CA1092105A - Pyrrolo(2,1-b) (3)benzazepines - Google Patents

Abstract

Abstract of the Disclosure 11-Aminopropylidene-Pyrrolo[2,1-b][3]benzazepines are disclosed to have pharmaceutical utility as skeletal muscle relaxants and tranquilizers. They are prepared by a Grignard reaction on pyrrolo[2,1-b3][3]benzazapin-11-ones followed by dehydration.

Description

Z~05 7 Back~round of the Invention 8 Over the past several yeaxs several so-called 9 tricyclic compounds such as amitriptyline, cyclobenzaprine, nortriptyline and protriptyline have gained importance as 11 centrally acting pharmacological agents. Now with the 12 present invention, there is provided new tricyclic com-13 pounds which have skeletal muscle relaxant and tranquilizer 14 activity.
Thus, it is an object of the present invention 16 to provide compounds of structural formula:

( X) CHCH2CH2N \ 2 17 . It is a further object to provide processes ,or 18 the preparation of the compounds; to provide phar~aceutical ~1~92~

1 compositlons comprising such compounds; and to provide

2 methods of trea~ment comprising administering such compounds

3 and compositions when a muscle relaxant and/or tranquilizing

4 effect is indicated.

Detailed Descript~on of the Invention 6 The compounds of the present in~ention may be 7 represented by the following structural formula:

8 ( )m CHC~2CH2N \ 2 9 or pharmaceutically acceptable salt thereof, wherein 11 the dotted line between positions 5 and 6 represents satu-12 ration or unsaturation;
13 n = 3, 2, 1, or O (X is hydrogen);
14 m = 4, 3, 2, 1, or O (Y is hydrogen);
X and Y are independently selected from 16 (1) hydrogen, 17 (2) halo, such as chloro, bromo, fluoro, or iodo, 18 (3) formyl, 19 (4) lower alkanoyl, especially C2 6 alkanoyl such as acetyl, pentanoyl, or 2-methylpropanoyl, 21 (5) lower alkyl, expecially Cl 5 alkyl, either 22 straight or branched chain, such as methyl, 23 propyl, or pentyl, 24 (6) lower alkoxycarbonyl, especially (Cl 5 alkoxy)-carbonyl, ~9Z~5 1 (7) hydroxy-lower alkyl, especially hydroxy-Cl 3-2 alkyl, 3 (8) perhalo-lower alkyl, especially perhalo Cl 3-4 alkyl, such as trifluoromethyl, (9) lower alkoxy, especially Cl 3 alkoxy, such as 6 methoxy or propoxy, 7 (10) cyano, 8 (11~ perhalo-lower alkylthio, especially perhalo-9 Cl 3 alkylthio, such as trifluoromethylthio, tl2) lower alkylthio, especially Cl 3 alkylthio, such 11 as methylthio or propylthio, 12 (13) lower alkylsulfonyl, especially Cl 3 alkyl sul-13 fonyl, such as methylsulfonyl or isopropylsulfonyl, 14 (14) perhalo-lower alkylsulfonyl, especially perhalo-Cl 3 alkylsulfonyl~ such as trifluoromethylsul-16 fonyl, 17 (15) lower alkyl sulfinyl, especially Cl 3 alkylsul-18 . finyl, such as methylsulfinyl, 19 (16) perhalo-alkylsulfinyl, especially perhalo-Cl 3 alkylsulfinyl, such as trifluoromethylsulfinyl, 21 (17) amino, 22 (18) lower alkanoylamino, especially C2 6 alkanoyl-23 amino, such as acetylamino, or pentanoylamino~
24 (19) lower alkyla~ino, especially Cl 3 alkylamino, (20) di(lower alkyl)amino~ especially di(Cl 3 alkyl)-26 amino, 27 (21) hydroxy, 28 (22) N-lower alkylcarbamoyl, especially N-Cl 3 alkyl-29 carbamoyl, 1 (23) N,N-di(lower alkyl)carbamoyl, especially N,M-2 di(Cl_3 alkyl)carbamoyl, 3 (24) nitror 4 t25) di(lower alkyl)sulfamoyl, especially di(Cl 3-alkyl)sulfamoyl, 6 (26) lower alkoxycarbonylamino, especially Cl 3 7 alkoxycarbonylamino, and 8 (27) N-lower alkylcarbamoyloxy, especially Cl 3 alkyl-9 carbamoyloxy; and Rl and R2 are independently selected from hydrogen; lower 11 alkyl, especially Cl 3 alkyl; lower alkenyl, especially 12 C2_5 alkenyl; lowex cycloalkyl, especially C3 6 cycloalkyl;
13 or R and R joined together form with the nitrogen to which 14 they are attached l-piperidyl, l-pyrrolidyl, or 4-morpho-linyl.
16 One em~odiment of the novel compounds of this 17 in~ention is that wherein n is 2, 1, or 0 (X is hydrogen) i8 and X is in the 2 and/or 3 position.
19 A preferred embodiment of the novel compounds of this invention is the compound of structural formula:

21 ~ /Rl CHCH2CH2N ~ R2 22 wherein X and Y are as defined above and Rl and R2 are 23 hydrogen or Cl 3 alkyl.

92lL1~5ii 1 A still more preferred emhodiment of the novel 2 compounds is where one o X and Y is hydrogen, and the other 3 is hydrogen, cyano, formyl, or C2_6 alkanoyl.
4 Also contemplated within the scope of the present invention are pharmaceutically accepkable N-acid addition 6 salts of the pyrrolobenzazepines of the present invention.
7 Such pharmaceutically acceptable forms, prepared by conven-8 ional means, include: the hydrochloride, maleate, sulfate, g phosphate, citrate, tartrate, succinate, and the like.
These pharmaceutically acceptable salts are generally 11 equivalent in potency to the free amino form taking 12 into consideration the stoichiometric quantities employed.
13 It will be appreciated that the compounds of 14 the present invention exist as cls-trans geometrical isomers and are isolable by conventional separation techniques.
16 Such isomers, individually and mixtures thereof, are I7 within the scope of the present invention.
18 Unexpectedly, it has been discovered that the 19 above-described pyrrolobenzazepines of the present inven-tion are useful as skeletal muscle relaxants and can be used 21 for treating muscle spasms and other similar muscle dis-22 orders associated with or caused by injury, disease, or 23 arising spontaneously with no kno~m cause. Muscle spasm, 24 spasticity and related clinical disoxders involving muscle hyperactivity or incxeased muscle tone affect a large sec-26 tion of the population. Such clinical disorders involving 27 muscle hyperactivity include the spasticity of cerebral 28 origin which may arise from brain injury or tumor. Another 29 related disorder is cerebral palsy. Other clinical disorders ~2~0S
l involving tonic skeletal muscle hyperactivity are Parkin-2 son's disease, muscular rigidity, and muscle spasm of 3 traumatic origin including low-back and cervical spine 4 syndromes, many orthopedic deformities, arthxitic states, myositis, whip-lash injuries, frac~ures, dislocation, 6 cramps, sciatica, and spinal cord injuries. At present, 7 a variety of medicinals axe used in an attempt to relieve 8 or correct the clinical disorders involving muscle hyper-9 activity including muscle spasm, spasticity, and rigidity and pain associated therewith. But administration of these ll various materials unfortunately is attended by concomitant 12 side effects and toxicity and/or lack of specificity which 13 limit their usefulness. There is an unsatisfied need at 14 the present time for a medication which has a highly speci-fic effect on the muscle hyperactivity associated with 16 various clinical disorders when administered either by the 17 oral or parenteral route which at the same time has a mini-18 mum of side effects or contraindications.
19 In the method of treatment and pharmaceutical composition aspects of the present invention it is to be 21 noted that the precise unit dosage form and dosage level 22 depend upon the case history of the individual being treated 23 and consequently are left to the discretion of the thera-24 pist. In general, however, the compounds of the present in~ention produce the desired effect of skeletal muscle 26 rPlaxation when given at from about 0.1 to about 30 mg./kg.
27 body weight per day. Any of the usual pharmaceutical forms 28 may be employed such as tablets, capsules, elexirs, and ~L~39Z~
1 aqueous suspensions comprising from about 0.1 to a~out 2 30.0 mg. of the compounds of this invention per kilogram 3 body weight given daily. Thus for example tablets given 4 2-4 times per day comprising from about 0.5 to about 75.0 S mg. of the compounds of this invention are suitable; how-6 ever, the preerred range for the unit dosage level in the 7 form of tablets is from about 2.0 to about 40.0 mg. of the 8 compounds of the present invention. Sterile solutions for 9 injection comprising from about 1 to 30.0 mg. per dose of the compounds of this invention given 2-4 times daily are 11 also a suitable means of delivery.
12 The novel compounds of this invention are also 13 tranquilizing agents. For this purpose, they may be admin-14 istered in the same manner and dosage rates described above for the muscle relaxant utility.
16 Accordingly, it is an object of the present 17 invention to provide the above-described pyrrolobenzaze-18 pines which are useful as skeletal muscle relaxants and 19 tran~uilizers. It is a further object of the present invention to provide pharmaceutical compositions comprising 21 such pyrrolobenzazepines and to provide methods of treat-22 ment comprising administering such compounds and composi-23 tions when a skeletal muscle relaxant and/or tranquilizing 24 effect is indicated.
The novel compounds of this invention are gen-26 erally prepared in accordance with the following reaction 27 scheme:

3ZlOS

( ~)m ~ ( a)m ~ / Rl)n R HO (CH2)3N
2 ~/ N(CH2)3Mg(halo) \ R2 3 / dration ( a)m ~ a)n II R~
wherein Xa and Ya are as defined in X and Y but exclusive 6 o~ formyl; and Rl and R2 are as defined in Rl and R2 but 7 that they are other than hydrogen. The ketone starting 8 material is treated with a Grignard reagent of formula 9 RlRaN(CH2)3Mg(halo) in a solvent such as tetrahydrofuran, 10 ether, or the like at a temperature of from about -10C.
11 to reflux for ~rom about 10 minutes to about 10 hours to 12 provide the ll-hydroxy-ll-alkylated intermediate, which 13 species is then dehydrated by treatment with an acid such 14 as hydrochloric, oxalic, trifluoroacetic, formic, acetic, trifluoroacetic anhydride, trichloroacetic acid, phosphorous 16 oxychloride with a tertiary amine, and the like at a tem-17 perature of from about 0 to about 100C. fox from about 18 5 minutes to about 24 hours to provide the final product 19 pyrrolobenzazepines. The Grignard reaction and the sub-sequent dehydration described above are substantially 21 identical to those disclosed in U.S. Patents 3,014,911 22 (issued December 26, 1961), 2,951,082 (issued August 30, 23 1960), 3,428,677 (issued February 18, 1969), 3,428,735 Q~

l (issued February 18, 1969), 3,454,643 (issued July 8, 1969), 2 and 3,499,037 (issued March 3, 1970), all to Edward L.
3 Engelhardt or Edward L. Engelhardt et al.
4 Nitro-pyrrolobenzaæepines of this invention are also useful as intermediates to the corresponding amino-, 6 alkylamino-, dialkylamino-, and alkanoylamino-pyrrolo-7 benzazepines.
8 The amino- compounds are prepared by catalytic g reduction of the nitro- compounds over a noble metal catalystJ pref~rably palladium on carbon in a lower alkanol.
ll The alkylamino- compounds are prepared by heating 12 the corresponding amino compound in a trialkyl orthoformate 13 up to reflux temperature for 2-8 hours, followed by reduc-14 tion of the product therefrom with an alkali metal boro-hydride reagent.
16 The dialXylamino- compounds are prepared by 17 reductive alkylation of the corresponding amine with form-18 aldehyde in the presence of a reducing agent such as sodium 19 cyanoborohydride, hydrogen in the presence of a noble metal catalyst, or refluxing formic acid as in the Eschweiler-21 Clarke reaction.
22 The alkanoylamino- compounds are prepared by 23 treatment of the corresponding amine with an alkanoyl 24 anhydride at 20~-50C. preferably in the presence of an organic base such as pyridine.
26 Formylpyrrolobenzazepines may be prepared by 27 reduction of the corresponding cyano compound or its 28 carbinol intermediate with nickel-aluminum alloy in formic 29 acid or aqueous formic acid at from 50C~ to reflux tem-perature for 30 minutes to 5 hours~

1 Alkyl-, and di(alkyl)carbamoyl compounds may be 2 prepared from the corresponding carboxy compounds by forming 3 the acid chloride therefrom followed by treatment with an 4 alkylamine or a di(alkyl)amine in an inert organic solvent such as methylene chloride or the like, at -20C. to reflux 6 temperature until the reaction is complete.
7 Alkoxycarbonyl compounds may be prepared by heat-8 ing at 50C. to reflux fox 1-8 hours the corresponding 9 carboxy compound in a lower alkanol in the presence of a strong mineral acid, such as hydrogen chloriae.
11 Novel compounds with a trifluoromethylthio or 12 alkylthio substituent in the benzo ring may be prepared by 13 reacting the corresponding iodo- or bromo- compound with 14 trifluoromethylthiocopper (formed by the reaction of copper powder with bisttrifluoromethylthio)mercury) or a cuprous 16 alkylsulfide respectively in a polar organic solvent such 17 as dimethylformamide, quinoline, or hexamethylphosphoramide 18 at 50C. to 200C. for 0.5-24 hours.
19 Similarly, cyano compounds may be prepared by treating the bromo- or iodo- compounds with cuprous cyanide.
21 In the ~ovel compounds of this invention where 22 one of Rl or R2 i~ hydrogen, they are prepared by reacting a 23 compound wherein one of Rl and Ra are alkyl with 2,2,2-tri-24 chloroethylchloroformate in an organic solvent such as ben-zene, toluene, or the like at 50-200C., conveniently at 26 reflux temperature, for 10-24 hours to provide an inter-27 mediate N-2,2,2-trichloroethoxycarbonyl compound. This 28 intermediate is then subjected to reduction, such as with ~Z~LOS

1 zinc dust in acetic acid at about ambient temperature ~or 2 10-24 hours to provide a final product wherein one of 3 or R2 is hydrogen.
4 Preparation of the secondary amines of this invention is also carried out in a conventional way by 6 reaction of the tertiary amine with cyanogen bromide, as 7 described in R. Adams et al., "Organic Reactions," Vol. VII, 8 pp. 198-262, followed by hydrolysis of the intermediate 9 cyanamide to the desired secondary amine. An alternative well-known route involves heating the tertiary amine with 11 ethyl chloroformate, followed by hydrolysis of the carba-12 mate derivative so formed.
13 The Grignard reaction product of structural 14 formula:

(Ya)m ~ (X )n ~ (CH2)3N ~ 2 16 wherein Xa, Y~, n, m, Rl, Ra, and the dotted line are as 17 previously deined forms another embodiment of this inven-18 tion.
l9 One embodiment of the novel compounds of this invention is that wherein n is 2, 1, or 0 tX is hydrogen) 21 and Xa is in the 2 and/or 3 position.
22 A preferred aspect o this embodiment is the 23 compound of structural formula:

~L~9;Z~,S

~Xa Ya HO (CH2)3N ~

2 A still more preferred aspect is where one of 3 Xa and Y~ is hydrogen and the other is hydrogen cyano or 4 C2_6 alkanoyl.
The ketones used as starting materials in novel 6 processes of this invention are prepared by th~ following 7 detailed descriptions.

~L~9~

2GRO~P A
36,11-Dihydro-SH-pyrrolo[2,1-b][3]benzazepines 4Example l 55,11-Dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one 6 ~ Preparation of 1-(2-phenethyl)-pyrrole-2-carboxylic 7acid and 1-(2-phenethyl)-4-cyanopyrrole-2-car-8boxYlic acid 9 Method A: Preparation of 1-(2-phenethyl)pyrrole-2-car-boxylic acid 11 Methyl pyrrole-2-carboxylate (10.0 g.) in 100 ml.
12 dimethylformami.de (DMF) was treated portionwise with 13 sodium hydride (2.21 g.) at 25C. After evolution of hydro-14 gen ceased, styrene oxide (11.52 g.) was added and the mix-ture was heated at 115~C. for 1 hour. The resulting mix-16 ture was poured into 600 ml. ice-water and extracted with 17 ether (2 x 100 ml.). The aqueous phase was acidified to 18 pH 1 with 6N HCl to precipitate the product, which was 19 collected by filtration, washed with water and dried, m.p. 183-185C.
21 The unsaturated acid, trans-l-styrylpyrrole-2-22 carboxylic acid, 24.4 g. was suspended in 200 ml. ethanol 23 in the presence of 1 g. 10% Pd/C and hydrogenated under 3 24 atmospheres hydrogen until uptake of hydrogen ceased. After removal of the catalyst by filtration, the product, 1-(2-26 phenethyl)-pyrrole-2-carboxylic acid was obtained by 27 evaporation of solvent, m.p. 124-lZ5C.

t'~
Z~S

i Metho~ B: Preparation of 1-(2-phenethyl)-4-cyanopyrrole-2 2-carboxYlic acid . . _ . .
3 To 75 g. of potassium carbonate in 300 ml. of 4 dimethylformamide was added successively 84 g. of 2-phenethyl hromide and 63.5 g. of 2-carbomethoxy-4-cyano-6 pyrrole. The mixture was heated in an oil bath at 85C.
7 for 4 hours, poured into 1000 ml. of water, and extracted 8 with 3 x 1~00 ml. of ether. The combined organic extracts 9 were washed with 2 x 100 ml. of water, dried over magnesium sulfate, filtered and evaporated. The residue was tritur-11 ated with 500 ml. of fresh ether and the resul~ing solid 12 was filtered to yield 82.8 gm. (77%) of 1-(2-phenethyl)-2-13 carbomethoxy-4-cyanopyrrole, m.p. 109-110C.
14 A mixture of 80.3 g. of 1-(2-phenethyl)-2-carbo-methoxy-4-cyanopyrrole, 23.3 g. of potassium hydroxide and 16 900 ml. of ethanol was heated at 75C. for 2 hours. The 17 solution was evaporated to aryness, the residue was dis-18 solved in 1000 ml. of water, and the solution was acidified 19 to pH 1 with 6N HCl to cause precipitation of 1-(2-pAen-ethyl)-4-cyanopyrrole-2-carboxylic acid. The product was 21 collected by filtration, washed with water and dried to give 22 72 g. (95%), m.p. 195-195.5C.
23 Following the procedure described in Example 1, 24 Step A, the nuclear substituted 1-(2-phenethyl)-pyrrole-2-carboxylic acids (A) of Table I are o~tained when the 26 indicated molar equivalent substitutions for the styrene 27 oxide (B) or 2-(phenethyl) halide (D) and the methyl-28 pyrrole-2-carboxylate (C) of Example 1 are made:
.

-~ 14985IA

~L0~2iO5

5' ~ 1 ~ ~4 2 ~ (~)n COOH

A
, 2(yl ~ ~ C ~
m 4- ~ 2' ~ CO2CX3 3' ' .

5, ~ CH2C~2 Z

3 ~Y~m -3' wherein Z is bromide, iodide, tosylate or mesylate 1~ ~v Jlr.
S

w ~ ~ ~ ~ ~ `) ~ Ul ~- w ~ 1- g ..
~ _ n ~= 3 z o 5: t W::: m ~ z~
w ~î~ w ~ w ~ O

t ~ ~C
~ O g n O O O O :a ~ W N O N N N N --tl ~ w ~x .
N - ~
N Z I H

P ~ ~
n z ~ ~c 3 n ~ o ~ o o o Z o o o o3 ~
w ~ n w ~ N O N N N N C
o mZ w~ ~n w~ ~ w~ nx ~n w~ ~ w~ ~-- ~

_ ~o ~n ~
tn _ W ~ ~- O

o o ~ 3-o , ~
~ N ~ tl1 ~

U ~ O

P p ~ ~ ~) ~ ~P ~ W ~n .P
Q Q Q Q ", ,'' ~ ~ ` Q ~ a ~

~ ~ W ~ ~ ~ ~ ~ ~ ~ ~ ~n ~ ~ ~ ~
n u~ ~ o~
O Z "~ z ~ ~ 3 n n g w ~ ~ ~ ~3 I ~ ~ ~ ~

Ul )t W .
1~ CO N o O ~

~L09Z~).5 1 Ste~ Preparation of 1-(2-phenethyl-2,3-dibromopyrrole-2 ~-carboxYlic acid chloride . ~
3 To a soluti~n of 1-~2-phenethyl)pyrrole-2-car-4 boxylic acid (105 g., 0.49 mole) in acetic acid (750 ml.) was added 156 g. of bromine over 30 minutes at 25C. Formic ~ acid (lOQ ml. ) was added and the reaction chilled in ice, 7 ko yield 66 gm. (0.18 moles) of 1-(2-phenethyl)-2,3-dibromo-8 pyrrole-5-carboxylic acid after solvent removal. Heating 9 the resulting acid in excess thionyl chloride for 1 hour yielded the acid chloride in near quantitative yield after 11 removal o~ solvent by evaporation, washing with petroleum lZ ether and drying in vacuum.
13 Following the procedure of Example 1, Step B, 14 bUt Using chlorine in place of bromine, there is obtained 1-t2-phene~hyl)-2,3-dichloro-5-pyrrole carboxylic acid 16 chloride.
17 Following the procedure of Example 1, Step B, 13 the mono- and dibrominated acid chlorides depicted in 19 Table II are obtained when an equi~alent amount of the appropriate free acid from Table I replaces the l-t2-21 phenethyl)-pyrrole-2-carboxylic acid used in Example 1, 22 Step B, and either 1 or 2 equivalents of bromine is reacted 23 therewith.

- (Br) 4' ~ ~ 2) SOC12 m ~ ~ n 3 COOH COCl 1(~9Z:lLOS

2 Starting Equivalents 4 from ~ ~m of Bromine ~Br)n Example lA ~ 1 4-~r

6 ~able I(12) 4'-CH3 ~ 4,5-Br2

7 Table I(10) 4'-OCONHCH3 2 4,5-Br2

8 Table I(ll) 4'-NHCOOCH3 2 4,5-Br2 g Table I(24) 4'-SCH3 2 4,5-Br2 ~able I(23? 4'-C~(CH3)2 2 4,5-Br2 11 Following the procedure of Example 1, Step B, 12 but omitting the nuclear halogenation step, there is ob-13 tained the corresponding acid chlorides when the 1-(2-14 phenethyl)-pyrrole-2-carboxylic acid of Example 1, Step B, i~ replaced by an equivalent amount of the free acids 16 enumerated in Table I, respectively~
17 ~ Preparation of 2,3-dibromo~-6,11-dihydro-SH-pyrrolo-18 [2,1-~][3]benzazepin-11-one ___ 19 ~o a solution of 1-(2-phenethyl)-4,5-dibromo-pyrrole-2-carboxylic acid chloride (40 g., 0.102 mole) in 21 800 ml. sym-tetrachloroethane at 140C. was added 40 gm.
22 ~0.30 mole) of aluminum chloride. After three minutes, 23 the reaction was cooled in ice, poured over 2000 g. of ice, 24 stirred for 10 minutes, filtered, and the organic layer was separated. The aqueous layer was extracted with 2 x 26 200 ml. of chloroform, which was combined with the first 27 organic layer. The combined organic solution was washed 28 with 3 x 500 ml. of water, dried and evaporated in vacuum 29 to provide a dark oil (29 g.) which was chromatographed on silica gel using benzene to elute in 50 mlO fractions.
31 ~ractions 5-13 were combined and evaporated to yield 20.3 32 gm. (O.057 moles) of 2,3-dibromo-6,11-dihydro-5H-pyrrolo-33 ~2,1-b][3]benzazepin-11-one, m.p. 130-132C.

~92111~5 1 Following the procedure of Example 1, Step C, 2 but substituting ~or the 1~(2-phenethyl)-4,5-dibromopyrrole-3 2 carboxylic acid chloride used therein an equimole~ular 4 amount of the acid chlorides prepared in accordance with S Example 1, Step B, there are produced the 6,11-dihydro-6 5H-pyrrolo[2,1-b][3~benzazepin~ ones described in Table 7 III by the followin~ process:

(Y~ ~ ~ 3) ~ (X)n COCl O

TABLE III

9 Compounda (Y)m (X)n m.p.(C.)

10 1 H 2-SO2N~CH3)2

11 2 H 2 SO2C~3

12 ~ H 2-so~cH(cH3)2

13 4 ~ 2 S2CF3

14 5 ~ 2-CN 146-147 6 H . 2-C2C2H5 16 7 H 2-No2 -19 10 ~II 3) 9-OCON~CH3 2,3-Br2 11 (II 4) 9-~HCOOCH3 2,3-Br2 21 12 (II 2) 9-CH3 2,3-Br 22 13 H 2,3 Br2 . 130-132 23 14 (II 1) H 2 Br 101~103 24 15 ~ 2-Cl 100-105 149~
l~Z~

1 TABLE III (continued) 2 Compounda (Y)m (~;)r. m.p.(C.) 4 17 H 1,2,3-Br3 150-155 6 19 H 2-CON(CH3)2 7 20 ~ ' 2 C 3 8 21 9-NHCOCH3 1,2,3-Br3 23 (II 6) 9-CHtCH3)2 2,3-Br2 11 24 (II 5) 9 SCH3 2,3-Br2 12 25 8,9-tCH3)2 2-CN
13 26 9-OH 2-C~

28 H 2,3-C12 16 a The numbers of the compounds described in Table III
17 correspond to the numbers of the starting materials 18 described in Table I from which ~hey were prepared, 19 unless otherwise indicated. For example, compound 5 of Table III was prepared from the compound 5 of Table I.
21 Compound 12 was prepared from compound 2 of Table II.
.

22 Step_~: Preparation of 6,11-dihydro-5H-pyrrolo[2,1-b][3]-23 benzazepin-ll-one 24 A suspension of 25 g. (0.070 mole) of 2,3-di-bromo-6,11-dihydro-5H-pyrrolo~2,1-b][3]benzazepin-11-one 26 in 200 ml. ethanol containing 25 ml. of triethylamine and 27 1 gm. of 10~ Pd on charcoal was hydrogenated under 3 ~8 atmospheres of hydxogen to yield 6,11-dihydro-5H-pyrrolo-29 [2,1-b][3]benzazepin-11-one, m.p. 54-55C. after removal of catalyst, recrystallization from petroleum ether and drying ~V~Z~O~

1 under vacuum. The same compound is also obtained by hy-2 drogenoly~is of the 2,3-dichloro ketone and the 1,2,3~
3 tribromoketone.
4 Following the procedure of Example 1, Step D, but substituting for the 2,3-dibromo-6,11-dihydro-5H-6 pyrrolo~2,1-b~[3]benæazepin-11-ones used therein, an 7 equimolecular amount of the halogenated ketones described ~ in Table III, there are produced the ketones described 9 in Table IV.
Table IV
IY) r x n 11 Starting M~terial 12 Compound '3 Table No. (Y)m ~ (X~n i4 III 10 9-OCONHCH3

15 III 11 9-NH-COOCH3 H

16 ~II 12 9-CH3 H

17 III 14

18 III 23 C~CH3)2 lg III 20 H 2-CH3 22 Example 2 23 Preparation of 2-cyano-6,11-dihydro-5H-pyrrolo[2,1-b]~3]-24 benzazepine-ll-one To a solution of 73~6 g. of 1-(2-phenethyl)-4-cyanopyrrole-2-carboxylic acid chloride in 850 ml. of Z~05 1 tetrachloroethane maintained at 140C. is added over a 2 period o~ 2 minutes 114 g. of aluminu~ chloride. Th~ re-3 sulting solution is stirred at 140C. for 4 minutes, poured 4 over 2000 g. of ice and the mixture stirred for 10 minutes.
It is then filtered to remove insoluble tarry material 6 and the organic layer separated. The aqueous layer is 7 extracted with 2 x 500 ml. of chloroform, which is com-8 bined with the original organic layer, washed with 500 ml.
9 of water and with 200 ml. portions of lN sodium bicarbonate until the aqueous washes remain basic. The organic layer 11 is dried over magnesium sulfate, filtered and evaporated 12 under vacuum to leave a residue. This residue upon tritu-13 ration with 300 ml. of ether readily crystallizes. The crystals are filtered and air-dried to yield 57.2 gm.
(90~) of 2-cyano-6,11-dihydro-5H-pyrrolo[2~1-b][3]benzaze-16 pin~ one, m.p. 146-147C.
17 Example_3 18 Preparation of 2-form ~ 1O[2,1-b~[3]-

19 benzazepine~ one 2-Cyano-6,11-dihydro-5H-pyrrolo[2,1-b][3]benza-21 zepin-ll-one (222 mg.) and 222 mg. nickel-aluminum alloy 22 in 2 ml. 75% formic acid is refluxed for 1-1/2 hours. The 23 solid is filtered off and washed with ethanol. ~he fil-24 trate is diluted with 50 ml. water and extracted twice with 50 ml. methylene chloride. The organic layer is 26 washed with water, 5~ sodium bicarbonate and with water;
27 it is then dried over magnesium sulfate and evaporated to 28 dryness. Addition of ether induces crystallization and the 29 crystals are filtered and air-dried to yield 125 mg. (56~) 2-formyl-6,11-dihydro-5H-pyrrolo[2,1-b]~3]benzazepine-11-31 one, m.p. 135-136C.

1 .. ..
~z~s 1 Exam~le 4 2 2-carbamoyl-6tll-dihydro-5H-pvrrolo[2~l-b][3]benzazepin 4 2-Cyano-6,11-dihydro-5H-pyrrolo[2,1-b][3Jbenzaze~
pin-ll-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid was refluxed 7 for 2 houxs. It was then poured onto 500 ml. of water 8 and continuously extracted with methylene chloride. The g solution, from which crystals deposited during the extrac-tion, was left to cool to room temperature and filtered 11 to afford 2-carbamoyl-6,11-dihydro-11-oxo=~H-pyrrolo[2,1-b]-12 [3]benzazepine (27 g. 83~), m.p. 228C.
13 Example 5 14 6,11-Dihydro-ll-oxo-5H-py~rolo[2~l-b]~3]benæazepine-2 carboxylic a_ d 16 To 2-carbamoyl-6,11-dihydro-pyrrolo[2,1-b]~3]-17 benzazepine~ one (27 g., 0.112 moles) in 300 ml. of 50%
18 sul~uric acid maintained at 50C., was added slowly 25 g.
19 of sodium nitrite in 75 ml. of water. At the end of the addition, the solid was filtered, washed with water and 21 air-dried to yield 6,11-dihydro~ oxo-pyrrolo[2,1-b][3]-22 benzazepine-2-carboxylic acid (24 g., 89~), m.p. 287-290C.
23 Example 6 24 2-Dimethylcarbamoyl-6~ll-dihydro-5H-pyrrolo[2~l b][3~-benzaze~in ll-one 26 ~ Preparation of 2-chlorocarbony~ dihydro-sH
27 pyrrolo~2,1-b~[3]benzazepin-11-one 28 6,11-Dihydro~ oxo-pyrrolo[2,1-b~[3]benzazepine-29 2-carboxylic acid (24 g., 99 mmoles) in 100 ml. of thionyl chloride was refluxed for 15 minutes. The volatiles were 31 removed under vacuum and the residue was triturated in :10~2~

1 ether. Filtration and air-drying yielded 2-chlorocarbonyl-2 6~ll-dihydro-5H-pyrrolo[2~l-b~[3~benzazepin-ll-one (23 g., 3 89%), m.p. 147 148.5.
4 Step B: Preparation o~ 2-dimethylcarbamoyl-6,11-dihydro-5H-~yrrolo[2,1-b]_[3]benzazepine-11-one 6 Anhydrous dimethyla~ine was bubbled through a 7 suspension of 2-chlorocarbonyl-6,11-dihydro-5H-pyrrolo-8 [2,1-b]13]benzazepin-11-one (23 g., 88.5 mmoles) in 100 ml.
g of methylene chloride. (Note: the introduction of di-methylamine caused the mixture to reflux and this reflux 11 stopped when all the acid chloride was reacted. This took 12 about 1 hour and complete solution was obtained.) 13 The reaction mixture was washed with water and 14 dried over sodium sulfate. It was then taken to dryness, triturated in ether, filtered and air-dried to yield 2-16 dimethylcarbamoyl-6~ll-dihydro-5H-pyrrolo[2~l-b]~3]benza 17 zepin-ll-one (20 g., 84~), m.p. 148-149.5C.
18 Ex_m~e 7 19 6,11-Dihydro-2-methoxycarbonyl-SH-pyrrolo~2,1-b] ~3 ] benzaze-pin~ one 21 6,11-Di~ydro-ll-oxo-SH-pyrxolo[2,1-b] E3] benzaze-22 pine-2-carboxylic acid (25.5 g., 0.11 moles) in 300 ml.
23 of methanol saturated with hydrogen chloride was refluxed 24 until a homogeneous solution was obtained (4 hours).
The volatiles were xemoved under vacuum and the residue was dissolved in 300 ml. of methylene chloride, 27 washed with dilute sodium hydroxide and then with water.
28 It was dried over sodium sulfate and concentrated. The 29 residue was triturated in ether, filtered and air-dried, yielding 6,11-dihydro-2-methoxycarbonyl-5H-pyrrolol2,1-b]-31 13]benzazepin-11-one (23.5 g., 85~), m.p. 125-127C.

1 ~ 9 _, ~z~s 1 Example 8 2 2-Trifluoromethylthio- and 3-trifluoromethylthio-6,11-3 dih~dro-5H-pyrrolo[2~1-b][3]benzazepin-11-one 4 6,11-Dihydro-5H-pyrrolo[2,1-b~[3]benzazepine-11-one (9.6 g., 48.7 mmoles) dissolved in pyridine (20 ml.) 6 and chloroform (50 ml.) was treated with trifluoromethyl-7 sulfenyl chloride (12 g., 86.6 mmoles) in chloroform (50 8 ml.). The reaction mixture was left at room temperature 9 for 2 hours.
The mixture was washed with water, dried over 11 sodium sulfate and concentrated to 16.2 g. of a black oil.
12 This oil was adsorbed on 800 g. of silica gel.
13 Elution with petroleum ether-ether 3:1 (v/v) yielded 3-14 trifluoromethylthio-6,11-dihydro-5H-pyrrolo[2,1-b~3]-lS benzazepine-ll-one (8.4 g., 57.7~), m.p. 95-95.5C.
16 Elution with ether yielded 2-trifluoromethylthio-17 6,11-dihydro-5H-pyrrolo[2fl-b][3]benzazepine-11-one (4.2 g., 18 28.8%), m.pD 77-78C.
19 Example 9 6,11-Dihydro-l-trifluoromethyl-(and -3-trifluoromethyl)-21 SH-pyrrolo~2,}-b~[3]benzazepin-11-one 22 A mixture of 8.9 g. of 6,11-dihydro-5~-pyrrolo-23 [2,1-b][3]benzazepin-11-one, 30 of trifluoromethyl iodide, 24 20 ml. of pyridine and 300 ml. of acetonitrile was irradi-ated with a 450 watt lamp for 18 hours. The mixture was 26 evaporated to dryness, and the residue was extracted with 27 ether and filtered. The filtrate was evaporated to an oil.
28 The oil was again treated with 25 g. of trifluoromethyl 29 iodide in pyridine/acetonitrile and irradiated for 12 hours.
Evaporation to dryness, extraction with ether, filtration 31 and evaporation to dryness gave a crystalline residue. The ~LO~Z~S

1 residue was chromatographed on silica gel, by elution with 2 benzene. Fraction 1 from the column provided 3.5 g. o 3 product contaminated with traces of the 2-trifluoromethyl 4 isomer. Fraction 2 provided 900 mg. of pure 6,11-dlhydro-3-trifluoromethyl-5H-pyrrolo[2,1-b][3~benzazepin-11-one, 6 m.p. 90-93C.
7 Rechromatography of Fractions 3-5 provided pure 8 6~ll-dihydro-l-trifluoromethyl-5H-pyrrolo[2~l-b~[3]benzaze 9 pin-11-one, m.p. 102-103~C.
Exam~le 10 11 6,11-Dihydro-?-p-e-ntanoyl-5H-pyrrolo[2~l-b]~3]benzazepin ..
13 6,11-Dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-14 one ~1.0 g.) was dissol~ed in 20 ml. of methylene chloride and 2.66 g. of al~minum chloride was added with cooling.
16 At room temperature there was added little by little 720 17 mg. of pentanoyl chloride. Fi~teen minutes after the 18 addition was complete the mixture was poured onto ice.
19 The organic phase was separated, filtered, dried and con-centrated to dryness. The residue was trit~rated with 21 ether, collected and dried to give 1.18 g. (85%) of 6,11-22 dihydro-2~pentanoyl-5H-pyrrolo[2~l-b][3]benzazepin~ oner 23 m.p. 135-136C. Chromatography on silica gel by elution 24 with benzene, and 5%lv/v) ethylacetate in benzene, raised the melting point to 137-138C.
26 Employing the procedure substantially as described 27 in Example 10, but substitutin~ for the pentanoyl chloride 28 used therein, the acid chlorides described in Table V, 29 there are produced the acyl-pyrrolobenzazepinones also described in Table V by the following procedure:

14985I~

9 Z~ ~ S

XCl _ O O

1 ~ABLE V
2 X product m.p._(C.) ,~ .
4 -C-C~3 16~-161 S i:) 6 -C CH~3)2 124-126 7 SO2N~CH3)2 134-137 8 a ~eaction conducted in nitromethane at reflux tempera-9 ture for 20 minutes.

~ Following the procedure of Ex~mple 10, but con 11 ~ucting the reaction at 100-130C. with excess alXanoyl 12 chloride as solvent a~d without the aluminum chloride, 13 there are produced mixtures of 2- and ~- alkanoyl ketones 14 whi~h upon chromatographic separation on silica gel provide ~5 the alkaroyl ~etone products described in Table V and in 76 E:cample 10 as well as the corresponding 3-pentanoyl-, 17 ~-acPtyl-, and 3-isobutyroyl- compounds.
18 Example 11 19 9-Iodo-6,11-dihydro~SH-pyrrolo[2,1-b~3]benzazepin-11-one ~ Step A: Pr~paration of 7-nitro-3,4 dih~dro-isocarbostyril 21 Fuming nitric acid (17 ml.) was added to 670 ml 2~ of concentrated sulfuric acid at 0C. 3,4-Dihydro~iso-23 carbostyril (50 g.j was added poxtionwise maintaining the 24 temperature below 0C. After 30 minutes at 0C., the .

1~92~L0~i 1 solution was poured into 8 1. of ice water. The crystalline 2 precipitate is collected, washed with wa~er and air dried 3 to give 62.0 g. (95~) of 7 nitro-3,4-dihydro-isocarbostyril, 4 m.p. 225-230C. After recrystallization from acetone it has m.p. 230-232C.
6 Step B: Prep ration_of 7-amino-3,4-dihydro-isocarbostyril 7 The product from Step A (20 g.) was hydrogenated 8 over 2.0 g. of 10% Pd/C in 350 ml. of methanol. The mix-g ture was filtered, and the filtrate was evaporated to dry-ness. The residue was suspended in ether and collected on 11 a filter to give 15.7 g. (9~%) of 7-amino-3,4-dihydro-12 isocarbostyril, mOp. 123-125C.
13 Step C: Preparation of 7-iodo-3,4-dihydro-isocarbostyril 14 ~ solution of 690 mg. of sodium nitrite in 5 ml.
of water was added dropwise to an ice-cold solution of 16 :L.62 g. of 7-amino-3,4-dihydro-isocarbostyril in 4 ml. of 17 concentrated hydrochloric acid and 12 ml. of water. After 18 about 15 minutes at 0-5C. a solution of 1.7 g. of potassium 19 iodide in 1 ml. of water was added and the mixture was allowed to warm to room temperature. Acetone (20 ml.) 21 was added and the solution was held at room temperature 22 for 1 hour and at 50-60C. for 1 hour. The mixture was 23 concentrated to dryness. The residue was taken up in 24 water, extracted with chloroform, the extract was dried and concentrated to dryness to give 2.0 g. ~73%) of 7-iodo-26 3,4-dihydro-isocarbostyril.
27 ~ Preparation of 2-aminoethyl-5-iodobenzoic acid 28 hydrochloride 29 A mixture of 1.0 g. of 7-iodo compound from Step C and 40 ml. of concentrated hydrochloric acid was 1 4 9 r ~
Oc5 1 heated in a pressure vessel at 145C. for 30 hours. The 2 solution was concentrated to dryness. The residue was 3 suspended in ether and collected to give 950 mg. (80~) of 4 2-aminoethyl-5-iodobenzoic acid hydrochloride, m.p. 200-205C.
6 Ste~ E: Preparation of 2 (2-pyrrol-1-yl)ethyl-5-iodobenzoic 7 acid 8 A mixture of 12.1 g. of product from Step D, 9 6.48 g. o 2,5-dimethoxytetrahydrofuran, 180 ml. of water and 30 ml. of acetic acid was stirred at 55C. for 2 hours 11 and at room temperature overnight. The mixture was 12 diluted with water/ extracted with chloroform, and the ex-13 tract was extracted with 0.5% (w/v) sodium hydroxide solu-14 tion. The alkaline extract was acidlfied with 6 N hydro-chloric acid and extracted with chloroform. The extract 16 was dried, filtered and concentrated to dryness. The 17 oily residue was triturated with cyclohexane and the solids 18 were collected to gi~e 8.1 g. (58%) of 2-(2-pyrrol-1-yl)-19 ethyl-5-iodobenzoic acid , m.p. 92-95C.
Step F: Preparation of 9-iodo-6,11-dihydro-5H-pyrrolo-21 [2,1-b]~3]benzaze~in-11-one 22 A mixture of 1 g. of the product from Step E
23 and 20 ml. of polyphosphate ester was stirred 1.5 hrs. at 24 room temperature. The mixture was cooled in ice and diluted with 75 ml. of water. The mixture was extxacted 26 with benzene and the extract was washed with water, dried 27 and concentrated to dryness to give S00 mg. of 9-iodo-28 6,11-dihydro-5H-pyrrolo~2,1-b~[3]benzazepin~ one, which 29 after recrystallization from cyclohexane had m.p. 120-122C.

1 Following the procedure of Example 11, Steps C, 2 D, E, and F but substituting for the potassium iodide used 3 in Step C thereo~ an equimolecular amount of cuprous 4 chloride, there is prepared 9-chloro-6,11-dihydro-SH-pyrrolo[2,1-b][3]benzazepin-11-one.
6 Example 12 7 9-Trifluoromethylthio-6,11-dihydro-5H~pyrrolo[2,1-b]_[3~-8 b-enæazepln-ll-one g A mixture of 2.4 g. of iodoketone (from Example 11), 5.14 g. of copper (electrolytic dust), 9.0 g. of 11 bis(trifluoromethylthio)mercury and 20 ml. of dimethyl 12 formamide was stirred and heated on a steam bath for 5 13 hours. The mixture was cooled in ice, treated with 75 ml.
14 of benzene and treated dropwise with 50 ml. of 10~ sodium hydroxide solution~ After 1 hour at room temperature the 16 mixture was filtered through diatomaceous earth followed 17 by a benzene wash. The filtrate was extracted with benzene.
18 The combined benzene fractions were washed with water, 19 dried, filtered and concentrated to dryness to give 2.0 g.
(90%) of 9-trifluoromethylthio-6,11-dihydro-5H-pyrrolo-21 [2,1-b~[33benzazepin-11-one, m.p. 81-83C.
22 Following the procedure of Example 12, but sub-23 stituting for the copper dust and the bis(trifluoromethyl-24 thio3mercury used therein an equimolecular amount of cuprous methylsulfide or cuprous isopropylsulfide, there 26 are produced 9-methylthio-6,11-dihydro-5H~pyrrolo[2,1-b]-27 ~3]benzazepin-11-one, respectively.
28 Example 13 29 9-Nitro-6,11-dihydro-5H-~yrrolo[2,_1-b]~3]benza2epin-ll-one Following the procedure of Example 11, Steps D, 31 E, and F, but substituting for the 7-iodo-3,4-dihydroiso-1 ~ ,- ., .~;

S

1 carbostyril used in Step D thereof, an equimolecular amount 2 of 7-nitro-3,4-dihydro-isocarbostyril, there is produced 3 in se~uence:
4 ~ 2-aminoethyl-5-nitrobenzoic acid, m.p. 230-232C.;
Ste~_~: 2 (2-pyrrol-1-yl)ethyl-5-nitrobenzoic acid, m.p.
6 147-149C.;
7 Ste~ C: 9-nitro-6,11-dihydro-SH-pyrrolo~2,1-b~[3]benzaze-8 pin-ll-one, m.p. 190-192C.
9 Example 14 9-Amino-6,11-Dihydro-5H-pyrrolo[2,1-b~3]benzaze~in- 1-one 11 Following the procedure of Example 11, Step B, 12 but substituting for the 7-nitro-3,4-dihydro-isocarbostyril 13 used therein an equimolecular amount of 9-nitro-6,11-14 dihydro-5H-pyrrolo[2,1-b][3~benzazepin-11-one, there is produced 9-amino-6,11-dihydro-5H-pyrrolo[2,1-b~[3]benzaze-16 pin-ll-one, mOp. 166-167C.
17 Example 15 18 9-Methylamino-6~ dihydro-sH-pyrrolo[2~l-b~t3]benzazepin 19 ll-one A solution of 9-amino-6,11-dihydro-~H-pyrrolo-21 ~2,1-b][3]benzazepin-11-one in triethyl orthoformate 22 (2.14 g.; 10 mmoles in 80 ml) is refluxed for 5 hours.
23 The volatiles are removed under vacuum and the residue 24 dissolved in 100 ml. sf absolute ethanol is stirred in an ice bath as sodium borohydride tO.88 g.; 0.024 moles) 26 is added over a period of 10 minutes. The mixture is 27 stirred for a period of 2 hours. After concentration 28 of the ethanol, the residue is dissolved in ethyl acetate, 29 washed with water, dried over Na2SO4 and concentrated to dryness to yield 9~methylamino-6,11-dihydro-5H-pyrrolo-31 t2,1-b][3]benzazepin-1].-one.

-3~-~Z~

1 Exam?le 16 2 9-Dime.hylamino-6,11-dih~dro-5H-pyrrolo~2,1-b~[3]benzaze-3 pin-ll-one 4 To a solution of 9-amino-6,11-dihydro-5H-pyrrolo~
[2,1-b][3]benzazepin-11-one (2.1 g., 10 mmoles) and 4 ml.
6 (50 mmoles) of 37% aqueous formaldehyde in 15 ml. of 7 acetonitrite is added 1 g. (16 mmoles) of sodium cyano 8 borohydride. A vigorous and exothermic reaction takes 9 place and a dark residue separates. The mixture is stirred for lS minutes and then glacial acetic acid is added drop-11 wise until the solution tests neutral on wet pH paper.
12 Stirring is maintained for an additional 2 hours. The 13 volatiles are removed under vacuum, and the residue is 14 dissol~ed in chloroform. The solution is washed with base and with water, dried o~er sodium sulfate, and concentrated 16 to leave a residue that is purified by chromatography on 17 silica gel. Elution with chloroform yields 9-dimethylamino-18 6,11-dihydro-5H-pyrrolo[2,1-b3[33ben2azepin-ll-one as a 19 aark brown oil.
Example 17 21 9-Cyano-6,11-dlhydro-5H-pyrrolo~2,1-b][3]benzazepin-11-one 22 A stirred mixture of 1 gm. of 9-iodo-6,11-23 dihydro-SH-pyrrolo~2,1-b][3]benzazepin-11-one, 1 g~. of 24 cuprous cyanide and 5 ml. of dimethylforma~ide is heated to reflux for 5 hr. The mixture is then poured into a 26 solution of 4 gm. of ferric chloride hydrate in 25 ml. of 27 2N hydrochloric acid. After stirring the resulting mixture 28 at 60 for 30 min., it is extracted with 3 x 50 ml. of 29 ethyl ~cetate, the organic extracts washed with 3 x 100 ml.
of water and dried over Na2SO4. Evaporation of the dried ~0~2~q.~ l~

1 solution ylelds 9-cyano-6,11-dihydro-5H-pyrro~o-[2,1-b]-2 [3]benzazepin-11-one.
3 Example 18 4 9-Trifluoromethylsulfinyl-6~ll-dihydro-5H-pyrrolo~2~l-b]
3 benzazepln-11-one 6 A solution of 3 gm. of 9-trifluoromethylthio-7 6,11-dihydro-5H-pyrrolo[2,1-b]~3]benzazepin~ one in 25 8 ml. of acetic acid containing 3 ml. of 50~ hydrogen peroxide 9 is stirred at 25C. for 6 hr. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride.
11 The solution is washed with 2 x 25 ml. of 5~ Na2C03 solu-12 tion, dried and evaporated. Chromatography of the residue 13 on silica gel yields 9-trifluoromethylsulfinyl-6,11-14 dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Employing the procedure of Example 18, but sub-16 stituting for the 9-trifluoromethylthio-6,11-dihydro-5H-17 benzazepin-ll-one used therein, an equimolecular amount 18 of the corresponding 9-methylthio- or 9-isopropylthio-lg compounds, there are produced respectively 9-methylsulfinyl~
6,11-dihydro-5~-pyrrolo~2,1-b][3]benzazepin-11-one and 9-21 isopropylsulfinyl-6,11-dihydro-5~-pyrrolo[2,1-b][3]benza-22 zepin-ll-one.
23 Example 19 24 9-Trifluoromethylsulfonyl-6,11-dihydro-5H-pyrrolo~2,1-b]-[3]benzazepin-11-one 26 A solution of 2 gm. of 9-trifluoromethylsulfinyl-27 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 20 28 ml. of acetic acid containing 5 ml. of 90~ hydrogen per~
29 oxide is stirred at 25C. for 4 days. The solvent is evaporated and the residue dissolved in 100 ml. of methylene -3~-1 ~ 9 ~ _ Ir, ~092~L~S

1 chloride. After ~ashing the organic solution with 2 x 25 2 ml. Or lN Na2C03, it is dried and evaporated, and the 3 residue chromatographed on silica gel to yield 9-trifluoro-4 methylsulfonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3~benzazepin-S ll-one.
6 Employing the procedure of Example 18, but sub-7 stituting for the 9-trifluoromethylthio-6,11-dihydro-5H-8 pyrrolo[2~1-b][3]benzazepin-11-one used therein, an equi-9 molecular amount of the corresponding 9-methylthio- or 9-isopropylthio~ compounds, there are produced respectively 11 9-methylsulfonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3~-12 benzazepin-ll-one and 9-isopropylsulfonyl -6,11-dihydro-13 5H-pyrrolo[2,1-bJ[3]benzazepin-11-one.
14 Example 20 9-Form~1-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-16 on~
17 Employing the procedure of Example 3 but sub-18 stituting for the 2-cyano compound used therein, an 19 equimolecular amount of 9-cyano-6,11-dihydro-5H-pyrrolo-[2,1-b]~3]ben-æazepine there is produced 9-formyl-6,11-21 dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
EXAMPLE ?l 9-Trifluoromethyl-6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepin-ll-one A mi~ture of 5 9. of the 9-iodo ketone, 25 9. of trifluoromethyliodide, 9 g..of precipitated copper and 150 ml.
of dimethylformamide is heated in a stainless steel tube with shaking for 12 hours at 140C. Work-up of the reaction mixture and chromatography yield the title compound.

l(J 9ZlC)~29 _ 3llH-PYRROLO[2,1-b][3]BENZAZEPINES

4Example 1 52-Cyano-llH-pyrrolo[2,1-b]~3]benæazepin-11-one 6Step A: Preparation of trans-2-carboxy-4-cyano-N-7styrylpyrrole 8A mixture of 5 g. of sodium hydride and 15 g.
9 of methyl 4-cyanopyrrole-2-carboxylate, in 75 ml. of di-methyl formamide was stirred until evolution of hydrogen 11 ceased. Styrene oxide (16 g.) was added and heated at 12110C. for 6 hours. The mixture was poured into 300 ml.
13 of water and extracted with 2 x 150 ml. of ether. The 14 aqueous phase was purged with nitrogen and acidified with 2 N hydrochloric acid. The precipitated solid is collected, 16 washed with water, air dried and washed with ether to give 15~86 1 6.4 g. of pure trans-2-carboxy-4-cyano-N-styrylpyrrole, 2 m.p. 195-196C. (decarboxylation).
3 The sodium hydride used in the above step can be 4 replaced by an equimolecular amount of potassium t-butoxide.
Ste~ Preparation of cis-2-carboxy-4-cyano-N-styryl-6 PYxrole 7 A solution of 50 mg. of trans-2-carboxy-4-cyano-8 N-styrylpyrrole in 1 ml. of acetonitrile was irradiated 9 with a 450 wat~ lamp for 45 minutes. The solution was concen~rated to dryness. The residue was triturated with 11 ether and the product was collected and air dried to give 12 37 mg. of c1s-2-carboxy-4-cyano-N-styrylpyrrole, m.p.
13 166-168C.
14 P~ollowing the procedure substantially as described in Example~l, Steps A and B, but substitutin~ for the methyl 16 4-cyanopyrrole~2-carboxylate and styrene oxide used in 17 Step A thereof, equimolecular amounts of the methyl pyrrole 18 carboxylates and styrene oxides, respectively, depicted in 19 Table I, there are produced the trans- and cis-N-styryl-pyrrole-2-carboxylic acids, also depicted in Table I by the 21 following process.

(Y~o ~ ~ ~ ~ 6' 1' 5' ~ ~ f CO2H
(Y)m ~ 2' /
' k~

(Y)m ~ (X)n COO~

15~86 ~092~ )S

1 Table I
2 Compound (Y)m n__ 5 3 4'-Cl H
6 4 4'-SCF3 H
7 5 4'-CN H
8 6 H 4-COCH(CH3)2 9 7 H 4-SO2N(CH3)2 10 8 H 4-SO2CH(CH3)2 11 9 H 4-Cl 12 10 4'-Br H

14 12 4'-OCH3 H
15 13 4'-CF3 H
16 ~Preparation-of 2-cyano-llH-pyrrolo[2,1-b][3]-benzazepi~-ll-one 17A solution of 35 mg cis-2-carboxy-4-cyano-N-18 styrylpyrrole in 0.5 ml. of dry methylene chloride was 19 treated with 45 ~1. of trifluoroacetic anhydride and stirred for 5 minutes. Stannic chloride (45 ~1.) was added and 21 the mixture stirred for 15 minute~. The mixtuxe was 22 poured into water, neutralized with ammonium hydroxide and 23 extracted twice with chloroform. The extract was washed 24 with water, dried over sodium sulfate, and concentrated to dryness. Trituration of the residue with 0.5 ml. of 26 ethyl acetate and filtering gave 2-cyano-11~-pyrrolo[2,1-b]-Z7 [3]benzazepin-11-one, m.p. 197C.

1 Following the procedure substant.ially as described 2 in Example 1, Step C, but substituting for the cis-2-3 carboxy-4-cyano-N-styxylpyrrole used therein, an equi-4 molecular amount of the cis-styrylpyrroles from Table I, th~re are produced the llH-pyrrolo[2,1-b~[3]benzazepin-11-6 ones described in Table II, by the following process:

6' , 1 5 7 4 5, ~ ~ (X)n 8 ~ ~ (X)n (Y)m ~ 2' ~ 4 ~ (Y)m t ~ 2 HOOC

7 Table II
8 Com- Starting material Product 9 pound (Y)m (X3n (Y)m (X)n a 12 3 4'-C1 H 9-Cl H
13 4 4'-SCF3. H 9-SCF3 H
14 5 4'-CN H 9-CN H
15 6 H 4-COCH(CH3~2 H 2-COCH(CH3)2 16 7 4-SO2N(CH3)2 H 2-SO2N(CH3)2 17 8 H 4-SO2CH(CH3)2 H 2-SO2CH(CH3)2 18 9 H 4-Cl H 2-Cl 1910 4'-Br H 9-Br H
(m.p. 210-214C.(dec.) 2111 H 4 NO~ H 2-NO2 22-12 . 4'-OCH3 H 9-OCH3 H
2313 - . 4 ' -CF3 H 9-CF3 H
a m. p. 113-114C.

158~6 Z~

1 xample 2 2 2-Cyano-llH-pyrrolo[2,1-b][3]benzazepin-11-one 3 Step A: Preparation of trans-4-cyano-N-styrylpyrrole-2-4 carbonyl chloride A mixture of 2.4 g. of trans-2~carboxy-4-cyano-6 N-styrylpyrrole ~from Example 1) and 10 ml. of thionyl 7 chloride was refluxed for 15 minutes, concentrated to dry-8 ness, treated with 10 ml. of toluene and concentrated to 9 dryness to give 2.45 g. (95%) of trans-4-cyano-N-styryl-pyrrole-2-carbonyl chloride, m.p. 119-121C.
11 Step B: Preparation of 4-cyano-N-(1,2-dichloro-2-12 phenylethyl)pyrrole-2-carbonyl chloride 13 A solution of 256.5 m~. of trans-4-cyano-N-14 styrylpyrrole-2-carbonyl chloride in 5 ml. of chloroform was treated with 1 mmole of chlorine dissolved in 1 ml.
16 of carbon tetrachloride. After 15 minutes, it was evapor-17 ated to dryness, txeated with 5 ml. of carbon tetrachloride, 18 and evaporated to dryness to give 307 mg. (94~) of oily 19 4-cyano-N~(1,2-dichloro-2-phenylethyl)pyrrole-2-carbonyl chloride.
21 Step C; Preparation of 2-cyano-5,6-dichloror-6,11-dihydro-22 5H-pyrrolo-[2,1-b] [3]benzazapin-11-one 23 Aluminum chloride (231 mg.) was added all at 24 once to a mixture of 160 mg. of 4-cyano-N-(1,2-dichloro-2-phenylethyl)pyrrole-2-carbonyl chloride and 0.5 ml. of 26 tetrachloroethane controlled at 140C. After 4 5 minutes, 27 the mixture is cooled, 15 ml. of water is added and the 28 mixtuxe is extracted with 4 x 10 ml. of chloroform. The 29 extract is washed with water, dried and chromatographed on 10 g. of silica gel by elution with benzene:ethyl acetate 15~8~
21~D5 1 (3:1 v/v). The irst fractior'provided 47 mg. (33%) of 2 2-cyano-5,6-dichloro-6,11-dihydro-5H-[2,1-b] [3]benzazapin-3 ll-one, m.p. 213-223C.
4 Step D: Preparation of 2-cyano-11~-pyrrolo[2,1-b] [3]-benzazepin-ll-one 6 Chromous chloride prepared under nitrosen from 7 30 mg. of 100 mesh chromium and 0.1 ml. of concentrated 8 hydrochloric acid in 0.4 ml. of water, was added to 20 mg.
9 of 2-cyano-5,6-dichloro-6,11-dihyaro-5H-pyrrolo[2,1-b] [3]-1~ benzazepin-ll-one in 0.1 ml. ol acetone at 70C. The 11 mixture is poured into 5 ml. of water and extracte~ with 12 3 x 3 ml. of chloroform.' The chloroform is washed with 13 water, drie~ and concentrated to dryness to give 13 mg.
14 (86~) of 2-cyano-llH-pyrrolo[2,1-b] [3]benzazapir.-11-or.e, m.p. 197C.
16 Following the procedure substantially as described 17 in Example 2 steps A, B, C, and D, but substitutin~ for the 18 trans-2-carboxy-4-cyano-N-styrylpyrrole use~ in st~p A
19 thereof the trans-2-carboxy-~-styrylpyrro'es ~escribed ir.
Table I, thexe are produced in sequence the carbonyl 21 chlorides, N-(1,2 -'i^hloro-2-pherylethyl)pyrrole carbonyl 22 chlorides, 5,~-dichloro-keto~es, and llH-pyrrolo[2,1-b]
23 [3]benzazapin-11-ones described in Table III by the 24 following procedure:

158~6 ~O9Z~O~LD

m ~ ~ SOC17~ ~ N ~ (X)n ~Y) C02E~ A (Y)m ~ COCl B J cl2 Cl Cl Cl Cl ~ \ ~ N ~ AlC13 ~ ~ ~ N (X)n (Y)m ~ C (Y) ClOC
- ~ CrC12 D ~

(Y)m~(x)n O
Table III
(Y)m ~ 2-Cl H . 2-SO2N(CH3)2 2-So2cH(cH3)2 H 2-CoCH(CH3~2 . Example 3 2-Cyano-llH-pyrrolo[2,1-b][3]benzazepin-11-one Method I
Step A: Preparation of methyl 4-cyano-N-phenacylpyrrole-2-carboxylate A mixture of 2 g. of methyl 4-cyanopyrrole-2~carboxylate, 2.7 g. of potassium carbonate, 2.7 g. of phenacylbromide and 15 ml. of dimethyl for~amide was heated -~2-~ 15~6 ~192~ S
at 100C. for 30 minutes. The mixture was poured into 200 ml. of water and extracted twice with ether. The ex-tract was washed with watcr, lried and concentrated to dryness. The residue was triturated with petroleum ether to give 3 g. (84%) of methyl 4-cyano-W-phenacylpyrrole-2-carboxylate, m.p. 169-172C.

Step B: Preparation of 4-cyano-N-(2-chloro-2-phenethyl)-p~rrole-2-carboryl chloride A mixture of 270 mg. of methyl 4-cyano-N-phen-acylpyrrole-2-carboxylate, 0.2 ml. of 6N sodium hydroxide solution and 5 ml. of ethanol was reflw:ed for l hour and the mixture was concentrated to a dry residue of 298 mg.
The residue was taken up in 5 ml. of aqueous ethanol (l:l v/v) and treated with 40 mg. of sodium boro-hydride at room temperature for 30 minutes. lrhe mixture was concentrated to dryness-.
The residue (351 mg.) was treated with 2 ml. of phosphorus oxychloride and 400 mg. of phosphorus penta-chloride and heated at 110C. for 18 hours. The mixture was concentrated to dryness, the residue was dissolved in 25 ml. of chlorsform, washed with 2 x 20 ml. of water, dried and concentrated to dryness. The residue was chrom-atographed on 5 g. of silica gel by elution with benzene-ethylacetate (l:l v/v). Concentration of the appropriate eluate provided 277 mg. of oily 4-cyano-N-(2-chloro-2-phenethyl)pyrrole-2-carbonyl chloride whose nmr and I.R.
spectrum confirmed the structuxe.

15~86 ~ Z~L0,5i Following the procedure substantially as described in Example 3, ~lethod I, Steps A and B, but substituting for the starting material employed therein, equimolecular amounts of the methylpyrrole-2-carboxylates described in Table IV in Step A thereof, there are produced the N-(2-chloro-2-phenylethyl)pyrrole-2-carbonyl chlories also des-cribed in Table IV by the following process.

~+ ~ '(X)n Cl n CDCl Table IV

(Y)m . (X)n .
X 4-Cl . H 4-so2N(cH3)2 H 4-So2CH(CH3)2 4-CoCH(CH3)2 - , lsa~6 ~lZ105i 1 Method II
2 Step A: Preparation of 4-cyano-N-(2-hydroxy-2-phenylethyl)-3 pyrrole-2-carbo~:ylic acid lactone 4 Following the procedure of Example 1, Step A, but substituting for the sodium hydride employed therein, 6 a catalytic amount of potassium t-butoxide, there is pro-7 duced 4-cyano-N-(2-hydroxy-2-phenylethyl)pyrrole-2-8 carboxylic acid lactone.
9 Step ~: Preparation of 4-cyano-~-(2-chloro-2-phenylethyl)-pyrroie-2-carbonyl chloride 11 A mixture of 0.54 g. of lactone from Example 3, 12 Method II, Step A, 1 g. of phosphorus pentachloride and 5 13 ml. of phosphorus oxychloride is refluxed for 36 hours.
14 The volatiles were removed in vacuo, and the residue was flushed three times by vacuum distillation of toluene to 16 give 0.54 g. (93%) of 4-cyano-N-(2-chloro-2-phenylethyl)-17 pyrrole-2-carbonyl chloride.
18 Following the procedure substantially as described 19 in Example 3, Method B, Steps A and ~ but substituting for the methyl 4-cyanopyrrole-2-carboxylate used in Step A, 21 thereof an equimolecular amount of the metllyl pyrrole-2-22 carbo~:ylates described in Table IV, thPre are produced 23 the N-(2-chloro-2-phenylethyl)pyrrole-2-carbonyl chlorides 24 also described in Table IV, b~ the following 2S process:

(Y~m~+ ~ (X)n '.' ' ~1POC13/PC15 (Y)m ~ ~ (X)n ClOC

158~6 1~92~5 Step C: Preparation of 2-cyano-llH-pyrrolo[2,1-b][3]-benzazepin-ll-one Following the procedure substantially as described in Example 2, Step C, but substituting for the starting material employed therein, an equimolecular amount of 4-cyano-N-(2-chloro-2-phenylethyl)pyrrole-2-carbonyl chloride, there is produced 6-chloro-2-cyano-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one. ThiS material was dissolved in 5 ml. of ethanol containing 2 pellets of potassium hydroxide and refluxed for 15 minutes. The ethanol was evaporated. The residue was partitioned between water and chloroform. The chloroform was washed with water, dried and evaporated to dryness to give 109 mg. of crude product.
This was chromatographed on 10 g. of silica gel by elution with benzene:ethyl acetate (3:1 v/v) to provide pure 2-cyano-llH-pyrrolo[2,1-b][3]benzazepin-11-one, m.p. 197C.
Following the procedure of Example 3, Step C, but substituting for the starting material used therein an equlmolecular amount of the carbonyl chlorides from Table IV, there are produced the ketones of Table V by the following process:
Cl (Y)m ~ ~ 1) AlC13 (~_ ~ (X~
Cl-lC 2) ~OH
O O

Table V
m (X)n H 2-S02N(CH3)2 H 2-S02CE~(CH3)2 H 2-COCH(CH3)2 Z~05 1 Example 4 2 3-Trifluoromethylthio-llH-pyrrolo[2 ! 1-b][3]benzazepin-11-one 3 A mixture of 100 mg. of llH-pyrrolo[2,1-b][3]-4 benzazepin-ll-one, 100 mg. of pyridine, and 1.5 ml. of chloroform, and 1 meq. of trifluoromethylsulfenyl chloride 6 after 200 minutes at 45C. was poured into water. The 7 organic phase was washed with dilute hydrochloric acid, 8 water, dried and concentrated to dryness. ~he residue on 9 recrystallization from ether ~ave 124 mg. of 3-trifluoro-methyltnio-llH-pyrrolo[2,1-b][3]benzazepin~ one, m.p.
11 137-137.5~C.
12 Example 5 13 2-Pentanoyl-ll~-pyrrolo[2ll-b][3]benzazepin-11-one 14 llEI-Pyrrolo[2,1-b][3]benzazepin-11-one (1.0 g.) is dissolved in 20 ml. of methylene chloride and 2.66 g.
16 of aluminum chloride is added with cooling. At room tem-17 perature there is added little by little 720 mg. of pent-18 anoyl chloride. Fifteen minutes after the addition is 19 complete the mixture is poured onto ice. The organic phase is separated, filtered, dried and concentrated to dryness.
21 The residue is triturated with ether, collected and dried 22 to give 2-pentanoyl-llH-pyrrolo[2,1-b] [3]benzazepin-11-23 one.
24 Employing the procedure substantially as de-scribed in Example 5, but substituting for the pentanoyl 26 chloride used therein equimolecular amounts of isobutyryl 27 chloride or dimethylsulfamoyl chloride, there are produced 28 2-isobutyroyl-llH-pyrrolo[2,1-b][3]benzazepin-11-one or 29 2-dimethyl-sulfamoyl-llII-pyrrolo-[2,1-b] [3]benzazepin-ll-one. In the latter case, the reaction is conducted in 31 nitromethane at reflux temperature.

15~86 ~09Z105 1 Following the proc~dure o~ Example 5, ~ut 2 conducting the reaction at 100-130C. with exccss 3 alkanoyl chloride as solvent and without the al~minum 4 chloride~ there are produced mixtures of 2- and 3-alkanoylketones which upon chromatograp}lic separation on 6 silica gel provides the alkanoyl ketone products described 7 in Example 5 as well the corresponding 3-pentanoyl- ar.d 8 3-isobutyroyl- compounds.

Example 6 2-Carbamoyl-llH-pyrrolo[2,1-b][3]benzazepin-11-one lI 2-Cyano-llH-pyrrolo[2,1-b]~3]benzazepin-11-one 12 (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric 13 acid and 100 ml. of acetic acid is refluxed for 2 hours.
14 It is then poured onto 500 ml. of water and ~ontinuously extracted with methylene chloride. The solution is left 16 to cool to room temperature and filtered to afford 2-17 carbamoyl-llH-pyrrolo[2,1-b][3]benzazepin-11-one.
18 Example 7 19 2-Carboxy=ll~I-pyrrolo[2~l-b] [3]berzazepine-11-one To 2-carbamoyl-11~-pyrrolo[2,1-b][3]benzazepine-21 ll-one (27 g., 0.112 moles) in 300 ml. of 50~ sulfuric acid 22 maintained at 50C. is added slowly 25 g. of sodium nitrite 23 in 75 ml. of water. At the end of the addition, the solid 24 is filtered, washed with water and air-dried to yield 2-carboxy-11~-pyrrolo[2,1-b] [3]benzazepire-11-one.
26 E~ample 8 27 2-Dimethylcarbamoyl-llH-pyrrolo[2,1-b][3]benzaZepin-ll-one 27 Step A: Preparation of 2-chlorocarbonyl-11~-pyrrolo-29 [2,1-b]~3]benzaze~in-11-one llH-ll-oxo-pyrrolo[2,1-b][3]benzazepine-2-31 carboxylic acid t24 g., 99 mmoles) in 100 ml. of thionyl 15~
~(~9~0~

1 chloride is refluxed for 15 minutes. The volatiles are 2 removed under vacuum and the residue is triturated in 3 ether. Filtration and air drying yields 2-chlorocarbonyl-4 llH-pyrrolo[2,1-b][3]benzazepin-11-one.
Step B: Preparation of 2-dimethylcarbamoyl-llH-pyrrolo-6 [2,1-b][3]benzazepine~ one 7 Anhydrous dimethyl amine is bubbled through a 8 suspension of 2-chlorocarbonyl-llH-pyrrolo[2,1-b][3]-g benzazepin~ one (23 g., 88.5 mmoles) in 100 ml. of methylene chloride. (Note: The introduction of dimethyl I1 amine causes the mixture to reflux and this reflux stops 12 when all the acid chloride is reacted.) 13 The reaction mixture is washed with water and 14 dried over sodium sulfate. It is then taken to dryness, triturated in ether, filtered and air-dried to yield 2-16 dimethylcarbamoyl-11~-pyrrolo[2,1-b][3]benzazepin-11-one.
17 Following the procedure of Example 8, Step ~, 18 but substituting for the dimethylamine used therein, an 19 equimolecular amount of methylamine, there is produced 2-methylcarbamoyl-llH-pyrrolo[2,1-b][3]benzazepin-11-one.
21 Example 3 22 2-Methoxycarbonyl-llH-pyrrolo[2,1-b]~3]benzazepin-11-one 23 11-Oxo-llH-pyrrolo[2,1-b][3]benzazepine-2-24 car~oxylic acid (25.5 g., 0.11 moles) in 300 ml. of methanol saturated with hydrogen chloride is re~iuxed until a homo-26 geneous solution is obtained (4 hours).
27 The volatiles are removed under vacuum and the 28 residue is dissolved in 300 ml. of methylene chloride, 9Zî~

1 washed with d lute sodium hydroxide and then with water.
2 It i5 dried over sodium sulfate and concentrated. The 3 residue is triturated in ether, filtered and air-dried, 4 to yield 2-methoxycarbonyl-lliI-pyrrolo[2,1-b][3]benzazepine-5 11-one.
6 Example 10 7 9-Trifluoromethylthio-llH-pyrrolo[2,1-b][3]benzazepin-11-one 8 A mixture of 42.56 g. of bis(trifluoromethyl-9 thio)mercury, 17.27 g. of 9-bromo-llH-pyrrolo[2,1-b][3]-benzazepin-ll-one, 28 g. of electrolytic copper dust, 98 ml.
11 of quinoline and 84 ml. of pyridine is stirred and heated 12 at 195C. for 18 hours. The mixture is shaken with 400 13 ml. of 6N hydrochloric acid and 400 ml. benzene. The 14 organic phase is washed with 5 x 300 ml. of 3N hydro-chloric acid and 5 x 300 ml. of water, dried over magnesium 16 sulfate, filtered and concentrated to dryness, to give 9-17 trifluoromethylthio-llH-pyrrolo[2,1-b][3]benzazepin-11-18 one.
19 Example 11 .
Pr~paration of 2-formyl-11~-pyrrolo[2,1-b][3~benzazepin-11-21 one 22 2-Cyano-llH-pyrrolo[2,1-b][3]benzazepin-11-one 23 (222 mg.) and 222 mg. nickel-aluminum alloy in 2 ml. 75 24 formic acid is refluxed for 1-1/2 hours. The solid is filtered off and washed with ethanol. The filtrate is 26 diluted with 50 ml~ water and extracted twice with 50 ml.

27 methylene chloride. The organic layer is washed with water, 28 5~ sodium bicarbonate and with water; it is then dried over 29 magnesium sulfate and evaporated to dryness. Addition of .

~LO~ OS

1 ether induces crystallization and the crystals are filtered 2 and air-dried to yield 2-formyl-llH-pyrrolo[2,1-b][3]ben-3 zazepin-ll-one.
4 Using substantially the pxocedure described in Example ll, but starting with 9-cyano-llH-pyrrolo[2,1-b]-6 [3]benzazepin~ one in place of the 2-cyano compound, 7 there is obtained 9-formyl-llH-pyrrolo[2,1-b][3]benzaze-8 pin-ll-one.
9 Example 12 ._ 9-Cyano-llH-~yrrolo[2,1-b] [3]benzazepin-11-one 11 A stirred mixture o~ 1 gm. of 9-bromo-llH-12 pyrrolo[2,1-b] [3]~enzazepin-11-one, 1 gm. of cuprous 13 cyanide and 5 ml. of dimethylformamide is heated to reflux 14 for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydro-16 chloric acid. After stirring the resulting mixture at 17 60 for 30 min., it is extracted with 3 x 50 ml. of 18 ethyl acetate, the organic extracts washed with 3 x 100 ml.

19 of water and dried over Na2SO4. E~aporation of the dried soiution yields 9-cyano-llH-pyrrolo[2,1~b] [3]benzazepin-21 ll-one.

22 Example 13 23 2-Hydroxymethyl-llH-pyrrolo[2,1~b] [3]benzazepin-11-one 24 A solution o~ 2.23 gm. of 2-formyl-llH-pyrrolo-[2,1-b] ~3] benzazepin-llH-one and 95 mg. of sodium 26 borohydride in 20 ml. o ethanol is stirred at 25C. for 27 2 hrs. The solvent is evaporated and the residue dissolved ~ 158~6 ~()9Z105 1 in methylene chloride to extract the crude product from 2 inorganic materials. After chromatography on silica 3 gel, there is obtained 2-hydroxymethyl-llH-pyrrolo[2,1-b]
4 [3]benzazepin-11-one.

Example 14 6 2-Tri1uoromethyl-11~-pyrrolo[2,1-b] [3]benzazepin-11-one 7 In a sealed Hasteloy-C line~ pressure vessel 8 a mixture of 10 gm. of 2-carboxy-ll~I-pyrrolo[2,1-b] [3]-g benzazepin~ one and 15 gm. of sulfur tetrafluoride is heated at 100 for 4 hrs., then at 130 for 4 hrs. The 11 vessel is cooled to room temperature and opened cautiously 12 (toxic fumes'). The contents of the vessel are e~tracte~
13 with 300 ml. of ether and the ether solution stirred 14 vigorously with 200 ml. of lN sodium hydroxide for 6 hrs.
The ether layer is separated, dried and evaporated and 16 the residue chromatographed over silica gel to yield 17 2-trifluoromethyl~ pyrrolo~2,1-b] ~3]benzazepin-11-one.

1~ Exam~le 15 19 9-Methylthio-llH-p~rrolo[2,1-b] [3]benzazepin-11-one

-20 - A mixture of 27 gm. of 9-bromo-11~-pyrrolo-

21 [2,1-b] [3]benzazepin-11-one, 15 sm. of cuprous methyl-

22 sulfide, 170 ml. of quonoline ana 15 ml. of pyridine is

23 stirred under a nitrogen atmosphere for 6 hrs. at a

24 temperature of 195C. The reaction mixture is cooled and poured into 500 ml. of 6N HCl containing 300 gm. of . , ~Z~

1 cracked ice. The resulting mixture is extracted with 2 3 x 200 ml. of benzene which is then filtered to remove 3 some insoluble black material. The benzene extracts 4 are washed with 3N HCl until the aqueous layer remains S acidic, then washed with 100 ml. H2O, dried (Na2SO4) 6 and evaporated to yield 9-methylthio-llH-pyrrolo[2,1-b]-7 [3]benzazepin-11-one.
8 Following the above procedure of Example 15 9 but replacing cuprous methylsulfide by cuprous isopropyl-sulfide, there is obtained 9-isopropylthio-llH-pyrrolo-11 [2,1-b][3]benzazepin-11-one.
12 Example 16 13 2-Trifluoromethylsulfinyl-llH-pyrrolo[2,1-b][3]-14 benzaze~ln-ll~one A solution of 3gm. of 2-trifluoromethylthio-16 llII-pyrrolo[2,1-b][3]benzazepin~ one in 25 ml. of 17 acetic acid containing 3 ml. of 50% hydrogen peroxide is 18 stirred at 25~C. for 6 hrs. The solvent is evaporated 19 and the residue dissolved in 100 ml. of methylene chloride.
~he solution is washed with 2 x 25 ml. of 5~ Na2CO3 21 solution, dried and evaporated. Chromatography of the 22 re idue on silica gel yields 2-trifluoromethylsulfinyl-23 llH-pyrrolo[2,1-b][3]benzazepin-11-one.
24 Using the procedure of Example 16 but starting with 9-methylthio-llH-pyrrolo[2,1-b][3~benzazepin-11-one, 26 there is obtained 9-me~hylsulfinyl-llH-pyrrolo[2,1-b][3]-27 benzazepin-ll-one~
28 Similarly, 9~isopropylthio-llH-pyrrolo[2,1-b]-29 [3]~enzazepin-11-one, using the procedure of Example 16, produces 9-isopropylsulfinyl-llH-pyrrolo[2,1-b][3]benza-31 zepin-ll-one-, 158~6 1~21~5 1 Example 17 2 2-Trifluor-omethylsulfony~ H-pyrrolo[2~l-b] [3]
3 benzazepin-ll-one ~ ' 4 A soiution of 2 gm. of 2-trifluoromethylsulfinyl-llH-pyrrolo[2,1-b] [3]benzazepin-11-one in 20 ml. of 6 acetic acid containing 5 ml. of 90% hydrogen peroxide is 7 stirred at 25C. for 4 days. The solvent is evaporated and 8 the residue dissolved in 100 ml. of methylene chloride.
9 After washing the organic solution with 2 x 25 ml. of lN
Na2CO3, it is dried and evaporated, and the residue chrom-11 atographed on silica gel to yield 2-trifluoromethylsulfonyl-llH-12 pyrrolobenzazepin-ll-one.
13 Using the procedure of Example 17 but starting 14 with 9-methylsulfinyl-llH-pyrrolo[2,1-b] [3]benzazepin-ll-one,there is prepared 9-methylsulfonyl-llH-pyrrolo-16 [2~1-b] [3]benzazepin-11-one.
17 Similarly using the procedure of ~xample 17 18 but starting with 9-isopropylsulfinyl-llH-pyrrolo[2,1-b]
19 [3]benzazepin-11-one there is'obtained 9-isopropylsulfonyl-llH-pyrrolo[2,1-b] [3]benzazepin-11-one.
21 Example 18 22 9-Hydroxy-llH-pyrrolo[2,1-b] [3]benzazepin-11-one 23 Ethanethiol (0.62 g., 10 mmoles), dissolved in 24 dimethyl formamide (10 ml.) is added to a suspension of sodium hydride (0.5 g. of 50% oil dispersion) in dry dimethyl formamide (5 ml.). The mixture is stirred until 27 all hydrogen has evolved and 9-methoxy-llH-pyrrolo[2,1-b]
28 [3]benzazepin-11-one (2.26 g., 10 mmoles) is added. The, 29 solution is refluxed fox a period of 3 hours. The cooled _54~
. ~ ' .

... ...

15~6 921~5 1 reaction mixture is acidified with 0.2N HCl and extracted 2 with chloro~orm. The organic layer is washed with water, 3 dried over sodium sulfate and concentrated to yield 9-4 hydroxy-llH-pyrrolo[2~l-b3 [3]benzazepin-11-one.
Example 19 6 9-Carbamoyl-llH-~yrrolo[2,1-b] [3]benzazepin-il-one 7 9-Cyano-llH-pyrrolo[2,1-b] [3]benzazepin-11-one 8 (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric 9 acid and 100 ml. of acetic acid is refluxed for 2 hours.
It is then poured onto 5G0 ml. of water and continuously 11 extracted with methylene chloride. The solution is left 12 to cool to room temperature and filtered to afford 9-13 carbamoyl-llH-pyrrolo[2,1-b] [3]benzazepin-11-one.
14 Example 20 9-Carboxy-llH-pyrrolo[2,1 b] ~3]benzazepin-11-one 16 To 9-carbamoyl-llH-pyrrolo[2,1-b] [3]benzazepin-17 ll-one (27 g., 0.112 moles) in 300 ml. of 50~ sulfuric 18 acid maintained at 50C. is added slowly 25 g. of sodium 19 nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to 21 yield 9-carboxy-llH-pyrrolo[2,1-b] [3]benzazepin-11-one.
22 Example 21 23 9-Ethoxycarbonyl amino-llH-pyrrolo[2,1-b] [3]benzazepin-24 ll-one To 9-carboxy-llH-pyrrolo[2,1-b~ [3]benzazepin-26 ll-one (96 g., 0.4 moles) in 500 ml. ethanol, and is added 27 successively triethylamine (52 g., 0.52 moles) and diphenyl-28 phosphoro azide(112 g., 0.40 mmoles). Reflux is maintained 15~6 ll)~Zl~S

1 for 3 hrs. The mixture is poured onto water, extracted 2 with ethyl acetate, washed with lN sodium hydroxide and 3 dried over magnesium sulfate to yield after evaporation 4 1.70 g. of a residue that is chromatographed on silica gel.
~lution with methylene chloride yields 9-ethoxycarbonyl-6 amino-llH-pyrrolo[2,1 b] [3]benzazepin-11-one.
7 Example 22 8 9-Amino-llH-pyrrolo[2,1-b] [3]benzazepin-11-one 9 To 9-ethoxycarbonyl amino-llH-pyrrolo[2,1-b]
[3]benzazepin-11-one (2.80 g., 10 mmole) in 100 ml. EtO~
11 is added 10 ml. 2N potassium hydroxide. Reflux is main-1~ tained for 42 hrs. The volatiles are removed under vacuum 13 and the residue is extracted with chloroform, washed with 14 water and dried over magnesium sulfate. Evaporation leaves a dark residue that is purified by chromotography on 16 silica gel. Elution with 10~ methanol in chloroform yields 17 9-amino-llH-pyrrolo[2,1 b] ~3]benzazepin-11-one that de-18 composes slowly on standing.
19 Example 23 9-Methylamino-llH-pyrrolo[2,1-b] [3]benzazep1n-ll-one 21 A solution of 9-amino-llH-pyrrolo[2,1-b] [3]-22 benzazepin~ one in triethyl orthoformate (2017 g., 23 10 mmoles in 80 ml.) is refluxed for 5 hrs. The volatiles 24 are removed under vacuum and the residue, dissolved in 100 ml. absolute ethanol is stirred in an ice bath as 26 sodium borohydride (0.88 g., 0.024 moles) is added over a 27 period o~ 10 minutes. The mixture is stirred for a period 28 of 2 hrs. After concentration of the ethanol, the residue -56~

1.0S

1 is dissolved in ethyl acetate, washed wi.th water, dried 2 over Na2S04 and concentrated to dryness to yield 9-3 methylamino-llH-pyrrolo[2,1-b] [3]benzazepin-11-one as a 4 brown amorphous solid.
Example 24 6 9-Dimethylamino-llH-pyrrolo_[2,1-b] ~3]benzazepin-11-one 7 To a solution of 9-amino-llH-pyrrolo[2,1-b] [3]-8 benzazepin-ll-one (2.1 g., 10 mmoles) and 4 ml. (50 mmole) 9 of 37% aqueous formaldehyde in 15 ml. of acetonitrile is added 1 g. (16 mmoles) of sodium cyano borohydride. A
11 vigorous and exothermic reaction takes place and a dark 12 xesidue separates. The mixture is stirred for 15 mins.
13 and then glacial acetic acid is added dropwise until the 14 solution tests neutral on wet pH paper. Stirring is maintained for an additional 2 hrs. The volatiles are 16 removed under vacuum, and the residue is dissolved in 17 chloroform. The solution is washed with base and with 18 water, dried over sodium sulfate, and concentrated to 19 leave a residue that is pu~ified by chromatography on ZO silica gel. Elution with chloroform yields 9-dimethylamino-21 llH-pyrrolo[2,1-b] [3]benzazepin-11-one as a dark brown 22 oil.
23 Example 25 24 9-Acetamido-llH-pyrrolo[2,1-b] [3]benzazepin-11-one 9-~mino-llH-pyrrolo[2,1-b] [3]benzazepin-11-one 26 (2.1 g., 11.4 mmoles) dissolved in 15 ml. pyridine is 27 treated with acetic anhydride (2 ml.) at room tempe`rature 28 for 19 hours. The volatiles are removed under vacuum and 29 the residue is dissolved in chloroform, and chromatographed on silica gel. Elution with chloroform yields 9-acetamido-31 llH-pyrrolo[2,1-b] [3]benzazepin-11-one.

~Z~S

1 The ollowing Examples illustxate the preparation 2 of the 11-(RlR2-aminopropylidene)-pyrrolo[2,1-b~[3]benza-3 zepines of this invention and are not meant to limit the 4 invention to the particular processes or novel compounds described therein.

8 11-(3-dimethylaminopropylidene~-6,11-dihydro-5H-pyrrolo-9 [2,1-b][3]benzazepine ~ Preparation of ll-Hydroxy-11-~3-dimethylamino-11 propyl)-6,11-dihydro-5H pyrrolo[2,1-b][3]benz-12 azepine 13 To a solution of 16 g., (0.081 mole) of 6,11-14 dihydro-5H-pyrrolo[2,1-b~[3]benzazepin~ one in 300 ml.
tetrahydrofuran (THF) is added 150 ml. of l.ON solution of 16 3-dimethylaminopropyl magnesium chloride in THF. After 17 stirring for 40 minutes at ice-bath temperature and for 18 1.5 hours at 25C., the bulk of the solvent is distilled 19 below 45C. under reduced pressure. The residue is dis-solved in 500 ml. of methylene chloride and the Gri~nard 21 adduct is hydrolyzed by the dropwise addition of 15 ml.
22 water with cooling in an ice bath. The methylene chloride 23 solution is decanted and the gelatinous precipitate is 24 extracted three times with 80 ml. portions of boiling benzene. The combined organic extracts are washed with 26 watex and then e~aporated under reduced pressure to yield, 27 after cxystallization from ethanol, ll-hydroxy 11-(3-di-28 methylaminopropyl)-6,11-dihydro-5H-pyrrolo-[2,1-b][3~benz-29 azepine, m.p. 68-70C.

~Z~q~5 1 Step B: Preparation of 11-(3-Dimethylaminopropylidene)-2 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine 3 Hydrogen chloride gas is bubbled through a solu-4 tion of 4.8 gm. (0.017 moles) of 11-hydroxy-11-(3-dimethyl-aminopropyl) 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine 6 in 70 ml. of chloroform at 0C. for 5 minutes. The 7 re~ulting dark mixture is stirred for an additional 5 8 minutes, and then washed with 6M NaOX to provide, after g evaporation of the chloroform, 4.3 g. of 11-(3-dimethyl-aminopropylidene)-6rll-dihydro-5H-pyrrolo~2~l-b][3]benz-11 acepine as an oil. It is converted to a crystalline oxa-~ late by adding a solution of 266 mg. of the free base in 13 5 ml. of ethanol to a mixture of 90 mg. of oxalic acid and 14 ~ ~ ml. of ethanol and collecting the precipitate by filtra-ion and air drying; m.p. 140-165C~ (dec.).
16 Following the procedure of Example I, Step B, 17 there may be substituted for the hydrogen chloride-chloro-18 fonm system (13 used therein trifluoroacetic anhydride-19 chloroform (2), trifluoroacetic acid t3), oxalic acid in ethanol (4), phosphorus oxychloride-pyridine (5), trichloro-21 acetic acid-ethanol (6), acetic acid (7), or formic acid 22 (8).
23 Following the procedure of Example I, Steps A and 24 B, but substituting for the 6,11-dihydro-5H-pyrrolo[2,1-b]-~3]benza~epin-11-one used in Step A thereof an equimolecular 26 amou~t of the ketones described in Table A, there are pro-27 duced in sequence the 11-hydroxy-11-(3-Rl,Ra-aminopropyl)-28 6,11-dihydro-5H-pyrrolo[2,1-b][3]be~zazepines and 11-(3-29 Rl,R2 aminopropylidene)-6~ll-dihydro-5H-pyrrolo[2~l-b][3]

benzazepines also described in Table A in accordance with 31 the following process:

C~S

~Ya)m~ (Xa)n 2 ( Ya ) m~~/XRl) n I ( a ) HO (CH2) 3N\ 2 3 (Ya)m~ /(RXla)n II(a) ( C 2 ) \ 2 ~21~)5i 2 DEHY- M.P. (C.) R~ Ra (Y~)m (X~)n AGENT COMPOUND II(a) 3 3 H 2-So2N(CH3)2 1128-136 CH3 CH3 H 2-CO2CH3 1115 (dec.) CH3 CH3 H 2-CO2H 1223-231 (dec.)*
3 3 H 2-CONH2 1190 (dec.)*
11 CH3 CH3 H 2-SCF3 1161 (dec.) 12 .CH3CH3 H 3-SCF3 1174 (dec.) 13 CH3 CH3 H 2-CON(CH3)2 1167 (decO) 16 CH3 CH3 H 2-CCH(CH3)2 1120-125 18 CH3 CH3 H 2-C(CH2)3CH3 1115-132 (dec.) 20 CH3 CH3 H 2-SO2CH(CH3)2 ~4 CH3 CH3 H 2-COCH3

25 CH3 CH3 H 2-CF3

26 CH3 CH3 9-OCONHCH3 2,3-Br2 4

27 CH3 CH3 9-NHCOOCH3 2,3-Br2 4

28 CH3 CH3 9-CH3 2,3-Br2 7

29 CH3 CH3 H 2,3-Br2 1180-185 (dec.) *hydrochloride salt 10~ 105 2 TA~LE A
(continued) 3 DEHY- ~.P. (~C.) Ra Ra (~a)m (Xa)n AGENT COMPOUND II(a) CH3 CH3 ~ 2-Br 7 CH3 CH3 H 3-CN 4 180-185 (dec.) 8 CH3 CH3 H 1,2,3-Br3 5 9 CH3 CH3 H 1,3 Br2 2 CH3 6 CH3 CH39-NHCOCH3 1,2,3-Br3 11 CH3 CH39-CH(CH3)2 2,3-Br2 4 12 CH3 CH3 9-SCH3 2,3-Br2 4 13 CH3 CH38,9-(CH3~2 2-CN 7 16 CH3 CH3 H 2,3-C12 5 CH3 ~39-CH(CH3)2 H 4 24 CH3 CH39-SCH(CH3)2 H 4 CH3 CH3 H l-CF3 5 26 CH3 CH3 H 3-CO(CH2)4H

28 CH3 CH3 H 3-COCH(CH3)2 CH3 CH3 9-SCF3 H 4 155-165 (dec.) 10921 13~

(continued) 3 DEHY- ~.P. (C.) S R~ Ra (Ya)m (Xa)n AGENT COMPOUND II(a) 9 CX3 CH3 9-N(CH3)2 H

13 CH3 CH3 9-SOCH(CH3)2 H 4 14 CH3 CH3 g S2CF3 H

16 CH3 CH3 9-SO2CH(CH3)2 H
17 CH3 CH3 9-Cl H 4 18 CH3 C~3 9-SCH(CH3)2 H 7 19 ~2H5 CH3 H 2-CN
~CH2)4 ~ H H 4 21~ (CH2)5 - H 2-Co(CH2)3CH3 22-(CH2)2O(cH2)2 H
23~ H H 2-CN
24H -CH=CH2 H 2-CN

~!L09Z~S

2 2-Cyano-ll-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b]-3 [3]benzazepine .
4 Step_A: Preparation of 2-Cyano-11-(3-dimethylaminopropyl)-ll-hydroxy-llH-pyrrolo[2,1-b]~3]benzazepine 6 A mixture of 4 g. of 2-cyano-ll~-pyrrolo[2,1-b]-7 [3]benzazepin-11-one in 50 ml. of tetrahydrofuran is treated 8 dropwise with 20 ml. of tetrahydrofuran containing 28.40 9 mmole of 3-(dimethylamino)propylmagnesium chloride while maintaining the temperature at 25C. Ten minutes after the ll addition is complete, 2 ml. of water is added and the mix-12 ture is poured into 200 ml. of methylene chloride, dried 13 over sodium sulfate and filtered. Concentration to dryness 14 provides 3.3 g. ~60~) of a solid residue of 2-cyano-ll-(3~dimethylaminopropyl)-11-hydroxy-llH-pyrrolo[2,1-b][3]-16 benzazepine, m.p. 123-126C.
7 Step B: Preparation of 2-Cyano-ll-(3-dimethylaminopropyl-idene)-llH-pyrrolo[2,1 b~[3~benzazepine A mixture of 2.8 g. of the ll-hydroxy compound in 50 ml. Qf chloroform i5 treated with hydrogen chloride 21 gas for 5 minutes while maintaining the tempera~ure at 22 25C. The mixture is neutralized with 2N sodium hydroxide 23 and extracted twice with chloroform. The extract is washed 24 with water, dried and concentrated to dryness to give 2.4 5 g. o~ oil.
26 The oil is dissolved in lO ml. of acetonitrile 27 and treated with 1.0 g. of oxalic acid. After 4 hours at 28 room temperature and overnight in the refrigerator, the 29 solids are collected, washed with ether and air dried to give 2.7 g. of 2-cyano-ll-(3-dimethylaminopropylidene)-31 llH-pyrrolo[2,1-h]~3]benzazepine, oxalate, m.p. 185-187C.

~09~

1 Following the procedure Gf Æxample II, Step B, 2 there may be substituted for the hydrogen chloride-chloroform 3 system (1) used therein, trifluoroacetic anhydride-chloroform 4 (2), trifluoroacetic acid (3), oxalic acid in ethanol (4), phosphorus oxychloride-pyridine (5), trichloroacetic acid-6 ethanol (~), acetic acid (7), or formic acid (8).
7 Following the procedure of Example II, Steps A
8 and B, but substituting for the 2-cyano-llH-pyrrolo~2,1-b]-9 [3]benzazepin-11-one used in Step A thereof an equimolecular amount of the ketones described in Table B, there are pro-11 duced in sequence th2 11-hydroxy-11-(3-Rl,Ra-aminopropyl-12 llH-pyrro lo ~ 2, 1-b~[3]benzazepines and 11-( 3~Ra, Ra -amino-13 propylidene)-llH-pyrrolo[2,1-b][3]benzazepines also described 14 in Table B in accordance with the following process:

(Ya)m ~ ~ (Xa)n tYa)m ~ (Xa)n I(b) HO (CH2)3~
\Ra ( a) ~ ( a)n II(b) CH(CH2)N
\Ra 1~1Z~05i 2 DEHY- M.P. (C.) 3 1 2 . DRATING OXALATE SALT OF
4 R~ Rc~ (Y~m (X~m AGENT COMPOUND II (a) -CH3 CH3 H H 4 100 (dec.) 6C~3 CH3 H 2-SCF3 4 7CH3 CH3 9-Cl H 4 8CH3 CH3 9-SCF3 H 4 110 (dec.) gCH3 CH3 9-CN H 8 10CH3 CH3 H 2-COCH(CH3)2 11CH3 CH3 H 2-SO2N(CH3)2 12C~3 c~3 H 2-So2CH(CH3)2 14CH3 CH3 9-Br H 4 15C~3 CH3 H 2-NO2 3 18C~3 CH3 H 2-CO(CH2)3CH3 19CH3 CH3 H 3 CO(CH2)3CH3 20CH3 CH3 H 3-COCH(CH3)2 213 3 H 2-CON(CH3)2 26CH3 CH3 9-SCH(CH3)2 H 4 27CH3 ~H3 H 2-SOCF3 4 29CH3 CH3 9-SOCH(C~3)2 30C~3 CH3 H 2-SO2CF3 2 ~W92~

2 (continued) 3 DEHY- M.P. (C.) 1 2 DRATING OXALATE SALr~ OF
5 Ra R~ g (~ ~ (X~mAGENT COMPOUND II(a) 7CH3 CH39-SO2CH(CH3)2 H

9CH3 c~3 9-COOC2H5 H
10CH3 ~H3 9-NH2 H

12CH3 CH3 9-N~CH3)2 H
13C~3 CH3 9-NHCOCH3 H 4 15- (CH2)4 - H H 4 16 - (CH2)5 - H2-CO(CH2)3CH3 1 17 -(CH2)20(CH2)2- 9-CN ~ 8 1 EXAMPLE_III
2 2-Formy~ (3-dimethylaminopropylidene)-6~ll-dihydro-5H
3 Ryrrolo[2,1-b][3]benzazepine 4 2-Cyano-11-(3-dimethylaminopropyl)-11-hydroxy-6,11-dihydro-5H-pyrrolo~2,1-b][3]benzazepine (.62 g.) and 6 6.2 g. Ni-Al 1:1 alloy powder (BDH Chemicals Ltd., Pool 7 England) in 50 ml. 75% formic acid is refluxed for 1 hr.
8 The dark red suspension is cooled, filtered to remove g the insolubles, washed with formic acid and evaporated to dryness. The yield of this red oil is 3.4 g. (57%) and it 11 slowly crystallizes on cooling. The oxalate salt of 2~
12 formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-13 pyrrolo[2,1-b][3]-benzazepine is prepared by dissolving 14 the above product in the minimum volume of ethanol and adding dropwise a saturated ethanolic solution of oxalic 16 acid. The resulting crystals are collected by filtration 17 and dried to give 2-formyl-11-(3-dimethylaminopropylidene)-18 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine oxalate, m.p.
lg 181C. (decomp.).
Employing 2-cyano-11-(3-dimethylaminopropylidens)-21 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine as starting 22 material results in the same product.
23 Employing the procedure substantially as described 2~ in Example III, but substituting or the starting material used therein an çquimolecular amount of 2-cyano-11-(~-26 dimethylaminopropy~ hydroxy-llH-pyrrolo[2~l-b][3]-27 benzazepine or 2-cyano-11-(3-dimethylaminopropylidene)-28 llH-pyrrolo[2,1-b][3]benzazepine, there is produced 2-29 formyl-11-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b]-[3]benzazepine, which yields a crystalline oxalate salt, 31 m.p. 185C. (decomp.).

, 14985IA

~L092~ ~5 1 Following the procedure substantially as de-2 scribed in Example III, but substituting for the starting 3 material used therein, an equimolecular amount of 9-cyano-4 11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo-[2,1-bl[31benzazepine or 9-cyano~ hydroxy-11-(3-dimethyl-6 aminopropyl)-6,11-dihydro-5H-pyrrolo[2,1-b~[3]benzazepine, 7 there is produced 9-f~rmyl-11-(3-dimethylaminoproplyi-8 dene)-6,11-dihydro-5~-pyrrolo[2,1-bl[3]benzazepine.
9 Similarly, by substituting 9-cyano-11-(3-dimethyl-aminopropylidene)-llH-pyrrolo[2,1-b][3]benzazepine or its 11 intermediate carbinol as starting material, there is 12 produced 9-formyl-11-(3-dimethylaminopropylidene)-llH-13 pyrrolo[2,1-b][3]benæazepine.
14 EXA~PLE IV
9-Trifluoromethylthio-ll-(3-dimethylaminopropylidene) 16 6,11-d ~ H-D~rrolo[2,1-b][3~benzaze~ine 17 A mixture of 2.9 g. of 9-iodo~ (3-dimethylamino-18 propylidene)-6~ll-dihydro-5H~pyrrolo[2/l-b][3]benzazepine 19 5.14 g. o copper (electrolytic dust), 9.0 g. of bis(tri-fluoromethylthio)mercury and 20 ml. of dimethylformamide 21 was stirred and heated on a steam bath for 5 hours. The 22 mixture was cooled in ice, treated with 75 ml. o~ benzene 23 and treated dropwise with 50 ml. of 10% sodium hydroxide 24 solution. ~fter 1 hour at room temperature the mixture ?5 was filtered through diatomaceous earth followed by a be~-26 zene wash. The filtrate was extracted with benzene. The 27 combined benzene fractions were washed with water, dried, 28 filtered and concentrated to dryness to give 9-trifluoro-~9 methylthio-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3Jbenzazepine.

~2~L05 1 Following khe procedure of Example IV, but sub-2 stitutin~ for the copper dusk and the bis(trifluoromethyl-3 thio)mercury used therein, an equimolecular amount of 4 cuprous methylsulfide or cuprous isopropylsulfide, there are produced 9-methylthio-11-(3-dimethylaminopropylidene)-6 6,11-dihydro-5H-pyrrolo~2,1-h][3]benzazepine, and 9-iso-7 propylthio-11-(3-dimethylaminopropylidene)-6,11-dihydro-8 5H-pyrrolo~2,1-b][3]benzazepine, respectively.

9-Trifluoromethylthio-11-(3-dimethylaminopropylidene)-llH-11 pyrrolo[2,1-b][3]benzazepine 12 Employing the procedure of Example IV, but sub-13 stitu~ing for the 9-iodo compound used therein an equi-14 molecular amount of 9-bromo~ (3-dimethylaminopropylidene)-11~-pyrrolo[2,1-b]~3]benzazepine, there is produced 9-16 trifluoromethylthio-ll-(3-dimethylaminopropylidene)-llH
17 pyrrolo~2rl-b]~3]benzazepine.
18 Employing the procedure of Example V, but sub-19 s~ituting for ~he copper dust and bis(trifluoromethylthio) mercury used therein an equimolecular amount of cuprous 21 methylsulfide or cuprous isopropylsulfide, there is produced 22 respectively-23 9-methylthio-11-(3 dimethylaminopropylidene)-llH-pyrrolo-24 [2,1-b][3~benzazepine, and 9-isopropylthio-11-(3-dimethylaminopropylidene)-llH-pyxrolo-26 [2,1-b][3]benzazepine.

28 9-Cyano-11-(3-dimethylaminopropylidene)-5,11-dihydro-5H~
29 pyrrolo[2,1-b][3]benzazepine A stirred mixture of 1 gm. of 9-iodo-11-(3-31 dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo~2,1-b]-32 [3]benzazepine, 1 gmO of cuprous cyanide, and S ml. of 33 dimethylformamide is heated to reflux for 5 hr. The ~O~Z1~5i 1 mixture is then poured into a solution of 4 gm. o~ ferric 2 chloride hydrate in 25 ml. of 2 N hydrochloric acid.
3 After stirring the resulting mix~ure at 60for 30 min., it 4 is extracted with 3 x 50 ml. of ethyl acetate. The aqueou~
acidic ~olution is then basified with sodium hydroxide 6 and extracted with 3 x 50 ml. of ether. The co~bined 7 ether extracts are then dried and evaporated to yield 9-8 cyano-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-g pyrrolo[2,1-b][3]benzazepine.
Employing the procedure of Example VI, but sub-11 ~tituting for the starting material used therein an equi-12 molecular amount of 9-bromo-11-(3-dimethylaminopropylidene)-13 llH-pyrrolo[2,1-b][3]benzazepine, there is produced 9-14 cyano-11-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b]-C3]benzazepine.
16 EXAMPhE VII
17 9-Amino-11-(3-dLmethylaminopropylidene)-6,11-dihydro-SH-18 p~rrolo[2rl-b][3]benzaze~ine 19 A mixture of 9-nitro-11-(3-dimethylaminopropyli-dene)-6~ dihydro-5H-pyrrolo[2~l-b][3]benzazepine (2.0 g.), 21 0.2 g. o~ 10~ Pd/C and 350 ml. o methanol is hydrogenated 22 until the theoretical amount of hydxogen is absorbed.
23 The mixture is filtered and the filtrate is evaporated to dryness to yield 9-amino-11-(3-dimethylaminopropylidene)-6,11 dihydro-5~-pyrrolo[2,1-b][3]benzazepine.

27 9-Ethoxycarbonylamino-11-(3-dimethylaminopropylidene)-llH-28 pyrrolo[2r-l-b][3]benzazepine 29 To 9-carboxy-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b][3]benzazepine (123.2 g., 0.4 moles) in 500 ml~

lO~Zl(~'~

1 ethanol, is added successively triethylamine (52 g., 0.52 2 moles) and diphenylphosphoroazide (112 gO, 0.40 mmoles).
3 Reflux is maintained for 3 hours. The mixture is poured 4 onto water, extracted with ethyl acetate, washed with 1 N
sodium hydroxide and dried over magensium sulfate to yield 6 after evaporation 70 gO o~ a residue that is chromatographed 7 on silica gel. Elution with methylene chloride yields 8 9-ethoxycarbonylamino~ (3-dimethylaminopropylidene)-llH-9 pyrrolo~2,1-b][~]benzazepine.
EXAMPLE IX
11 9-Amino-11-(3-dimethylaminopropylidene)-llH-pyrrolo-12 [2,1-b][3]benzazepine 13 To 9-ethoxycarbonylamino-11-(3-dimethylamino-14 propylidene)-llH-pyrrolo~2~l-b][3]benzazepine (2.80 g.) in 100 ml. EtOH is added 10 ml. 2 N potassium hydroxide.
16 Reflux is maintained for 42 hours. The volatiles are 17 removed under vacuum and the residue is extracted with 18 chloroform, washed with water, and dried over magnesium 19 sulfate. Evaporation leaves a dar~ residue that is puri-fied by chromatography on silica gel. Elution with 10~
21 methanol in chloroform yields 9-amino-11-(3-dimethylamino-22 propylid~ne)-llH-pyrrolo[2,1-b][3]benzazepine.
~3 EXAMPLE X
.
24 9-Methylamino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolor2_1-b]r3~benzazepine 26 A solution of 9-amino-11-(3-dimethylaminopropyli-27 dene)-6,11 dihydro-5H-pyrrolor2,1-b~r3]benzazepine in tri-28 ethyl orthoformate (2.8 g.; 10 mmoles in 80 ml.) was refluxed 29 for 5 hours. The volatiles were removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol was 31 stirred in an ice bath as sodium borohydride (0.88 g., 0.024 ~Z~O~

1 moles) was added over a period of 10 minutes. The mixture 2 was stirred for a period of 2 hours. After concentration 3 of the ethanol, the residue was dissolved in ethyl acetate, 4 washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11-(3-dimethylaminopropyli-6 dene)-6,11-dihydxo-5H-pyrrolo[2,1-b][3~benzazepine.
7 Employing the procedure as described in Example 8 X but substituting for the startin~ material used therein 9 an equimolecular amount of the 9-amino-11-~3-dimethylamino-propylidene)-llH-pyrrolo[2,1-b][3]benzazepine, there is 11 produced 9-methylamino-11-(3-dimethylaminopropylidene)-12 llH-pyrrolo[2,1-b][3]benzazepine.
13 ExAMæLE XI
14 9-Dimethylamino-11 (3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3~benzazepine 16 To a solution of 9-amino-11-(3-dimethylamino-17 propylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine 18 (2.0 g., 10 mmoles) and 4 ml. (50 mmoles) of 37% aqueous 19 formaldehyde in 15 ml. of acetonitrite is added 1 g.
(16 mmoles) of sodium cyano borohydride. A vigorous and 21 exothenmic reaction takes place and a dark residue separates.
22 The mixture is stirred for 15 minutes and then glacial 23 acetic acid is added dropwise until the solution tests 24 ne~tral on wet pH paper. Stirring is maintained for an additional 2 hours. The volatiles are removed undex vacuum, 26 and the residue is dissolved in chlorofoxm. The solution is 27 washed with base and with water, dried over sodium sulfate, 28 and concentrated to leave a residue that is purified by 29 chromatography on silica gel. Elution with chlor~form-methanol yields 9-dimethylamino-11-(3-dimethylaminopropyli-31 dene)-6,11-dihydro-5H-pyrrolo[2,1-b]~3]benzazepine.

~921~.tj 1 Employing the procedure of Example XI, but sub-2 stituting for the starting material used therein an equi 3 molecular amount of 9-amino-11-(3-dimethylaminopropylidene)-4 llH-pyrrolo[2,1-b][3]benzazepine, there is produced 9-S dimethylamino-11-(3-dimethylaminopropylidene)-llH-pyrrolo-6 [2,1-b~[3]benzazepine.
7 EX~MPLE XII
_.
8 9-Acetamido-11-(3-dimethylaminopropylidene)-llH-pyrrolo-9 [2,1-b~[33benzaze~ine 9-~mino 11-(3-dimethylaminopropylidene)-llH-11 pyrrolo[2,1-b][3]benzazepine (11~4 mmoles) dissolved in 12 15 ml. pyridine is treated with acetic anhydride (2 ml.) 13 at room temperature for 19 hours. The volatiles are re-14 moved under vacuum and the residue is dissolved in chloro-form, and chromatographed on silica gel. Elution with 16 chloroform-methanol yields 9-acetamido-11-(3-dimethyl-17 aminopropylidene)-llH-pyrrolo[2,1-b]~3]benz~zepine.
18 Employing the procedure of Example XII but sub-1~ stituting for the starting material used therein, an equi-olecular amount of 9-amino-11-(3-dimethylaminopropylidene)-21 ,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine, there is 22 produced 9-acetamido~ (3-dimethylaminopropylidene)-6,11-23 dihydro-5H-pyrrolo~2,1-b][3]benzazepine.

2-Dimethylcarbamoyl-11-(3-dime~hylaminopropylidene)-llH-26 pyrrolo[2,1-b][3~benzaZepine 27 Step A: Preparation of 2-carbamoyl-11-(3-dimethylamino-28 propylidene)-llH-29 2-Cyano-11-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b]~3]benzazepine (0~135 mole) in 100 ml.
31 of concentra~ed hydrochloric acid and 100 ml. of acetic 32 acid is refluxed for 2 hours. It is then poured onto -7~-.0~

1 500 ml. of water and continuously extracted with methylene 2 chloride. The solution is left to cool to room temperature 3 and filtered to afford 2-carbamoyl-11-(3-dimethylamino-4 propylidene)-llH-pyrrolo[2,1-b][3]benzazepine.
Step B: Preparation of 2-carboxy-11-(3-dimethylamino-6 propYlidene)-llH-PYrrolol2~l-b][3]benzaze~ine .. r___ 7 To 2 carbamoyl-11-(3-dimethylaminopropylidene)-8 llH-pyrrolo[2,1-b][33benzazepine (0.112 moles) in 300 ml.
g of 50% sulfuric acid maintained at 50C. is added slowly 25 g. of sodium ni~rite in 75 ml. of water. At the end 11 of the addition, the solid is filtered, washed with water 12 and air-dried to yield 2-carboxy-11-(3-dimethylaminopropyli-13 dene)-llH-pyrrolo[2,1-b][3]benzazepine.
-14 Ste~ C: Preparation of 2-chlorocarbonyl-11-(3-dimethyl-aminopropylidene)-llH-pyrrolo[2,1-b][3]benzazepine 16 2-Carboxy~ (3-dimethylaminopropylidene)-llH-17 pyrrolo[2,1-b][3]benzazepine (99 mmoles) in 100 ml. of 18 thionyl chloride is refluxed for 15 minutes. The vola-19 tiles are removed under vacuum and the residue is triturated in ether. Filtration and air drying yields 2-chlorocarbonyl-21 11-(3-dimethylaminopropylidene)-11~-pyrrolo[2,1-b]~3] -22 benzazepine.
23 ~e_~ Preparation of 2-dimeth~lcarbamoyl~ (3-dimethyl-24 aminopropylidene)-llH-pyrrolo[2,1 b][3]benzazepine Anhydrous dimethyl amine is bubbled through a 26 suspension of 2-chlorocarbonyl-11-(3-dimethylaminopropyli-27 dene)~ -pyrrolo[2,1-b][3]benzazepine (88.5 mmoles) in 28 100 ml. of methylene chloride. (Note: The introduction 29 of dimethyl amine causes the mixture to reflux and this reflux stops when all the acid chloride is reacted.) 1(~"3ZlOS

1 The reaction mixture is washed with water and 2 dried over sodium sul~ate. It is then taken to dryness, 3 triturated in ether, filtered and air-dried to yield 2-4 dimethylcarbamoyl-11-(3-dimethylaminopropyliaene)-llH-pyrrolo[2,1-b][3]benzazepine.
6 Following the procedure of Example XIII, Step D, 7 but substituting for the dimethylamine used therein, an 8 equimolecular amount of methylamine, there is produced 9 2-methylcarbamoyl-11-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b][3]benzazepineO

-12 2-Methoxycarbonyl-11-(3-dimethylaminopropylidene)-llH-13 Fyrrolo[2,_1-b][3]benzazepine 14 2-Carboxy-11-(3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b][3]benzaæepine (0.11 moles) in 300 ml. of 16 methanol saturated with hydrogen chloride is refluxed until 17 a homogeneous solution is obtained (4 hours.).

18 The volatiles are removed under vacuum and the 19 residue is dissolved in 300 ml. of methylene chloride, washed with dilute sodium hydroxide and then with water.

21 The organic solution is dried over sodium sulfate and 22 evaporated to yield 2-methoxycarbonyl-11-(3-dimethylamino-23 propylidene~-llH-pyrrolo[2,1-b][3]benzazepine.

24 ExAMæLE XV

2-Cyano-6,11-dihydro-11-(3-methylaminopropylidene)-5H-26 pyrrolo[2,1-b][3]benzazepine oxalate salt _ _ 27 Step A: Preparation of 2-cyano-6,11-dihydro~ll-(N-2,2,2-28 tr~chloroethoxycarbonyl-3-methylaminopropylidene)-29 5H-pyrrolo[2,1-b][3~benzazepine 2-Cyano-6,11-dihydro-11-(3-dimethylaminopropyli-31 dene)-SH-pyrrolo[2,1-b][3]benzazepine (5 g., 17.2 mmoles) 32 and 2,2,2-trichloroethylchloroformate (4 g., 18.8 mmoles) ~9%~0~i 1 in 100 ml. benzene were refluxed for 18 hours. The mixture 2 was poured onto water, washed with dilute hydrochloric 3 acid and then with water, dried over sodium sulfate and 4 concentrated under vacuum to yield 7.1 g. of dark red oil. It was adsorbed on 250 g. silica gel and eluted with 6 2 liters benzene. The eluate was discarded.
7 Elution with 1.2 liters of methylene chloride 8 le~t, after evaporation, 2-cyano-6,11-dihydro-11-(N-2,2 r 2-9 trichloroethoxy-carbonyl-3-methylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine as a brown oil (5.0 g., 63%), 11 R~, 0.6 (benzene-ethyl acetate 3-1, on silica gel TLC).
12 Step B: Preparation of 2-cyano-6,11-dihydro-11-(methyl-13 aminopropylidene)-5H-pyrrolo[2,1-b][3]benzaze-14 pine-oxalate salt 2-Cyano-6,11-dihydro-11-(N-2,2,2-trichloroethoxy-16 carbonyl-3-methylaminopropylidene)-5H pyrrolo[2,1-b][3]-17 benzazepine (4.0 g., 8.7 mmole) and zinc dust (8 g.) in 18 25 ml. acetic acid was stirred at room temperature for 19 18 hours. The solid was ~iltered o~f and washed with ace~ic acid. The ~iltrate was taken to dryness. The resi-21 due was dissolved in dilute hydrochloric acid and extracted 22 with ethyl acetate. The aqueous phase was then made basic, 23 extracted with methylene chloride; the organic layer was 24 washed with water, dried over sodium sulfate and concen-~rated to yield 2-cyano-6,11-dihydro-11-(methylamino-26 propylidene)-SH-pyrrolo[2,1-b][3]benzazepine (2.3 g., 95%) 27 as a brown oil.
28 This oil was dissolved in 25 ml. ethànol and 29 treated with oxalic acid (1 g.). The oxalate salt was filtered, washed with ethanol and air-dried. The yield was 31 2.54 g., m.p. 190C. (dec.).

9Z~L05 l Employing the procedure of Example XV, Steps A
2 and B, but substituting for the 2-cyano-6,11-dihydro-11-3 (3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzaze-4 pine used in Step A thereof, an equimolecular amount of any of the 11-(3-dialkylaminopropylidene)pyrrolo~2,1-b][3]-6 benzazepines described in Tables A and B and Examples I
7 through XIV, there are produced the corresponding ll (3-8 alkylaminopropylidene)pyrrolo[2,1-b][3]benzazepines such 9 as those depicted in Table C by the following process:

~-(X)n H~CH2)2N\
~ alkyl2 (Y)m ~ -(X)n It /alkyll CH t CH2 ) 2N ~

(Y) m~ ( X) n CEI ( CH2 ) 2N~Ialk S

2 6-5 positlons (Y)m (X)nalkyll alkyl2 3 unsaturated H 2 CNH3 CH3 4 saturated H 2-CHOCH3 CH3 5 unsaturated H 2-CHOCH3 CH3 6 Saturated H 2-CO(CH2)4H CH3 CH3 7 unsaturated H 2-CO(CH2)4H CH3 CH3 8 saturated H H CH3 CH3 g unsaturated H H CH3 CH3 10 Saturated 9-CN CH3 C~3 11 unsaturated9-CN H CH3 CH3 12 unsaturated9-CHO CH3 CH3 13 Satuxated 9-CHO H CH3 CH3 14 Saturated H 2-CNC2H5 CH3 15 'lnsaturated ~ 2-CN 2 5 CH3 6 EXAMP~E XVI

17 Separation of the isomers of 11-(3-dimethylaminopropylidene)-18 6,11-di~ dro-5H-~rrolo[2,1-b][31benzazepine 19 To a solution of 24 gO (0.0775 moles) of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydro-5H-pyrrolo-21 ~2,1-b][3]benzazepine in 35 ml. of ethanol was added a 2~ solution of 7.8 gO (0.086 moles) of oxalic acid in 90 ml.
23 of ethanol at 25C. over 20 minutes. The mixture was then 24 stirred ~or 16 hours at 25C. and the insoluble oxalate salt removed by filtration to yield 22.7 g. (0.064 moles) 26 of crude oxalate of isomer I. Recrystallization from 27 150 ml. of hot water gave 15.4 g. of isomer I oxalate, 2~ m.p. 188-189C., unchanged by further recrystallization.

la~zlos 1 The filtrate from cxude isomer I was worked up 2 by basification to yield 4.18 g. (0.016 moles) of crude 3 isomer II as the free base. To a solution of this crude 4 free base in 80 ml. of methanol was added 1.41 g. (0.016 5 moles) oxalic acid, and the resulting solution was treated 6 ~ith charcoal at reflux for 5 minutes. The solution was 7 filtered, evaporated and the residual oil taken up in 100 8 ml. of acetonitrile and treated with charcoal at reflux 9 for 5 minutes This charcoal treatment was repeated twice 10 more, and the solution evaporated to leave a semi~solid 11 which was dissolved in 100 ml. of methanol. The methanol 12 solution was evaporated and the resulting oil dissolved in 13 20 ml. of acetonitrile, seeded and held at 5C. The 14 resulting crystals were pulverized, filtered, washed with acetonitrile and finally with ether to give 2.68 gm.
16 (0.0075 moles) of isomer II oxalate, m.p. 110-120C.
17 Each isomer was shown to be at least 90% pure by 18 nmr analysis.
19 EX~MPLE XVII
-Chromatographic separation of the geometrical isomers of 21 2-formyl-6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-22 pyrrolo[2,1-b][3]benæazepine 23 2-Formyl-6,11-dihydro-11-(3-dimethylaminopropyli-24 ene)-5H-pyrrolo[2,1-b][3]benzazepine (3.2 g.) was absorbed on 300 g. silica gel and elution was carried out using 2%

26 methanol in chloroform with fractions of 10 ml. The first 27 isomer came out between tubes (fractions~ 70 and 109;

28 evaporation of the eluent from these fractions yielded 29 0.8 gO of an oil which solidified on standing. This was isomer I, m~p. 104-105C. Between tubes 110 and 159, a 31 mixture of the two isomers was obtained (1.62 g.) and ~2~g).5 1 finally 0.49 g. of isomer II was obtained by evaporating 2 to dryness tubes 160 to 210.
3 The difference between the two isomers was best 4 seen by nmr. For the isomer I, the formyl proton absorbed at 9.56 ppm and the N-(CH3)2 protons at 2.10 ppm; for the 6 isomer II, the formyl proton was at 9.61 ppm and the 7 N-(CH3)2 protons were at 2.20 ppm.
8 Following the procedure substantially as described 9 in Example XVII, but substituting for the 2-formyl compound employed therein an equimolecular amount of any of the 11 pyrrolo[2,1-b~[3]benzazepines described in Examples I
12 through XV and XX, and Tables A, B, and C, there are pro-13 duced the corxesponding geometric isomers.

.
2-Cyano-6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-16 pyrxolo[2,1-b][3~benzazepine, oxalate salt; isom_r I
17 2-Formyl 6,11-dihydro-11-(3-dimethylaminopro-18 pylidene)-5H-pyrrolo[2,1-b][3]benzazepine (Isomer I from 19 Example XVII) ~1.4 g., 4.8 mmoles), hydr~xylamine hydro-chloride (0.7 g., 10 mmoles~ and sodium formate (0.85 g., 21 12.5 mmoles) in 20 ml. ethanol were heated on a steam-22 bath for 5 minutes. The volatiles were removed under 23 vacuum; 5~ sodium bicarbonate was added to ~he residue and 24 the solution was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sul-26 fate and concentrated to yield 1.4 g. of oxime.

27 The oxime in 10 ml. trichloroacetonitrile was 28 heated on a steam-bath for 15 minutes. The solution was 29 taken to dryness under vacuum, water was added, and the resul~ing mixture was extracted with methylene chloride to ~3Z105 1 yield after usual washings and drying 1.9 g. of crude 2 2-cyano-6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-3 pyrrolo[2,1-b][3]benzazepine as a brown oil.
4 It was adsorbed on 100 g. silica gel and eluted with chlorofonm to yield trichloroacetamide which was discarded.
6 Elution with 10~ methanol in chloroform yielded pure 2-7 cyano-6,11-dihydxo~ (3-dimethylaminopropylidene)-5H-8 pyrrolo[2,1-b][3]benza~epine as a brown oil (0.84 g., 60%).
gDissolved in 5 ml. of ethanol and treated with 10300 mg. of oxalic acid in 0.5 ml. ethanol, the ~ree base 11 yielded the oxalate salt (0.85 g., 45~), m.p. 217C. (dec.).

132-Cyano-6,11-dihydro-11-(3-dimethylaminopropylidene)-14 5H-pyrrolo[2,1-b][3]benzazepine, oxalate salt; Isomer II
Employing the procedure oE Example XVIII but 16 starting with Isomer II of the 2-formyl derivative from 17 Example XVII, there was produced 2-cyano-6,11-dihydro-11-18 (3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzaze-19 pine, oxalate salt; Isomer II, m.p. 223C. (dec.).
EXAMæLE XX
21 2-Formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-22 5H-pyrrolo[2!1-b][3]benzaze~ine .

23 Step A: Preparation of 6,11-dihydro-2-(2-dioxolanyl)-24 5H-p~rrolo[2,1-b][3]be_zazepin_11-one A mixture of 5 gm. of 6,11-dihydro-2-formyl-26 5~-pyrrolo~2,1-b][33benzazepin-11-one, 2.5 gm. of ethylene 27 glycol, 0.5 gm. of p-toluenesulfonic acid and 100 ml. of 28 toluene is refluxed for 16 hr. in an apparatus desisned to 29 remove water foxmed during the reaction (Dean-Stark appara-tus~. The reaction mixture is cooled to O~C. and washed 31 rapidly with ice cold 5% sodium carbonate solution (2 x 32 50 ml.~ and dried over Na2SO4. Evaporation of the solvent 1 leaves 6,11-dihydro-2-(2-dioxolanyl)-5H-pyrrolo~2,1-b][3]-2 benzazepin-11-one as an oil which is of sufficient purity 3 or use in the next step.
~ Step B: Preparation of 6,11-dihydro-2-(2-dioxolanyl)-11-hydroxy~ (3-dimethylaminopropyl)-5H-pyrrolo-6 [2,1-b]~3]benzazepine 7 Employing substantially the procedure of Example I, 8 Step A, but using the ketone acetal from Step A of the g present example, there is obtained 6,11-dihydro-2-t2-dioxolanyl)-11-hydroxy-11-(3-dimethylaminopropyl)-5H-11 pYxrOlo[2~l-b][3]benzazepine.
12 Step C: Preparation of 2-formyl-11-(3-dimethylaminopropyli-13 dene)~6,11-dihydro 5H-~rrolo[2,1-b][3]benzazepine 14 To a solution of 3 gm. of 6,11-dihydro-2-(2-dioxolanyl)-11-hydroxy-11-(3-dimethylaminopropyl)-5H~
16 pyrrolo[ ,1-b][3]benzazepine in 20 ml. of ethanol contain-17 ing 1 ml. of water is added 2 gm. of oxalic acid, and the 18 resulting mixture heated to reflux for 2 hr. Upon cooling 19 to QC. for 4 hr., there is obtained the crystalline oxalate of 2-formyl-11-(3-dimethylaminopropylidene)-6,11-21 dihydro-5H-pyrrolo[2,1-b][3]benza~epinet m.p. 181C.
22 (decomp.).
23 Using substantially the same procedure as in 24 Example XX, Steps A, B, and C (the present example) but starting with 2-formyl-llH-pyrrolo~2,1-b][3]benzazepin-26 ll-one, 6,11-dihydro-9-formyl-5H-pyrrolo[2,1-b][3]benzaze-27 pin-ll-one, or 9-foxmyl-llH-pyrrolo[2,1-b][3~benzazepin-28 ll-one, thexe is obtained 2-fonmyl-11-(3-dimethylamino-29 propylidene)-llH-pyrrolo[2,1-b][3]benzazepine, 9-formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-SH-pyrrolo-31 ~2,1-b][3]benzazepine, or 9-formyl-11-(3-dimethylamino-3~ propylidene-llH-pyrrolo[2,1-b][3]benzazepine, respectively.

~09Z~O~

2 Pharmaceutical Compositions 3 A typical tablet containing 5 mg. 2-formyl-11-4 (3-dimethylaminopropylidene)-llH-pyrrolo[2,1-b][3]benzaze-pine per tablet is prepared by mixing together with the 6 active ingredient calcium phosphate, lactose and starch 7 in the amounts shown in the tables below. After these 8 ingredients are thoroughly mixed, the dry mixture is 9 blended for an additional three minutes. This mixture is then compressed into tablets weighing approximately 129 mg.
11 each. Similarly prepared are tablets containing 2-formyl-12 11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo-13 [2,1-b][33benzazepine, 11-(3-dimethylaminopropylidene)-14 6,11-dihydro-5~-pyrrolo[2,1-b][3]benzazepine, or any of the novel compounds of this invention.
16 Tablet Formula 17 Ingredient Mg. per Tablet 18 2-formyl-11-(3-dimethylaminopropyli-19 aene)-llH-pyrrolo-[2,1 b][3]-20 benzazepine 5 mg.
21 Calcium phosphate 52 mg.
22 Lactose 60 mg.
23 Starch 10 mg.
24 Magnesium stearate 1 mg.

1 The no~el compounds of the pxesent invention can 2 be prepared by a number of alternate procedures.
3 One alternate procedure is illustrated as 4 follows:

(Y)m ~ ~ amination> (Y) ~ (X) CHC~2CH2Q CHCH2CH2N~ R2 wherein Q is a leaving group such as chloro, bromo, iodo 6 p-toluenesulfonate, methanesulfonate, or the like.
7 The last step of this process comprises heating 8 in a pressure vessel a mixture of the starting material, 9 an inert organic solvent such as be~zene, and amine of formula:

14 at 80-120 for 10-24 hours.

EXAMPLE XXII

16 5,11-Dihydro~ (3-dimethylaminopropylidene)-5H-pyrrolo-17 [2rl-b][3]benzazepine hydrochloride 18 5tep A: Preparation of 6,11 Dihydro-ll-allyl-ll-hydroxy-19 5H-~yrrolo[2,1-b][3]benzazepine To a 125 ml., 3-neck flask (flamed out and cooled 21 under dry nitrogen) equipped with a stirrer, addition 22 funnel and ether-type condenser, are charged 4.8 g. of 23 clean magnesium turnings and 15 ml. of dry ethyl ether.

24 17 G. of allyl bromide :in 10 ml. of dry ether is added dropwise with stirring at a rate sufficient to maintain a 26 gentle reflux. Stirring and refluxing are continued until ~9Z~

1 all the metal is gone. The reaction mixture is then cooled 2 below the poin~ of reflux, but not so low as to cause the 3 Grignard reagent to precipitate, and 10 g. of 6,11-dihydro-4 5H-pyrrolo[2,1-b][3]benzazepin-11-one in 20 ml. of dry ether is added with stirring in 15 minutas. The reaction mixture 6 is stirred and allowed to react at room temperature for 7 1/2 hour~ The reaction mixture then is chilled in an 8 ice-bath and treated with 45 ml. of saturated ammonium g chloride solution. The layers are separated and just enough water is added to dissolve the solid salts in the 11 aqueous layer. The latter is extracted with 2 x 25 ml.
12 of ether. The combined organic layers are washed with 25 13 ml. of saturated salt solution, dried over magnesium sul-14 fate, and the solvent removed in vacuo to yield the hydroxy intermediate.
1~ 5tep B: Preparation of ll-allylidene-6,11-dihydro-5H-17 pyrrolo[2,1-b][3]benzazepine 18 Distillation of the product of Example XXII, 19 Step A, at 1 mm. pressure to provide the oily product.
Step C: Preparation of 6,11-dihydro-11-(3-hydroxypropyli-21 dene)-5H-pyrrolo[2,1-~][3]benzazepine 22 A solution of 0.5 g. of the product of Step B
23 in 15 cc. of tetrahydrofuran is treated with 1 mole equi-24 valent of bis-3-methyl-2-butylborane at 0-5aC. for a period Of 3 hours. At the conclusion of this period, 3 cc. of 26 water is added, followed by 8 cc. of 2.5 n sodium hydroxide 27 and the dropwise addition of 6-7 cc. of 30% hydrogen per-28 oxide~ The aqueous phase is then salted with potassium 29 carbonate and the tetrahydrofuran layer is separated, dried over magnesium sulfate, and the solvent is removed in vacuo.

31 ~he residue is crystallized from ether to give the desired 37 3-hydroxy compound.

, . , 2~5 ~ D: Preparation of 6,11-dihydro-11-(3-chloropropyli-2 dene)-5H-pyrrolo[2,1-b][3]benzazepine 3 Treatment of a solution of 50 mg. of 6,11-dihydro-4 11-(3-hydroxypropylidene)-5H-pyrrolo[2,1-b][3]benzazepine in 3 ml. of dry benzene containing one drop of pyridine 6 with 65 mg. of thionylchloride in 2 ml. of dry benzene and 7 refluxin~ for 3 hours on a steam bath yields the product.
8 Use of thionyl bromide in the abo~e reaction g yields the corresponding 3-bromide compound.
Similarly, treatment of the 3-hydroxy compound 11 with methanesulfonyl chloride or p-toluenesulfonyl chloride 12 in pyridine at 0C. for 16 hours provides the corresponding 13 3-mesyloxy and 3-tosyloxy compounds respectively.
14 Step E. Preparation of 6,11-dihydro-11-(3-dimethylamino-propylidene)-5H-pyrrolo[2,1-b][3]benzazepine 16 hydrochloride 17 A solution of 100 mg. of 6,11-dihydro-11-(3-18 chloropyropylidene)-5H-pyrrolo[2,1-b][3~benzazepine in 1 19 ml~ of benzene in a thick-walled Pyrex~tube is saturated with dimethylamine at 10C. The tube is sealed, allowed 21 to stand at 95C. for 18 hours, then cooled and opened.
22 The benzene solution is washed successively with 5% po-23 tassium bicarbonate, water and saturated salt solution, 24 dried over maynesium sulfate, and taken to dryness in vacuo.
The residual oil is dissolved in ether and treated with 26 ether saturated with HCl. The resulting mixture of oil 27 and ether is blown dry to remove the excess HCl, and the 28 residue upon trituration with ether yields crystalline 29 6~ dihydro-ll-(3-dimethylaminopropylidene)-5~-pyrr ~2,1-b][3]benzazepine hydrochloride.

L~3 -~Z~S

1 Employing the procedure substantially as de-2 scribed in Example XXII, Step E, but substituting for the 3 dimethylamine and the 3-chloropropylidene used therein, 4 the 3-Q-prop~lidenes described in Table D, there is pro-duced the (3-Rl,R2-aminoprop~lidene)pyrrolo[2,1-b]C3]-6 ~enzazepines also described in Table D.

~ TABLE D

9 Rl Ra (Ya)m (X~)n Q position , . _ .. . . _ 1 CH3 C~3 H 2-So2N~CH3)2 Cl saturated 11 CH3 CH3 H 2-CN Cl saturated 12 CH3 CH3 H 2-Cl Cl saturated 13 CH3 CH3 H 2-SCF3 S2 ~ CH3 saturated 1 H3 CH3 H 3-SCF3 Cl saturated 15 CH3 CH3 H 3-CF3 Cl saturated 17CH3 CH3 H 2-CCH~CH3)2 Cl saturated 18 o 1~3 CH3 (CH2)3CH3 Cl saturated CH3 CH3 H2-SO2CH3 -OSO2CH3 saturated 21CH3 CH3 H 2-S02CH(CH3)2 Cl saturated 22CH3 CH3 H 2-SO2CF3 Cl saturated 23CH3 CH3 CO2C2H5 Cl saturated 24 CH3 CH3 H 2-NO2 Cl saturated 25 CH3 CH3 H 2 COCH3 Cl saturated 26 CH3 CH3 H 2-CF Cl saturated 7 H3 CH3 9-OCONHCH3 2,3-Br2 Cl saturated 28 CH3 CH3 9-NHCOOCH3 2,3-Br Cl saturated 29 CH3 CH3 9-CH3 2,3-Br Cl saturated ~ -8~-1/L~9;~S

1 TABLE D (continued) 23 Rl R2 (~)m (Xa)n Q 5-6 ~ ~ . . __ . .. .. _ _ _ 4 3 3 2,3-Br Cl saturated 5 H3 CH3 H 2-Br Cl saturated 6 CH3 CH3 H 3-CN Cl saturated 7 C~3 CH3 H 1,2,3-Br3 Cl saturated 8 CH3 CH3 H 1~3 Br2 2 CH3 Cl saturated g CH3 CH3 9-NHCOCH3 1,2,3-Br3 Cl saturated CH3 C~3 9 CH(CH3)2 2,3-Br2 Cl saturated 11 CH3 CH3 9-SCH3 2,3-Br2 Cl saturated 12 CH3 CH3 8,9 (CH3)2 2-CN Cl saturated 13 CH3 CH3 9-OH 2-CN Cl saturated 14 3 3 H 2,3-C12 Cl saturated 15 CH3 CH3 9-OCONHCH3 H Cl saturated 16 CH3 CH3 9-NHCOOCH3 H Cl saturated 17 CH3 CH3 9~~3 ~ Cl saturated ~18 CH3 CH3 9-CH(CH3)2 H Cl saturated 19 CH3 CH3 H 2-CH Cl saturated 20 CH3 CH3 9-NHCOCH3 H Cl saturated 21 3 3 9-SCH3 H Cl saturated 22 CH3 CH3 9 SC~CH3)2 Cl saturated 23 CH3 CH3 H 3-CO(cH2)3cH3 Cl saturated 24 CH3 CH3 H 3-COCH3 Cl saturated 25 CH3 H3 H 3-COCH(CH3)2 Cl saturated 26 CH3 CH3 9-I H Cl saturated 27 CH3 H3 9-SCF3 H Cl saturated 28 C~3 C~3 9-No2 H Cl saturated 29 CH3 CH3 9 CN H Cl saturated ~89-1 TABLE D (contlnued) 3 R R (Y ) (X ) Qposition a (I__ a m a n 3 H3 SOCF3 H Clsaturated 3 H3 SOCH3 H Clsaturated 6 CH3 CH3 9-SOCH(CH3)2 H Clsaturated 7 CH3 CH3 9-S02CF3 ~ - Clsaturated 8 CH3 CH3 9-SO CH H Clsaturated 9 CH3 CH3 9-SO2CH(CH3)2 Clsaturated 10 C2H5 CH3 ~ 2-CN Clsaturated 11 -(CH2)~- H H Clsaturated 12 -(CH2)5- H 2-CO(CH2)3C~3 Cl saturated 13 -(CH2)20(CH~)2- 9-CN H Clsaturated 14 H H 2-CN Clsaturated 15 H -CH=CH2 H 2-CN Clsaturated 16 CH3 CH3 H H Clunsaturated 17 CH3 CH3 H 2-SCF3 Clunsaturated 18 CH3 CH3 9-Cl H Clunsatuxated 19 CH3 C~3 9 SCF3 H Clunsaturated O H3 C~3 9-CN H Clunsaturated 21 CH3 CH3 H 2-COCH(CH3)2 Clunsaturated 22 CH3 CH3 H 2-S02N(CH3)2 Clunsaturated 23 CH3 C~3 H 2-SO2CH(CH3)~ Cl unsaturated 24 CH3 CH3 9-Br H Clunsaturated 25 C~3 C~3 H 2-NO2 -OSO2 ~ CH3unsaturated 26 CH3 CH3 9-OCH3 H Clunsaturated 27 CH3 CH3 ~ 2-CO(CH2)3CH3 Cl unsaturated 28 CH3 CH3 H 3-CO(CH2)3CH3 Cl unsaturated 29 CH3 CH3 H 3-COCH(CH3)2Clunsaturated CH3 CH3 H 2-CON(CH3)2-OSO2CH3unsaturated ~2110S

1 TABLE D (contlnued) 2 Rl R2 (Ya)m (Xa)nQ 5-6 4 CH3 CH3 H 2-COOCH3Cl unsaturated 5 H3 CH3 H 2-CF3 Cl unsaturated 6 CH3 CH3 9-SCH3 H Cl unsaturated 7 CH3 CH3 9-SCH (CH3) 2 H Cl unsaturated 8 ~3 CH3 H 2-SocF3~S02CH3 unsaturated 9 CH3 CH3 9-SOCH3 H Cl unsaturated 10 CH3 CH3 9-SOCH (CH3) 2 H Cl unsaturated 11 CH3 CH3 H 2-SO2CF3 Cl unsaturated 12 CH3 CH3 9 S2CH3 H Cl unsaturated 13 C~3 CH3 9 S2CH (CH3) 2 H Cl unsaturated 14 CH3 CH3 9-OH H Cl unsaturated 15 CH3 CH3 9-C~OC2H5 H Cl unsaturated 16 CH3 CH3 9 NH2 H Cl unsaturated 17 CH3 CH3 9 NHC~3 H Cl unsaturated i8 CH3 CH3 9-N (C~3) 2 H Cl unsaturated l9 CH3 CH3 9-NHCOCH3 ~ Cl unsaturated 20 3 3 H 2-CN Cl unsaturated Zl CH3 CH3 H 2-S02CH3 Cl unsaturated 14985I~

l~g;21~

1 Another procedure which may be used is illus-trated as follows:

(Y)m ~ xeductive (y) ~ (X) C~-CH2CHO amination CH CH2CH2N
(amine + H2 + catalyst) \ R2 or NaCNBH3 3 The process xequires a reductive amination of the 4 starting material aldehyde, which may be carried out by xeacting the 11-(3-oxOpropylidene) derivative with a 6 primary or secondary amine in an organic solvent to form 7 the corresponding dienamine, which is then hydrogenated 8 to give the desired product. Alternatively, the 11-(3-g oxopropylidene) derivative and the amine can be dissolved in a solvent such as ethanol and the mixture hydrogenated 11 as above to yield the desired product. A third alternative 12 reducti~e amina~ion consists in dissolving the 11-(3-oxO-13 propylidene) derivative and the amine in a suitable solvent 14 and carrying out the reduction by addition of sodium cyanoborohydride, controlling the pH between 6 and 8.
16 This last procedure is advantageous when the final product 17 contains substituents which may be reduced in the course 18 of a catalytic hydrogenation.

6,11-Dihydro~ (3-dimethylaminopropylidene)-5H-pyrrolo-21 [2,1-b][3]benzazePine hydrochloride .
2~ Preparation of 11-(2,3-epoxypropylidene)-6,11-23 dihydro-5H-PYrrolo[2,1-b][3]benzaze~ine .. ,." ,. . . ,~
24 A solution of 500 mg. of 11 allylidene-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine is dissolved in ~9~0~

1 25 cc. of benzene and the resulting solution is reacted 2 with 1.1 mole e~uivalents of perbenzoic acid. The course 3 of the reaction is followed by the disappearance of the 4 diene absorption in the U.V. At the conclusion of the epoxidation, excess perbenzoic acid is removed by washing 6 the benzene solution of the reaction product with 5~
7 aqueous sodium carbonate solution~ Evaporation of the 8 benzene under reduced pressure yields 11-(2,3-epoxypropyli-9 dene)-6,11-dihydro-5H-pyrrolo[2,1-b~[3]benzazepine as a nearl~ colorless oil.
11 Step B: Preparation of 11-(3-oxopropylidene)-6,11-dihydro-12 5H- ~ ~2,1-b~[3]benzazepine 13 400 Mg. of 11-(2,3-epoxypropylidene)-~ dihydro-14 5H-pyrrolo[2,1-b3~3]benzazepine is dissolved in 50 cc. of benzene and to the resulting solution there is added 4 cc.
16 of boron trifluoride etherate. The reaction mixture is 17 then allowed to stand for two hours~ At the end of this 18 period, the boron trifluoride etherate is removed with a 19 water wash and the dried benzene solution evaporated to ~ield 11-(3-oxopropylidene~-6,11-dihydro-5H-pyrrolo[2,1-b]-21 [3]benzazepine.
22 Step C: Preparation of 6,11-dihydro-11-(3-dimethylamino~
23 propylidene)-5H-pyrrolo[2,1-b][3]benzazeplne 24 A mixture containing 200 mg. of 11-(3-oxopropyli dene)-6,11-dihydro-5H-pyrrolo~2,1-b]~3]benzazepine, 80 cc., 26 of benzene, 4 mole equivalents of dimethylamine and 10 ~7 grams of magnesium sulfate is refluxed for approximately 28 10 hours at 80C. in an appropriate container set up with 29 a water separator apparatus (Dean-Stark apparatus). After 3o the reaction period the mixture is filtered to yield a 31 benzene filtrate containing the ll-(dieneamine) derivative.

0~

1 The benzene solution is then transferred to a hydrogenation 2 bomb along with 200 mg. of 10% palladium on carbon and the 3 solution is hydrogenated at room temperature by intro-4 ducing a molar amount of hydrogen into the solution.
When the uptake of hydrogen is complete,6,11~dihydro-11-6 (3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine 7 is isolated by filtering off the catalyst and concentrating 8 the solution under reduced pressure to an oil~ The desired g product can also be isolated as its hydrochloride salt by dissolving the oil obtained above in ethyl ether and 11 passing dry hydrogen chloride gas through the solution.

12 Alternatively, 6,11-dihydro-11-(3-dimethylamino-13 propylidene)-5H-pyrrolo[2,1-b][3]benzazepine can be pre-14 pared as follows: 200 mg. of crude 11-(3-oxopropylidene)-6,11-dihydro-SH-pyrrolo~2,1-b][3]benzazepine as prepared 16 in Example XXIII, Step B, is dissolved in 10 cc. of a 6%
solution of dimethylamine in ethyl alcohol. The resulting 18 solution is then hydrogenated at room temperature, and at 19 atmospheric pressure in the presence of 200 mg. o~ Raney nickel catalyst in an appropriate hydrogenation bomb by 21 the introduction of a molar amount of hydrogen into the 22 solution. When the hydrogen uptake is complete, the 23 6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-pyrrolo-24 [2,1-b]~3]benzazepine formed is isolated by filtering off the catalyst and evaporating the filtrate under vacuum 26 to an oil. Similarly, as described previously, the de-27 sired product can be isolated as the hydrochloride salt by 28 dissolving the resulting oil in ethyl ether and passing 29 dry hydrogen chloride gas through the solution.

1 Alternatively, the title compound can be prepared 2 as follows: 200 mg. of crude 11-(3-oxopropylidene)-6,11-3 dihydro-5H-pyrrolo[2,1-b][3]benzazepine is dissolved in 4 10 cc. of a 8% solution o dimethylamine in ethyl alcohol.
To the resulting solution i5 added one equivalent of 6 sodium cyanoborohydride. The solution is maintained at a 7 pH of 6-8 by appropriate addition of acid or base as re 8 quired and after stirring at 25 for 4 hr. the 6,11-dihydro-9 11-~3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b]~3]-benzazepine is isolated by evaporating the solve~t. The 11 residue is dissolved in 50 cc. of 1 N HCl which is washed 1~ with 2 x 100 cc. of ether. The aqueous acid solution is 13 basified with 3N NaOH and extracted with 2 x 100 ml. of 14 ether. From this dried ether solution, 6,11-~ihydro-11-(3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzaze-16 pine can be isolated as its hydrochloride salt by passing 17 dry hydrogen chloride gas through the solution.
18 Employing the procedure substan~ially as de-19 scribed in Example XXIII, Step C, but substituting for the dimetAylamine and the 3-ox~propylidenes used therein the 21 amin~s and 3-oxopropylidenes described in Table E, there ~2 are produced the 3 (Rl,R2-aminopropylidene)pyrrolo[2,1-b]-23 ~3]benzazepines also described in Table E.

26 Rl Ra (~a)n (Xa)n position _ 27 CH3 CH3 H SO2N(CH3)2 unsaturated 2~ CH3 CH3 H 2-CN unsaturated 29 CH3 CH3 H 2-CO2CH3 unsaturated

30 CH3 CH3 H 2-Cl unsaturated ~O g Z ~ or;i 1 TA~LE E (contlnued) 3 Ra Ra (Ya)n (Xa)n position 4 CH3 CH3 H 2-SCF3 unsaturated 5 CH3 CH3 H 3-SCF3 unsaturated 6 CH3 CH3 ~ 2-CON(CH3) 2 unsaturated 7 CH3 CH3 H 3-CF3 unsaturated 9 CH3 CH3 H 2-CCH (CH3) 2 unsaturated o 11 OEI3 CH3 H 2-C(CH2)3CH3 unsaturated 1~ CH3 CH3 H 2-SO~CH3 unsaturated 13 CH3 CH3 H 2-SO2CH(CH3) 2 unsaturated 14 C~I3 CH3 H 2-S02CF3 unsaturated 15 CH3 CH3 H 2 C2C2H5 unsaturated 16 CH3 CH3 H 2-N02 unsaturated 17 CH3 c~3 H 2-COC~3 unsaturated 18 CH3 CH3 H 2-CF3 unsaturated I9 CH3 3 9 OCONHCH3 2,3-Br2 unsaturated 20 CH3 CH3 9-NHCOOCH3 2,3-Br2 unsaturated 21 CH3 CH3 9-CH3 2,3-Br2 unsaturated 22 CH3 CH3 H 2,3-Br2 unsaturated 23 CH3 CH3 H 2-Br unsaturated 24 CH3 CH3 H 2-Cl unsaturated 25 CH3 CH3 ~ 3-CN unsaturated 26 C~3 CH3 H 1,2,3-Br3 unsaturated 27 CH3 CH3 H 2-SCF3 unsaturated ~8 CH3 CH3 H 1,3-Br~-2-CH3 unsaturated 29 CH3 CH3 9-NHCOCH3 1,2,3-Br3 unsaturated 30 CH3 CH3 9-CH(CH3)2 2,3-Br2 unsaturated ~L09Zl(~5 TABLE E (continued) 3 Rl Ra (~a) n (X~) n position .... ~
4 CH3 CH3 9-SCH3 2, 3-Br unsaturated 5 CH3 CH3 8 ~ 9- (CH3) 2 2-CN unsaturated 6 CH3 CH3 9-OH 2-CN unsaturated 7 CH3 CH3 9-OCH3 2-CN unsaturated 8 CH3 CH3 H 2, 3-C12 unsaturated 9 CH3 CH3 9- OcoNHcH3 H unsaturated 10 CH3 3 9-NHcoocH3 H unsaturated ll CH3 CH3 9-CEI3 H unsaturated 12 CH3 CH3 9-CH (CH3) 2 H unsaturated 13 CH3 CH3 H 2-CH unsaturated CH3 9-NHCOCH3 H unsaturated 15 CH3 CH3 9-Sc~3 H unsaturated 16 C~3 CH3 9-SCH (CH3) 2 H unsaturated 17 CH3 CH3 E l-CF3 unsaturated 18 CH3 CH3 H 3-CO(CH2)4 unsaturated 19 CE3 3 ~ 3-CoCH3 unsaturated 20 CH3 CH3 H 3-COCH (CH3) 2 unsaturated 21 CH3 CE3 9-I H unsaturated 22 CH3 CH3 9-SCF3 H unsaturated 23 CH3 CH3 9-No2 H unsaturated 24 CH3 CH3 9-NH2 EI unsaturated 25 CH3 CH3 9-NHCH3 EI unsaturated 26 CH3 CH3 . 9-N (CH3) 2 H unsaturated 27 CH3 CE~3 9-CN H unsaturated 2 8 C~3 CH3 9-SoCF3 H unsaturated 2 9 CH3 CH3 9-SOCH3 EI unsaturated 30 CH3 CH3 9-SOCH (CH3) 2 EI unsaturated ~Z~S' TABLE E (continued) 3 Rl R2 (Ya)n (Xa)n posltion ,_ _ 4 CH3 CH3 9~SO2CF3 H unsatura~ed 5 CH3 CH3 9-SO2CH3 H unsaturated ~ CH3 CH3 9 SO2CH(CH3)2 H unsaturated 7 CH3 CH3 9-Cl H unsaturated 8 C2H5 C~3 ~ 2-CN unsaturated g -(CH2)4- H H unsaturated 10 -(CH~5- H 2-CO(CH2~3CH3 unsaturated ll -(CH2)2O(CH2)2 9-CN H unsaturated 12 ~ H H 2-CN unsaturated 13 H -CH=CH2 H 2-CN unsaturated 14 CH3 CH3 H H unsaturated 15 CH3 CH3 H 2-SCF3 unsaturated 16 C~3 CH3 9-Cl H unsaturated 17 CH3 CH3 9-SCF3 H unsaturated 18 CH3 CH3 9-CN H unsaturated 19 C~3 CH3 H 2-COCH(CH3)2 unsaturated 20 CH3 CH3 H 2-SO2N(CH3)2 unsaturated 21 CH3 CH3 H 2-SO2CH(CH3)2 unsaturated 22 CH3 CH3 H 2-Cl unsaturated 23 CH3 CH3 9-Br H unsaturated 24 CH3 CH3 H 2-NO2 unsaturated 25 C 3 3 9-OCH3 H unsaturated 26 CH3 CH3 H 2-Cl unsaturated 27 CH3 C~3 H 2-CO(CH2)3CH3 unsaturated 28 CH3 CH3 H 3-CO(CH2)3CH3 unsaturated 29 CH3 CH3 H 3-COCH(CH3)2 unsaturated CH3 CH3 H 2-CON(CH3)2 unsaturated , ~2~0~i 1 TABLE E (continued) 3 ~1 Ra (Ya)n (Xa)n position .
4 C~3 CH3 H 2-COOCH3 unsaturated 5 CH3 CH3 H 2-CH2OH unsaturated 6 CH3 C~3 H 2-CF3 unsaturated 7 C~3 CH3 9-SCH3 H unsaturated 8 CH3 CH3 9-SCH(CH3)2 H unsaturated 9 C~3 CH3 H 2-SOCF3 unsaturated 10 CH3 C~3 9-SOCH3 H unsaturated 11 CH3 CH3 9-S(CH(CH3)2 H unsaturated 12 CH3 CH3 H 2-SO2CF3 unsaturated 13 CH3 CH3 9-SO2c~3 H unsaturated 14 CH3 CH3 9-SO2cH~c~3)2 H unsaturated 15 CH3 CH3 9-OH H lmsaturated 16 ~H3 CH3 9-COOC~H5 H unsaturated 17 C~3 CH3 NH2 H unsaturated 18 CH3 CH3 9-NHCH3 H unsaturated 19 CE3 CH3 9-N(CH3)2 H unsaturated 20 CH3 CH3: 9-NHCOC~3 H unsaturated 21 CH3 CH3 H 2-CN unsaturated 22 CH3 CH3 H 2-S02CH3 unsaturated _99_ ~''3~

1 Yet another alternate procedure is illustrated as 2 follows:

(Y) m~ < ') g (Y~ ~( x) n ¦ R 2) ROCH2NRlR2 CH-CH2X
C~C~2CH2N~ Step C

3 In the last step of the process (Step C), the 4 haloethylidene derivative is reacted with magnesium to form the Grignard reagent and the latter coupled with 6 an alkoxymethyl dimethylamine. The preparation of the 7- Grignard reagent is accomplished by contacting the 8 haloethylidene derivative with magnesium in an inert, sub-9 stantially anhydrous, organic solvent, and at an elevated temperature. However, neither the solvent or temperature 11 employed is critical. As suitable solvents, there may be 12 mentioned tetrahydrofura~, ether or mixtures of ethers 13 with hydrocarbons. Although alevated temperatures are 14 preferred, the rsaction can be carried out at room tempera-ture. The coupling of the Grignard xeagent with the alkoxy-16 methyl dimethylamine is carried out -in an inert, substan-17 tially anhydrous, organic solvent, and at elevated tempera-18 tures. Preferably, the same solvent and temperature used 19 for the preparation of ~he haloethylidene Grignard reagen~
is employed. ~owever, again, the choice of solvent and 21 temperature is not critical and other solvents and tempera-22 tures, as mentioned above with regard to the preparation 23 of the haloethylidene Grignard reagent, may be employed.
24 Recovery of the product is accomplished using conventional techniques.

--1~0--~0~21~5 1 EX~MPLE XXIV
2 6,11-Dihydro-11-(3-dimethylaminopropylidene)-5H-pyrrolo-3 [2,1-b~[3]benzazepine Hydrochloride 4 Step A: Preparation of 6,11-dihydro-11-vinyl-11-hydroxy-5E~yrrolo[2,1-b]~3]benzazepine 6 A 100 ml. 3-neck flask ~itted with stirrer, Dry 7 Ice-acetone condenser, nitrogen inlet and addition funnel 8 is charged with 1.17 g. (48 millimoles) of magnesium turn-g ings. The system is "flamed-out" with a heat gun and cooled under dry nitrogen. The magnesium metal is covered 11 with 10 ml. of dry tetrahydrofuran and 2-3 ml. of a solu-12 tion of S.25 g. (49 milli~oles) of vinyl bromide in 10 ml.
13 of tetrahydrofuran is added. The reaction mixture is 14 warmed slightly until the reaction is started. The vinyl bromide solution is added dropwise, with stirring, at such 16 a rate as to maintain a temperature of 50-60C. The 17 addition is complete in 15 minutes and stirring is con-1~ tinued under ~entle reflux until all of the magnesium is 19 consumed (2 hours). A solution of 5.0 g. (25 millimoles) of 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 21 25 ml. of tetrahydrofuran is added, with stirring, to the 22 warm reaction mixture at a rate sufficient to maintain a 23 temperature of 40-50C. The addition is complete in 25 2~ minutes. Stirring and heating (50C.) are continued for 1 hour. At the end of this time, a thin-layer chromato-26 graphic probe (A12O3-1:1 benzene-cyclohexane) indicates 27 that the reaction is complete. The reaction mixture is 28 chilled in an ice-bath and treated, dropwise, with 25 ml.
29 of saturated ammonium chloride solution. The aqueous layer is extracted with two 15 ml. portions of ether and the com-

31 bined ether-tetrahydrofuran solutions are washed with .~
10 32~

1 15 ml. o~ saturated sodium chloride solution, dried over 2 anhydrous magnesium sulfate and taken to dryness ln vacuo 3 to yield 5.90 g. of the vinyl carbinol as a yellow oil.
4 Step B Preparation of 6,11-dihydro ll-(~-bromoethylidene)-5H-pyrrolo[2,1-b]_[3]benzazepine_ 6 A solution of 1.20 g. of crude 6,11-dihydro-7 11-vinyl~ hydroxy-5H-pyrrolo[2,1-b][3]benzazepine in 8 15 ml. of glacial acetic acid is chilled to 10C. and 10 g ml. of a 15% solution of anhydrous hydrogen bromide in glacial acetic acid added. The reaction mixture is stirred 11 at 10-15C. for 1/2 hour, then taken to dryness in vacuo, 12 flushed with xylene and pumped down on an oil pump to yield 13 1.44 g. of 6,11-dihydro-11~ bromoethylidene)-SH-pyrrolo-14 [2,1-b][3]benzazepine as an oil.
~ Preparation of 6,11-dihydro-11-(3-dimethylamino-16 propylidene)-5H-pyrrolo[2,1-b~[3]benzazepine 17 hydrochloride 18 A "cyclic reactor", as described in the litera-19 ture, is employed in the Grignard reaction. This reactor consists, in ascending order, of a 100 ml. 3-neck reservvir 21 ~lask (2 necks stoppered) of refluxing ether, a sidearm 22 column containing magnesium turnings immersed in ether, a 23 condenser and a dropping funnel with a nitrogen inlet.
24 The magnesium in the reactor column is amalgamated by standing overnight under a saturated ether solution of 26 mercuric bromide. Ater draining off this solution, the 27 reactor column is refluxed with ether for 1.5 hours, and, 28 finally, the magnesium is further activated with 0.2 ml.
29 Of methyl iodide in 1 ml. of ether, followed by refluxing in ether for 1.5 hours. In these and all subsequent steps, 31 the ether level in the reactor is maintained just above Z1~5 1 the surface of the magnesium and the system is kept under 2 dry nitrogen. The reservoir flask is charged with 15 ml.
3 of dry ether and refluxing begun. The dropwise return 4 rate (from the reactor column to the reservoir flask) is adjusted such that the ether level in the reactor remains 6 constant. One gram of 6,11-dihydro~ -bromoethylidene)-7 5H-pyrrolo[2,1-b][3]benzazepine dissolved in 30 ml. of dry 8 ether is added to the reactor column at a steady rate of g 1 drop/30 seGonds (ratio of reflux-drop rate to addition-drop rate is 30:1). Addition is complete in 3.5 hours.
11 after which time the reactor column is refluxed for an 1~ additional 30 minutes. The reaction mixture is cooled 13 to 25C., the reactor column assembly on the reservoir 14 flask is replaced by a stirrer, and a reflux condenser (with nitrogen inlet) and addition funnel added to the pre-16 viously stoppered necks of the reservoir flask. A solution 17 of 0.533 g. of isobutoxymethyl dimethylamine in 10 ml. of 18 dry ether is added dropwise, with stirring, to the Grignard 19 solution over a period of 5 minutes. The resulting mixture is refluxed for 0.5 hour, kept overnight at room tempera 21 ture, and refluxed for an additional hour. The reaction 22 mixture is chilled in an ice-bath and treated with 20 ml.
23 of saturated amm~nium chloride solution. The aqueous 24 layer is extracted with ether and the ether extract washed successively with 10 ml. of 2.S N HCl and 15 ml. of wat~r.
26 The aqueous phase is made alkaline with concentrated 27 ammonium hydroxide and extracted with ether. The basic 28 ether extxact is washed with 15 ml. of saturated salt 29 solution, dried over magnesium sulfate, and evaporated to l~z~osj 1 dryness ln vacuo, yielding 540 mg~ of oily free amine. The 2 free amine, in 10 ml. o ether, is treated with 4 ml. o~
3 ether saturated wi~h hydrogen chloride and the mixture 4 taken to dryness. The gummy residue is dissolved i~
ethanol, txeated with charcoal and filtered through 6 celite. The fil~rate is boiled down to a small volume, 7 diluted wi h ether to the point of cloudiness a~d scratched, 8 yielding crude 6,11-dihydro~ (3-dimethylaminopropylidene)-g 5H-pyrrolo~2,1-b][3]benza epine hydrochloride.
Employing the procedure of Example XXIV, Step C, 11 but substituting for the bromoethylidene compound used 1~ therein, the bromoethylidenes described in Table F, there 13 are produced the 3-(Rl,R2-aminopropylidene)pyrrolo[2,1-b]-14 [3]benzazepines also described in Table F.
~ABLE F

17 R R (Y~)n (X~)n position 18 ~H3 CH3 H 2 SO2N(CH3)2 saturated 19 CH3 CH3 H 2-CN saturated 20 CH3 CH3 H 2-CO2CH3 saturated 21 CH3 CH3 H 2-Cl saturated 22 CH3 CH3 H 2-SCF3 saturated 23 CH3 CH3 H 3-SCF3 saturated 24 CH3 CH3 H 2-CON(CH3)2 saturated 25 CH3 CH3 H 3-CF3 saturated 26 C~3 CH3 H 2-SO2CH3 saturated 27 CH3 CH3 H 2-S02CH(CH3~2 saturated 28 CH3 CH3 H 2-SO2CF3 saturated 29 CH3 CH3 H 2 C2C2H5 saturated 9Zl~)S

1 TABLE F (continued) 2 l 2 5-6 3 R R (Y~)n (X~)n position ~ .
4 CH3 c~3 H 2-CF saturated 5 CH3 CH3 9-CH 2,3-Br saturated 6 CH3 C~3 ~ 2,3-Br2 saturated 7 CH3 CH3 H 2-Br saturated 8 CH3 CH3 H 2-Cl saturated 9 C~3 CH3 H 3-CN saturated 10 CH3 C~3 H 1,2,3-Br3 saturated ll CH3 CH3 H 2-SCF3 saturated 12 CH3 CH3 H l,3-Br2-2-CH3 saturated 13 . CH3 CH3 9-CH (CH3) 2 2,3-Br2 saturated 14 CH3 CH3 9-SCH3 2,3-Br saturated 15 CH3 CH3 8, 9 (CH3) 2 2-CN saturated 16 CH3 C~I3 9-OCH3 2-CN saturated 17 CH3 CH3 H 2,3-C12 saturated 18 CH3 CH3 9-CH3 H saturated l9 CX3 CH3 9-CH(CH3)2 H saturated 20 CH3 ~I3 H 2-CH3 saturated 21 CH3 3 9-SCH3 H saturated 22 CH3 C~3 1-CF3 saturated 23 CH3 C~3 9-SCF3 H saturated 24 CH3 CH3 9-N(CH3)2 H saturated 25 CH3 CH3 9-CN H saturated 26 CH3 CH3 9-SOCF3 H saturated 27 CH3 CH 9-SOCH3 H saturated 28 CH3 3 9 SCH(CH3)2 H saturated ~()92~t~

1 TABLE F (continued) 3 R R (Y~) n (X~3 n position 4 CH3 CH3 9-SO2CF3 H saturated 5 CH3 CH3 9-SO2CH3 H saturated 6 CH3 CH3 9-S02CH ~CH3) 2 saturated 7 C2H5 CH3 H 2-CN saturated 8 -(CH2)4 H H saturated g -(CH2)2O(cH2)2 9-CN H saturated H H 2-CN saturated 11 H -CH=CH2 H 2-CN saturated 12 CH3 CH3 H H unsaturated 13 CH3 CH3 H 2-SCF3 unsaturated 14 CH3 CH3 9-Cl H unsaturated 15 CH3 CH3 9-SCF3 H unsaturated 16 CH3 CH3 9-CN H unsaturated 17 CH3 CH3 H 2-SO2N(CH3)2 unsaturated 18 CH3 CH3 H 2-SO2CH (CH3) 2 unsaturated 19 CH3 CH3 H 2-Cl unsaturated 20 CH3 CH3 9-Br H unsaturated 21 C~3 C~3 9-OCH3 H unsaturated 22 C~3 CH3 H 2-Cl unsaturated 23 CH3 CH3 H 2-CON(CH3)2 unsaturated 24 C~3 CH3 H 2-COOCH3 unsaturated 25 CH3 CH3 H 2-CF unsaturated 26 CH3 c~3 9-SCH3 H unsaturated 27 CH3 3 9 SCH (CH3) 2 ~ unsaturated 28 CH3 CH3 2-SOCF3 unsaturated 29 CH3 CH 9-SOCH3 H unsaturated 30 CH3 CH3 9-S (CH (CH3) 2 H unsaturated .

1~92~DS

1 TABLE F (continued) 3 R R (Y~)n (X~)n position 4 CH3 ~H3 H 2-SO2CF3 unsaturated 5 CH3 CH3 9-SO2CH3 H unsaturated 6 CH3 CH3 9-SO2CH(CH3)2 H unsaturated 7 CH3 CH3 9-COOC2H5 H unsaturated 8 CH3 CH3 9-N(C~3)2 H unsaturated 9 CH3 CH3 H 2-CN unsaturated lO CH3 CH3 H 2-SO2CH3 unsaturated 14985~

Z~ S

1 A fourth procedure for preparing the compounds 2 Of the present invention is illustrated as follows:

)n'~3(x)n Br) 2 2 xR

3 The last step of the process involves the 4 coupling of the Grignard reagent with the dimethylamino-ethyl halide. This reaction is conveniently effected in 6 a suitable inert organic solvent, preferably tetrahydro-7 furan, and at elevated temperatures. However, neither the 8 solvent or temperature employed is critical and the con-g ventional solvents and temperatures heretofore employed for carrying out coupling reactions with Grignard reagents lI may be utilized. Recovery of the product is accomplished 12 using conventional techniques.

146,11-Dihydro-2-cyano-11-(3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazeplne Ste~ A: Preparation of 6,11-dihydro-2-cyano-11-methyl-1611-hydroxy-5H-pyrrolo[2,1-b][3]benzazepine___ 1767 Grams of 6,11-dihydro-2-cyano-5H-pyrrolo-18[2,1-b]~3~benzazepin-11-one is dissolved in 200 milliliters 19 of anhydrous tetrahydrofuran and a solution of 0.6 mole of methylmagnesium bromide in ether is added while stirring 21 and under reflux. Then water and excess acetic acid are 22 added to the reaction mixture, whereupon the etherlayer 23 is separated, washed with water and evaporated on a steam 108~

1 bath to leave 6,11-dihydro-2-cyano--11-methyl-11-hydroxy-2 5H-pyrrolo[2,1-b][3]benzazepine as a viscous oil.
3 ~ Preparation of 6,11-dihydro-2-cyano-11-methylene-4 5H-pyrrolo[2~l-b][3]benzazepine A solution of 5 gm. of 6,11-dihydro-2-cyano-11-6 methyl~ll-hydroxy-5H-pyrrolo[2,1-b][3]benzazepine and 1 gm.
7 of oxalic acid in 25 ml. o ethanol is heated to reflux for 8 2 hx., evaporated to dryness, and the residue dissolved in 9 100 ml. of chloroform. The chloroform solution is washed with 2 x 50 ml. of 5% sodium carbonate solution, dried over 11 Na2SO4 and evaporated to yield 4.1 gm. of 6,11-dihydro-12 2-cyano-11-methylene-5H-pyrrolo[2,1-b][3]benzazepine.
13 Step_C: Preparation of 6,11-dihydro-2-cyano-11-bromo-14 methylene-5H-pyrrolo[2~l-b][3]benzazepine lS A solution of 1.85 g. of 6,11-dihydro-2-cyano-16 11-methylene-5H-pyrrolo[2,1-b][3]benzazepine in 15 cc. of 17 chloroform is brominated by dropwise addition of 1.45 g.
18 of bromine dissolved in 9 cc. of chloroform. Bromine 19 absorption is instantaneous, accompanied by copious evolution of hydrogen bromide. The reaction mixture is 21 washed wi~h 5~ aqueous sodium bicarbonate until the washings 22 remain basic, dried and evaporated to yield 2 gm. of 23 6,11-dihydro-2-cyano-11-bromomethylene-5H-pyrrolo[2,1-b][3]-24 benzazepine as a dark oil.
Step D: Preparation of 6,11-dihydro-2-cyano-11-(3-dimethyl-26 aminopropylidene)-5H-pyrrolo~2/1-b][3]benzazepine 27 A solution of 2.00 g. of 6,11-dihydro-2-cyano-11-28 bromomethylene-SH-pyrrolo[2,1-b][3]benzazepine in 10 ml.
29 of tetrahydrofuran is added slowly under nitrogen to a stirred mixture of 170 mg~ of magnesium turnings and 2 ml.
31 of tetrahydrofuran. The reaction is started by initially

32 adding a trace of methyl iodide. When addition is com-Z~05 1 plete, the dark brown solution is refluxed for 90 minutes.
2 It is then cooled to room temperature and a solution of 3 760 mg. o~ ~-dimPthylaminoethyl chloride is added. The 4 stirred mixture is refluxed 2 hours, kept at room tempera-ture overnight, and then cooled to 10C. 20 Ml. of 10%
6 aqueous ammonium chlorid0 and 10 ml. of 2.5 N hydrochloric 7 acid are then added. Following ether extraction of the 8 mixture to recover by-products, the acidic layer is made 9 basic with 2.5 N sodium hydroxide and extracted with ether.
From the latter extract, 230 mg. of basic material is ob-11 tained which, on treatment with hydrogen chloride in ether 12 and crystallization from ether gives the hydrochloride of 13 6,11-dihydro-2-cyano-11-(3-dimethylaminopropylidenel-5H-14 pyrrolo[2,1-b][3]benzazepine.
Employing the procedure substantially as de-16 scribed in Example XXV, but substituting for the 2-cyano-17 bromomethylene compound employed therein, the bromomethylene 18 compounds described in Table G, there are produced the 3-19 (Rl,R2-aminopropylidene)pyrrolo[2,1-b~[3]benzazepines also described in Table G.

23 R R (Y~)m (X~)n position ~ , . ~
24 CH3 CH3 H 2~SO2N(CH3)2 saturated 25 CH3 CH3 2 C2CH3 saturated 26 CH3 CH3 H 2-Cl saturated 27 CH3 CH3 H 2-SCF3 saturated 28 CH3 CH3 H 3-SCF3 satuxated 29 CH3 CH3 H 2-CON(CH3)2 saturated 30 CH3 CH3 H 3-CF3 saturated 1 TABLE G (continued) 3 R R ( ~)m (X~)n position 4 CH3 c~3 H 2-SO2CH3 saturated 5 CH3 CH3 H 2-SO2CH(CH3)2 saturated 6 CH3 CH3 H 2-S02CF3 saturated 7 C~3 CH3 H 2 C2C2H5 saturated 8 CH3 CH3 H 2-CF3 saturated g CH3 CH3 H 2,3-Br2 saturated 10 CH3 CH3 ~ 2-Br saturated 11 C~3 CH3 H 2-Cl saturated 12 CH3 CH3 H 3-CN saturated 13 CH3 CH3 H 1,2,3-Br3 saturated 14 CH3 CH3 H 2-SCF3 saturated CH3 CH3 H 1,3-Br2-2-CH3 saturated 16 CH3 CX3 9-CH(CH3)2 2,3-Br2 saturated 17 C~3 CH3 9-SCH3 2,3-Br2 saturated 18 CH3 CH3 8,g-(cE3)2 2-CN saturated 19 CH3 CH3 9-OCH3 2-CN saturated CH3 CH3 H 2,3-C12 saturated 21 C~3 3 1-CF3 saturated 22 C2H5 CH3 H 2-CN saturated 23 ~ CH3 H 2-CN saturated 24 CH3 -CH=CH2 H 2-CN saturated 25 C~3 C~3 H 2-SCF3 unsaturated 26 CH3 CH3 H 2-SO2N(CH3)2 saturated 27 CH3 CH3 H 2-SO2CH(CH3)2 saturated 28 CH3 CH3 2-Cl saturated 29 CH3 CH3 H 2-Cl unsaturated ~V~ S

1 TABLE G (continued) 3 Rl R2 ( ~)m (X~)n 5-6 4 CH3 CH3 H 2-CON(CH3)2 saturated 5 CH3 CH3 H 2-COOCH3 saturated 6 CH3 CH3 H 2-CF3 saturated 7 CH3 c~3 H 2-SOCF3 saturated 8 CH3 CH3 H 2~S02CF3 saturated 9 CH3 C~3 H 2-S02CH3 saturated ~0~Z~(~5 1 A fifth procedure for preparing the novel com-2 pounds of the present invention is illustrated as follows:

n ~_( X) n CHC~ CH N
2 2 \ ~ H CH-CH2CH2NRlR2 OH
3 The course of reaction for the dehydration 4 step G was not predictable as the dehydration might have taken placa between two of the carbon atoms of the side 6 chain. This dehydration is preferably carried out under the 7 influence of strong dehydrating inorganic acid halides such 8 as phosphor~us-oxychloride or thionylchloride in the g presence of a tertiary amine, such as pyridine or quinoline as a hydrogenhalide binding agent at a temperature of from 11 -10C. to 100C. for a time of from 15 minutes to 5 hours.

13 6,11-Dihydro-2-cyano-11-(3~dimethylaminopropylidene)-14 5H-~vrrolo[2rl-b]~3]benzazePine ~ Preparation of 6,11-dihydro-2-cyano-11-ethyl-11-16 hydroxy-5H-pyrrolo[2,1-b][3]benzazepine 17 Following substantially the procedure of Example 18 XXV, Step A, but substituting ethylmagnesium bromide for 19 methyl magnesium bromide, there is obtained 6,11-dihydro-20 2-cyano~ ethyl-11-hydroxy-5H-pyrrolo[2,1-b3[3]benzaze-21 pine.
22 Step B: Preparation of 6,11-dihydro-2-cyano-11-ethylidene-23 5H-~rrolo[2,1-bl[3]benzazepine 24 Following substantially the procedure of Example XXV, Step B, but using the product fxom Example XXVI, 1~9Z~

1 Step A, there is obtained 6,11-dihydro-2-cyano-11-ethyli-2 dene-5H-pyrrolo[2,1-b][3]benzazepine.
3 Step C: Preparation of 6,11-dihydro-2-cyano-11-(1-hydroxy-4 ethyl)-11-hydroxy-5~-pyrrolo[2,1-b3[3]benzazepine 63 Grams of the ethylidene compound from Step B
6 are dissolved in 315 milliliters of anhydrous formic acid 7 and 40 milliliters of 35% hydrogenperoxide are added drop-8 wise a~ a ~emperature of 60 degrees centigrade while g - stirring. The mixture is kept for two hours at 70 degrees centigrade, whereupon it is chilled and diluted with one 11 liter of water and extracted with ether. The etherlayer 12 is sepaxated, washed with water and dilute sodium hydroxide 13 solution and the ether evaporated on a steam bath to 14 leave 40 gm. of crude 6,11-dihydro~2-cyano~ (1-hydroxy-ethyl)~ hydroxy-5~-pyrrolo[2,1-b][3]benzazepine as a 16 viscous oil.
17 Step D: Preparation of 6,11-dihydro-2-cyano-11 acetyl-18 5H-pyrrolo[2,1-b][3]benzazepine 19 Following substantially the procedure of Example XXV, Step B, but starting with the dihydroxy compound of 21 Example XXVI, Step C, there is obtained 6,11-dihydro-2-22 cyano-11-acetyl-5H-pyrrolo[2,1-b][3]benzazepine.
23 tep E: Preparation of 6,11-dihydro-2-cyano-11-(3-di~
24 methylaminopropionyl)-5~-pyrrolo[2,1-b][3]-benzazepine ~drochloride _ _ 26 A mixture of 12 gram5 of 6,11-dihydro-2-cyano-27 11-acetyl-5H-pyrrolo~2rl-b~[3]benzazepine, 2.5 grams of 28 paraformaldehyde, 6.5 grams of dimethylamine hydrochloride, 29 30 milliliters of ethanol and 0.3 milliliter of concentrated hydrochloric acid is refluxed on a steam bath for 19 31 hours. Thereupon the solvent is evaporated and the resi-32 due is shaken with water and ether. The water phase is ~09Zl(~5 1 separated, and aqueous ammonia is added in excess, to effect 2 the separation of an oil which is extracted with ether.
3 The ether phase is dried and evaporated at last in vacuo.
4 The residue is dissolved in 50 milliliters of acetone, and a solution of hydrogenchloride in ether is added until a 6 sli~ht acid reaction. Thereby 10 grams of 6,11-dihydro-7 2-cyano-11-(3-dimethylaminopropionyl)-5H-pyrrolo[2,1-b]-8 [3]benzazepine hydrochloride crystallizes out.
9 Step F: Preparation of 6,11-dihydro -2-cyano-11-(1-hydroxy-3-dimethylaminopropyl)-5H-pyrrolo[2,1-b]-11 [3]benzazepine hydrochloride 12 The hydrochloride from Step E is dissolved in 13 250 milliliters of methanol and is hydrogenated at 25 C.
14 and a pressure of 3 atmospheres for 4 hours with shaking and 0.5 gram of platinumoxide (Adams catalyst) as a cata-16 lyst. After filtering off the catalyst the filtrate is 17 evaporated to dryness on a steam bath and 50 milliliters of 18 ace~one added to the residue. Thereby 9.5 grams of 6,11-19 dihydro-2-cyano~ (1-hydroxy-3-dimethylaminopropyl)-5H-pyrrolo[2,1-b]13]benzazepine hydrochloride crystallizes.
21 Where the pyrrole ring carries bromo- or chloro-22 substituents, these are hydrogenolyzed during the re-23 duction.
24 Alternatively, the product from Step C is treated with sodium borohydride in ethanol, following a conven-26 tional isolation procedure and treatment with hydrochloric 27 acid to give 6,11-dihydro-2-cyano-11-(1-hydroxy-3-dimethyl-28 aminopropyl)-5H-pyrrolo[2,1-b][3~benzazepine hydrochloride.
29 Step G: Preparation of 6,11-dihydro-2-cyano-11-(3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]-31 benzazepine _ ;

32 Five grams of the hydrochloride from Step F

Z~

1 dissolved in 10 milliliters of pyridine, and while cooliny 2 a solution of 10 milliliters of phosphorous oxychloride in 3 25 millimeters pyridine is added dropwise keeping ~he 4 temperature of ~he reaction below 30 degrees centigrade.
The mixture is then kept for 15 minutes at 30 degrees centi-6 grade and for 40 minutes at 95 degrees centigrade. After 7 cooling the reaction mixture is poured in 200 grams of 8 finely crushed ice, and the resulting solution made alka-9 line with sodium hydroxide. Then the mixture is extracted with ether, which is separated, dried and evaporated on a 11 steam bath in vacuo. The residue is dissolved in a ]ittle 12 acetone and a solution of hydrogen chloride in ether is 13 added dropwi~e until slight acid reaction. Thereby the 14 hydrochloride of 6,11-dihydro-2-cyano-11-(3-dimethylamino-propylidene)-5H~pyrrolo[2,1-b~[3]benzazepine are obtained.
16 It is to be noted that, if either or both of Rl or 17 R? is a hydrogen atom, the alkaline mixture in this pro-18 cedure is heated to 90C~ for 1 hour prior to extraction 19 with ether.
Employing the procedure substantially as described in 21 Example XXVII Step G, but substituting for the starting 22 material employed therein, the carbinols described in 23 Table H, there are produced the 3-(Rl,R2-aminopropyli-24 dene)pyrrolo~2,1-b][3]benzazepines also described in Table H.

10~3Zi(~S

2 Rl R2(Y~)m _ _X~)n position 4 CH3 CH3 H 2-SO2N(CH3)2 saturated S C~3 CH3 H 2-CO2CH3 saturated 6 CH3 CH3 ~ 2-Cl saturated 7 CH3 CH3 H 2-CON(CH3)2 saturated 8 CH3 CH3 H 3-CF3 saturated g CH3 CH3 H 2-S02CH3 saturated 10 CH3 C~3 H 2-SO2CH(CH3)2 saturated 11 CH3 CH3 H 2-SO2CF3 saturated 12 CH3 CH3 H 2 C2C2H5 saturated 13 CH3 CH3 H 2-CF3 saturated 14 CH3 CH3 9-OCONHCH3 2,3-Br saturated 15 c~3 CH3 9-NHCCOCH3 2,3-Br2 saturated 16 CH3 CH3 9-CH3 2,3-Br2 saturated 17 CH3 CH3 H 2,3-Br2 saturated 18 CH3 CH3 H 2-Br saturated 19 H3 CH3 H 2-Cl saturated 20 CX3 CH3 H 3-C~ saturated 21 CH3 CH3 H 1 2 3-Br3 saturated 22 CH3 CH3 H 1,3-Br2-2-CH3 saturated 23 CH3 CH3 9-NHCOCH3 1,2,3-Br3 saturated 24 CH3 C~3 9-CH(CH3)2 2,3-Br2 saturated ~H3 CH3 8,g-(cH3)2 2-CN saturated 26 CH3 CH3 9-OCH3 2-CN saturated 27 CH3 CH3 H 2,3-C12 saturated 28 CH3 CH3 9-OCONHCH3 H saturated 29 CH3 CH3 9-NHCOOCH3 H saturated s 1 ~ABLE H (Continued) 2 Rl R2 (Y )m (X )n position 4 CH3 C~3 9-CH3 H saturated 5 CH3 CH3 9-CH (CH3) 2 H satura~ed 6 CH3 CH3 9-NHCOCH3 H saturated 7 CH3 CH3 H l-CF3 saturated 8 CH3 CH3 H H saturated 2 5 C~3 H 2-CN saturated 10 CH3 CH3 H H unsaturated 11 CH3 CH3 H 2-S02N(CH3)2 unsaturated 12 CH3 CH3 H 2-SO2CH (CH3) 2 unsaturated 13 CH3 CH3 H 2-Cl unsaturated 14 C~3 CH3 H 2-NO2 unsaturated 15 C~3 C~3 H 2-Cl unsaturated 16 CH3 CH3 2-CON(CH3~ 2 unsaturated 17 CH3 C~3 H 2-COOCH3 unsaturated 18 CH3 CH3 H 2-CF3 unsaturated 19 CH3 CH3 H 2-SO2CF3 unsaturated 20 CH3 CH3 X 2-CN unsaturated 21 CH3 CH3 H 2-S02CH3 unsaturated 21(~S

1 Another procedure for preparing the novel com-2 pounds of the present invention is exemplified as outlined 3 below:

6 5 3~al~ \ R~ Hal lbase (C6H5) P=CHCH2C~2 -- R

~(Y)m ~ X)n ~ N~(x)n (y) mt~/~ / R
C~-CH2 CH2N' R2 4In this procedure, an aminopropylphosphonium S halide hydrohalide is converted to an aminopropylidene-~ trisubstituted phosphorane by treatment with a strong 7 base. This reaction may be carried out in a medium such 8 as dry ether, tetrahydrofuran or dimethylsulfoxide with g appropriate strong bases such as alkoxides, alkyl lithium reagents, sodium hydride and the like.
11 The aminopropylidene-trisubstituted phosphorane 12 so prepared is caused to react with the desired ketone in 13 the solvent in which it i5 prepared at temperatures from 1~ about -lO~C. to about 100C. for from about 1 hr. to 12 hr., depending on the reactivity of the ketone.
16 It is to be noted that normally 2 equivalents 17 Of strong base are used per equivalent of aminopropyl 18 phosphonium halide hydrohalide. However, if the ketone 19 to be used contains one or more "active'l hydrogens such as ~9~S

l is present in a N-H or O-EI functionality, an additional 2 equivalent of strong base is used per "active" hydrogen.

4 6,11-Dihydro~ (3-dimethylaminopropylidene)-5H-pyrrolo-[2,1-b][3]benzazepine 6 Anhydrous 3~dimethylaminopropyltrlphenylphos-7 phonium bromide hydrobromide, 15.30 g., is suspended in 8 45 ml. dry tetrahydrofuran and 0.06 moles of butyl lithium 9 in heptane is added during 1 hour. After an additional 30 minutes, 4.83 g. of 6,11-dihydro-5H-pyrrolo[2,1-b][3]-11 benzazepin-ll-one is added to the deep red solution and 12 the reaction is maintained at reflux for 10 houxs. Water, 13 500 ml., is added at room temperature and the solvent is 14 removed in vacuo. The crude residue is treated with 10 hydrochloric acid until acidic (pH 2) and then 30 ml.
16 benzene is added. After stirring, the mixture separates 17 into three phases (an insoluble hydrochloride salt product 18 phase, an aqueous phase, and an organic phase). The l9 benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution 21 and is extracted with 3 x 30 ml. portions of benzene. The 22 benzene extracts are washed, then dried with anhydrous 23 sodium sulfate and concentrated in a vacuum leaving a 24 residue of 6,11-dihydro~ (3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3~ben2azepine.
26 Following the procedure substantially as de-27 scribed in Example XXVII, but substituting for the ketone 28 used therein, the ketones described in Table I, there are 29 produced the 3-(Rl,R2-amlnopropylidene)pyrrolo~2,1~b][3]-benzazepines also described in Table I.

~120-~09ZgLOS

3 R R ~Ya) m ( a) n position 4 CH3 CH3 H 2-SO2N(CH3)2 saturated 5 CH3 CH3 H 2-CN saturated 6 CH3 CH3 H 2-CO2CH3 saturated 7 CH3 CH3 H 2-Cl saturated 8 CH3 CH3 H 2-SCF3 saturated g CH3 CH3 H 3-SCF3 saturated CH3 CH3 H 2-CON(CH3)2 saturated 11 H3 CH3 H 3-CF3 saturated 13 CH3 CH3 H 2-CCH(CH3)2 saturated CH3 CH3 H 2-C(CH2)3CH3 saturated 16 CX3 CH3 H 2-SO~CH3 saturated 17 C~3 CH3 H 2-5O2CH(CH3)2 saturated 18 CH3 CH3 H 2-S02CF3 saturated 19 CH3 CH3 H 2 2H5 saturated 20 CH3 CH3 H 2-N02 saturated 21 CH3 C~3 2-COCH3 satuxated 22 CH3 CH3 H 2-CF saturated 23 CH3 CH3 9-OCONHCH3 ~,3-Br2 saturated 2~ CH3 3 9-NHCOOCH3 2,3-Br2 saturated 25 CH3 CH 9-CH3 2,3 Br saturated 26 CH3 CH3 H 2,3-Br2 saturated 27 CH3 CH3 H 2-Br saturated 28 CH3 C~3 H 2-Cl saturated 29 CH3 CH3 ~ saturated 1~985IA

1()9ZhOS

1 TABLE I (Continued) 3 Rl R2 ( a) m (Xa) n position .
4 C~3 CH3 H 1 2 3-Br3 saturated 5 CH3 CH3 H 1,3-Br2-2-CH3 saturated 6 CH3 CH3 9-NHCOCH3 1,2,3-Br3 saturated 7 CH3 CH3 9-CH(CH3)2 2,3-Br2 saturated 8 CH3 C~3 9-SCH3 2,3-Br saturated g CH3 CH3 8,9-(CH3)2 2-CN saturated 10 CH3 CH3 9-OH 2-CN saturated ll CH3 CH3 9-OCH3 2-CN saturated 12 CH3 CH3 H 2,3-C12 saturated 13 CH3 CH3 9-OCONHCH3 H saturated 14 C~3 CH3 9-NHCOOCH3 H saturated 15 C~3 C~3 9-CH3 H saturated 16 CH3 CH3 9-CH(CH3)2 H saturated 17 CH3 CH3 H 2-CH3 saturated 18 CH3 CH3 9-NHCOCH3 H saturated l9 CH~ c~3 9-SCH3 H saturated 20 CH3 CH3 9-SCH(CH3)2 H saturated 21 CH3 CH3 H l-CF3 saturated 22 CH3 CH3 H 3-CO(CH2)4 saturated ~3 CH3 CH3 H 3-COCH3 saturated 24 CH3 CH3 H 3-COCH(CH3)2 saturated ~5 C~3 C~3 9-I H saturated 26 CH3 CH3 9-SCF3 H saturated 27 CH3 CH3 9-N02 H saturated 28 CH3 CH3 9-NH2 H saturated 29 CH3 CH3 9-NHCH3 H saturated 30 C~3 CH3 9-N(CH3)2 H saturated ~9~)5i 1 TABLE I (Continued) .. . ..

3 R R (~)m (X )n position - . _ a 4 H3 CH3 9-CN H saturated 5 CH3 CH 9-SOCF H saturated 6 CH3 CH 9-SOCH H saturated 7 CH3 CH3 9-SOCH (CH3)2 H saturated 8 CH3 CH3 9-S02CF3 H saturated g CH3 CH3 9-S02CH3 H saturated 10 CH3 CH3 9-5O2CH(CH3)2 H saturated 11 C~3 CH3 9-Cl H saturated 12 C2H5 CH3 H 2~CN saturated 13 (CH2)~ H H saturated 14 -tCH2)5- H 2-CO(CH2)3CH3 saturated 15 ~CH2) 20(CH2) 2 9-CN H saturated 16 ~ H H 2-CN saturated 17 H -CH=C~2 H 2-CN saturated 18 CH3 CH3 H H unsaturated 19 CH3 CH3 H 2 SCF3 unsaturated 20 CH3 CH3 9-Cl H unsaturated 21 CH3 CH3 9-SCF3 H unsaturated 22 CH3 CH3 9-CN H unsaturated 23 CH3 CH3 H 2-COCH(CH3) 2 unsaturated ~4 CH3 CH3 H 2-SO2N(CH3) 2 unsaturated 25 C~3 CH3 H 2 S02CH(CH3)2 un tura 2 6 CH3 CH3 H 2-Cl unsaturated 27 CH3 CH3 9-Br H unsaturated 2B CH3 CH3 H 2-N02 unsaturated 29 CH3 CH3 9-OCH3 H unsaturated 30 CH3 CH3 H 2-Cl unsaturated , .
~9~ 5 1 TABhE I (Continued) 3 R R (Ya)~ ( a)n position 4 CH3 CH3 H 2-CO(CH2) 3CH3 unsaturated 5 CH3 CH3 H 3-CO(CH2) 3CH3 unsaturated 6 CH3 CH3 H 3-COCH (CH3) 2 unsaturated 7 CH3 CH3 H 2-CON (CX3) 2 unsaturated 8 CH3 C~3 H 2-COOCH3 unsaturated 9 CH3 CH3 ~ 2-CH20H unsaturated 10 H3 CH3 H 2-CF unsaturated 11 CH3 CH3 9-SCH3 H unsaturated 12 CH3 3 9 SCH (CH3) 2 H unsaturated 13 CH3 CH3~ H 2-SOCF3 unsaturated 14 CH3 CH 9-SOCH3 H unsaturated 15 CH3 C~3 9-SQCH (CH3) 2 H unsaturated 16 C~3 CH3 H 2-S02CF3 unsa~urated 17 C~3 CH3 9-SO2CH3 H unsaturated 18 CH3 CH3 9-S02CH (CH3) 2 unsaturated 19 CH3 CH3 9-OH H unsaturated 20 CH3 CH3 9-COOC2H5 unsaturated 21 CH3 CH 9-~H2 H unsaturated 22 CH3 CH3 9-NHCR3 H unsaturated 23 CH3 CH3 9-N ~CH3) 2 H unsaturated 24 CH3 CH3 9-NHCOCH3 H unsaturated 25 CH3 CH3 H 2-S02CH3 unsaturated --1~4-~9Z~

1 A ~urther procedure for the synthesis of the 2 novel compounds of this invention may be illustrated as 3 follows:

~ \ ~ (X)n (Y) ~ \ ~ ~ ~ (X')n (Y) ~ ~ ~V~ R

CHCH2CH2N~ 1 CHCH2CH2N

4 As shown in the flow sheet above, the method of the present invention involves the hydrogenation of an 6 aminopropylidene derivative of a llH-pyrrolo[2,1-b][3]-7 benzazepine to produce the corresponding aminopropylidene 8 derivative of a 6,11-dihydro-5H-pyrrolo[2,1-b][3]benza-g zepine.

In accordance with the present invention, a 11 variety of hydrogenation catalysts may be used, including 12 Raney nickel, palladium on carbon, and platinum dioxide, 13 to illustrate a few.
14 The starting material is preferably reacted with one mole of hydrogen in a suitable solvent, such as eth2nol.
16 After the requisite amount of hydrogen is absorbed by the 17 unsaturated starting material, the reaction is stopped 18 and the reaction mixture is filtered to remove the catalyst.
19 The resulting solution then is acidified and concentrated to dryness under vacu~m to yield a solid residue which is 21 the crude product. Upon recrystallization from a suitable 22 solvent, there is obtained the desired dihydro product as 23 its acid salt.

. , ~IL09X:105 1 It will be evident to those skilled in the art 2 that, if X and/or Y in the starting llH-pyrrolo[2,1-b~3~-3 benzazepine is an easily reduceable group, it will be re 4 placed by a hydrogen atom if the hydrogenation is allowed to proceed beyond the absorption of one equivalent of 6 hydrogen.

8 6,11-Dihydro~ (3-dimethylaminopropylidene)-5H-pyrrolo-9 [2,1-b][3]benzazepine hydrochloride A solution of 11-(3 dimethylaminopropylidene)-11 llH-pyrrolo[2,1-b][3]benzazepine (42 g.) in 105 ml. of 12 ethanol is hydrogenated o~er Raney nic~el (1.5 g.) at 13 6S under an initial hydrogen pressure of 450 lbs. After 14 1 mole of hydrogen is absorbed (3.5 hours), the reaction mixture is filtered to remove the catalyst and is acidi-16 fied with 80 mlO of 2.5 N hydrochloric acid (0.2 mole).
17 The acidic solution is concentrated to dryness under 18 vacuum and is flushed three times with 100 ml. of benzene 19 to remove residual water. The solid residue then is dried under vacuum at 40 to yield the crude product.
21 Recrystallization from isopropyl alcohol and ether affords 22 the pure 6,11-dihydro~ (3-dimethylaminopropylidene)-23 5H-pyrrolo~2,1-b~[3]benzazepine hydrochloride.

25 Rl R2 (Y~)m (X~)n 26 CH3 CH3 H 2-SO2N(CH3)~

28 C~I3 CH3 H 2-Cl 29 CH3 CH3 H 2-CON(CH3)2 l TABLE J (Continued) 2 Rl R2 (Y~)m (X~)n .

4 CH3 CH3 H 2-CCH(CH3)2 O
6 CH3 CH3 H 2-C(CH2)3CH3 9 CH3 CH3 ~ 2-CF3 12 CH3 CH3 H 3-CO(CH2)CH3 13 CH3 CH3 H 3-COCH(CH3)2 16 CH3 CH3 9-N(CH3)2 19 CH3 CH3 9-SO2CH(CH3)2 H
20 CH3 CH3 9-Cl H
21 -(C~2)4 - H H
22 -(CH2)5 - H 2-CO(CH2)3CH3

Claims (14)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of formula:
or pharmaceutically acceptable salt thereof, wherein the dotted line represents saturation or unsaturation;
n is 3, 2, 1, or 0 (X is hydrogen);
m is 4, 3, 1, or 0 (Y is hydrogen);
X and Y are independently selected from hydrogen, halo, lower alkanoyl, perhalo-lower alkyl, cyano, perhalo-lower alkylthio, N,N-di(lower alkyl)carbamoyl, di(lower alkyl)-sulfamoyl; and R1 and R2 are independently selected from hydrogen, lower alkyl, which comprises dehydrating a compound of the formula:
wherein X, Y, m and n are as defined above but excluding formyl, and R1 and R2 are as defined above excluding hydrogen;
followed or preceded, if desired, when X and/or Y is -CN by treatment with nickel-aluminum alloy in formic acid to yield the compound where X and/or Y is CHO; followed, if desired, wherein at least one of R1 and R2 is lower alkyl by dealkyl-ation to produce the compound wherein one of R1 or R2 is hydrogen, and if desired separating the cis-trans mixture thus obtained into its respective isomers.

2. A process for the preparation of a compound of the formula:
wherein X and Y are independently hydrogen and halogen, R1 and R2 are independently hydrogen or lower alkyl and the dotted line represents saturation or unsaturation, which comprises dehydrating a compound of the formula:

3. A process for the preparation of a compound of the formula:
wherein X and Y are independently hydrogen and halogen, R1 and R2 are each lower alkyl, which comprises dehydrating a compound of the formula:

wherein X, Y, R1 and R2 are as defined above.

4. The process of Claim 3, wherein X and Y are independently hydrogen and chloro and R1 and R2 are each lower alkyl.

5. The process of Claim 4, wherein X is chloro and Y is hydrogen and R1 and R2 are each lower alkyl.

6. The process of Claim 3, wherein X is hydrogen and Y is chloro and R1 and R2 are each methyl.

7. The process of Claim 3, wherein X is chloro and Y is hydrogen and R1 and R2 are each methyl.

8. A compound of the formula:

wherein X and Y are independently selected from hydrogen, halogen, lower alkanoyl, perhalo-lower alkyl, cyano, perhalo-lower alkylthio, N,N-di(lower alkyl)carbamoyl; R1 and R2 are independently hydrogen or lower alkyl, n is 3, 2, 1 or 0 when X is hydrogen and m is 4, 3, 1 or 0 when Y is hydrogen and the dotted line represents saturation or unsaturation, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

9. A compound of the formula:

wherein X and Y are independently hydrogen and halogen and and R2 are each lower alkyl and the dotted line represents saturation or unsaturation, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.

10. A compound of the formula:

where X and Y are independently hydrogen and halogen and and R2 are each lower alkyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

11. The product of Claim 9, wherein X and Y are independently hydrogen and chloro and R1 and R2 are each lower alkyl, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

12. The product of Claim 9, wherein X is chloro and Y is hydrogen and R1 and R2 are each lower alkyl, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

13. The product of Claim 9, wherein X is hydrogen and Y is chloro and R1 and R2 are each methyl, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

14. The product of Claim 9, wherein X is chloro and Y is hydrogen and R1 and R2 are each methyl, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.