HEXAHYDROPYRROLO (2,1-A) ISOQUINOLINE DERIVATIVES

Abstract: Novel compounds are disclosed, which are derivatives of 1, 2, 3, 5, 6, 10b-hexahydropyrrolo [2, 1-a]- isoquinolines, represented by general formula (I): as well as pharmaceutical compositions and methods for the treatment of depression in warm-blooded animals, e.g., man. Novel intermediates are also part of the invention.

Description: Hexahydropyrrolo2,1-alisoquinoline Derivatives This invention relates to novel chemical compounds, which are derivatives of 1,2,3,5,6,10b-hexahydropyrroloC2,1-al- isoquinolines, and nontoxic, pharnaceutically-acceptable salts thereof. It also relates to novel synthetic intermediates and processes leading to said compounds. Conpounds and pharmaceutically-acceptable acid addition salts thereof, of the invention are of free base form of the general formula (I): EMI1.1 wherein R1 is hydrogen or lower alkyl having one to four carbons; R2 is hydrogen, lower alkyl having one to four carbons, fluoro, hydroxy, or lower alkoxy having one to four carbons; R3 is hydrogen, methyl or phenyl; R4 and R5 are the same and both are hydrogen, or different and each is selected from the group of hydrogen or lower alkyl having one to four carbons; R6 and R7 are the same or different and each is selected from the group hydrogen, lower alkyl having one to four carbons, lower alkoxy having one to four carbons, hydroxy, or halogen, or else are taken together as luethyleneflioxy; ; and A is selected from the group of units of the following formulas (1), (2), or (3), EMI2.1 wherein in the benzene unit of formula (1), R8 and R3 are selected from the group hydrogen, lower alkyl having one to six carbons, perfluoro(lower)alkyl having one to four carbons, hydroxy, lower alkoxy having one to four carbons, carb(lower)alkoxy having one to five carbons, lower acylamino (one to five carbons), benzoylamino(C6H5CONH-), cyano, carboxamido(H2NCO-), lower acyl of one to five carbons, lower alkylthio having one to four carbons, lower alkylsulfonyl having one to four carbons, nitro, anino, loweralkyl- or di(lower)alkyl-amino having one to four carbons in each alkyl, or halogen; wherein in the heteroaromatic unit of formula (2), X is oxygen or sulfur, and wherein in the cycloalkyl unit of formula (3), n = 0, 1 or 2. Formulas (1), (2) and (3) may be attached at any carbon atom vertex thereof. As used herein, the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "lower alkylsulfonyl", and "perfluoro (lower)alkyl" refer to straight- or branched-chain 'carbon skeletons, within the carbon-atom limits defined. The term halo (or halogen) is generic for fluorine, chlorine, bromine, and iodine. Each formula (I) compound describes and comprises diastereomeric substances, themselves pairs of enantiomers. The diastereomers, isolated in their pure form, may differ in biological activity. The compounds of formula (I) constitute valuable therapeutic agents by their possession of psychotropic activity, particularly antidepressant activity. The various diastereomers of each formula (I) compound are distinguished herein using the nomenclature reconmended by Chemical Abstracts for representing the relative configuration of diastereoners of fused-ring compounds (a/B nomenclature). This requires that the stereocenter corresponding to the lowest numbered atom in the ring system (numbered according to convention) be designated a and that the remaining stereocenters be labeled a or ss relative to the first-assigned center. For example: EMI3.1 The new compounds of the present invention can be prepared by various nethodologies, known to those skilled in the art of organic chemistry. Some examples of important synthetic routes are illustrated below; these are exemplary methods and should not be taken as exhaustive. For the sake of simplicity, the routes are depicted without substituents on the aliphatic chains or aronatic rings, but this should not be construed to limit necessarily tl-te scope of the synthetic process. The R1, R2, R3, R4 R5, R6 and R7 groups of formula (I) are depicted in the following routes as a specific moieties, e.g., hydrogen or methyl, for the purpose of specific exemplification. However the other R1 - R7 possible moieties may be used in their place by choice of a different starting material. For example, substitution of di-(para-tolyl)ethylamine for diphenylethylanine as (II) in Route (A) will result in formula (I) with R6 as 9methyl and A as para-tolyl. (A) Keto-Acid, Acyliminium-Ion Route: EMI4.1 (B) Imide, Acyiminium-fon Route: EMI4.2 (C) Mandelic-Acid Route: EMI5.1 (D) Styrene-Oxide Route: EMI5.2 (E) Butyrolactone Route: EMI6.1 The keto-acid route (A) entails condensation of an arylethylamine, such as II, with (a) a-angelicalactone (or congeners thereof) in an inert solvent, such as ithylene chloride or ethyl acetate, around ambient temperature, or (b) the mixed carbonic anhydride of levulinic acid (or congeners thereof) in an inert solvent, such as tetrahydrofuran, ethyl ether or toluene, around OOC, or (c) a simple ester of levulinic acid (or congeners thereof) without solvent at elevated temperatures around 175-225iC. The adduct (not shown) is then cyclized with an acid catalyst to a lactam internediate, such as III. The acid catalyst must be strong when cyclization is to take place on an aromatic ring not bearing a good electron-donating substituent (e.g., methoxy) ortho or para to the site of. ring closure: e.g., polyphosphoric acid, liquid hydrogen fluoride, pyridinium polyhydrogen fluoride, or trifluoromethanesulfonic acid. When an electron-donating group is present in a proper orientation, cyclization can be effected with weaker acid catalysts, e,g., ethanolic hydrogen chloride or trifluoroacetic acid, and cyclization will preferentially occur on the ring having the greater activation in a competitive situation. The final product, such as IV, is then obtained by reduction of the anide functionality, employing aluminum or boron hydrides, e.g., lithium aluminum hydride or borane-tetrahydrofuran. The imide route (B) is analogous to the keto-acid route, but yields 10b-unsubstituted derivatives. This route involves reaction of an arylethylamine, such as II, with succinic anhydride V (or congeners thereof) in an inert solvent such as methylene chloride, ethyl acetate, or tetrahydrofuran, around anbient temperature. The amideacid interpediate (not shown) is converted to a succinimide, such as VI, by heating without solvent at 150-200 C, or by addition of acetylchloride to the original mixture and heating at 4070b C. The succininide is then reduced with sodium borohydride in ethanol, as described by speckamp (J. C. Hubert, et al., Tetrahedron, 31, 1437 (1975)), or by diisobutylaluminum hydride, as described by Hart(D. J. Bart and K. Kanai, J. Org. Chem., 47, 1555 (1982)). One may employ either a hydroxy or ethoxy species, such as VII or VIII, in an acid-catalyzed cyclization as described above for the keto-acid route, affording a lactam such as IX. The lactam is then reduced to a target amine, such as X, as described above for t'ne keto-acid routed The mandelic-acid route (C) entails thermal condensation (140-170 C) of a 2-arylpyrrolidine, such as XI, with a mandelic acid, such as XII, with continuous removal of water, to give a mandelamide, such as XIII. The nandelamide is cyclized to a lactam, such as XIV, wit'n a strong acid catalyst, e.g., polyphosphoric acid, sulfuric acid, or liquid, hydrogen fluoride. The lactam is reduced preferably with a Lewis acid-type hydride reagent such as with borane-tetrahydrofuran to yield a target anine such as X. The styrene-oxide route (D) involves condensation of a 2 arylpyrrolidine, such as XI, with a styrene oxide, such as XVI, in refluxing ethanol or in sulfolane at 140-170iC, to give an amino alcohol, such as XVII. The amino alcohol is cyclized by heating with an acid catalyst, e.g., polyphosphoric acid, 48% hydrobromic acid, or sulfuric acid, to furnish a product amine, such as X. The butyrolactone route (E) is based on reaction of an arylethylamine, such as II, with butyrolactone (or congeners thereof), without solvent around 1000C1 to give an amido alcohol, such as XVIII. The anido alcohol can be converted to a key intermediate of the imide route, such as VII, for transformation into target compounds of fornu- la (I), as indicated in route (B), by careful oxidation with chromium trioxide in pyridine. Alternatively, the amido alcohol can be converted to an minium salt, such as XIX, with phosphorus oxychloride in toluene at llO*C, followed by treatment of the toluene-insoluble material with aqueous sodium hydroxide and heating in toluene solution. The iminium salt can be reduced to a target amine, such as X, with NaBH4 or LiAlH4. The minium salt can also be reacted with an organometallic reagent, such as an organolithium or organornagnesium (Grignard) compound to afford 10b-substituted target anines of formula (I). For example, a Grignard reaction with methyl magnesium bromide, in ether or tetrahydrofuran, leads to a lObmethyl compound of formula (I), such as IV. The cyclization reactions in routes (A)-(E) afford mixtures of diastereomers. In certain instances, product mixtures may be highly enriched in specific diastereomers. The diastereomers may be separated and purified by standard techniques known to those skilled in the art of organic chemistry, such as fractional crystallization or liquid chromatography of free bases, or fractional crystallization of acid-addition salts. Diastereomers may be interconverted by base-induced exchange of protons at the 6 and/or 10b positions. specifically, heating of lactan diastereomers related to formula (X) compounds possessing 6 andjor 10b protons in aqueous-dimetylsulfoxide around 100-1500C in the presence of an alkali metal carbonate, such as K2CO3, for 1-1000 hours can give rise to equilibriummixtures of diastereomars. Also, heating of anine diastereomers of formula (I) possessing 6 andlor 10b protons in aqueous dimethyl- sulfoxide around 80-150 C in the presence of an alkali netal hydroxide such as NaOH, for 1-60 hours, can give rise to equilibrium mixtures of diastereomers. Such equilibration tactics can enhance the proportions of minor diastereomers in comparison to the original product mixtures from cyclization. In appropriate instances, the equilibration method can alter relative configuration between the 6 stereocenter in relation to the 2, 5, and 10b stereocenters for compounds of general formula (I) bearing a 6-posîtion proton, between the 10b stereocenter and the 2, 5, and 6 stereocenters for compounds of formula (I) bearing a 10b-position proton, but not between the 2 and 5 stereocenters in compounds of formula (I). Another means of changing the original diastereomeric composition of formula (I) compounds bearing a lObposition proton involves oxidation with mercuric acetate, followed by direct reduction of the intermediate minium salt, such as XVIII, with NaBH4, LiAlH4, or catalytic hydrogenation, see route (E). Also, the iminium salt can be isomerized to an enamine such as XXI and reduced by catalytic hydrogenation over platinun oxide. EMI10.1 The compounds of this invention can be prepared and utilized in the form of the free base. The compounds can also be used as pharmaceutically-acceptable, nontoxic addition salts of inorganic or organic acids such as halogen acids, e.g., HC1, HBr, HI sulfuric acid, naleic acid, hexanic acid, perchloric acid, funaric acid, saccharin, and the like. Compounds of formula (I) wherein A is hydroxyphenyl were generally prepared from the corresponding nethoxy derivatives by standard demethylation using 48% HBr in acetic acid at 100-1300C or BBr3 in methylene chloride at -78 to -20 C. Compounds of formula (I) wherein A is aminophenyl were obtained from nitrophenyl congeners by reduction of the nitro compound with hydrogen in the presence of a catalyst, such as PtO2, in ethanol. From the aminophenyl derivative, the, compound wherein R8 or Rs is loweracylamino or benzoylamino may be prepared by reaction with the desied alkanoyl chloride or benzoyl chloride, respective 'ly as described in the Examples. The acylamino derivative may be reduced with ,;BH3 to yield a compound wherein R8 or is is alkylamino, e.g., by reducing the compound wherein A is acetylamino (CH3CONH-) substituted phenyl to one wherein A is ethylaminophenyl. The compounds of the invention wherein A is phenyl substituted by cyano may be obtained by reaction of, the corresponding bromo compound with cuprous cyanide with tetrakistriphenyl-phosphine palladiun and from such a cyano product, the corresponding carboxamide, e.g., R8 = -CONH2 may be obtained by reaction with a strong base such as potassium hydroxide. When R4 and/or R5, of formula (I) are alkyl, the corresponding hydrogen substituted compoufnds may be prepared and then alkylated by reaction with lithium diisopropylamide in tetrahydrofuran with the appropriate alkyl iodide. The formula (I) compounds are endowed with useful biological activity in the central nervous system. More particularly, the formula (I) compounds exhibit antidepressant activity in warm-blooded animals. In the group of formula (I) compounds, useful antidepressant activity may be associated with particular diastereomers. EMI11.1 The utility of the novel compounds of this patent is based on a standard test for antidepressant agents involving antagonism of the depressant effects of tetrabenazine (TBZ). This is the "classical" tetrabenazine antagonism assay described in U.S. Patent No. 3,787,577. In this test, mice are injected with a test compound 30 minutes prior to the injection of 32 mg/kg i.p. of TBZ, a drug which decreases normal exploratory activity and induces ptosis. After 30 minutes, the mice are tested for two parameters: the presence of normal exploratory activity (EA) and reversal of ptosis (Pt). A control group of mice is given only 32 mg/kg i.p. of TBZ. The biological activity of the novel compounds of this invention may be understood by some representative, nonlimiting examples, presented in Tables I and II. Table I lists the compounds tested by a compound number, structural formula, HX or acid addition salt form in which the compound was tested, test data, and internal' code number (McN'No.). Table II names the various Table Ì compounds'. TABLE 1++ EMI13.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> IVb <SEP> # <SEP> hexamic <SEP> acid <SEP> 9.2/3.8 <SEP> 4803 <tb> <SEP> (136-38; <SEP> P/EE) <tb> Xb <SEP> # <SEP> fumaric <SEP> acid <SEP> 0.34/0.07 <SEP> 4612-Z <tb> <SEP> (170-72; <SEP> E) <tb> XXIV <SEP> # <SEP> fumaric <SEP> acid <SEP> CA. <SEP> 40/8.7 <SEP> 5531 <tb> <SEP> (199-205 <SEP> d; <SEP> E/W) <tb> XXV <SEP> # <SEP> HBr <SEP> 27/0.7 <SEP> 4985 <tb> <SEP> (261-65; <SEP> M/P) <tb> XXVI <SEP> # <SEP> HBr <SEP> 0.87/0.33 <SEP> 5175 <tb> <SEP> (255-57; <SEP> M) <tb> EMI14.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> XXVII <SEP> # <SEP> fumaric <SEP> acid <SEP> 17/7.2 <SEP> 5199 <tb> <SEP> (129-32; <SEP> M/P) <tb> XXVIII <SEP> # <SEP> HBr <SEP> 6.4/1.9 <SEP> 5254 <tb> <SEP> (169-72; <SEP> M/EA) <tb> XXIX <SEP> # <SEP> HBr <SEP> 0.27/0.13 <SEP> 5292 <tb> <SEP> (290-93; <SEP> M) <tb> XXX <SEP> # <SEP> fumaric <SEP> acid <SEP> 8.1/5.4 <SEP> 5321 <tb> <SEP> (179-81; <SEP> M/P) <tb> XXXI <SEP> # <SEP> HBr <SEP> ca.60/3.0 <SEP> 5344 <tb> <SEP> (202-204; <SEP> M/P) <tb> EMI15.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> XXXII <SEP> # <SEP> HClO4 <SEP> 37/4.0 <SEP> 4914 <tb> <SEP> (244-24 <SEP> d: <SEP> M) <tb> XXXIII <SEP> # <SEP> HBr <SEP> 7.0/0.19 <SEP> 5346 <tb> <SEP> 9241-44; <SEP> M/P) <tb> XXXIV <SEP> # <SEP> fumaric <SEP> acid <SEP> 8.4/1.6 <SEP> 5335 <tb> <SEP> (178-81; <SEP> E) <tb> XXXV <SEP> # <SEP> HBr <SEP> 1.4/0.13 <SEP> 5376 <tb> <SEP> (244-48 <SEP> d: <SEP> B) <tb> XXXVI <SEP> # <SEP> HBr <SEP> ca.14/10 <SEP> 5394 <tb> <SEP> (257-60: <SEP> M/P) <tb> EMI16.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> XXXVII <SEP> # <SEP> HBr <SEP> 30/1.8 <SEP> 5416 <tb> <SEP> (246-48 <SEP> d: <SEP> M/B) <tb> XXXVIII <SEP> # <SEP> HBr <SEP> 0.51/0.15 <SEP> 5462 <tb> <SEP> (227-29 <SEP> d: <SEP> E/W) <tb> XXXIX <SEP> # <SEP> HBr <SEP> ca. <SEP> 40/8 <SEP> 5480 <tb> <SEP> (209-12: <SEP> E/W) <tb> XL <SEP> # <SEP> fumaric <SEP> acid <SEP> ca. <SEP> 0.17/ <SEP> 5494 <tb> <SEP> ca. <SEP> 0.07 <SEP> (185-91: <SEP> P) <tb> XLI <SEP> # <SEP> HBr <SEP> > 10/0.11 <SEP> 5497 <tb> <SEP> (244-46: <SEP> P) <tb> EMI17.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> XLII <SEP> # <SEP> tosic <SEP> acid <SEP> 100/37 <SEP> 4721 <tb> <SEP> (182-184; <SEP> M/EE) <tb> XLIII <SEP> # <SEP> HBr <SEP> 33/5.0 <SEP> 5386 <tb> <SEP> (211-12; <SEP> M/P) <tb> XLIV <SEP> # <SEP> HBr <SEP> 37% <SEP> &commat;30/ <SEP> 5498 <tb> <SEP> 3.1 <SEP> (252-53; <SEP> E/EE) <tb> XLV <SEP> # <SEP> HBr <SEP> 33% <SEP> &commat;30/ <SEP> 5426 <tb> <SEP> 0.14 <SEP> (235-37 <SEP> d; <SEP> A) <tb> XLVI <SEP> # <SEP> HBr <SEP> 22.5/16 <SEP> 4981 <tb> <SEP> (219-26: <SEP> M/P/EE) <tb> EMI18.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> XLVII <SEP> # <SEP> None <SEP> 2.8/ca. <SEP> 6.5 <SEP> 5605 <tb> <SEP> (151-52: <SEP> E) <tb> XLVIII <SEP> # <SEP> HBr <SEP> 1.4/0.41 <SEP> 5556 <tb> <SEP> (220-245 <SEP> d: <SEP> M/P) <tb> XLIX <SEP> # <SEP> HCl <SEP> 1.2/0.43 <SEP> 5558 <tb> <SEP> (180-83 <SEP> d: <SEP> D/S) <tb> L <SEP> # <SEP> HBr <SEP> 6.1/5.6 <SEP> 5687 <tb> <SEP> (244-46: <SEP> P) <tb> EMI19.1 No. <SEP> Compound <SEP> HX <SEP> TBZ <SEP> ED50* <SEP> McN <SEP> No. <tb> <SEP> EA/Pt <SEP> (i.p.) <SEP> (m.p. <SEP> ; <SEP> solv.)+ <tb> LI <SEP> # <SEP> HBr <SEP> 37% <SEP> &commat; <SEP> 60/ <SEP> 5707 <tb> <SEP> 0.20 <SEP> (213-220; <SEP> N/P) <tb> LII <SEP> # <SEP> HBr <SEP> Ca. <SEP> 30/32 <SEP> 5250 <tb> <SEP> (230-2325: <SEP> E) <tb> LIII <SEP> # <SEP> HClr <SEP> 60% <SEP> &commat; <SEP> 40.12 <SEP> 5603 <tb> <SEP> (192-193: <SEP> P) <tb> *ED50 given in mg/kg for each parameter (except for percent inhibition at a certain dose in mg/kg, given for four examples: XLIV, XLV, LI and LIII). +m.p. of the acid-solution salt in C (d = decomposition); recrystallization solvent (E = absolute ethanol; M = methanol, P = 2-propanol; EE = ethyl ether: EA = ethyl acetate; B = t-butanol; W = water; A = acetonitrile; Ac = acetone; D = dichloromethane ; T = tetrahydrofuran). ++Structure assignments are based mainly on 1H NMH spectral data. X-ray crystallographic analyses were performed on XXV, XLVI, the lactam precursor to XXVIII, and the lactam precursor to Xa (i.e., IXa) to establish stereochemistry for the entire series. TABLE II No. McN Name of compound No. IVb 4803 L6a,lOb]-1,2,3,5,6,1Ob-Hexa- hydro-lOb-methyl-6-phenylpyrrolo E2, 1-a)isoquinoline Xb 4612-Z [6&alpha;,10bss]-1,2,3,5,6,10b-Hexa- hydro-6-phenyl-pyrrolo[2,1 a]isoquinoline XXIV 5531 6&alpha;-(3,4-Dichloropophenyl)- 1,2,3,5,6,10b&alpha;-hexahydro- pyrrolo[2,1-a]isoquinoline XXV 4985 1,2,3,5,6,10bss-Hexahydro-6 methyl-6&alpha;-phenylpyrrolo[2,1- a]isoquinoline XXVI 5175 [6&alpha; 10bss]-1,2,3,5,6,10b-Hexa- hydro-8,9-dihydroxy-6-phenyl pyrrolo[2,1-a]isoquinoline XXVII 5199 [6&alpha;10bss]-1,2,3,5,6,10b-Hexa- hydro-8,9-dimethoxy-6-phenyl pyrrolol: 2,1-a3isoquinoline XXVIII 5254 [6&alpha;10b&alpha;]-6-Cyclohexy- 1,2,3,5,6,10b-hexahydropyrrolo- [2,1-alisoquinoline XXIX 5292 [6&alpha;10bss]-6-(4-Chlorophenyl)- 1,2,3,5,6,10b-hexahydropyrrolo- [2,1-&alpha;]isoquinoline TABLE II (cont.) No. McN Name of compound No. XXX 5321 6a-(4-Cblorophenyl)- 1,2,3,5,610&alpha;-bexahydropyrrolo {2,1-a3isoquinoline XXXI 5344 1,2,3,5,6,10b&alpha;-Hexahydro-6&alpha;-(4- methoxyphenyl)pyrroloC2,1- a) isoquinoline XXXII 4914 6a,10bS1-9-Chloro-6-(4-chloro- phenyl)-1,2,3,5,6,10b-hexahydro pyrrolo[2,1-a]isoquinoline XXXIII 5346 1,2,3,4,5,6,10bss-Hexahydro-5&alpha;-(4- methoxyphenyl)pyrrolo[2,1] a)isoquinoline XXXIV 5335 1,2,3,5,6,10b-Hexahydro-6-phenyl pyrrolo[2,1-a]isoquinolin-6-ol XXXV 5375 4-(1,2,3,5,6,10bss-Hexahydro pyrroloC2,1-alisaquinolin-ba- yl)benzene-1,2-diol XXXVI 5397 4-(1,2,3,5,6,10ba-Hexahydro pyrrolo[2,1-a]isoquinolin-6&alpha; ;- yl)phenol XXXVII 5416 4-(1,2,3,5,6,10ba-Hexahydro- pyrrolo[2,1-a]isoquinolin-6&alpha;-yl)- 1,2-benzenediol TABLE II (cont.) No. McN Name of compound No. XXXVIII 5462 1,2,3,5,6,10bss-Hexahydro-6&alpha;-(4- nitrophenyl)-pyrroloE2, 1- azisoquinoline XXXIX 5480 1,2,3,5,6,10b&alpha;-Hexahydro-9- methoxy-6&alpha;-phenylpyrrolo[2,1 azisoquinoline XL 5494 1,2,3,5,6,10bss-Hexahydro-6&alpha;-[3- methoxyphenyl)pyrroloL2,1- a)isoquinoline XLI 5497 3-(1,2,3,5,6,10bss-Hexahydro pyrrolo[2,1-a]isoquinolin-6&alpha;- yl)phenol XLII 4721 [6&alpha;,10b&alpha;]-9-Chloro-6-(4-chloro- phenyl)-1,2,3,5,6,10b-hexahydro pyrrolo[2,1-a]isoquinoline XLIII 5386 1,2,3,5,6,10b-Hexahydro-6-phenyl pyrroloC2,1-a]isoquinolin-6-ol XLIV 5498 3-(1,2,3,5,6,10b&alpha; ;-Hexahydro- pyrrolo[2,1-a]isoquinolin-6&alpha;- yl)phenol XLV 5426 1,2,3,5,6,10bss-Hexahydro-6&alpha;-(3,4- dimethoxyphenyl)pyrrolo[2,1 a)isoquinoline TABLE II (cont.) No. McN Name of compound No. XLVI 4981 1,2,3,5,6,10b&alpha;-Hexahydr-6- methyl-6&alpha;-phenylpyrolo[2,1 a)isoquinoline XLVII 5605 1,2,3,5,6,10bss-Hexahydro-7 methoxy-6&alpha;-phenylpyrrolo[2,1 a) isoquinoline XLVIII 5556 4-(1,2,3,5,6,10b&alpha;-Hexahydro- pyrrolo[2,1-a]isoquinoline-6&alpha;- yl)benzenemine XLIX 5558 1,2,3,5,6,10bss-Hexahydro-6&alpha; [(3 trifluoromethyl)phenyl] pyrrolo[2,1-a]isoquinoline L 5687 9-Fluoro-6 a - (4- fluorophenyl) - 1,2,3,5,6,10b-hexahydro-10bss methylpyrolo[2,1-a]isoquinoline LI 5707 [6&alpha;,10bss]-6-(2-chlorophenyl)- 1,2,3,5,6,10b-hexahydropyrrolo- [2,1-&alpha;]isoquinoline LII 5250 1,2,3,5,6,10b&alpha; ;-Hexahydro-5&alpha; phenylpyrolo[2,1-a]isoquinoline LIII 5603 6&alpha;-Fluoro-1,2,3,5,6,10b&alpha;-hexahy dro-6-phenylpyrrolo[2,1-a]iso quinoline Other specific compounds which may be produced include the following: LIV 1,2,3,5,6,10b&alpha;-hexahydro-5&alpha;-(4-nitrophenyl)-pyrrolo [2,1-a]isoquinoline; LV [6&alpha;,10bss]-6-(4-bromophenyl)-1,2,3,5,6,10b-hexahydro pyrroloL2, l-a)isoguinoline; and LVI 1,2,3,5,6,10bss-hexahydro-6&alpha;-(4-methylthiophenyl)- pyrroloE2, l-a)isoquinoline. The compound designated LVI was produced through Route (C) and isolated by crystallization in methanol/ethanol as the perchlorate, mp = 202-203.5 C. Preferred compounds of the invention include those designated XLIX, LI and LVI. In general, the lObss compounds show greater activity than the corresponding 10ba compounds. The invention will be further understood by referring to the following examples, which illustrate the preparation of compounds according to the invention. These examples are given for the purpose of illustration and are not to be construed as limiting the invention in spirit or scope. The following formulae (4), (5) and (6) are described hereinafter in Examples 1 and 2. EMI25.1 Example 1 - INTERMEDIATE LACTAMS The following procedures for the (A) route refer to the subroutes (a), (b) and (c) shown above. General Procedure A/(a). The enelactone (0.11 mol) shown in the scheme, e.g., a-angelica-lactone, in 30 ml of methylene chloride is combined with the arylethylanine, e.g., diphenylethylamine as shown in Route (A), above, (0.10 mol) in 30 ml of methylene chloride and let stand for 30 minutes. The solution is evaporated in vacuo to an oil, which is combined with PPA (200 g) and heated on a steam bath for four hours. The reaction mixture is poured into water and extracted with methylene chloride. The organic phase is washed once with water, once with saturated NaCl, and dried (MgS04). Evaporation in vacuo gives the lactam. Example A( a). A(a). 1,5,6,l0b-Tetrahydro-I0ba-methyl-6R- phenylpyrrolo[2,1-a]isoquinoline-3(2H)-one (IIIa). 2,2 Diphenylethylamine (6.0 g, 0.03 mol) and a-angelicalactone (3.24 g, 0.033 mol) were combined according to the general procedure. Work-up gave a mixture (94/6, GLC) of diastereoneric lactams IIIa and IIIb. Recrystallization from ethyl acetate/petroleum ether gave white crystalline IIIa, m.p. 135-136'C. General Procedure A/(b). Ketoacid (0.10 mol) and dry triethylamine (10.2 g, 0.10 mol) are combined in 50 ml of methylene chloride and cooled to OOC. Ethyl chioroformate (11.3 g, 0.10 mol) in 25 ml of methylene chloride is added slowly at O" to 50C, stirred at 0 C for two hours and then at 10 C for one hour. 2-Arylethylamine (0.10 mol) in 50 ml of methylene chloride is added to the mixture at 50C and the solution is stirred overnight at ambient temperature. Water (50 ml) is added and the reaction is stirred for two hours. The organic phase is separated and washed once with 5% HC1, once with 5% Na2C03, and dried (Na2SO4) The solution is filtered and evaporated in vacuo to give the crude keto amide. To this crude material is added PPA (ca. 100 g) and the mixture is stirred on a steam bath for 20 hours. The mixture is poured into water and extracted with chloroforn. The organic layer is washed once with H20, once with 5% Na2CO3, and dried (CaCl2). Evaporation in vacuo gives crude lactam. Example A/(b). 1.5.6.10b-Tetrahydro-10b&alpha;-methyl-6&alpha;- phenylpyrrolo[2,1-a]isoquinoline-3(2H)-one (IIIa). Following the above procedure, levulinic acid (11.8 g, 0.10 mol) was reacted with 2,2-diphenylethylamine -(19.7 , 0.10 mol) to give a mixture (16/1, GLC) of crude lactams IIIa and IIIb. The mixture was recrystallized from ethyl acetate/hexane to afford white crystalline IIIa, m.p. 177.5-1795C General Procedure A/(c). The keto ester (0.10 mol) and arylethylanine (0.10 nol) are combined and heated at 1300C to 180 C for 24 hours. The oil is placed under vacuum to remove any residual water or ethanol. This residue is combined with PPA (200 ml) and heated on a steam bath for 24 hours. Water (750 ml) is added and solid lactam is filtered or extracted. Example A/(c). 1,5,6,10b-Tetrahydro-10b&alpha;-methyl-6&alpha;- phenylpyrrolo[2,1-a]isoquinoline-3(2H)-one (IIIa). 2,2 Diphenylethylamine (19.7 g, 0.1 mol) and ethyl levelunate (14.6 g, 0.10 mol) was reacted according to the general procedure to give the lactams mixture lIIa and IIIb (ca. 15/1). General Procedure B. The arylethylamine (0.10 mol) in 100 ml of dry TF is added slowly to succinic anhydride (0.105 mol) in 100 ml of dry THF at OOC. (Methylene chloride was also used). The reaction is stirred at ambient temperature for one hour and then evaporated in vacuo to the amide-acid. Cyclization of the amide-acid to the anide is accomplished by either (a) heating it without solvent at 170"C for four hours or (b) combining it with 25 ml of acetyl chloride (AcCl) in 100 ml of ethyl acetate and heating the solution at reflux for ten hours. The imide may be recrystallized before use. The resulting imide is mixed with 400 ml of absolute ethanol, cooled to -10"C with an ice/nethanol bath, and stirred efficiently. NaBH4 (0.40 mol) is added followed by 15 drops of CH3S03H. The temperature is maintained at -100C to 0 C with efficient stirring, and five drops of 2 N ethanolic CH3S03H are added every 15 minutes. After five hours, the 2 N CH3SO3H is added more rapidly maintaining the temperature at oeC until the pH is less than three. During this addition, 200 ml of ethanol is added to thin out the foamy reaction solution. The reaction is then stirred for 16 hours at ambient temperature. The reaction is treated with water and methylene chloride. The organic solution is separated, washed once with water, once with saturated NaCl, and dried (MgSo4). Evaporation in vacuo gives the ethoxypyrrolidinone. This ester is combined with PPA (100 ml) and heated on a steam bath for six hours (refluxing ethanolic HC1 may be used instead of PPA when cyclizing onto electron rich aromatic groups). The reaction is poured into water and extracted with nethylene chloride. The organic layer is separated, and washed once with. water, once with saturated NaCl, dried (MgSo4), and evaporated in vacuo to give the crude lactam. Example B1. 1,5,6,10b&alpha;-Tetrahydro-6&alpha;-phenylpyrrolo-[2,1- azisoquinoline-3(2H)-one (IXa). Following tti.e general procedure, 2,2-diphenylethylanine (19.7 g, 0.10 mol) an-3 succinic anhydride (10.6 g, 0.105 mol, 998 assay) were combined and heated at 1750C to give the inide. After reduction and cyclization with PP, work-up gave white solid lactams IXa and IXb (93/7, GLC). Recrystallization from ethyl acetate/methanol furnished white crystalline IXa, m.p. 204.5-205. C, Example B2. 1,5,6,10b&alpha;-tetrahydrl-8,9-dimethoxy-6&alpha;- phenylpyrrolo[2,1-a]-isoquinoline-3(2H)-one (4a). According to the general procedure, 2-(3,4-dimethoxyphenyl)-2- phenethylamine (35 g, 0.1 mol) and succinic anhydride (14.3 g, 0.143 nol) were combined and heated at 1750C. The crude imide was recrystallized from methanol to give purified imide. Imide material (15.0 g, 0.4 mol) was reduced the usual way to give the ethoxypyrrolidinone, which was dissolved in 100 ml of ethanol. Twenty drops of ethereal HC1 was added and the reaction was heated at reflux. Every ten minutes, over the next 30 minutes, 1 ml of ethereal HC1 was added to the reaction solution. The reaction was evaporated in vacuo to give an oily mixture (9/1, GLC) of lactams 4a and 4b. The mixture was recrystallized from ethyl acetate to afford white crystalline lactam 4a, m.p. 140-141 C. General Procedure C. The mandelic acid (0.10 mol) is combined with 2-arylpyrrolidine (0.10 mol) in xylenes (300 ml) and heated at reflux under a Dean-Stark trap for 45 hours. The solution is evaporated in vacuo to an oil, which is combined with PPA (20 g) and heated at 100 C with occasional stirring for one hour. The mixture is poured into ice water (400 ml) and extracted with methylene chloride. The organic layer is washed with saturated NaCl, dried (MgSO4), and evaporated in vacuo to give the crude lactam. Example C. 1,2,3 ,10b-Tetrahydro-6-(4-methoxyphenyl) pyrrolo2,1-a)isoquinoline-5(6H)-one (6). 4-Methoxynan- pelic acid (26 g, 0.133 mol! was reacted with 2-phenylpyrrolidine (21 g, 0.143 nol) to give a brown oil, which ws combined with PPA (300 g) and heated at 1000C. Work up furnished the desired lactams as a nearly 3:2 mixture of diastereomers (6a:6b) which were separated by HPLC. General Procedure D. The styrene oxide (0.10 mol) and 2aryl-pyrrolidine (0.10 mol) are combined in absolute ethanol or tetramethylene sulfone (100 ml) and the solution is refluxed for 2 to 8 hours. For ethanol, the solution is evaporated in vacuo to an oil and, for sulfolane, it is diluted with. a 5-fold volume of water. The oil is partitioned between ether and 1N HC1 (1 liter). The aqueous solution is made alkaline with 50t NaOH and extracted with ether. The ether solution is dried (K2C03) and evaporated in vacuo to an oil, which is combined with polyphosphoric acid (250 g), heated at 1000C forw 30 minutes and poured into 1 liter of crushed ice. The mixture is extracted with CH2C12 (4 x 500 ml portions). The organic layer is washed once with 50t NaOH, 3 tines with water, dried (K2C03), and evaporated in vacuo to give products. Example D. 1,2,3 ,5,6,lOb-Hexahydro-6a-((3-trifluoro- methyl)phenyl]pyrrolo[2,1-a]isoquinoline (XLIX). m-Trifluoromethylstyrene oxide (28.0 g, 80% assay, 0.12 mol) and 2-pllenyl-pyrrolidine (19.9 g, 88% assay, 0.12 mol) were combined in absolute ethanol (120 ml) and treated according to the general procedure to give the crude product mixture (3/1 by GLC). The isomeric amines were separated by preparative HPLC (chloroform/ethyl acetate, 9:1) to give title compound XLIX, which was converted to its HC1 salt. Example 2 - REDUCTION OF LACTAMS Generla Procedure. The intermediate lactamae, e.g., III, IX and XIV, may be reduced to form the con pounds of this invention by careful reduction with borane-THF. The lactam (0.018 mol) is dissolved in THF (40.0 mol) and added slowly to borane-THF (1.0 M, 0.05 mol) at OOC. The solution is heated at reflux for one hour and cooled to OOC. Water (10.0 ml), followed by hydrochloric acid (12.0 M, 15.0 ml), are added (both slowly). The reaction is stirred for two hours at ambient temperature. The THF is distilled off, 50 ml of water is added, and the solution is heated at reflux for 15 minutes. The solution is cooled in an ice bath, made alkaline with 1 N NaOH, and extracted with methylene chloride. The organic phase is washed once with water, once wit'n saturated NaCl, and dried (K2C03). The solution is evaporated in vacuo to give the amine. Example 9-Chloro-6&alpha;-(4-chlorophenyl)-1,2,3,5,6,10-bss- hexahydropyrrolo[2,1-a]isoquinoline (XXXII). Lactam 5b (6.0 g, 0.018 mol) and borane-THF (50.0 ml, 0.05 r:iol) were combined according to the general procedure. Work-up gave crude anine XXXII. The perchlorate salt was prepared from methylene chloride/2-propanol. Recrystallization from methanol afforded pure anine salt, XXXII HC104, m.p. 242-245 C. Example 3 - EQUILIBRATION Equilibration of Lactams. General Procedure. The lactam (0.10 mol) is dissolved in 200 ml of DMSO. Water (20 ml) and K2C03 (100 g) are added. The reaction is heated at reflux (generally using an oil bath at 1300C) until equilibrium is reached. This usually required one to three hours of heating. Reaction progress is nonitored by removing aliquots, quenching them in ice water, extracting with methylene chloride, and analyzing by GLC. The reaction is rapidly cooled with an ice bath and treated with water (500 ml) and methylene chloride (500 ml). The organic layer is separated, washed three times with water, once with saturated NaCl, and dried (MgS04). The solution is evaporated in vacuo to give a mixture of lactams, which is generally separated using liquid chromatography. Example . 1,5,6,10bss-tetrahydro-6&alpha;-phenylpyrolo[2,1- a3isoquinoline-3(2H)-one (IXb). The crude mixture (93/7, GLC) of lactams IXa and IXb (19.5 g, 0.075 mol) was coribined with 150 ml of DMSO, 15 ml of water and K2C03 (7.5 g) according to the general procedure. At equilibrium the reaction was worked up to give a mixture (1/1, GLC) of lactams IXa and IXb (16.0 g, 82%). The lactans were separated using high performance liquid chromatography on a silica gel column. tactaim IXb was recrystallized froia ethyl acetate to give white crystals, m.p. 126-5-132.5 C. Equilibration of Amines. General Procedure. The amine (0.01 mol) is dissolved in 30 ml of DMSO and 30 ml of 10 N NaOH (aqueous) and heated at reflux under N 2. When equilibrium is attained, the reaction is quickly cooled in an ice bath and treated with water (200 ml) and methylene chloride (300 ml). The organic phase is separated, washed three times with water, once with saturated Nail, and dried (K2C03). The solution is evaporated in vacuo to give a mixture of the amines. Example. 9-Chloro-6&alpha;-(4-chlorophenyl)-1,2,3,5,6,10bss- hexahydropyrrolo[2,1-a]isoquinoline (XXXII). Compound XLII (0.50 g, 1.57 mmol) was dissolved in 5.0 ml of DMSO and 5.0 ml of 10 N NaOH and heated at reflux under N2. After one hour the reaction was worked up to give a mixture (2/1, GtC) of amines XLII and XXXII, which were separated by liquid chronatography. The perchlorate salt was obtained as in Example II. Example 4 1,2,3,5,6,10b-Hexahydro-6-phenylpyrrolo [2,1-a] isoquinoline-6-ol (XLIII). A solution of 1,2,3,10b- tetrahydrlo-6-phenylpyrolo[2,1-a]isoquinoline-5(6H)-one (XIV) (25.0 g, 0.095 mol) dissolved in 500 ml of dry THF under an atmosphere of N2 was cooled to 5 C. Sodium hexamethyldisilazide (33.0 g, 0.18 mol) was added and the solution was vigorously stirred as dry 02 was bubbled into the solution for 1.5 hours. The solution was evaporated in vacuo to an oil, which was partitioned between water (1.0 liter) containing sodium sulfite (50 g, 0.40 mol) and methylene chloride. The organic layer was washed one tine with water, once with brine, dried over anyhydrous magnesium sulfate and evaporated in vacuo to give crude hydroxy lactams (26 g, 98%). These hydroxy lactams were separated using high performance liquid chromatography on silica gel columns. The lactan (3.9 g, 0.014 mol) in dry THF (75 ml) was added slowly to 1M BH3.THF (55 ml, 0.055 mol) with ice bath cooling. The solution was refluxed for 1 hour under N2 and then cooled to 50C. Methanol (50 ml) was slowly added and the solution was stirred at ambient temperature for 30 minutes and then evaporated in vacuo to yield an oily product. The hydrobromide salt was prepared in a mixture of methanol and 2-propanol, a white solid, mp 211-212 C. Example 5 6-Fluoro-1,2,3,5,6,10b-hexahydro-6-phenylpyrolo [2,1-a] isoquinoline. A solution of 1,2,3,5,6,10b-Hexahydro-6- hydroxy-6-phenylpyrrolo[2,1-azisoquinolin-5-one (prepared as shown in the hydroxy lactan preparation of Example IV) (39.0 g, 0.14 mol) in dry methylene chloride (100 ml) was added dropwise over a period of 45 minutes to a cold (-78"C.) solution of diethylaminosulfotri-fluoride in dry methylene chloride (70 ml) under N2. After stirring at 70"C. for 10 minutes, the solution was allowed to warm to room temperature over a period oE 1 hour. The solution was cooled to 50C. and water (200 ml) was added slowly. The organic layer was separated and washed one time with water, one time with brine, dried (K2C03) and evaporated in vacuo to give a yellow solid (38 g, 978). The isomeric fluoro amides were separated using high perfornance liquid chromatography on silica gel columns. The fluoro lactam (12.8 g, 0.045 mol) in dry THF (200 ml) was added slowly to 1M BH3-THF (190 ml, 0.19 mol) at 50C. The solution was refluxed for 1 hour and then cooled to 5eC. Methanol (200 ml) was added slowly and stirred at ambient temperature for 2 hours. The solution was heated on a steam bath for 15 minutes and then evaporated in Vacuo to an oil. This oil was partitioned between 1 N hydrochloric acid (500 ml) and ether (200 ml). The aqueous solution was basified with 10t sodium hydroxide solution and extracted with methylene chloride. The organic solution was washed one tine with water, one tine with brine, dried (K2C03) and evaporated in vacuo to yield an oily product (9.3 g, 77%). This was converted to its hydrocliloride salt, a white solid, mp 192-1930C after recrystallization from 2-propanol. For pharmaceutical purposes, the compounds according to the present invention are administered to warm-blooded animals enterally or parenterally as active ingredients in customary dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit (1-500 mg) of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, and the like. The daily hunan dosage range for the treatment of depression is about ln to 2000 mg of a compound of the invention, e.g., 200 to 500 mg, for an average hunan. OF. course, the exact dosage will vary according to the activity of the particular compound chosen and the weight and need of the patient. Such a dosage may be divided into 2-4 administrations per day. The following examples illustrate a few pharnaceutical dosage unit compositions comprising a con. pound of the present invention as an active ingredient and represent suitable nodes for putting the invention into practical use. The parts are parts by weight unless otherwise specified. Example 6 Tablets The tablet composition is compounded from the following ingredients: 1,2,3,5,6,10bss-Hexahydro-6&alpha;- phenylpyrrolo[2,1-a]isoquino line (Xb) Fumarate 100.0 parts Lactose 45.0 parts Corn Starch 45.0 parts Colloidal silicic acid 2.0 parts Soluble starch 5.0 parts Magnesium stearate 3.0 parts TOTAL 200.0 parts The active ingredient is admixed with part of the excipients, and the mixture is granulated with a solution of the soluble starch in water. after drying of the granulate, the remaining excipients are admixed with it, and the mixture is compressed into 100 mg tablets. Each tablet contains 50 mg of the pyrroloisoquinoline compound and is an oral dosage unit with effective pharmacologic action. Example 7 Coated Pills The pill core composition is compounded from the following ingredients: 1,2,3,5,6,10bss-Hexahydro-6a- phenylpyrroloF 2,1-a) isoquino- line (Xb) Fumarate 100.0 parts Lactose 75.0 parts Corn starch 65.0 parts Colloidal silicic acid 2.0 parts Soluble starch 5.0 parts Magnesium stearate 3 > 0 parts TOTAL 250.0 parts The ingredients are compounded as described in Example 6, and the composition is compressed into 100 mg pill cores which are subsequently coated in a conventional nanner with a thin shell consisting essentially of a mixture of sugar, talcum and gum arabic. Each coated pill contains 40 ing of the pyrroloisoquinoline compound and is an oral dosage unit composition with effective pharmacologic action. Exanple 8 Syrup The syrup composition is compounded from the following ingredients: 1,2,3,5,6,10bB-Hexahydro-6a- phenylpyrrolo[2,1-a]isoquino line (Xb) Fumarate 100.0 parts Cane Sugar 150.0 parts Glycerol (twice distilled) 250.0 parts Methyl p-hydroxybenzoate 3.0 parts Propyl p-hydroxybenzoate 2.0 parts Flavorings, as desired Water (distilled) 1,995.0 parts TOTAL 2,500.0 parts Example 9 Tablets The tablet composition is compounded from the following ingredients: : 1,2,3,5,6,10bss-Hexahydro-6&alpha;- (4-nitrophenyl)pyrrolo[2,1,a] isoquinoline (XXXVIII) Hydro bromide 100.0 parts Lactose 20.0 parts Corn Starch 20.0 parts Colloidal silicic acid 2.0 parts Soluble Starch 5.0 parts Magnesium 'stearate 3.0 parts TOTAL 150.0 parts The active ingredient is admixed with part of the excipients, and the mixture is granulated with a solution of the soluble starch in water. After drying of the granulate, the renaining excipients are admixed with it, and the mixture is compressed into 100 mg tablets. Each tablet contains 50 mg of the pyrroloisoquinoline confound and is an oral dosage unit with effective pharmacologic action. Example 10 Coated Pills The pill core composition is compounded from the following ingredients: 4-(1,2,3,5,6,10bss-Hexahydro pyrrolo(2, l-a]isoquinolin-6a-yl) benzenanine (XLVIII) Hydrobromide 100.0 parts Lactose 45h.0 parts Corn Starch 45.0 parts Colloidal silicic acid 2.0 parts Soluble starch 5.0 parts Magnesium stearate 3.0 parts TOTAL 200.0 parts The ingredients are compounded as described in Example 'V, and the composition is compressed into 150 ing pill cores which are subsequently coated in a conventional manner with a thin shell consisting essentially of a mixture of sugar, talcum and gum arabic. Each coated pill contains 75 mg of the pyrroloisoquinoline compound and is an oral dosage unit composition with effective pharmacologic action. Example 11 (6a, 1Oba)-6-(4-aminophenyl)-1,2, 3,5,6,10b-hexahydro- pyrrolo[2,1-a]-isoquinoline. 24.2 g of the nitro compound 1,2,3,5,6,10b&alpha;-hexahydro-6&alpha;-(4-nitrophenyl)pyrrolo[2,1- azisoquinoline (LIV) in 600 ml of ethanol is treated with 2.5 g of PtO2 and warned to dissolve the substrate, if necessary. The mixture is hydrogenated at 45 psig for about 45 minutes. Filter aid (3g) is added and the reaction is filtered. The solution is evaporated to a light tan syrup, which eventually crystallizes on prolonged standing. The nonohydrobromide salt, prepared in 2-propanol with 48% HBr, is recrystallized from methanol to give light tan leaflets, mp 252-2585C. Example 12 (6a, lOba]-6-(4-acetylaminophenyl)-l, 2,3,5,6, lOb- hexahydropyrrolo2,1-a)-isoquinoline. To 2.0 g of the aniline product of Example 11 in 15 ml of dry CH2C12 was slowly added 650 mg of acetylchloride in 5 ml of CH2C12, with stirring. After 16 hours, the acetylchloride reaction was basified with 1N aqueous NaOH and the organic layer was separated. The aqueous layer was extracted and the combined CH2C12 solution was dried (Na2SO4) and concentrated to a tan solid. Recrystallization from ethyl acetate gave tan leaflets, mp 175-178 C. Example 13 [6&alpha;,10b&alpha;]-6-(4-benzoylaminophenyl)-1,2,3,5,6,10b- hexahydropyrrolo[2,1-a]isoquinoline. To 2.0 g of the aniline product of Example 11 in 15 ml of dry CH2C12 was added slowly 1.10 g of benzoylchloride in a 5 ml of CH2C12 with stirring. After 16 hours, the benzoylchloride reaction was diluted with dry ether, cooled to OOC, and filtered to give a gray solid. The solid was recrystallized from methanol to give a white powder, mp 261-2740C. Example 14 [6&alpha;10b&alpha;]-6-(4-ethylamino)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline. To 2.6 g of the amide produced in Example 12 in 20 ml of dry THF was slowly added 30 ml of 1M BH3-THF at 5 C under an inert atmosphere. The reaction was refluxed for 1 hour, cooled in ice and treated with 6 ml of H20 and then 9 ml of 12N HC1. The THF was distilled off and the reaction refluxed an additional 10 minutes. The solution was ice bath cooled and 3N NaOH was added until the pH was greater than 11 and then extracted with methylene chloride. The organic layer was dried (K2C03) and evaporated in vacuo to an oil. The fumarate salt was prepared from methanol/2-propanol to give white crystalline material (1.95g), mp 170172 C. Example 15 [6&alpha;10b&alpha;]-6-(4-ethylamino)-1,2,3,5,6,10b-hexahydro- pyrrolo(2,1-a)isoguinoline. 35.2 g (0.107 mole) of the bromide, a mixture of t6a,10ba]- and [6&alpha;10b&alpha;]-6-(4- broinophenyl) -1,2,3,5,6, 10b-hexahydropyrroloE 2,1- a"]isoquinoline produced via the styrene-oxide route (D), 19.21 g (0.215 mole) of cuprous cyanide and 1.0 g of tetrakistriphenylphosphine palladium (0) were combined in 107 ml of N,N-dimethylacetamide under an inert atmosphere. The reaction was refluxed for 18 hours, cooled and partitioned between 1 liter of conc. ammonium hydroxide and 250 ml of ether. The aqueous layer was extracted several times with ether and the combined ether solution was washed 2 times with ammonium hydroxide, 2 tines with water, 3 times with brine, dried (K2C03) and evaporated in vacuo to an oily product (22.6g, 77%). The a and B isomers were separated by preparative HPLC and the lObss isomer was isolated. The lObss HC1 salt was recrystallized from methanol to give an off-white soldi, mp 271-276 C. Example 16 [6&alpha;10b&alpha;]-6-(4-ethylamino)-1,2,3,5,6,10b-hexahydro- hypropyrrolo2,1-alisoquinoline. 200 mg of the oily cyano compound produced in Example 15 as the lOba and lObB isomer mixture was combined with 150 mg of KOH in 1 ml of t-butanol and refluxed for 30 minutes. The cooled solution was extracted between methylene chloride and saturated NaC1. The organic layer was dried (K2C03) and evaporated in vacuo to a glassy material. The glassy material was then subjected to preparative HPLC to separate the a and ss isomers whereby the 10bss isomer was isolated.

Claims: CLAIMS 1. A compound of the following Formula I including diastereomers and the nontoxic, dharmaceutically- acceptable acid addition salts thereof, EMI42.1 wherein R1 is hydrogen or lower alkyl having one to four carbons; R2 is hydrogen, lower alkyl having one to four carbons, fluoro, hydroxy, or lower alkoxy having one to four carbons; R3 is hydrogen, methyl, or phenyl; R4 and R5 are the same and both are hydrogen, or are different and each is selected from the group of hydrogen or lower alkyl having one to four carbons; Rs and R7 are the same or different and each is selected from the group hydrogen, lower alkyl having one to four carbons, lower alkoxy having one to four carbons, hydroxy, or halogen, or else are taken together as methylenedioxy; and is selected from the group of units of the following formulas (1), (2) or (3): EMI42.2 wherein for the benzene unit of formula (1), R8 and R9 are selected from the group hydrogen, lower alkyl having one to six carbons, perfluoro(lower)alkyl having one to four carbons, hydroxy, lower alkoxy having one to four carbons, carb(lower)alkoxy having one to five carbons, lower acylanino (one to five carbons), benzoylamino, cyan, carboxamido, lower acyl of one to five carbons, lower alkylthio having one to four carbons, lower alkylsulfonyl having one to four carbons, nitro, amino, loweralkyl- or di(lower)alkyl-amino having one to four carbons in each alkyl, or halogen; wherein for the heteroaromatic unit of formula (2), X is oxygen or sulfur; and wherein for the cycloalkyl unit of formula (3), n = O to 2, which units of formulas (1), (2) and (3) may be attached at any carbon atom vertex. 2. A compound according to Claim 1 wherein in formula (I), R3, R4, and R5 are all hydrogen. 3. A compound according to Claim 1, wherein in formula (I), $2, R3, R4, R5, R6 and R7 are hydrogen and A is a unit of Formula 1. 4. A compound according to Claim 1 which is the free base or acid addition salt form of: ±6a , l0b ) -1,2,3,5,6, 10b-hexahydro-l0b-methyl-6-phenyl- pyrrolo[2,1-a]isoquinoline; [6&alpha;10b&alpha;]-1,2,3,5,610b-phenylpyrolo[2,1- a]isoquinoline; 6&alpha;-(3,4-dichlorophenyl)-1,2,3,5,6,10b&alpha;-hexahydropyrrolo- [2,1-a]isoquinoline; 1,2,3,5,6,10bss-hexahydro-6-methyl-6&alpha;-phenylpyrrolo[2,1 azisoquinoline; [6&alpha;,10bss]-1,2,3,5,6,10b-hexahydro-8,9-dihydroxy-6-phenyl- pyrrolo[2,1-a]isoquinoline; [6&alpha;,10b&alpha;]-6-cyclohexyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1- a]isoquinoline; [6&alpha;,10bss]-6-(4-chlorophenyl)-1,2,3,5,6,-10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 6&alpha; ;-(4-chlorphenyl)-1,2,3,5,6,10b&alpha;-hexahydropyrrolo[2,1- a]isoquinoline; 1,2,3,5,6,10bss-hexahydro-6&alpha;-(4-methoxyphenyl)pyrolo[2,1- a]isoquinoline; 1,2,3,5,6,10b-hexahydro-6-phenylpyrolo[2,1-a]isoquinolin 6-ol; 4-(1,2,3,5,6,10bss-hexahydropyrolo[21,-a]isoquinolin-6&alpha;- yl)benzene-1,2-diol; 1,2,3,5,6,10bss-hexahydro-6&alpha;-(4-nitrophenyl)pyrrolo[2,1- a]isoquinoline 1,2,3,5,6,10bss-hexahydro-6-&alpha;-(3-methoxyphenyl)pyrrolo[2,1- a]isoquinoline; 3-(1,2,3,5,6,10bss-hexahydropyrolo[2,1-a]isoquinolin-6&alpha;- yl)phenol; 1,2,3,5,6,10bss-hexahydro-6&alpha;-(3,4-dimthoxyphenyl)pyrrolo- [2,1-a]isoquinoline; 1,2,3,5,6,10bss-hexahydro-7-methoxy-6&alpha; ;-phenylpyrrolo[2,1- a]-isoquinoline; 4-(1,2,3,5,6,10b&alpha;- hexahydropyrrolo[2,1-a]isoquinolin-6&alpha;- yl)benzenamine; 1,2,3,5,6,10bss-hexahydro-6&alpha;-[j(3-rifluoromethyl)phenyl]- pyrolo[2,1-a]isoquinoline; 9-fluoro-6&alpha;-(4-fluorophenyl)-1,2,3,5,6,10b-hexahydro-10bss- methylpyrrolo[2,1-a]isoquinoline; [6&alpha;10bss]-6-(2-chlorophenyl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; or 1,2,3,5,6,10bss-hexahydro-6&alpha;-(4-methylthiophenyl)- pyrrolo[2,1-a]isoquinoline. 5. A compound of Claim 1, which is the free base, or acid addition salt of 1,2,3,5,6,10bss-hexahydro-6&alpha;-[(3-trifluoro methyl)phenyl]pyrrolo[2,1-a]isoquinoline. 6. A compound of Claim 1, which is the free base or acid addition salt of (6a,l0b]-6-(2-chlorophenyl)- 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline. 7. A compound of Claim 1, which is the free base or acid addition salt of 1,2,3,5,6,10bB-hexahydro-6a-(4-methyl thioFhenyl)pyrroloC2,l-a)isoquinoline. 8. A compound which is the free base or acid addition salt of 1,2,3,5,6, lOboC-hexahydro-5-phenylpyrrolo t2,1-ag isoquinoline. 9. A compound of any one of claims 1 to 3 which is in the form of 10b ss. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9 in combination with a pharmaceutically acceptable diluent or carrier, 11. A compound of any one of claims I to 9 or a composition of claim 10 for use in treating depression in a mammal. 12 A compound of Claim 1, wherein for the benzene unit of formula (1), Ra and R9 are selected from the group hydrogen, lower alkyl having one to six carbons, per fluoroClower)alkyl having one to four carbons, hydroxy, lower alkoxy having one to four carbons, carb(lower)alkoxy having one to five carbons, lower acylamino (one to five carbons), lower acyl of one to five carbons, lower alkylthio having one to four carbons, lower alkylsulfonyl having one to four carbons, nitro, amino, loweralkyl- or di(lower)alkyl-amino having one to four carbons, or halogen.

Inventors: MARYANOFF, BRUCE E.
Applicants: MCNEILAB, INC.
Application year: 1984
Main classification: C07D471
IPC codes: C07D471, A61P25, A61K31, C07D491, C07D207