration of the appropriate fractions yielded U4,5-

dihydro-2,3-dimethyl-4- (3-methyl-2-thienyl)-3H-1, 3-benzodiazepine as an oil. The corresponding hy- drochloride salt was made by dissolving the oil in methanol and treating with ethereal hydrogen chlo- 6 ride. After diluting with anhydrous ether, a pre- cipitate separated. The solid was collected and dried overnight at 40°C under vacuum to yield 2.52 g of ky5-dihydro-2,3-dimethyl-4¢3methyl-2-thienyl) 3H~ 1,3-benzodiazepine hydrochloride monohydrate, mplL40- 142%.

ANALYSIS:

Calculated for C,6H18N,S<HC1IH,0: . 59.1Mc 6.51% 8.62n CC 0 Tr

Found: 59.36%¥C 6.25%H 8.S5&N

EXAMPLE 17 . 445-Dihydro-2-ethyl-3-methyl-4(3-methyl-2-thienyl)- 2H 1,3-benzodiazepine hydrochloride monohydrate

A stirred solution of 2.94 g of 2-amino-N- methyl-ol -(3-methyl-2-thienyl)benzeneethanamine and 12.58 g of triethyl obtthoprpionate was treated rapid- ly with glacial acetic acid (4.0 ml). T,e solution wag refluxed for 8 hours, cooled to room temperature and concentrated on a rotary evaporator at 80°. The residue was slurried with ether and treated with 50ml of 10% hydrochloride acid solution. The aqueous phase - ho was washed with ether, basified with 10% sodium hydroxide solution (60 ml), and extracted with dichloromethane (2 x 50 ml). The combined or- ganic phase was dried over anhydrous sodium sul- fate, filtered and concentrated to an oil. purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500A; silica gel; sample applied in dichloromethane (20 ml); elution with 2% triethylamine in methanol. “oncentration of the appropriate fractions yielded

I,5-dihydro-2-ethyl-3-methyl-L-(3-methyl-2~thienyl) 3§-1,3-benzodiazepine as an 0il. The oil was dis- solved in methanol (5 ml) and ether (2 ml), and the resulting solution treated with a slight excess of ethereal hydrogen chloride. Further dilution with ether precipitated the corresponding hydrochloride salt. The precipitate was isolated by vacuum filtra- - tion, washed twice with ether, and dried in vacuo at 40°C to yield 1.9 g of 4,5-dihydro-2-ethyl-3-methyl-

L-( 3-me thyl-2-thienyl)-3H-1,3-benzodiazepine hydro- chloride monohydrate, mp 185-206°C.

ANALYSIS:

Calculated for Cy Hol 8+ HCL. H,0 60.25%C 6.84%H 8.27%N

Found: 60.15%C 6.88%H 8.46EN

EXAMPLE 18 , 5=Dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl- 2-thienyl)-3H-1,3-benzodiazepine hydrochloride

A solution of 5.86 g of 2-amino-N-methyl- of (3-methyl-2-thienyl) benzene thanamine and 19.56 g of trimethyl orthoisobutyrate was treated rapidly with 7.94 ml of glacial acetic acid. The solution was refluxed for 8 hours under nitrogen and concentrat- ed on a rotary evaporator at 40°C. The residual oil was acidified with 10% hydrochloric acid solution and extracted with ether (3 x 100 ml). The aqueous phase was basified with 10% sodium hydroxide solu- tion and extracted with dichloromethane (3 x 100 ml).

The organic phases was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Puri- fication ‘was :accdmplished by HPLC (Water's Associates prep LC/System 500A; silica gel, utilizing methanol followed by 2% triethylamine in methanol as succesive . eluents). Concentration of the appropriate fractions yielded 1.88 g of 1.88 g of L,5-dihydro-3-methyl-2- (1-methylethyl)-l-(3-methyl-2-thienyl)-3H-1,3-benzodia- gepine as an oil. The oil was treated with ethereal : hydrogen chloride and the resulting precipitate was triturated with ether to yield 1.80 g of 4,5-dihydro _3-me thyl-2-(1-methylethyl)-k-(3-me thyl-2-thienyl)-3H-

1,3-benzodiazepine hydrochloride, mp 240,5-241.0°C.

ANALYSIS:

Calculated for C,gH MN S.HCl: 64,55%C 6.92%H 8.37%N 64.23%C 6.96%H 8.27%N

EXAMPLE 19 4,5-Dihydro-3-methyl-l-(3-methyl-2-thienyl)-2-phenyl- 3H-1,3-benzodiazepine hydrochloride 8 stirred solution of 2.19 g of 2-amino~N-methyl- of -(3~methyl-2-thienyl)benzenethanamine and 0.88 g of trimethyl orthobenzoate was treated rapidly with 2.4 ml of glacial acetic acid, and heated under reflux for 8 hours. The solution was concentrated at 75°C on a ro- tary evaporator (vacuum pump) to a syrup. The syrup was then partioned between 10% hydrochloric acid solu- tion (50 ml) and ether. The aqueous phase was extracted again with ether, basified with 10% sodium hydroxide solution (60 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic phase was dried over an- hydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by preparative HPLC (Water's or Associates Prep Lc/ ystem 500 A, silica gel, sample . applied in dichloroemthane, 2% triethyjamine in metha- nol as the eluent). Concentrated of the appropriate fractions yielded 2.80 g of 4,5-dihydro-3-methyl-4-(3- methyl-2-thienyl)-2-phenyl-3H-1,3-benzodiazepine as an

- oil.

A solution of the oil and methanol (5 ml) was treated with a slight excess of ethereal hydrogen chloride. further dilution with ether precipitated the corresponding hydrochlokide salt. The precipi- tate was isolated and dried in vacuo at 40°C to yield 2.13 g of 445-dihydro-3-me thyl-k-(3-me thyl-2-thisnyl) -2-phenyl-3H-1,3-benzodiazepine hydrochloride, mp221- 224°.

ANALYSIS:

Calculated for Co Hol, S.HCL: 68.37%C 5.74%H 7.59%N

Found: 67.95%C 6.01%H 7.57%N

EXAMPLE 20

N-/2-72-(Methylamino)-2-(2-pyridinyl)ethyl/phenyl7-2,2- dimethylpropanamide "A chilled solution (=5°C) of 38.26 g of 2,2-dime- thyl-N-/3-me thyl) phenyl /propanamide in 300 ml of tetra- - - hydrofuran was treated dropwise over 1.25 hour with 176 ml of a 2.5 M solution of n-butyllithium in hexanes.

After the addition was complete, the resultant solution . was stirred for 2.5 hours with cooling and then was . treated dropwise over 15 minutes with a solution of 28.84g of 2-pyridinecarboxaldehyde methylimine in: 60 ml of to- luene. The solution was stirred for an additional 15 minutes, quenched by the rapid addition of water (250 ml), and concentrated. The residue was extract- ed with dichloromethane (750 ml). The organic phase was dried ever anhydrous magnesium sulfate, and con- centrated to an oil.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the a appropriate fractions yielded an oil which was fur- ther purified by preparative HPLC until free impuri- ties to yield 10 g of N-/2/2-(methylamino)-2-(2- pyridinyl)ethyl/phenyl/2,2-dimethylpropanamide as an oil.

Cy ANALAYSIS:

Galculated for CygHo5N 508 73.28%C 8.09%H * ound 72.84C 7.89%H

EXAMPLE 21 2-Aminoe-N-Methyl-of -(2-pyridinyl)benzeneethanamine

A solution of 8.0 g of N-/2-/2-(methylamino)-2- (2-pyridinyl)ethyl/phenyl/-2,2-dimethylpropanamide in 100 ml of 6N hydrochloric acid was refluxed for 8 hours. The solution was then decanted into ice- water (250 ml) and basified with 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane (500 ml), dried over anhydrous mag- : nesium sulfate and concentrated to an oil,

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the - appropriate fractions yielded 2.5 g of 2-amino-N-~ methyl-¢/ -(2-pyridinyl)-benzeneethanamine aa an oil.

ANALYSIS:

Cc . alculated for CH pHs 73-98%c 7.54%H ¥ound: 73.7W%C 7.54%H

EXAMPLE 22 4,5-Dihydro-2,3-dimethyl-2-(2-pyridinyl)-3H-1,3- _ benzodiazepine hemihydrate

A solution of 8.00 g of 2-amino-N-methyl- og- (2-pyridinyl)benzeneethanamine and 36 ml of triethyl- orthoacetate was treated with glacial acetic acid (12 m1). After refluxing for eight hours, the vola- tile components were removed at 70°%¢ on a rotary evaporator. The residual oil was decanted into an } ice-water mixture and basified with 10% sodium hydro- xide solution. The aqueous mixture wae extracted with dichloromethane, dried over anhydrous magnesium sul- fate and concentrated to an oil.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System, silica gel, eluted with 2% triethylamine in methanol).

Concentrated of the appropriate fractions afforded an 0il which solidified on standing. The solid was re- €rystallized from acetonitrile to yield 2.19 g of 4,5-dihydro-2,3-dimethyl-4-(2-pyridinyl)-3H-1, 3- benzodiazepine hemihydrate, mp. 123-125%.

ANALYSIS:

Calculated for C, Hy N35 0-5H,01 73.90%C 6.97%H

Founds 74.38%C 6.93%N

EXAMPLE 23 4,5-Dihydro-2-ethyl-3-me thyl-4-(2-pyridinyl)-3H-1,3~ benzodiazepine dihydrachloride monohydrate

A solution of 5.0 g of 2-amino-N-methyl- o~

Co pyridinyl)benzeneethanamine and 13.3 ml of triethyl orthopropionate was treated with § ml of glacial ace- : tic acid. After refluxing for eight hours, the vola- tile components were removed at 20°¢c on a rotary eva- porator. The mixture residual oil was decanted into an jce-water mixtures and basified with 10% sodium hydro- xide solution. The aqueous mixture was extracted with dichloromethane, and the organic phase was filtered, dried over anhydrous magnesium sulfate, and concentrat- ed to an oil.

Cos

Purification was accomplished by preparative

HPLC (Water's Associates Frep LC/System 500, sili- ca gel, elution with 2% triethylamine in methanol)/

Concentrated of the appropriate fractions afforded 4,5. Ce 6 dihydro-2-ethyl-3-methyl-b-(2-pyridinyl)-3H-1,3-benzo- diazepine as an oil. The oil was dissolved in methanol ~ and treated with ethereal hydrogen chloride. Dilution with diethyl ether precipitated the corresponding hy- drochloride salt. The salt was collected and dried in ) 10 vacuo to yield 3.18 g of 4,5-dihydro-2-ethyl-3-methy- k-(2-pyridinyl)-3H-1,3-benzodiazepine dihydrochloride monohydrate, mp 235 0 240°C.

ANALYSIS:

Calculated for

Cy fyoly ZHCL Ho 57.28%C 6.58%H 11.79%N

Found: | 57.72%C 6.32% 1L.79%N

EXAMPLE 2h ~ 4y5-Yinydro-3-methyl-2-phenyl-4-(2-pyridinyl)-3H-1,3- benzodiazepine dihydrochloride hydrate (4:1)

A solution of 3.5 g of 2-amino-N-methyl-o( -2- pyridinyl)benzeneetharamine and 14 ml of trimethyl orthobenzoate was treated with 8 ml of glacial acetic acid. After refluxing for eight hours, the volatile components were removed at 70°C on a rotary evarorator.

The residual oil was decanted into an ice-water mixture and basified with 10% sodium hydroxide solution. The aqueous mixture was extracted with "dichloromethane and the organic phase was dried over anhydrous mag- nesium sulfate, filtered, and concentrated to an oil.

Purification was accomplished by preparative : HPLC (water's Associates Prep LC/System 500, silica

Cc gel, elution with 2% triethylamine in methanol). Con- centration of the appropriate fractions afforded an oil which was dissolved in methanol and treated with ethereal hydrogen chloiide. Dilution with diethyl . ether precipitated the hydrochloride salt. The salt was collected by vacuum filtration and dried in vacuo to yield 1.42 of k,5-dihydro-3-me thyl-2-phenyl-h-(2- pyridinyl)-3H-1,3-benzodiazepine dihydrochloride hy- drate (4:1), mp 244-247°C.

ANALYSIS:

Calculated for C,H gg 2HC1.0.25H,0: 64.51%C 5.54%H 10.75%N

Found: gh. b6%C 5.64%H 10.508N

EXAMPLE

_ N-Acetyl-2-amino-N-Methyl-d. ~(2-pyridinyl)benzeneethan- amine

A solution of 4.5 g of 2-amino-N-methyl- « -2- pyridinyl)benzeneethanamine in 60 ml of potassium hy- droxide dried pyridine was thoroughly chilled and treat- ed dropwise with 3.0 ml of acetic anhydride. After stir- ring overnight at room temperature, the reaction mix- ture was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, vacuum filtered, and concentrated to an oil, which solidified on standing.

The solid was recrystallized from acetonitrile and dried for 6 hours at 60°C under vacuum to yield 2.96 g of N-acetyl-2-amino-N-methyl-ot.~(2-pyridinyl)benzene- ethanamine, mp 103-107°C, .

ANALYSIS: * 15 Calculated for Cy6H1gN308 71.34%C 7.11%H 15.60%N

Found: 71.01%C 7.03%H 15.42%N

EXAMPLE 26 © N=/2-/Z-(N-Acetyl-N-methyl)amino-2-(2-pyridinyl)ethyl] phenyl/acetamide

A chilled solution of 4,5 g of 2-amino-N-methyl o~-(2-pyridinyl)benzenethanamine in 60 ml of potas- sium hydroxide dried pyridine was treated dropwise with 6 ml of acetic anhydride. After stirring over- night at room temperature, the reaction mixture was basified with 10% hydroxide solution and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, vacuum filtered, and concentrated to a solid. The solid was recrys- tallized from acetonitrile and dried for 6 hours at 60°C under vacuum to yield 3.52 g of N-/2-/2-(N- acetyl-N-methyl)amino-2-(2-pyridinyl)ethyl/phenyl/ acetamide mp 121-124°C, : ANALYSIS: for C,gHpy M050 69.43%C 6.80%¥H 13.50%N

Found: 69.33%C 6.76%H 13,50%N

EXAMELE 27

N-/2-/2-(Methylamino)-2-(3-pyridinyl)ethyl/phenyl/ -2,2-dimethylpropanamide

A stirred, chilled (-5°C) solution of 57.38 g of N-(2-methylphenyl)-2,2-dime thylpropanamide and 600 ml of tetrahydrofuran was treated dropwise over 1.25 hour with 264% ml of 2.5 M m-butyllithium in he- ~ xane during which time the temperature did not exceed +3%C (dry nitrogen atmosphere). The resultant solu- tion was stirred for 35 min. with cooling and was then treated dropwise over 30 min, with a solution of 39.21 g of 3-pyridinecarboxaldehyde methylimine and 90 ml of toluene (temperature maintained below +3°%C). “fter stirring of 0°C for 15 mén. the solu-

tion was quenched by the addition of water (200 ml) ’ and concentrated. The residue was extracted with : dichloromethane (2 x 200 ml). The combined organic phase was dried over anhydrous sodium sulfate, fil- tered, and concentrated to an oil (117.4 g). purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500A, silica . gel, sample applied in dichloromethane, eluted with me thanol) « Concentration of the appropriate fract- jons yielded an oil. A solution of the oil and diethyl . ether was filtered, and the filtrate was concentrated to give 14.6 of crude product. The crude product was purified by preparative HPLC (sample applied to the silica gel comuns in 25 ml of dichloromethane, ebiited first with ethyl acetate followed by elution with 10% “ methanol in dichloromethane). The appropriate fract- jons were combined and concentrated to an oil (10.6 g)

Bh which crystallised on trituration with hexane, The solid was isolated, washed with hexane, and dried in vacuo at ambient temperature to afford 9.24 g of N- [5.5 (an thylamino)-2-(3-pyridinyd) ethyl phensif 2 Ee . : dimethylpropanamide, mp 91.5-96°C.

ANALYSIS: talculated for Cy gf 5M 50? 73.28%C 8.09%H

Found: 72.75%C 7.9uH : - 61 = oo oo

: . : . ‘

EXAMPLE 28 2-Amino-N-methyl-o -(3-pyridjnyl)benzeneethanamine

A stirred solution of 7.13 g of N-/2-/2-(me- thylamino)-2-(3-pyridinyl)ethyl/phenyd/-2,2-dime- thylpropanamide in 90 ml of 6N hydrochloric acid was refluxed for 5.5 hours and then allowed to stand overnight at room temperature. The solution was decanted . over crushed ice, diluted with water (200 ml) and basi- : | fied with 50% sodium hydroxide solution. The mixture was extracted with dichloromethane (3 x 150 ml) and the combined, organic phase das dried anhydrous sodium sul- fate, filtered, and concentrated. to an oil. The oil was purified by preparative HPLC (Water's Associates

Prep LC/System 500 A, silica gel, sample applied in dichloromethane, eluted with 2% triethylamine in me tha- nol). “oncentration of the appropriate fractions yield- ed 4.69 g of 2-gmino-Npmethyl-of ~(3-pyridinyl)benzene- : ethanamine as an oil. © ANALYSIS:

Calculated for Co Hi Ny: 73.98%C 7.54%

Found: 7%.82%C 7.U49%H

Co EXAMPLE __ 29 b,5-Dinydro-2-ethyl-3-methyl-B-(3-pyridinyl)- 3H=1,3- benzodiazepine : A stirred solution of 4.47 g of 2-amino-N-methyl-

~ a~(3-pyridinyl)benzeneethanamine and 20.8 g of triethyl orthopropionate was treated rapidly with glagial acid (4.4 m1). After refluxing for 7 hours with exclusion of moisture, the solution was concentrated on a rotary evaporator. The residual syrup was dissolved in 10% hydrochloric acid (100 ml) and the solution was extracted with diethyl ether (2 x 100 ml). The aqueous phase was basified with 10% sodium hydroxide solution and the turbid mixture was extracted with dichloromethane (2 x 100 ml). The or- ganic phase was dried over anhydroys sodium sulfate, filtered, and concentrated to an oil.

Purification was accomplished by preparative HPLC (silica gel, sample applied in dichloromethane, eluted _ with 2% triethylamine in methanol). Concentration of the appropriate fractions and trituration with hexane , afforded 2.51 g of 4y5-dihydro-2-ethyl-3-methyl-4-(3- i» pyridinyl)3H-1,3-benzodiazepine, mp 72-75%. - ANALYSIS: “alculated for CoH) gM 76 .95%8 7.22%H

Found: 77.16%C 7.22%H

EXAMPLE 30 by 5-Dihydro-2,3-dime thyl-b~( 3-pyridinyl)-3H-1,3- benzodiazepine oo - 63 -

A stirred solution of 2.5 g of 2-amino-N- methyl-o -(3-pyridinyl)benzenethanamine and 10.71 g of triethyl orthoacetate was treated with 2.5 ml of glacial acetic acid. After refluxing foe eight hours, the volatile components were removed 70°C on a rotary evaporator. The residual syrup was dissolved in 10% hydrochloric acid (120 ml) and the solution was ex- tracted with ether. The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichlo- romethane (2 x 70 ml). The combined organic phase was oo dried over anhydrous sodium sulfate, filtered, and con- centrated to an oil.

Purification was accomplished by HPLC (Water's As- . 15 sociates Prep LC/System 500A, silica gel, oil applied in dichloromethane, eluted with 2% triethylamine in me- thanol). Concentration of the appropriate fractions yielded an oil which was dissolved in diethyl ether, filtered to remove a trace of insoluble material, and : 20 concentration until most of the ether was removed, The residual oil was sealed with crystals obtained from a previous synthesis and dried in vacuo to give 1.32 g of 4,5-dihydro-2,3-dimethyl-h (3-pyridinyl)-3H-1,3-benzo- diazepine, mp 145-148%C.

ANALYSIS:

Calculated for C,H Ny: 76. 46%C 6.82%H * ound: 76. 37%C 6.78%H - 6h =

. : .

EXAMPLE 31 2-/2-(Methylamino-2-(4-pyridinyl)ethyl/phenyl/-2,2- dimethylpropanamide

A chilled solution (-5°C) of 95.65 g of 2,2- dime thyl-N-/2-/2-(methylamino)-2-(4-pyridinyl)~-ethyl/ phenyl/ propanamide in 800 ml of teterahydrofuran was treated dropwise over 2 hours with 440 ml of a 2.5 M solution of n-butylithium in hexanes. After the addi- tion was complete, the resultant solution was stirred for 2 hours with cooling, and then was treated drop- wise over 20 min. with a solution of 71.0 g of h- pyridine carboxaldehyde methylimine. The solution was stirred for an additional 20 minutes, quenched by the addition of water (350 ml), and concentrated. The re- sidue was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, fil- tered, and concentrated to an oil. : Purification was accomplished by preparative HPLC ("ater's Associates Prep LC/system 500A, silica gel, eluted with ethyl acetate). Concentration of the appro- priate fractions yielded an oil which was further puri- . fied by preparative HPLC until free of impurities, tri- turated with hexane, and dried under vacuum to yield 2-/2-/methylam no-2-(2-pyridinyl)ethyl/phenyl/-2,2~ dimethylpropanamide, mp 114-116°C.

. ANALYSIS:

Calculated for C,H,gN,O: 73.28%C 8.09%H 13.B9%N

Found: 73.18%C 8.33%H 13.77%N

EXAMPLE 32 2-Amino-N-methyl-ol - (lk-pyridinyl)benzenethanamine

A solution of 25 g of N-/2-/2-methylamino-2-(4- ’ : pyridinyl)ethyl/phenyl/-2,2-dimethylpropanamide in 6N hydrochloride acid (260 ml) was refluxed for 8 hours.

The solution was then decanted into an ice-water mix- ture (800 ml), basified with 50% sodium hydroxide solution, and the mixture extracted with dichloromethane (2000 ml). The extract was dried over anhydrous mahne- sium sulfate and concentrated to an oil which solifified upon standing. purification was accomplished by preparative HFLC (Water's Associates Prep LC/Syetm 500A, silica gel, elut- ed with methanol). Concentration of the appropriate fractions yielded a solid which was triturated with he- xane and dried overnight in vacuo at ambient temperature to yield 13.52 g of 2-amino-N-methyl-oC -(4-pyridinyl) benzenethanamine, mp 69-71°C.

ANALYSIS:

Calculated for C,H Ng: 73.98%C 7 ..54%H

. Found: 73.97%C 7. 5U%H

EXAMPLE 33 : b, 5.Dihydro-2,3-dimethyl-k- (4-pyridinyl)-3H-1,3- benzodiazepine }

A solution of 4.0 g of 2-amino-N-methyl-ol - (4-pyridinyl)benzeneethanamine and 18 ml of triethyl orthoacetate was treated with glacial acetic acid (6 ml). After refluxing for 8 hours, the volatile . components were removed at 70°C on a rotary evaporator.

The residual oil was decanted into an ice-water mix- ture, basified with 10% sodium hydroxide solution, ex~ tracted with dichloromethaneg dried over anpydrous mag- - I nesium sulfate, and concentrated to an oil.

Furification was accomplished by preparative HPLC (Water's Associates Prep/System 500, silica gel, eluted with triethylamine in methanol). The appropriate fract- Pe jons were combined and concentrated to an 0il which so- 1idified upon standing. The solid was recrystallized from acetonitrile (10 ml) to yield 2.18 g of 4,5-dihydro . _2, 3-dime thyl-b-(i-pyridinyl)-3-1,3-benzodiazepine, mp . 159-161°C.

ANALYSIS: : J 6.82%

Calculated for Cygiiinls 76. 46%C H

Found: 76 .50%C 6.59%H

. a

EXAMPLE 34 4,5-Dihydro=2-cthyl-3-methyl-4-(4-pyridinyl)-3H-_ 1,3-benzodiazepine hemihydrate :

A solution of 5.00 g of 2-amino-N-methyl-of - (4-pyridinyl)benzeneethanamine and triethyl orthopropio- nate (24.33 ml) was treated with glacial acetic acid (7.34% m1), After reflusing for 8 hours, volatile com- ponents were removed at 40°C on a rotary evaporator.

The residual oil was acidified with 10% hydrochloride acid aqueous solution (75 ml) and extracted with diethyl ether (3 x 100 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichlo- romethane {3 x 100 ml). The combined dichloromethane layers were washed with water (100 ml), dried over an- hydrous sodium sulfate and concentrated on a rotary eva- porator to an oil.

Furification was-accomplished by preparative HPLC (¥ater's Associates Prep/System 500A, silica gel, elut- ed with 2% triethylamine in methanol). Concentration of ' the appropriate fractions afforded an oil, which solidi- : fied upon refrigeration. The solid was triturated with . - ether, and dried in vacuo to afford 2.98 g of 4,5-dihydro- -2-ethyl-3-methyl-4(4-pyridinyl)-3H-1,3-benzodiazepine hemihydrate, mp 58-68°¢C.

¥

ANALYSIS: } :

Q .

Calculated f . or Cpt 0 5H,0, 74. 42%C 7.35%H 15.32%N

Found: 75:22%C 7.22%H 15.43%N

EXAMPLE 35 ~ 4,5-Dihydro-3-methyl-k-(3-me thyl-2-thienyl)-2-(1- propyl)-3H-1,3-benzodiazepine hydrochloride mono-

HYDRATE

A solution of 5.0g of 2-amino-N-methyl-o, -(3- methyl-2- thienyl) benzeneethanamine, 18.02 ml tri- methyl orthobutyrate and 6.8 ml of glacial acetic acid was refluxed for 8 hours under a nitrogen at- mosphere. The solution was concentrated at 40°C on a rotary evaporator and the residual oil was acidified wi with 10% hydrochlokrte acid solution (60 ml) and ex- tracted with diethyl ether (3 x 70 ml). The acidic ’ aqueous phase was basified with 10% sodium hydroxide solution (100 ml) and extracted with diethyl ether : (3 x 100 ml). The ethereal phase was dried over so- dium sulfate/ magnesium sulfate, filtered and concen- . trated to an oil. Purification was accomplished by

HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of

. . * the appropriate fractions yielded 4,5-dihydro-3- me thyl-l=(3-methyl-2-thienyl)-2-(1-propyl)-3H-1,3- benzodiazepine as an oil.

The oil was treated with ethereal hydrogen chloride, and the resultant precipitate tritutated with ethyl acetate to afford 2.93 g of 4,5-dihydro -3-me thyl-k-( 3-me thyl-2-thienyl)-2-(1-propyl)-3H- 1,3-benzodiazepine hydrochloride monohydrate, mp 181.5 -182.0%.

ANALYSIS:

Calculated for C, gH, NS HCL H,0: 61.25%C 6.57%H 7.9WEN

Found: 61.60%C 6.96%H 8.L1%N

EXAMPLE _ 36 oo 15 (a) 2-Amino-5-bromo-N-methyl-a -(3-methyl-2-thimnyl)- benzeneethanamine

A stirred solution of 5.02 g of 2~-amino~-N-methyl- o.-(3-methyl-2-thienyl)benzeneethanamine and 79 ml of . dimethylformamide was treated with a solution of 4.71g

N-bromosuccinimide in 55 ml of dimethylformamide. The solution was stirred for 8 hour with the exclusion of moisture and then concentrated to an oil on a rotary evaporator (70°@) under high vacuum. he oil was diltt- ed with distilled water (100 ml) and basified with a 10%

sodium hydroxide solution (25 ml). The basic solu- tion was extracted with dichloromethane (3 x 100 ml).

The organic phase was dried over anhydrous sodium sul- fate, filtered and concentrated to an oil. Thin la- yer chromatography (silica gel, methanol eluent) in- dicated a 2-component mixture.

Purification was accomplished by preparative

HPLC (Water's Associates Prep LC/System 500, silica gel, utilizing methanol as the eluent). Concentra- tion of the slower eluting fractions yielded an oil which was dissolved in diethyl was collected and dried ' to afford 2.6 g of 2-amino-5-bromo-N-methyl- ol ~3~ methyl-2-thienyl)-benzenethanamine, mp 68-70°C.

ANALYSIS:

Calculated for Cy Hy Br SH 51.70%4C 5.27%H 8.61%N

Found: 52.11%C S5.18%H 8.L43%N (b) 2-Amino -3,5-dibromo-N-methyl-o -(3-methyl-2- thienyl)-benzenethanamine dihydrochloride

The faster eluting fractions obtained from the

HPLC separation described supra were concentrated to an oil which was dissolved in diethyl ether, filtered free of insoluble material and concentrated. Tritura- tion of the resultant oil with hexane afforded 2-amino-3, 5-dibromo-N-methylmoC ~(3-methyl-2-thienyl)benzeneethan-

8 amine as a solid, The solid was dissolved in me- thanol and treated with ethereal hydrogen chloride.

Dilution with diethyl ether precipitated 0.9 g of the ebrresponding dihydrochloride salt, mp 141-143.

ANALYSIS:

Calculated for C,H, gBr N,S8.2HC1: 35.25%C 3.80%H 5.87%N

Found: 35.55%C 3.89%H 5.51%N

EXAMPLE 37

N-/2-/2-(Methylamino) ~2-(5-methyl-2-thienyl) e thyl/phenyl/- 2,2-dimethylpropanamide hydrochloride hemihydrate

A stirred, chilled (5°C) solution of 60 g of 2,2- dime thyl-N/T2-methyl) phenyl/propanamide and 470 ml of tetrahydrofuran was treated over one hour with 284 m of a 2.5M solution of n-butyllithium in hexane (nitro- gen atmosphere). The solution was stirred for 45 min. at 0°C and the resultant suspension was then treated © over one hour with a solution of 52.41 g of 5-methyl-2- thiophenecarboxaldehyde methylimine in 479 ml of tetra- hydrofuran (temperature maintained below 10°C). After stirring the mixture at room temperature for bs minutes 225 ml of water was added to quench the reaction. The mixture was concentrated on a rotary evaporator and the aqueous residue was extracted with diethyl ether (3 x

100 ml). The combined organic phase was dried over anhydrous sodium sulfate and magnesium sul- fate, filtered, and concentrated to yield 11k g of N-/Z-/3-(methylamino) -2-(5-methyl-2-tnienyL) ethyl/ 2,2-dimethyl propanamide as an oil.

A 10 g aliquot of the 0il was purified by preparative HPLC (Water's Associates Prep LC/Sys- tem S00 A, silica gel, sample applied in dichlo- ’ romethane, eluted with 25% acetone in hexane). A solution of the oil and methanol was treated with a slight excess of ethereal hydrogen chloride and then diluted with diethyl ether to yield N-/2-/2- (me thylamino)-2- ( 5-me thyl-2-thienyl) -ethyl/phenyl/ 2,2-dimethylpropanamide hydrochloirde hemihydrate (3.0 g), mp 91-101°C.

ANALYSIS: - calculated for C, gH gH 0+HC1. 0.5008 60.70%C 7.51%H 7.45%N "Found: 60.55%C 7.45%H 7. 34%N

EXAMPLE _38 >—Anino-N-methyl-q -(5-me thyl-2-thienyl)benzenee than: amine

A solution of 22.73 g of N-{2-/2-(methylamino)-2- (8-me thyl-2-thienyl)ethyl/phenyl/-2,2-dimethylpropan- amide and 100 ml of 6N hydrochloric acid solution was refluxed for eight hours. The solution was decant- ed over 200 ml of ice and basified with 70 ml of a 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane and the organic 6 phase was dried over anhydrous sodium sulfate, fil- tered, and concentrated to an oil.

Purification was accomplished by preparative - HPLC (Water's Associates Prep LC/System 500, silica gel, eluted with methanol). Concentration of the appropriate fractions afforded an oil which was dis- solved in 100 ml of diethyl ether, filtered to re- move any insuloble impurities, and concentrated to yield 10.77 g of 2-amino-M-methyl-e -(S5-methyl-2-thienyl) benzeneethanamine as an oil.

ANALYSIS:

Calculated for C,H, oN. 8: 68.25%C 7.36%H 11.37%N

Founds 68.07% 7.2090 11l.1L%N

EXAMPLE 39 l,5-Dihydro-2,3-dime thyl-l-(5-me thyl-2-thienyl)-3H~- 1, 3-benzodiazepine

A stirred solution of 7.1 g of 2-amino~-N-methyl- o- (5 methyl-2-thienyl)benzeneethanamine and 31.6 ml IE of triethyl orthoacetate was treated with 6.9 ml of glacial acetic acid. After refluxing for 8 hours the ) 25 solution was concentrated at 20°¢ on a rotary evaporator.

The resulting oil was washed with 10% hydrochloric gcdi solution (120 ml), followed by ether (2 x 100 ml). The aqueous phase was basified with a 10% so- dium hydroxide solution (120 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic phase was dried over anhydrous sodium sulfate, fil- tered and concentrated. The concentrate was puri- fied by preparative HPLC (Water's Associates Prep Lc/ :

System 500, silica gel, eluted with 2% triethylamine } 10 in methanol). Concentration of the appropriate frac- tions yielded an oil. * The oil was dissolved in diethyl ether and filtered to remove insuluble impurities. Con- centration of the filtrate yielded 3.15 g of 4,5-dihy- 'dro-2, 3-dimethyl-2-(5-methyl-2-thienyl)-3H-1,3-benzo- diazepine, mp 139-140°C.

ANALYSIS: ’ o

Calculated for Ciel, 8M 058 71.07%C 6.71%H 10. 36%N : ~- Founds 71.06%C 6.88% 10:.22%N

EXAMPLE _ 40 \,5-Dihydros2-othyl-3-metnyl-b-(S-nethyl-2-thiewD) 3 1,3-benzodiazepine

A stirred solution of 5.88 g of 2-amino-N-methyl- o - (5-methyl-2-thienyl)benzeneethanamine and 29 ml of triethyl orthopropionate was treated with 5.5 ml of glacial acetic acid. After refluxing for & hours, the solution was concentrated to an oil at 70% on . a rotary evaporator. The oil was washed with a 10% hydrochloric acid solution (100 ml) and water was added to dissolve observed solids. The aqueous phase was washed with diethyl ether (2 x 50 ml) and then - basified with a 10% sodium hydroxide solution (100 ml). The mixture was extracted with dichloromethane (3 x 100 ml) and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concen~ trated,

Purification was accomplished by prep arative HPLC (Water's Associates Prep LC/System 500, silica gel, 2% triethylamine in methanol as the eluent). Concentration of the appropriate fractions yielded an oil which was } dissolved in ether and filtered to remove all traces ’ of inséluble material. The filtrate was concentrated to an oil, which has triturated with hexane to afford 1.51 g of 4,5-dihydro-2-ethyl-3-methyl-b-(S-methyl-2- . : 20 thienyl)3H-1,3-benzodiazepine as a solid, mp 66°C.

ANALYSIS:

Calculated for CypHooN 8: 71.79%C 7.09%H 9-85%N

Found: 71.74%C 7.21%H 9.90%N v

EXAMPLE 41 2,/(2,5-Dioxo-1-pyrrolidinyl)me thyl/amino-N-formyl

N-me thyl-o&.~ (3-mcthyl-2-thicnyl)benzence thananine

A stirred solution of 8 g of 2-amino-N~-formyl-N me thyl-c -( 3-methyl-2-thienyl)benzenethanamine in 30 ml of 95% ethanol was treated with 2.4 ml of a 37% formal- dehyde solution and 3,6 g of succinimide. The solution was heated for 6 hours at 98°¢ and then allowed to stand at ambient temperature for 24 hours. The resulting pre- cipitate was filtered, washed (95% ethanol; 3 x 50 ml), and dried in vacuo (40°8) to afford 7.62 g of 2-/2,5- dioxo-1-pyrrolidinyl)methyl/amino-N-formyl-N-methyl-c- (3-methyl-2-thienyl)benzenethanamine, mp 160-164°C.

ANALYSIS:

Calculated: for Coola 30358 62.30%C 6.01%H 10.90%N

Found: 62.09%C 6.99% 10.82%N

EXAMPLE L2 —_ N-* ormy]-N-me thyl-2-methylanino-cE~(3-me thyl-2-thienyl)- benzneethanamine hydrochloride monohydrate :

A mixture of 6.39 g of 2-/T2,5-dioxo-1-pyrrolidinyl)- methyl amino-N-formyl-N-me thyl-d ~(3-me thyl-2-thienyl) . benzeneethanamine, 20 ml of anhydrous dimethyl sulfoxide and 0.72 g of sodium borohydride was gtirred at ambient temperature for 15 minutes and then heated on a steam bath :

for 15 minutes with occasional agitation. After standing for 2 hours at ambient temperature, the reaction mixture was decanted into 15 ml of water and extracted with diethyl ether (2 x 100 ml). The organic phase was washed with water (2 x 100 m1), dried over anhydrous sodium sulfate, and concentra- ted to an oil. Thin layer chromatography of the re- sult oil indicated a multi-component mixture. Puri- fication of the mixture was accomplished by HPLC (Waters Associates Frep LC/System 500, silica gel, elution with me thanol/. Concentration of the appro- priate fractions afforded N-formyl-N-methyl-2-methylami amino-qz, - (3-methyl-2-thienyl)benzeneethanamine) as an oil.

A solution of the 0il and diethyl ether was treat ed with ethereal hydrogen chloride to precipitate the corre corresponding hydrochloride salt. The precipitate was dried in vacuo to yield 1.7 g of N-formyl-N-methyl-2- - methyl-amino-ol-(3-methyl-2-thienyl)-benzeneethanamine hydrochloride monohydride, mp 140-145°C,

ANALYSIS:

Calculated for C,gHooN 08 «HCL. HO: 56.05%C 6.76%H 8.17%N

Found: | 56.00%C 6.79%H 7.85%N

: EXAMPLE 43 : 2-Amino-5-chloro-N-me thyl-oC. ~(3-methyl-2-thienyl)- benzeneethanamine

A stirred solution of 8 g of 2-amino-N-methyl- oc ~(3-methyl-2-thienyl)benzeneethanamine in 40 ml of

NyN-dimethylformamide was treated with a solution of "6.41 g of N-chlorosuccinimide in 40 ml of N,N-dimethyl- formamide and then stirred at room temperature for 8 - hours. Evaporation of the volatiles afforded an oil which was decanted into 100 ml of water, basified with 30 ml of 10% aqueous sodium hydroxide and extracted with dichloromethane (2 x 100 ml). The extract was washed - with water (2 x 100ml) dried over anhydrous sodium sul- : | fate and concentrated. This layer chromatography of the resultant oil indicated a multicomponent mixture. Puri- : fication of the mixture was accomplished by successive _ HPLC separations (Water's Associates Prep LC/System 500, . silica gel, elution with methanol). oncentration of the appropriate fractions afforded a residue which was dis- solved in diethyl ether, filtered free of incolubles and €foncentrated. The resultant oil crystallized upon stand- ing to yield 1.05 g of 2-amino-5-chloro-N-methyl- of-(3- methyl-2~thienyl)-benzeneethanamine, mp 59-61°C. : ANALYSIS:

Calculated for Cy Ho CIN Se 59.89%C 6.10%H 9.97%N

Found: 60.24%C 6.108H 9.99%N

EXAMPLE Lh :

N/2-(2-(methylamino)-2-(2-methyl-3-thienyl)ethyl) phenyl/-2,2-dimethylpropanamide

A chilled solution (-2%) of 37.9 g of 2,2- dime thyl-N~7/{2-methyl)phenyl/propanamide in 350 ml . of tetrahydrofuran was treated dropwise over 2 hours with 100 ml of 2.5 m n-butyllithium in hexane, and t ‘then stirred for 45 minutes with codling. The result- ant suspension was treated dropwise over 15 minutes with a solution of 13.6 g of 2-methyl-3-thiophenecar- boxaldehyde methylimine in 40 ml of tetrahydrofuran.

The reaction mixture was stirred for 1 hour, quenced by the addition of 17.4 ml of methanol and 200 ml of water, and concentrated. The concentrate was extract- - ed with dichloromethane and the combined extract was dried over mnhydrous sodium sulfate, filtered, and evaporated to an oil. Freliminary purification of the oil was achieved by HPLC separations (Water's | Associates Prep LC/System 500, silica, elution with } 20% methanol in ethyl acetate). “oncentration of the appropriate fractions afforded an oil which was dis- solved in diethyl ether and concentrated to yield 2k.0 g of N-/3-(2-methylamino) -2-€2-me thyl-3~thienyl) phenyl/

(2,2-dimethyl-propanamide, mp 95-96°¢.

ANALYSIS:

Calculated for Cy gH ogN 08: 69.05%C 7.93%H 8..48%N

Found: 68.97%C 7.95%H 8.L1%N

EXAMPLE 45 2-Amino-N-methyl-oc (2-methyl-3-thienyl)benzene than- tL amine dihydrochloride - A solution solution 11.0 g of N-/2-(2-(gethyl , amino)-2-(2-methyl-3-thienyl)ethyl)phenyl/-2,2- dimethylpropanamide in 300 ml of 6 N hydrochlpric acid was refluxed for 8 hours. The solution was then _.. ooo. | -

Co decanted into an ice-water mixture and basified with. 50% aqueous sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane (900 m1) and the organic phase was dried over anhydrous sodium — | sulfate, filtered and concentrated to yield 9.5 g of 2-amino=N-methyl-o -(2-methyl-2-thienyl)benzeneethan- . dmine as an oil.

A 3.0 g aliquot of the oil was dissolved in 45 ml of metganol and the resultant solution was acidified : } to a pH of 1 with ethereal hydrogen chloride. Dilution with anhydrous diethyl ether (45 ml) precipitated the corresponding hydrochloride salt,

The prefipitate was dried in vacuo (40°) over so-

dium hydroxide to yield 2.5 g of 2-amino-N-methyl- .~-(2-methyl-3-thienyl)benzeneéthanamine dihydrochlo- ride, mp 229-230°C.

ANALYSIS: . 5 Calculated for C,H, gh, 8" 2HCL: 52.66%C 6.31%H 8.78%N : Found: 52.40%C 6.29%H 8.59%N oo EXAMPLE 46

N-Acetyl-2-amino-N-methyl-o ~(2-methyl-2-thienyl)- benzenee thanamine

A stirred, ice water chilled solution of 5.07 g of : 2-amino-N-methyl-of ~(3-methyl-2-thienyl)benzenethanamine in 40 ml of pyridine was treated dropwise with 2.25 g of acetic anhydride. The solution was stirred with cool- ing for 15 minutes and then at room temperature for 3 hours. After standing overnight, the reaction mixture : ~~ was decanted into water (200 ml), treated with dichloro- methane (100 ml) and basified with 10% sodium hydroxide solution. The aqueous phase was extracted with dichloro-~ methane (150 ml), and the combined organic phase was fil- tered and concentrated. The resulting solid was stirred with toluene and evaporated to dryness. Recrystallization from propionitrile (14 ml) afforded 3.0 g of N-acetyl-2-amino =

Co N-methyl-di -(3-methyl-2-thienyl)benzeneethanamine, mp 176-

et stn —— -181.5%,

ANALYSIS:

Calculated for C16H20N,08: 66.63%C 6.99%n 9.71%N

Found: 66.82%c 7,00%y 9.73%N 4

EXAMPLE 47 (2) 2-Amino-N-formyl-N-me thyl-o - (3-mbthy)-2-thieny1)- : benzeneethanamine - A stirred solution of 5,00 g of 2-amino-N-methy]- of ~ (3-methyl-2-thienyl)benzenee thanamine and 235 ml of : formate was refluxed for 8 hours. Volatile components were removed at 60°C on a rotary evaporator, Thin la- yer chromatography (silica gel, ethyl acetate as the ‘ eluent) of the resultant oil indicated a multi-component ' mixture. HPLC of the mixture (Water's Associates Prep

LC/System 800, silica gel, elution with ethyl acetate) - acetatey permitted component separation. The faster elut- ing fractions were concentrated to an oil which crystal- lized upon standing, oo

Recrystallization from methanol-water afforded 1,2 g of 2-amino-N-formyl-N-methy] -d_~(3-methyl-2-thieny1)- benzeneethanamine, mp 111-112%,

ANALYSIS:

Calculated for Cyst; gN,08¢ 65.66%C 6.61%H 10.21%N

Found 65.46%C 6.66%H 10.26%N a - 83 o

(b) N-/2-/2-(N-FormyleN-methyl)amino-2-(3~methyl-2- thienyl)-ethyl/phenylformamide

Concentration of the more slowly eluting fract- : . ions obtained from the HPLC separation described supra afforded a residue which was dissolved in diethyl ether, filtered, and concentrated to an oil which so- 1idified upon standing. The crystalline product was tritutated in hexane, filtered, and dried in vacuo at 40°C to afford 10 g of N-/2-/2-(N-formyl-N-methyl) amino-2-(3-me thyl-2-thieny1)-e thyl7phenyLl7 formamide, mp 128-130°C. B

ANALYSIS:

Calculated for C,gHy8H5) 058

IE 63.56%C 6.00%H 9.27%N

Found: 63.34%C 6.06%H 9.18%N © EXAMPLE _148 Co - 2-Aming-N,N-dine thyl~g -( 3-me thyl-2-thienyl) -benzene- " ethanamine : A stirred solution of 5.79 g of 2-amino-N-formyl- 20 .N-methyl-of, (3-methyl-2-thienyl)benzenethanamine in 400 ml of tetrahydrofuran was treated dropwise under nitrogen with 90 ml of a 1 M solution of borane in tetrahydrofuran. The solution was stirred overnight at room temperature and then quenched with 60 ml of

. a 10% sodium hydroxide solution. The aqueous mix- ture was extracted with dichloromethane (2 x 100 ml), , dried over anhydrous sodium sulfate, filtered and

EE } concentrated. The concentrate was treated with 15 ml of glacial acetic acid and 35 ml of concentrated hydrochloric acid. After stirring at room tempera- ture overnight, the solution was decanted over 200 g of ice, basified with 20 ml of 50 aqueous sodium hydro- xide, and extracted with dichloromethane (3 x 100 ml). — 10 | The organic phase was dried over anhydrous sodium sul- : fate, filtered and concentrated. Purification was ac- complished by means of HPLC (Water's Associates Frep

LC/System 500, silica gel, slution with me thano1)“on- ) : Co ) "centration of the appropriate fraction afforded a so- lid which was recrystallized from diethyl ether to afford 3.7 g of 2-amino-N-N-dimethyl-a’ -(3-methyl-2- thienyl)benzeneethanamine, mp 75-77°C. oo ANALYSIS:

Calculated for CigHyooS: 69.19%C 7.74%H 10.76%N N ~ Found: 69.25%C 7.81%H 10.66%N

EXAMPLE 49 Co 2-Amino-5-bromo-N-me thyl-o -(2-me thyl-3-thienyl)- ~~ benzenethanamine

A stirred solution of 3.0 g of 2-amino-N-methyl-of (2 -methyl-3-thienyl)benzeneethanamine in 50 ml of N,N-

dimethylformamide was treated with a solution of 2.6 g of N-bromosuccinimide in 50 ml of N,N-dime- thylformamide and allowed to stand overnight at room temperature. Evaporation of the volatiles afforded an oil which was purified by HPLC (Water's Associates

Frep LC/System 500, silica gel, elution with methanol). . The resultant oil was dissolved in diethyl ether, fil- tered and concentrated. Trituration with diethyl ether afforded 1.2 g of 2-amino-5-bromg-N-methyl-q -(2-methyl -3-thienyl) benzenethanamine, mp 72.5. 5-74°C,

ANALYSIS:

Calculated for Cy Hy ,BrN Se 51.69%C 5.27% 8.61%N

Fpund: 52.10%C - 5.25%H 8.57%N

EXAMPLE 50

M-Methyl-2-methylamino-« -(3-methyl-2-thienyl)-benzene- ethanamine dihydrochloride Ea N-Formyl-N-me thyl-2-methylamino-al-(B3-me thyl-2- : thienyl)benzenethanamine (L4.1 g) was treated with 18 ml : of 3N hydrochloric acid. After refluxing for 1.5 hours the solution was decanted over ice, basified with 12 ml of a 50% aqueous sodium hydroxide solution and extracted with dichlorormethane (3 x 60 ml). The organic phase , was dried over anhydrous sodium sulfate and concentrated to an oil. Purification of the oil was accomplished by

HPLC (Water's “ssociates Prep LC/System 500, silica gel, - 86 - Co elution with methanol). Concentration of the appro- priate fractions afforded a residue which was dis- solved in diethyl ether, filtered free of insolubles, and concentrated to afford N-methyl-2-methylamino-

KL -(3-methyl-2-thienyl)- benzeneethanamine as an oil.

The oil was dissolved in methanol and treated with ethereal hydrogen chloride. VYilution with diethyl ether grecipitated 2.4 g of the corresponding dihydro- chloride salt, mp 191-192°C.

ANALYSIS:

Calculated for CygtioN,S 2HCL: : 54.05%C 6.65% 8.40%N

Found: 5h.19%C 6.6L%H 8.36%N EXAMFLE 51

N,N-Dimethyl-2-methylamino-o -( 3-methyl-2-2thienyl)- benzeneethanamine

A solution of 7.2 g of N-/2-/2-(N-formyl-N- } methyl) -amino-2-(3-methyl-2-thienyl)ethyl/phenyl/ formamide in €00 m1 of tetrahydrofuran vas treated with 144 ml of a 1M borane«tetrahydrofuran complex under nitrogen at room temperature. After stirring oo overnight, the mixture was quenched with 10% sodium

So hydroxide solution, and concentrated to remove the : é ' solvent. The concentrate was extracted with dichlore methane (3 x 1580 ml), dried cver anhydrcus sodium sulfate, filterrd, and conce trated to an oil. The pil wns dirsclved in 22 ml of plrcial acetic acid, and treated dropwise with 120 ml of concentrated hy- drochloric acid, and left to stir at room tempera- ture overnight. The solution wns then decanted over : 300 g of ice, basified with 50% sodium hydroxide so- luticn, extracted with dichloromethane (3 x 200 ml), dried over anhydrous sodium sulfate, filtered and con- centrated to an oil, purification of the oil wns accomplished by pre- parative 111.C¢ (water's Associates I'rep LC/System 500, silica rel, elution with rethancl). The appropriate fractions were collected, combined and concentrated to give 4.6 5 of N,N-dimethyl-2-methylamino-ol~(3-methyl-2- thienyl)benzencethanamine as an oil.

ANALYSIS:

Calculated for C,H, N 8: 70,03%C 8.08%H 10.21#N

Found: 70.13%C 8.,21%H 10.10%N

SXAMLE 52

NyN-Yimethyl-2-dimethylamino-oL-(3-methyl)-2-thienyl)= benzeneethanamine & solution of 5.4 g of 2-amino~N-methyl-o =-(3- " methyl-2-thienyl)benzeneethanamine in 50 ml of aceto- nitrile and 11.5 ml of a 37% (w/w) formaldehyde solu- - 8 lao ORIGINA- b,

tion was treated with 3.1 g of sodium cyanoboro- hydride. After stirring at room temperature for 2.5 hours, the reaction mixture was dissolved in 80 ml of diethyl ether and extracted with an aqueous potassium hydroxide solution (3 x 75 ml).

The ethereal layer was washed with 150 ml of satu- rated brine, dried with anhydrous potassium carbonate, } filtered and concentrated. purification of the resultant oil was accomplish- ed by preparative HPLC (Water's Associates Prep Lc/ :

System 500, silica gel, elution with methanol). The appropriate fractions were collected, combined and _ concentrated. The concentrate was dissolved in diethyl

Co ether, filtered and concentrated to afford 3.1 g of N,

EE 15 N-dime thyl-2-dimethylamino-o ~(3-methyl-2-thienyl) . benzeneethanamine as an oil.

ANALYSIS:

Calculated for Co HypHo8: 70.79%C 8.40%H 9.71%N

Found: 70.70%C . 8. 41%H 9.79%N

EXAMPLE 53 »

N-Formyl-2-hydroxy-N-methyl-« ~(3-methyl-2-thienyl)- benzeneethanamine :

A stirred suspension of 8.87 g of 2-amino-N-formyl

Neme thyl-of -( 3-me thyl-2-thicnyl)benzeneethanamine and 71 ml of 50% (w/v)sulfuric acid was chilled with an ice. : _ i i -

water bath for 15 minnten. he oaasptazieon end eon? dropwise over one minute with a solution of sodium ni- trite (2.045 ¢) and water (13 ml). After stirring with chilling for 1% minutes, the mixture was strained throush glass wool into a dropring funnel and then add- ed over a few minutes to a refluxing sclution of 63,84 g of copper sulfate and 130 m)l of water. After a few mi- nutes of vigorous stirring, the reaction mixture was cool- ed to room temperature with an ice bath, diluted with wa- ter and dichloromethane and transferred to a separatory funnel. The phase were separated and the aqueous phase was extracted with dichloromethane (2 x 200 ml). The com- bined organic phase was dried over anhydrous sodium sul- fate, filtered, and concentrated to an 0il. The oil wes purified by means of preparative HFLC (vater's Associates

Frep LC/System 500, silica gel, sample applied in dichloro- methane and eluted with ethyl acetate-hexane (1:1)). The appropriate fractions were combined and concentrated to an oil which crystellized of refrigerated storage over- night. Recrystallization from ethyl acetate (20 ml) af- forded 1.62 g of N-formyl-2-hydroxy-N-methyl-of -(3-methyl- -2-thienyl)-benzenethanamine, mp 142-144°C,

ANALYSIS: : Calculated for C,H NO St 65.43%C 6.22%H 5.09%N

Found: 65.37%C 6.20%H S5.00%N - 90 ~ ano ORIGINAL 9

EXAMPLE S54 oo _ 2-Hydroxy-N-methyl-of -(3-methyl-2-thienyl)benzene- © ethanamine hydrochloride

A stirred suspension of 4.0 g of N-formyl -2- hydroxy-N-me thyl-q ~(3-methyl-2-thienyl)benzene- i ethanamine and 40 ml of methanol was treated with 40 ml of 3N hydrochlorid acid to afford a turbid yellow mixture. After heating to reflux, suffi- cient methanol (40 ml) Fas added to give a yellow = 10 solution. After refluxing for 5 hours, the solution was concentrated on a rotary evaporator to remove the : methanol. The residual oil-water mixture was diluted with dichloromethane and basified with 5% sodium bicarbonate "solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 100 ml). The com- bined organic phase was dried over sodium sulfate and con- centrated to an oil which was shown to be a three compo- nent mixture by thin layer analysis,

T The oil was purified by preparative HPLC (Water's

Co 20 Associates Prep LC/Syetem 500, silica gel, sample applied oo in dichloromethane (20 ml), elution with ne thanol-ethyl ‘ acetate gichloromethaps). Concentration of the appropriate fractions afforded an oil, which was repurified by prepa- : rative HPLC to remove a trace of the starting amide. Con-

Co 25 centration of the approprihte fractions gave 2.35 g of-2- hydroxy-N-me thyl-o -(3-methyl-2-thienyl)benzeneethanamine ; ‘ } .

Ceo as an oil. The oil was dissolved in anhydrous ether and the solution was treated with ethereal hydrogen chloride to give a precipitate, which was collected and dried in vacuo at 40°C, over sodium hydroxide pellets. Recrystallization from absolute ethanol (20 ml) by gradual dilution with diethyl ether gave 1.54 g (37%) of 2-hydroxy-N-methyl-o( -(3-methyl- : -2-thienyl) benzeneethanamine hydrochloride, mpl95.5- 196.5°C.

ANALYSIS:

Calculated for Cy Hy pNOS "HCL: 59. 25%C 6.%9%H bh. ol%N

Found: 59.24%C 6.38%H L.88x%N

SXAWFLE 55 1,5-Dihydro-2ethyl-3-methyl-k=(2-methyl-3~thienyl)-3H- 1,3-benzodiazepine

A solution of 3.95 g of 2-amino-N-methyl-ot -(2- methyl-3-thienyl) benzeneethanamine, 5 ml of glacial acetic acid and 17.0 g of triethylorthopropionate was refluxed for © hours (under a nitrogen atmosphere).

The solution was concentrated in vacuo at 20°C and the residual oil} dissolved in diethyl ether (50 ml) and acidified with 10% hydrochloric acid solution. The aqueous phase was washed with diethyl ether (50 ml), - 97 - 01 ORIGINAL 9 no i : basified, and extracted with dichloromethane (2 x 100 ml). The combined organic phase was dried an- hydrous sodium sulfate, filtered and concentrated.

The resultant oil was purified by preparative HFLC (Water's Associates Frep LC/System 500, silica gel, elution with methanol followed by 2 % triethylamine in methanol). Concentration of the appropriate frac- tions afforded 2.26 g of lt,5-dihydro-2-ethyl-3-methyl-k- (2-methyl-3-thienyl)~3H-1,3-benzediazepine as an oil.

Trituration with hexane afforded a solid which was com- bined with product obtained from previous run to afford the analytical sample, mp 82-83.5°C.

Analysis:

Calculated for CynlipoHySs 71.79%C 7.09%H 9.85%N

Found: 71.68%C 7.19%H 9.75%N

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SE 77 bi - mn EE i - © > ren / I iF ={ t+ - 7 \ '

TR n 2 7 a a ~ - Jewry :

Lo > 3 "2 : o o Cl > : ow 8B : . ve #8 no" n !

So . " 1 2 !

J

” ® f a =

Sn "

OQ = “ 2 ve a wv nn 2 m0 oc -~ on . , rye oo - . 7. re . i . 8 F " : ow ae A ~~ 5 5 fen ( 2 / [3 - — 0 . To a ” 4g IR . Ne ot i .

Th 8 oo : z . . = 3 a. | i o = sw ~ » - : . r-Q no a . = : , . } . » fy" ] . no. - ( !

Is : . ~ ~ "4g 2 .

Wo at { .

LS yo {TI

H - i : = oo : ’ J 6 | 'BAD ORIGINAL P vo 18 : i wd aks,

Cd

. i : ay , . . : pt . . , : ag i : - 84 - Io

IR

’ "a : LS

LA

} % . ® : ‘ + ’ . ° ox I Ny ol \= . - non hn por . . NN T 2 ~ :

I - ~~ ] -

Soe ¥ E - m > ve ; . [yt { , . -— = t ° » » * + . : . - ab : © . nM” Ai] . - ’ Ped Me 3 Tm . , 23 oon 9 fi 58, 2 Ta } : SA : omRen £-" : g . ” . 2 Ng > N fr we 8 . < w = ® ~~ Q g — € c ow f ’ # nN = v p =

Ho 2 i a 2 ;

Oy : ® ] » 7 \ -

IS (= { i | ’ . ~ - . ¥ 5m } - vo . . . : - . * - i o * GAD Oru J :

Claims (6)

1. ‘ ., : . . - . } : § CLAIMS:

   : 1. A compound of the ‘formula II : rR , 2d! | 11 CH_CH-N-R . 3, Ar wherein Ar is a radical of the formulae Cd ; wherein Y is loweralkyl; n is an integer having a . value from O to 1 inclhasive, X is halogen; m is an integer having a value from O to 2 inclusives} : r! is hydrogen or loweralkyl, - ’ a. " R> is hydroxy, amino, loweralkylamino, diloweralkyl- amino or nrbc(o)r" wherein R and g® are independently " hydrogen or loweralkylj and "R’ is hydrogen, loweralkyl or C(0)R’ wherein R’ is . oo hydrogen or loweralkyl and the pharmaceutically aécept-

   able acid addition salts thereof,
2. 2. A compound asdefined in claim 1 where- in R> is amino, m is 0 or 1 and Ar is a radical : of the formulae ~ ner || =D, wherein Y is loweralkyl and n is an integer having a value of 0 or 1.
3. 3, The compound as defined in claim 2 which is 2-amino~N-methyl-q -(3-methyl-2-thienyl)benzene- ethanamine or a pharmaceutically acceptable acid addition salt thereof. .
4. 4, The compound as defined in claim 2 which is 2-amino-5-bromo-N-methyl- of -(3-methyl-2-thienyl) benzeneethanamine or a pharmaceutically acceptable acid addition salt thereof,
5. 5. A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 as the active ingredient and a suitable carrier therefor.
6. 6. A method of treatment wherein anticonvulsant activity is achieved,

   which comprises administering to a subject in " need of said treatment , an effective amount of a compound as defined in claim 1. LAWRENCE LEO MARTIN JOSEPH FRANCIS PAYACK SALVATORE BRUCATO

   Inventors