IL44042A - Octahydropyrido (4',3':2,3) indolo (1,7-ab) (1) benzazepines and their preparation - Google Patents

Description

ιΊιυ' κ_3 ,2:3', AJ' \Ί' τ s 11 ' πκαΡ 1 κ BNDO LABORATORIES, INC.

BACKGROUND OF THE INVENTION Certain octahydropyridoindolobenzazepines are known Tom U.S. Patents 3,373,168 and 3,157,271, assigned to Hoffmann-La Roche, Inc. Those compounds can be represented according to the above-mentioned patents by the following Formula ( 1 ) : wherein R is a straight chain or branched alkyl having 1-7 carbon atoms.

According to the IUPAC 1957 Rules, the same com- oounds are represented by the formula: a d nre named 1 , 2 , 3 ,8 ,0 , l^a-octahydropyridof'l ' , ' : 2 , ]= 44042/2 lndolo[l , 7-ab][l ]benzazepines . The IUPAC representation and nomenclature will be ueed herein.

The compounds of Formula ( 1 ) are said in Patents Nos. 3 , 373 , 168 and 3 , ^ 57 ,271 to have antidepressant activity and to be useful antidepressant agents. These compounds are prepared according to the above two patents by reduction of the corresponding hexahydro compounds either with sodium in a mixture of tetrahydrofuran and liquid ammonia or with zinc in hydrochloric acid. The former method is preferred by the patentees since it gives higher yields.

The compounds of this invention have a different steric con iguration of the hydrogen atoms at the Ma and lMa positions from those of the above patents. The evidence is that the compounds of this invention have the trans configuration of the Ma and l a hydrogens and that the compounds of the above patents have the cis configuration. The compounds of this invention are made, either directly or indirectly, by reducing a l,2 , 3, ,8 ,9-hexahydropyrido- [ *» ' » 3 ' : 2 , 3]indolo[l, 7-ab]benzazepine with boron hydride ,_ , m followed by acidification with hydrochloric acid tetrahydrofuran complex, Which Kas been found to result in the trans configuration. The compounds of the present invention are in general CMS depressants, in contrast to the compounds of the above patents, which are antidepressants.

SUMMARY OF THE INVENTION This invention is a class of compounds of the formula: 44042/2 I wherein: Y is R or a group -COOR3; n is zero or one; X is an anion of a pharmaceutically suitable acid; and R is hydrogen; 3-chloro-2-butenyl ; benzyl; phenethyl; acetonyl; C^-C^ alkyl; C3~C5 alkenyl; C^-C^ alkynyl; cyclopropyl; C4-C8 cycloalkylmethyl; Cg-C8 cyclo- alkenyImethyl; exo-7-norcarylmethyl ; l-adamantyImethyl ; or 2-adamantyImethyl , R3 is C1~C4 alkyl, and the hydrogens in the 4a and 14a positions are in trans relationship to each other.

Those compounds cf formula I above where 3 Y is a group -COOR are intermediates for the preparation of the corresponding compounds in which Y = R.

The invention includes pharmaceutical compositions containing a pharmaceutically -uitable vehicle and a compound of formula I in which Y = R.

The invention also includes a method for producing an analgetic effect in a warm-blooded animal (other than men) comprising administering to said animal an analgetically effective amount of a compound of formula I.

Finally, the invention includes the method of nakinn; the compounds, characterized in that a 3-substi-tuted 1,2,3,4 ,8,9-hexahydropyrido[H' ,3' : , 3 ]indolo[ 1 ,7-ab ]= [ 1 ]benz azepine is reduced with boron hydride/tetrahydro= followed by acidification with hydrochloric acid furan conplex/ and the resulting compound of formula I is optionally further treated, e.g. by dealkylation optionally followed by alkylation or acy lation/reduction , to convert it to another compound of formula I.

DESCRIPTION OF THE INVENTION Synthesis of the Comnounds All of the compounds are made, either directly or indirectly, by reaction (1). The compounds obtained directly in reaction (1,) can, if desired, be. treated as shown in reactions (2)-(Ό to obtain other compounds of the invention. _ H - 44042/2 44042/2 In the foregoing formulae, and whenever used herein : 44042/3 RA is benzyl; phei ethyl ; C^-C^- alkyl ; cyclo- propyl ; C^-Cg cycloalkylmethyl ; exo-7- norcarylmethyl; 1-adamantylmethyl r or 2-adainantylmethyl . x^ is the same as RA or is 0 where " 7 Π7 i.s the same as Π4 -C-R' R R , excluding C2-<~4 al^ynyl 2-chloro-l-propenyl ; R3 is methyl; ethyl; benzyl; or cyclopropylmethyl ; 3 R is C, -C4 alkyl; R is the same as R, excluding hydrogen and cyclopropyl ; R4 is 2-·· hloro-l-propenyl; phenyl; benzyl; phcncthyl ; hydrogen; C^-C^ alkyl; ^2~C alkenyl ; C2~C4 alkynyl; c3~ 7 cycloalkyl; methylcyclopropyl ; C^-C^ cycloalkenyl ; exo-7-norcaryl ; 1-adamantyl; or 2-adamantyl; 44042/2 R is the same as R, excluding hydrogen, acetonyl and cyclopropyl ; 0 Q io -CI, -Br, C-^-C^ alkoxy; H^-C-O-; . 0 0 i- it . II HJ-C-0-; or R°0-C-0-; 5 R is different from R and is ^-C^ alkyl, provided that when R is hydrogen, R"* is methyl ; R6 is C1-C1 alkyl; Z is -CI; -Br; -I; or -OS(0)2R8; g R is CH^, phenyl or p_-tolyl ; and nCZ can also be R9OS(0)2OR9, where R9 is C1-Clj alkyl.

Starting Materials The l,2,3,4,8,9-hexahydropyrido[ ,3' :2,3]indol [ 1 , 7-ab 1 [ 1 jnenzazepines of formula II can be made, for example, by the method disclosed' in the above-cited Hoffraann-La Roche U.S. patents; namely, by N-nitrosating iminodibenzy 1 , reducing the product to N-aminoiminodi= benzyl, condensation with an appropriately substituted ij-piperi dinone , and cyclization with an acid. The methyl and ethyl-substituted hexahydropyridoindolobenzazepines are prior art com ounds; several other 3-substltuted hexahydropyrldolndolobenzazeplnes are described in U.S.

Patent 3>764,684, issued October 9, 1973. The com- 0 " 7 pounds of formula II wherein R is -C-R can of course be made by conventional acylation of the corresponding 2 compound wherein R is hydrogen, using an appropriate acylating agent such as an acyl chloride; alternatively, these compounds can be obtained by condensation of M-aminoimlnodibenzyl with appropriate 1-acy1-4-piperidone .

Reaction (1) The reduction of the hexahydro precursors to the octahydro compounds is best carried out with a four- to fivefold excess of boron hydride/tetrahydrofuran complex at a temperature as low as 0°C. or as high as the reflux temperature of tetrahydrofuran. The reducing power of the boron hydride/tetrahydrofuran reagent may be further enhanced by dilution with a higher-boiling ether, for example, diglyme, which allows the reaction to be conducted at a higher temperature, usually not over 100-110°C. The reaction mixture is then acidified with about k-10 molar hydrochloric acid, heated to 100°C., allowed to cool, and neutralized with caustic. The product can be recovered in any suitable manner, including extraction, evaporation followed by extraction, conversion to an addition salt, etc.

The mo^t outstanding characteristic of the compounds of formula la, i.e., those compounds of formula I which can be made directly by BH^/THP reduction of a hexa= hydro precursor, is their CNS depressant (more specifically, sedative tranquilizer) activity, which is totally unexpected from the disclosures of U.S. Patents Nos . 3,373,168 and 3,^57,271. While it is believed that this activity is related to the steric configura ion of the compounds of the present invention, applicant does not wish to be bound by this theory. Nevertheless, the proposed structure of the conpounds of the present invention is based on the following considerations: (a) reduction of a hexahydro compound (3) with boron hydride in tetrahydrofuran increases the molecular weight by 2, as found by mass spectroscopy _ this means that two hydrogens have been added; (b) ultraviolet spectroscopy shows that the di- phenylanine chromophore, constituted by rings C and E, and the nitrogen in position l , is intact after the reduction - this means that the aromatic rings C and E have been preserved; (c) reductive cleavage of the Cg-Cg bond, involving benzylic carbon atoms, is ruled out by both ultraviolet and nuclear magnetic resonance spectroscopy; (d) the only possibility left is the saturation of the double bond; (e) nuclear magnetic resonance spectroscopy of the prior art octahydro compounds suggests that they have the cis configuration.

The formation by the process of this invention of octahydroindolobenzazepines in which rings B and C constitute an indoline moiety is not only novel but also totally unexpected, especially in view of the results of a recent study of the reaction of indoles with diborane, Monti et al., Tetrahedron 27, 5531 (1971). 44042/2 the compounds of the present invention will be referred to as the trans-, compounds to distinguish them from the compounds having the configuration of those described in U.S.

Patents 3,373,168 and 3,157,271. This designation is used, however, with the understanding that if it is ultimately shown that either this isomer assignment is incorrect or an altogether different isomerism exists, the term "trans" as used herein still will designate the compounds having the configuration of the compounds specifically disclosed herein. The steric configuration of the compounds of the present invention can thus be characterized as that identical with one resulting v.'hen the Ci^-C^ double bond is reduced with the boron hydride/ tetrahydrofuran complex, followed by acidification with hydrochloric acid.

Reaction Series 2 Compounds of formula I wherein R is H (formula Ie) cannot be produced directly by BH^/THP reduction of the corresponding hexahydro compound; the hexahydro compound is recovered unchanged on attempted reduction with even BH^/THF in diglyme. Consequently, compounds of formula Ie must be produced from compounds of formula lb according to reaction series (2).

In series (2), the compound of formula lb is first reacted with a chloroformate CICOOR^. This reaction can be carried out at a temperature in the range of 20° to 110°C, preferably 90° to 110°C. , in an inert organic solvent such as benzene, toluene or dioxane . The quaternary ammonium salt III initially produced upon reaction with the chloroformate is not isolated, and the reaction proceeds to the compound of formula JCV. The latter compound can, but need not, be isolated. Hydrolysis of the compound of formula to produce the Ie compound can be carried out in a alkanol containing 0-10Ϊ water and a hydroxide of potassium, sodium, lithium or calcium, at a temperature in the range of 65-l¾0°C. Alternatively, it can be carried out in aqueous mineral acid (e.g., acetic or hydrochloric acid) at a temperature in the range of 20-110°C. The hydrogenolysis , applicable when R^ is benzyl or substituted benzyl, can be carried out 1-3 atmospheres hydrogen pressure, a temperature in the range of 30-60°C. , and a platinum, palladium or Raney nickel catalyst .

Reaction (3) The BH-j/THP complex reduction of reaction (1) reduces not only the indolic double bond of the hexa~~ hydro precursor but also any carbonyl group and/or ole-finic or acetylenic unsaturation of the R group. Consequently, compounds of formula I having reducible R groups must be prepared by alkylation or acylation/re-duction of the octahydra: compounds wherein R is hydrogen (formula Ie) according to reaction (3) and reaction series (^). Of course, compounds having non-reducible R groups can also be prepared by these methods, except for those compounds wherein R is hydrogen or cyclopropyl.

Reaction (3) is a conventional alkylation reaction. The reagent RCZ is an organic halide, (Z = CI, Br or I), sulfate (RCZ = R9OS(0)2OR9) or sulfonate (Z = -OS(0)2R8). The reaction is carried out in a polar organic solvent such as dimethylformamide , dimethyl sulfoxide, hexamethylphos-phoramide, acetone, methyl ethyl ketone, methanol or 44042/2 earth metal carbonate or bicarbonate, or a tertiary amine, for example pyridine or triethylamine . Reaction temperatures in the range of 0 to 100°C. can be used; preferred range is 20 to H0°C.

Reaction Series (Ό Reaction Series (M) is a conventional acylatlon/-reduction, the acylating agent 0 is an acid halide QCRU 0 (Q . CI, Br), ester (Q » C^ alkoxy), anhydride (Q ■ R -C-0) ,or mixed anhydride (Q - c ? ) including mixed anhydrides with R -C-0- g 0 an ester of carbonic acid (Q - R 0-C-0-) . The acylation is carried out in an organic solvent such as benzene, chloroform or dichloromethane at a temperature of 0° to 80°C, preferably 0° to 10°C. When the acylating agent is an acid halide, an inorganic or tertiary amine base is present to react with liberated acid. The reduction is carried out with a conventional reducing agent such as lithium aluminum hydride in an ethereal solvent, such as tetrahydrofuran , glyme or di= lyme, or sodium bis(2-methox ethox )aluminum hydride in a solvent such as benzene or toluene, at a temperature in the ranee of 30 to 100°C. , preferably 30 to 65°C. Glyme and diglyme are trivial names for ethylene glycol ddiethyl ether and diethylene glycol diethyl ether, respectively.

Salts Representative pharmaceutically suitable acids which can be used to make the acid addition salts of this invention are the following: hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, citric, pamoic, succinic, methanesul- 1,2— fonic,/ethanedisulfonic, acetic pro ionic tartaric 44042/2 citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p_-arainobenzoic , glutamic, and^ ioluene-sulfonic .

Stereoisomers All compounds of formula I have at least two asymmetric centers, resulting from the reduction of the li e llln Δ * to the trans-fused system. The invention includes the racemate as well as the individual enantiomers. In addition if the 3-substltuent includes a grouping capable of existing in stereoisomeric forms all the resulting diastereoisomers are also included in this invention.

Examples The preparation of the compounds of the present invention is illustrated by the following examples, wherein all parts, proportions, and percentages are by weight unless otherwise indicated.

EXAMPLE 1 A solution of 4 .76 g. of methylpyridoCU' ,3' :2,3]indolo[l, 7-ab][l]benzazepine (which can be made according to the teachings of U. S. 3, 57 , 271 , Column 4 , lines 27-54 ) in 50 ml. of tetrahydrofuran was added dropwise to a stirred IN-solution of boron hydride in tetrahydrofuran ( 42 ml.) under a nitrogen blanket. After the addition was complete, the mixture was refluxed under nitrogen for five hours, then cooled in ice and quenched with 20 ml. of 6N hydrochloric acid. The mixture was distilled, the removed liquid being from time to time replaced by addition of dl- 44042/2 oxane. The mixture was again refluxed at 91°C. for one hour with additional 6N hydrochloric acid, then cooled to 70°C, made basic with sodium hydroxide, and evaporated in vacuum. The semisolid residue was treated with water and chloroform, and the chloroform layer was further worked up to yield 1.50 g. of a solid product, m.p. 128-131°C.

The mother liquors yielded an additional amount of material, m.p. 129.5-I30.5°C . Crystallization from ether raised the melting point to 132-13¾°C; UV spectrum: XCH3°H 279.5 my max (loge 1.15).

Reduction of l^^^e.g-hex hydro-S-meth l y ido* [Ί' ,3' :2,3]indolo[l,7- b][l]benzazepine with sodium in (+)-liquid ammonia gave the prior art/ oiaroctahydro compound, m.p. 287 my (loge ¾.08). 2,3 , ,4a,8,9,l4a-octahydro-3-meth ls pyrido[4',3» :2,3]indolo[l,7-ab][l]benzazepine of the present invention can also be made by the following alternative route involving the reductive cleavage of the 3-methoxymethylhexa- hydro compound as shown below.

A. A mixture of 2.74 g (0.01 mole) of 1,2,3,4,8,9-hexahydro- pyrido[4',3' :2,3]indolo[l,7-ab][l]benzazepine, prepared as shown in Section A of Example 2, and 75 ml of dry benzene was heated to boiling until solution occurred. Triethylamlne (10.5 ml, O.075 mole) was added to the warm solution, followed by dropwise addition of 2.0 ml (0.026 mole) of chloromethyl methyl ether. The resulting mixture was refluxed for 15 minutes, cooled to room temperature, and filtered. The filtrate gave on evaporation 3.05 g of a yellow oil, which was found by infrared spectroscopy to contain no free BNH groups. 44042/2 in 50 ml. of freshly purified tetrahydrofuran was added dropwise with stirring, under a nitrogen blanket, to 75 ml. of a 1M solution of boron hydride in tetrahydrofuran. The resulting mixture was refluxed under nitrogen for 26 hours; then it was cooled in ice and carefully decomposed with 50 ml of 5.5N hydrochloric acid. About 30 ml. of the liquid was removed by distillation, and 50 ml. of glacial acetic acid was added to redlssolve the precipitate formed. The solution was refluxed for one hour, cooled to 55-60°C, and made alkaline with 0* caustic. The product was recovered by extraction with ether, evaporation of the solvent, and column chromatography in benzene solution on basic alumina I. The pure product melted at 136-138°C, and was identical with the material prepared by the first method described in this example.

EXAMPLE 2 (+ )-trans-3- (Cyclopropylmethyl)-1, 2,5 , ha ,8, 9, l a- octahydropyrido[4' ,3* :2,3]indolo[l,7-ab [l]- benzazepine A. A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino- 10,ll-dihydro-5H-dibenz[b, ]azepine) and 14.8 g. of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes and cooled; a solution of 20 g. of concentrated sulfuric acid in 250 ml. ethanol was added.

The resulting mixture was reheated on the steam bath for additional Ί0 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 1. of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal 44042/2 extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and IN hydrochloric acid, and dried in vacuo at 100° to yield 1, 2, 3,1», 8,9-hexahydropyrido[ ,3' :2,3]indolo[l,7-ab][l]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystalllzlng it from benzene regenerated the free 1 ,2 , 3 ,1» ,8 ,9-hexahydropyrido[4 ' , 3' :2 ,3]indolo[l,7-ab]» [l]benzazepine.

B. To a solution of 16.4 g of l^^.^B^-hexahydropyrido- [¾' ,3' :2x3]indolo[l,7-ab][l]benzazepine in 500 ml. of dichloromethane, 7.3 g. of cyclopropanecarbonyl chloride wasadded, followed by dropwise addition of 10 ml. of tri- ethylamine. A mildly exothermic reaction took place, after which stirring of the mixture was continued at room temperature overnight. The mixture was then washed with IN hydrochloric acid and water and dried over anhydrous sodium carbonate. On evaporation to dryness, crude 3-(cyclopropyl~ carbony1 )-l , 2 , 3, *» , 8 , 9-hexahydropyrido[ H ' , 31 : 2 , 3] indoloC 1 , 7-ab ] [l]benzazepine (Formula V R« » cyclopropyl) was obtained as a glassy product. Recrystalllzation from ethanol yielded the pure material, m.p. 154-156°C.

A solution of 8.6 g of the above compound in 120 ml. of tetrahydrofuran was added dropwise to a suspension of 2.3 g of lithium aluminum hydride in 180 ml. of tetrahydrofuran. On completion of the addition, the mixture was first refluxed 44042/2 overnight and finally decomposed in the usual manner. After filtering off the inorganic salts, the filtrate was dried over anhydrous sodium carbonate and evaporated in vacuo; the residu was dissolved in a 1:1 mixture of ethyl acetate-benzene and chromatographed on a 14 x 2.2 cm. column of basic alumina, activity I. The eluate was taken down to dryness; the residual oil dissolved in absolute alcohol, saturated with ethanolic hydrogen chloride, and once again evaporated to dryness. Upon crystallization of the residue from acetone, 3- (cyclopropylmethyl )-l,2, 3, 4, 8, -hexahydropyrido[ 4 » , 3 ' : 2 , 3 3 s indoloC 1 , 7-ab] [ 1]benzazepine hydrochloride (Formula II, R = cyclopropylmethyl) , m.p. 267° , was obtained.

C. A solution of 9.25 g. of the free base of the above hexahydro compound in 75 ml. of tetrahydrofuran was reduced with 100 ml. of a 1 solution of boron hydride in tetrahydrofuran according to the method of Example 1. The title compound weighed 4.43 g. and had a melting point 152. 5-155°C.; U.V. spectrum: XC"3°H 281 my (log e 4.10 ) . The hydro- IUGLX chloride salt melted at 273-276°C.

Reduction of 3-(cyclopropylmethyl )-l,2,3,4,8,9-hexa-hydropyrido[4»,3» :2, 33indojLo[l, 7-ab][l]benzazepine with sodium liquid ammonia gave the /cis-product which formed a hydrochlorld CH,0H m.p. 241-243 C, U.V. spectrum: λ mix 285 mu (log ε 4.10).

The above two octahydro compounds were found to have different Rf values in a thin layer chromatography system employing chloroform-butanol-28% aqueous ammonia in volume ratios 95:10:5, respectively, as solvent.

EXAMPLE 3 (+ )-gratis-3- (Cyclopropyltaethy1 )-1, 2,3 , , a,8, 9, l4a- octahydropyrido[i»« ,3' :2,3]ir.dolo[l,7-a J[l] = benzazenlne (by a one-step reduction) A solution of 100 g. of 3-(cyclopropylcarbonyl )-l,2>3,¾,8,9-hexahydropyrido[4' ,3' :2,3]indolo[l,7-ab][l]= benzazepine in 500 ml. of tetrahydrofuran was added during a period of about 30 minutes to about 9^6 ml. (1 U.S. quart) of a 1M solution of boron hydride in tetrahydrofuran. The resulting solution v/as allowed to stand for 72 hours; then, a solution of 50 ml. of concentrated hydrochloric acid in 100 ml. of water was added, and the mixture was distilled until the pot temperature reached 100°C. The remaining material was cooled and diluted with 200 ml. of water and 75 ml. of 50% sodium hydroxide. The product was extracted with methylene chloride and was recovered as a crystalline material after treatment with acetone of the methylene chloride distillation residue. Yield 60.3 g., m.p. 1 6-151°C. After recrystallizatlon from methanol-chloroform 9:1 by volume, the meltin point increased to 153-155°C.

A sample of the above material was converted to the mesylate (methanesulfonate) salt, m.p. 227-232°C.

EXAMPLE l\ (+)-trans-3-Ethyl-1, 2,3, , a,8, , l^ -octa- hydropyrido[4» ,3 ' :2,3 ]indolo[l,7-ab]» (ljbenzazeplne v.

To a mixture of 9.0 g. of N-nitrosolminodibenzyl, 12 g. of l-acetyl-^-piperidone and 33.0 g. zinc dust in 75 ml. absolute ethanol there was added dropwise 24 ml. of glacial acetic acid with constant stirring and occasional cooling to keep the reaction temperature at 20-25°C. After six hours, the unchanged zinc was filtered off and the mother liquor evaporated to near dryness. After extracting the residue with benzene, the extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent stripped off. The yellowish-brown residue was dissolved in 50 ml. ethanol, treated with a solution of 8 ml. concentrated sulfuric acid in 50 ml. ethanol, and heated on a steam bath for about ten minutes. On pouring into cold water, a gum separated, from which the aqueous layer was decanted. After dissolving the gum in ethyl acetate, the solution was washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a yellowish-white solid, which on crystallization from acetone yielded 3-acetyl-l ,2 ,3 ,1* ,8 ,9-hexahydropyrido[4 ' ,3' : 2 , 3] indolo[l,7-ab][l]benzazepine as a white solid, m.p. 193-196°C.

The above 3-acetyl compound was reduced with boron hydride in tetrahydrofuran according to the procedure of Example 3· The title compound was isolated, in a 36% yield, a its hydrochloride salt, m.p. 258-260°C. (dec); U.V. : XCH3UH max 276 my (loge H.ll).

Alternatively, the above compound can be made by reduction of the 3-acetyl compound under more drastic conditions, as follows: A warm solution of the 3-acetyl compound (11. 53 g-> Ο. Ο365 mole) in 300 ml. of diglyme is rapidly added dropwise to a mixture of 250 ml. of diglyme and 150 ml. of 1-molar boron hydride in tetrahydrofuran. The stirred mixture is then heated under nitrogen at 100°C. for twenty hours. The mixture is cooled to 20°C, decomposed with 75 ml. of 10N hydrochloric acid, and refluxed at 90°C. for one hour. It concentrated in vacuum, and extracted with chloroform.

The chloroform extract yields a 67% yield of the 3-ethyl product .

EXAMPLE 5 (+)-4;rans-l,2,3^»4a,839,l4a-0ctahydro-3-isobutyl» pyridoCV ,3' :2,3]indolo[lt7-ab]Ci;ibenzazepine 1> 2,3, ,8, -Hexah dro-3 - isobutyrylpyrido [4» ,3 ' : 2 ,3 ]= indolo[ 117-ab] [ 1]benzazepine , m.p. 122-12¾°, was made by a reaction of ,3' :2,3]indolo= [l,7-ab][l]benzazepine with isobutyryl chloride. This amide was reduced with boron hydride-tetrahydrofuran in diglyme in the manner described above as the alternate method of reducing the 3-acetyl compound to the 3-ethyl compound of Example ¾.

The title compound was isolated as its hydrochloride addition salt, m.p. 286-289°C (dec).

EXAMPLE 6 (+) -trans-3-Benzyl-l,2,3, , a,8,9»l^a-octahydro= yrlQ'of4l , ' :2, 1indoloflt7-abiri1benzazepine Condensation of N-nitrosoiminodibenzyl with 1-benzyl- 4-piperidone under conditions described in Example 4 for condensation with l-acetyl-¾-piperidlnone gave 3-benzyl- ,3' :2,3]indolo[l,7-ab][l benzazepine (hydrochloride, m.p. 2d"0°C). Reduction of the free base with boron hydride-tetrahydrofuran in diglyme under the conditions of the alternate method described in Example Ί for the reduction of the 3-acetyl compound gave an yield of the title compound, which was isolated as its hydrochloride salt, m.p. 210-212°C. (dec). The free base 44042/2 was obtained by treating the hydrochloride salt in methanol solution with anhydrous ammonia. The free base melted at CH OH m6-m8°C. ; U.V.: λ _ V 279 mp (loge l|.13).

EXAMPLE 7 (+)-trans-l,2,3, , a,8, 9,l^a-Octahydro-3- (exo-7-norcarylmethyl)pyrldo[4' ,3' :2,3]a indolo[l,7-ab] [l]benzazeplne A solution of 7.05 g (0.0178 mole) of 1,2,3,4*8,9-hexahydro-3- [ (exo-7-norcaryl)carbonyljpyrido[41 ,31 !2 ,3 ]ln- dolo[l,7-ab] [l]benzazepine, which was made from 1,2,3*4,8,9- hexahydropyrido[4« ,3» :2,3 ]indolo[l,7-ab] [l]benzazepine and (exo-7-norcaryl)carbonyl chloride, in 100 ml of diglyme was added dropwise in a nitrogen atmosphere to a stirred mixture of 100 ml of 1M boron hydride in t^trahydrofuran and 400 m>. of diglyme. The mixture was heated at 110eC for twenty-three hours and cooled to about 20°C. Hydrochloric acid, 75 ml of ION HC1, was added; the mixture was refluxed at 100eC for one hour, cooled to about 60eC, and made basic with 100 ml of 505$ NaOH.

The product was isolated and purified by several extraction and recrystallization steps. Its m.p. was 186-l87eC.

Additional representative compounds of Formula (1) which can be made by the above-described processagare listed below: (lXt)trans-3-cyclohexylmeth l-l ,2,3, ,1»a,8,9,lita-octahydro= pyrido[ ,3' :2,3]indolo[l ,7-ab][l]benza?.epine hydro= chloride, m.p. 180°C. (dec.) 44042/3 (2 -)trans-3-cyclopentylmethyl-l,2 ,?,'( ,^a,8,9,l^a-octa yrtro pyridoC'i 1 , 31 : , 3 ]indolo[ 1 ,7-ab ][1 ]benzasepine hydrochloride, m.p. 263°C. (dec.) (3)&- rans-3-cyclopropyl-l ,2 ,3,** ,¾a,8,9 ,l¾a-octahydro= pyridoC^' ,3' :2,3]indolo[l,7-ab_][l]benzazepine hydro= chloride, m.p. 195¾ (dec.) (4 )tr nsi-3-(l-adainantylinethyl )-l ,2 , 3 ,JI ,'la , 8 ,9 ,lfia-octa= hydropyridoC1! 1 ,3' : ,3]indolo[l ,7-ab] [1 Jbenaazepine hydrochloride f m.p. 195-196°C (dec.) ( 5 ¾)irans_-3- (2-adamantylmethyl ) -1 , 2 , 3 , 1 , *»a, 8 , 9 , 1Ίa-octa» hydropyridoC^ * ,3* ; 2 , 3 ]indolo [1 , 7-ab ] [1Jbenzazeplne hydrochloride , m.p. 169-170°C (6)(f)Jtrans-3-cyc lohe tyInethyl-1 , 2 , 3 , *» , *»a , 8 , 9 , 1Ί a-oc a= hydropyrido[3J¾>¾a,8J9al|»a-ocbahydro-3-pen ylpyrldo'» [V ,3' :2,3]indolo[l,7-ab][l]benzazepine (9)(-+)ferans-l ,2,3 l ,* a,8,9 >l^a-octahydro-3-neopentylp.vrido= [Ί ' , 3' :2,3]indolo[l ,7-a ] [1 ]benzazepine Example 8 ( + )-trans-l ,2 ,3>4 ,4a,8,9,l4a-octahydropyrido[4 ' ,3' :2 ,?]= lnrtolo[l ,7-ab ][1 ]benzazeplne and salts thereof A solution of 4.2 ml of ethyl chloroformate in 35 ml dry benzene was added to a solution of 3.9 grains ( + )-trans-3-(cyclopropylmethyl)-l,2 ,3,** ,4a ,8 ,9 ,l4a-octahydro-pyrido[4' ,3' :2,3]indolo[l,7-ap_][l]benzazepine in 100 ml. dry benzene. The stirred solution was heated to reflux whereupon a white precipitate formed. Heating at reflux was continued for 3-1/2 hours and the reaction mass was cooled and filtered; 0.43 grams of solids were collected. Filtrate was evaporated to dryness leaving a heavy yellow oil. This was dissolved in 100 ml. n-butanol, 10 grams KOH pellets were added and the mixture was stirred at reflux for 1 hour. The mass was then cooled and concentrated and the residue was partitioned between toluene and water. The toluene solution was then extracted with water until the extracts were neutral, then the toluene solution was extracted four times with 100 ml. of 2N aqueous tartaric acid. The combined extracts were washed once with ether then basified with sodium hydroxide. The oily product was extracted twice into methylene chloride. The combined extracts were washed and dried over potassium carbonate. The solution was then filtered and evaporated to get a pale, yellow oil which crystallized under pentane. Recrystallization from about 50 ml. hexane/benzene gave 1.68 grams (+)-tran -l,2,3,4,4a,8,9,l4a-octahydro« pyrido[4« ,3» :2,3]indolo[l,7-ab][l]benzazepine, yellow crystals melting point 148.5-149.5°C.

The mother liquors from above were evaporated to dryness dissolved in ethanol, then treated with excess tartaric acid in ethanol. A yellow oil formed which ton heating at reflux in ethanol gave a white solid, the tartrate of ( + )-trjms-l ,2 , 3,4 ,4a, 8 ,9 ,l4a-octahydropyrido[ ' , ' : 2 , 3]indolo[l ,7-ab ][l ]benzazepine , Similarly, treatment of the mother liquors with ethanolic HC1 provides the corresponding hydrochloride , m.p. >325°C Example 9 ( + )-trans_-l,2,3,4 ,4a ,8 ,9 ,l4a-octahydropyrido(;4 ' ,3' :2,3 indoloLl »7-ab ][1 ]benzazepine A suspension of 70 grams of (+)-trans-3-(cyclopropyl= methyl)-l ^jS^i^ajS^jl^a-octahydrop ridoCi* ' ,3' : 2 , 3]indolo= [1 ,7-ab ][1 ]benzazepine in 500 ml. dry benzene was heated with a solution of 83 ml. ethyl chloroformate in 250 ml. benzene.

The solution was then heated at reflux for 3-1/2 hours, solids were filtered off (6.2 grams) and the filtrate was evaporated to give an oil which began to solidify. Recrystallization from 600 ml. ethanol gave 53. grams ethyl (+)-trans-» l^^ a^^.l^a-octah drop ridoC1*' ,3' :2 , 3]indolo[l ,7-ab ]» [l]benzazepine-3-carboxylate as a white solid, melting point m6.5-9°c.

The recrystallized ester was added to a solution of 60 grams KOH in 500 ml. n-butanol. The solution was heated 2 hours at reflux. The reaction mass was then cooled and concentrated to about 1/2 volume, then treated with toluene and water. The toluene layer was washed with water until the extracts were neutral. The toluene layer was then extracted with six portions of 250 ml. 1M tartaric acid in water. The combined extracts were then extracted once with ether, -then cooled and basified to pH greater than 11 with 50? sodium hydroxide. This caused formation of a precipitate. The material was then extracted with several portions of CH2C12. The extracts were combined, washed with water, dried over I^CO^, filtered, and evaporated to give an oil. This^ oil was taken up in about 75 ml. benzene arid the mixture was then diluted with about 300 ml. hexane. The solution was held at 4°C. overnight and crystalliza- tion occurred. The crystals were filtered, washed with benzene/hexane and dried. The product was 26.9 grams of (i )-trans-l,2 ,3 ,M .Ma .8.9. lMa-octahvdropyridor ' ,3' :2,3 indoloC l,7-ab][l]benzazepine in the form of yellow crystals with melting point 1¾8-1¾ °σ.

Example 10 (- )-trans-3-( 3-chloro-2-butenyl)-l ,2 ,3 ,M ,¾a ,8 ,9 ,l¾a-octa- hydropyridoC 4 ' ,3' :2 ,3]indolo[ l,7-ab][ ljbenzazepine A suspension of 2.76 g of (±)-trans-l ,2 ,3 ,Ma , 8 ,9 ,11 octahydropyridoCV ,3' ;2,3]lndolo[l,7-ab][l]benzazepine in 20 ml of dlmethylformamlde (D F) containing 2.3 ml triethyl3 amine was treated with 1.25 g of l,3-dichloro-2-butene.

Solution resulted immediately. The solution was stirred at room temperature for hours, by which time some white precipitate had formed. The reaction mixture was ooured into 150 ml of cold water, a gummy solid was separated and wasned oy decantation witn cold water, hecrystailization from ethanol gave 2.93 g of the title compound, .p .130-132°C .

Example 11 (±)-£raris-l,2 ,3,4 ,*»a ,8 ,9 ,l1'a-octahvdro-3-(2-propynyl)pyrido= CM' ,3' : 2,31 indolo[l,7-ab] [ljbenzazepine Propargyl bromide, 2.38 g, was added to a solution of (*)-trans-l,2,3, a,8,9,lMa-octahydropyrldo[M' ,3' :2,3 indoloC 1 ,7-ab ][ l]benzazepine (5.52 g) and trlethylamine (3 ml) in 90 ml DMP. The reaction mixture was stirred at room temperature for Ί-1/2 hours. Some precipitate had formed. The reaction mixture was poured into 300 ml of cold water. A solid precipitated which was filtered off and washed with cold water. Recrystallization pale yellow needles, m.p. 160-I6l.5°. An analytical sample was recrystalllzed again from ethanol to give almost colorless needles m.p. 162-163°C.

Example 12 (*)-trans- ~acetonvl-l ,2 , 3 , ^ ,^,8 ,9 , l^a-octahydropyrido- [ ,3' :2,3]lndolo[l,7- b][l]benzapeplne Trlethylamlne (5 ml) was added to a solution of 2.8 g of (i)-trans-l .2.3 ^ ^.g^l^a-oct hydro yrido" ,3' :2,3]indolo[lJ7-ab][l]benzazepine in 50 ml DMF, followed by addition of 1 g of chloroacetone in 5 ml DMP.

The mixture was stirred for 3.5 hours at room temperature, poured into 100 ml water, then extracted with ether. The ether was washed with water, dried with filtered, and evaporated to dryness in vacuo. The residue was dissolved in benzene, then chromatographed through basic alumina using benzene as eluant, to yield 1.5 g of the title compound with m.p. 128.5° (dec). An alternative name for the title comoound is (±)-trans-l-(l ,2 ,3, ,^,8,9,1^-= octahydropyridoC ,3' :2,3]indolo[l,7-ab][l]benzazepin-3-" yl)-2-propanone.

Example 13 (-)-trans-3-allyl-l ,2 ,3 , >^a ,8 ,9 ,lMa-octahydropyrido= [¾' ,3' :2,3]indolo i,7-ah][l]benzazepine, hydrochloride Triethylamine ( .2 ml))was added to 2.8 g (ti-trans-l^^^^a^^jl^ -octahydro yridoC ,3' :2,3 indolo[l,7-ab][l]benzazepine in 50 ml DMF, followed by slow additon of 1.6 g of allyl bromide in 5 ml DMP. This was stirred at room temperature for 3.5 hours then poured in 125 ml water and extracted with ether. The ether was to dryness in vacuo. The residue was dissolved in anhydrous ether and the title compound was precipitated by addition of hydrogen chloride. After recrystallization from acetone, m.p. of the product was 231-232.5°C (dec).

Example 14 (+) -trans-3-C ( 3-cyclohexen-l-yl )methyl ]-l ,2 , 3 ,4 ,4a , 8 ,9 ,l4a-= octahydropyrido[4 ' , ' : 2 , 3 lindoloCl , 7-ab_][ 1 ]benzazepine Triethylamine (10 ml.) was added with stirring to a solution of 5.5 g. (+ ) -trans -1,2, 3, 4, a, 8, 9 ,l4a-octahydro-= pyrido[ » ,3' :2,3]indolo[l,7-a_][l]benzazepine in 100 ml. chloroform, followed by addition, with stirring, of 5.76 g. (0.04 moles) 3-cyclohexene-l-carbonyl chloride in 10 ml. chloroform. The mixture was refluxed 2 hours then cooled and water was added. The organic layer was separated, dried over K^CO^, and evaporated to dryness in vacuo. Trituration of the residual oil in hexane pave (+)-trans-3-[ ( -cyclohexen-l-yl )carbonyl ]-l ,2 , , ,4a , 8 ,9 ,l4a-oct ahydropyrido[ ' , 3 ' : 2 , 3 ]= indolo[l ,7-ab_][l ]benzazepine , m.p. 156.5-158.5°.

This amide (7.4 p., 0.02 moles) was dissolved in 200 ml. benzene and added to 34 ml. of a reducing agent in 200 ml. benzene, with stirring, under a nitrogen atmosphere. The reducing agent was a 70¾ solution of sodium bis (2-methoxy= ethoxy )aluminum hydride in benzene. The resulting mixture was refluxed for 2 hours, then decomposed by slow dropwlse addition of 100 ml. aqueous 10% sodium hydroxide solution while coolinp in an ice bath. The organic layer was washed with water until neutral, dried over I^CO.-,, filtered and evaporated to dryness to yield the title compound as a solid which, after trituration in hexane, melted at 154.7-157.5°. 44042/3 The following additional compound"? of formula T can be prepared, p.p., by alkylation or by noylat! on/rerinct 1 <υ of the correspondlnp; compound wherein R is H, as described in Examples 10-11. (1) (i)-trans-3-[(3-cyclohexen-l-yl)methyl]-l,2,3,1,1a ,8,9 ,11; - octahydropyrido[1 ' ,3' : 2 , 3 ]indo] o[ ,7-ab ][1 ]benzazepine (2) (+)-trans-l ,2 , 3 , , a , 8 ,9 ,Ha-octahydro-3-( 3-methyl-2-= butenyl)pyrido[1' ,3' :2 ,3]indolo[l ,7-ab"][l]benzazepine (3) ( + )-tra^-3-(tr3ns-2-butenyl)-l,2,3,1>1aJ8,?,11a-octa= hydropyrido[1' ,3' :2,3]indolo[l,7-ab][l]benzazepine <4) (t)-trans^3-(cis-2-butenyl)-l,2,3,1,1a,8,9,11a-octa» hydropyrido[1< ,3' :2 ,3i]indolo[l,7-ab][l]benzazepine (5) (i)~trans-3-(3-butenyl)-1.2.3. .1a .8.9.Ha-octahydro- pyrido[1' ,3* :2,3]indolo[l,7-ab][l]benzazepine 6) (±)-tl^.3-(?-butynyl)-l,2.3,'»,fta.8.9.1'»a-octahydro. pyridoC 4 · , 3 ' : 2 , 33indolo[ 1 ,7-ab ][ l]ben*a*epine ( 7) (±)-tr^ns-3-L(3-cyclopenten-l-yl)methyl3-l^,3,1< ,^,= 8, ,li^a-octahydropyrido[^l, ,3' :2,3]indolo[l,7-ab]=» [l]benzazepine Pharmacological Testing The compounds of this Invention exhibit analgesic activity and sedative-tranquillzer effects. The analgesic activity is demonstrated by the Phenylquinone Writhing (PQW) test and the sedative-tranquillzer effects are demonstrative in the results of the rodent screen. The procedures used are described as follows: Primary Rodent Screens Decreased Locomotor Activity (L.M.A. ) Results given in: mg/kg po/mouse This reaction sign is measured subjectively by observing how an animal behaves when it Is removed from an observation cage and placed on a table ton. Untreated animals will immediately begin active exploration of their environment. Animals that have received a depressant compound will show a gradually decreasing responsiveness to a new environment. The degree of stimulation by the observer needed to produce active locomotion is rated on an arbitrary scale. This ranges from a score of -1 where only a slight touch of the animal's body is required to a -4 where the animal is unresponsive or minimally responsive to the application of a pain stimulus (pressure at the base ¾ of the tail). The is the oral dose producing an obvious decrease of locomotor activity (with a score of at least -1). Groups of 5 mice are given decreasing oral doses at 0.5 log intervals (300, 100, 30... etc.) until no behavioral effects are evident. Decrease of locomotor activity is indicative of general central nervous system depressant activity.

Ptosis (Pto.) Results given in: mg/kg po/mouse Degree of eyelid closure is used as a measure of central nervous system deoression. An animal is removed from its observation cage and allowed to remain outside of degree of eyelid closure is made on an arbitrary scale. Passive ptosis, i.e., eye closure that can be temporarily reversed by handling, is generally indicative of sedative activity for a psychotropic compound. (Active ptosis, i.e., eyelid closure that remains unchanged with handling is generally suggestive of a adrenergic blocking activity. It is a relatively rarely seen phenomenon). Only passive ptosis was observed for these compounds, the ED Λ for which is 50 reported.

Catalepsy (Cat . ) Results given in: mg/kg po/mouse The ability of an animal to remain in an abnormal position is used as another indication of central nervous system depressant activity. A test animal is removed from its observation cage and positioned so that its hind legs are on the table top and its front legs rest on the side of the observation cage. If an amimal maintains this position for at least 10 seconds, it is considered to be showing cataleptic behavior.

The analgesic activitv of the compounds of the present invention is f<"»v The results obtained with some compounds of this invention are presented in the Table below, in which codeine and chlorpromazine are used as the standards for comparison.

Compou d L.M. A. Cat. Pto. uu50 P.Q.W, I,R -CH2-CSCH > 300 > 300 > 300 > 300 86 0 CH^CH-(HCl) 11 11 > 300 Compound L.M.A. Cat . Pto. LD50 P.Q.W.

I,R » H- 56 178 80 >300 1 5 chlorpromazine (HC1) 5 6 6 - — codeine phosphate - - - - 19 * estimated The free amines of formula I and some of their pharmaceutically acceptable inorganic or organic acid addition salts are substantially insoluble in water. As C S depressants, they are best administered orally at a level of about 0.1 to about 10 milligrams per kilogram of body weight of the animal. Some addition salts of the compounds having formula I are more water-solu le and can be administered by subcutaneous or intramuscular injection. The dosage employed in such cases generally would be within the range of about 0.02 to about 5 milligrams per kilogram of body weight.

As analgesics, the compounds of this invention are administered orally at a level of about 0.1-10 mg/kg or parenterally at the rate of about 0.05-5 mg/kg of body The compounds of the present invention can be formulated into compositions comprising a compound of formula I together with a pharmaceutically acceptable carrier. The carrier may be either a solid or liquid, and the compositions can be in form of tablets, liquid- filled capsules, dry filled capsules, aqueous solutions, non-aqueous solutions, suppositories, syrups, suspensions, and the like. The compositions can contain suitable preservatives, coloring and flavoring agents. Some examples of the carriers which can be used in the preparation of the products of the invention are gelatin capsules; sugars such as lactose' and sucrose; starches; dextrans and cellulosics, such as methyl cellulose and cellulose acetate phthalate; gelatin; talc; stearic acid salts; vegetable oils such as peanut oil, sesame oil, olive oil, corn oil and oil of theobroma; liquid petrolatum; poly= ethylene glycol; glycerine; sorbitol; propyl ne glycol; ethanol; agar; water and isotonic saline.

In preparing the compositions of the invention for pharmaceutical uses, the conventional practices and precautions are used. The composition intended for parenteral administration must be sterile, and this can be accomplished either by using sterile ingredients and carrying out the production under aseptic conditions, or by sterilizing the final composition by one of the usual procedures such as autoclaving under appropriate temperature and pressure conditions. Customary care should be exercised that no incompatible conditions exist between the active components and the diluent preservative or flavoring agent or in the The compositions of the invention can be introduced into warm-blooded animals by the oral, rectal or parenteral route. This can be done by swallowing, in the case of liquid or solid preparations; by suppositories; or by injecting the liquid preparations intravenously, intramuscularly, intraperitoneally , or subcutaneous ly .

The compounds of this invention are administered to warm-blooded animals to produce the desired pharmacologic response. Dosage forms are prepared at various strengths depending on the potency of the compound and the desired effect. It is possible, for example, to estimate the probable human dose for analgesia by comparing the animal analgetic dose for the compound of this invention to the dose of a standard drug in the same animal system. Thus, the compound of Example 13 is shown to have analeesic activity compared to codeine phosphate.

Dosage Analgesic ED^-, Usual Form ^_ Human Dose S ronrth Codeine phosphate 19 mg/kg 15-300 mg/d y 15-60 mg Comoound of 1 m~Ag 1-15 mg/day 1-15 mg. Example 13 Since the compound of Example 13 is about 20X more potent than codeine phosphate its human dose is estimated to be 1-15 mg/day (1/20 the codeine dose). Dosage forms of the compound will ordinarily contain 1 to 15 mg of the active ingredient, however lower or higher strengths may be required depending on the age and condition of the patient being treated, the severity of the pain and the frequency of treatment required.

In a similar manner, by comparing the effects of a standard drug like chlorpromazine in the same animal systems as the compounds of this invention, the strengths of dosage forms for human use may be determined.

Dosar;* Cata- Usual Hu- Form LMA lepsy Ptosis man Dose Strem Chlorpromazine 5 6 6 10-1000 mg/day 10-200 Compound of . Example 12 2 15 ¾ 10-1000 mg/day 10-200 Compound of Example 13 j η n 10-1000 mg/day 10-200 Since the above compounds of this invention are similar in potency to chlorpromazine in animal tests, the human doses are estimated to be similar to those recommended for chlorpromazine .

Typical formulations of the type listed above which may be used for the administration of these compounds are: Example A Ingredients mp;/t¾blet (i)-3-(allyl)-l,?,3,1<,ila,8,9,li All of the above ingredients are passed through a suitable sieve, blended for 20 minutes, and compressed directly into tablets of 200 mg on a suitable tablet press using a 11/32" punch and die.

Examole B Ingredients mg/tablet lactose, USP 215 mg methylcellulose, USP 15 mg * talc, USP 6 mg starch, USP 10 mg magnesium stearate, USP mg color (If desired) q.s.

The lactose and active ingredient are wet granulated with a solution of methylcellulose in a blender until a satl: factory mass is achieved. The mass is dried and classified through an appropriate sieve. The remaining ingredients arc passed through an 80 mesh sieve and blended with the dried granulated material. The blend is then compressed into tablets on a suitable tablet press at a weight of 300 mg using a 3/8" punch and die.

Example C Ingredients mg/capsule (-)- S-aceton l-l^j . a.S^l^a-octahydro- 25 mg pyrido[ ,3' :2 ,3]indolo[l,7-ab][l]benza- zepine lactose, USP 100 mg magnesium stearate, USP 1 mg colloidal silicon dioxide, N.F. 2 mg The combined ingredients are blended and passed through a 0 mesh sieve, and the mixture is encapsulated into a two-piece hard gelatin No. 3 capsule on a suitable encapsulating machine at a net weight of 128 mg.

Claims (20)

CLAIMS:

1. Compounds of the formula: wherein : 3 Y is R or a group -COOR ; n is zero or one; X is an anion of a pharmaceutically suitable acid; and R is hydrogen; 3-chloro-2-butenyl ; benzyl; p¾«n€thy-l; acetonyl; C^-C5 alkyl; C^-C-. alkenyl; C^- ^ alkynyl; cyclopropyl; C4~Cg cycloalkylmethyl ; Cg-Cg cyclo- alkenylinethy1 ; exo-7-norcarylniethyl ; 1-adamanty] methy or 2-adamantylmethyl , 3 R is C1~C4 alkyl, and the hydrogens in the 4a and 14a positions are in trans relationship to each other.

2. The free base and the hydrochloride salt of Claim 1 in which R is hydrogen.

3. The free base and the hydrochloride salt of Claim 1 in which R is methyl.

4. The free base and the hydrochloride salt of Claim 1 in which R is cyclopropylmethyl.

5. The free base and the hydrochloride salt of Claim 1 in which R is ethyl.

6. The free base and the hydrochloride salt of Claim 1 in which R is isobutyl.

7. The free base and the hydrochloride salt of Claim 1 in which R is benzyl.

8. The free base and the hydrochloride salt of Cl,aim 1 In which R is exo-7-norcarylmethyl . - 2 -

9. The free base and the hydrochloride salt of Claim 1 in which R is l-adamantylme'thyl .

10. ; · 10. The free base and the hydrochloride salt of \ \ Claim 1 in wbichXR is 2-adamantyimethyl .

11. The free base and the hydrochloride salt of Claim 1 in which R is 3-chloro-2 -butenyl .

12. The free base and the h drochloride salt of Claim 1 in which R is 2-propynyl.

13. The free base and the hydrochloride salt of Claim 1 in which R is acetonyl.

14. 1¾. The free base and the hydrochloride salt of Claim 1 in which R. is allyl.

15. A pharmaceutical composition consisting essentially of a pharmaceutically suitable vehicle and means for producing an analgetic effect selected from compounds of Claim 1 wherein Y = R.

16. A -method for producing an analgetic effect in a warm-blooded animal (other than men) comprising administering to said animal an analgetically-effective amount of a compound of Claim 1 wherein Y = R.

17. A method of making a compound of Claim 1 having the formula Ia wherein the hydrogens in the ^a and l^ positions are in trans relationship to each other; n is zero or one; X is an anion of a pharmaceutically suitable acid; and Ra is benzyl; phenethyl; C^-C^ alkyl; cyclo- propyl ; cycloalkylmethyl ; exo-7- norcarylmethyl ; l-adamantylmethyl or 2-adaranty1methy ; which comprises reducing with boron hydride/tetrahydrofuran complex a compound of the formula - 1 If _ 44042/3 wherein 2 a R is the same as R , or is methoxy ethy 1 , 0 " 7 7 or is -C-R , where R is phenyl; benzyl; phenothyl ; hydrogen; C^-C^ alkyl; C2~C4 alkenyl; C3-C7 cYcl°alkyl methylcyclopropyl ; C^-C-j cycloalkenyl ; exo- 7-norcaryl ; 1-adamantyl; or 2-adamantyl; and thereafter optionally converting the free base to a salt by reaction with a pharmaceutically suitable acid.

18. A method of making a compound of Claim 1 wherein R is hydrogen which comprises reacting a compound of Claim 1 having the formula wherein the hydrogens in the ^a and l^a positions are in trans relationshin to each other and n is 0 or 1; ■* X is an' anion of a pharmaceutically suitable acid, and 44042/2 R^ is methyl; ethyl; benzyl; or cyclopropylmethyl ; 3 with a compound of the formula ClCOOR wherein 3 R xs C1-C4 alkyl; to form a compound of the formula: \ COOR then subjecting the latter comnound to hydrolysis or, when is benzyl to hydrolysis or hydrogenolysis .·

19. A method of making a compound of Claim 1 wherein ■ - i6 - 44042/3 *. R is as defined below, n is zero or one, X is the anion of a pharrriaceuticall v suitable acid, and v- the hydrogens in the ^a and lHa positions are in trans relationship to each other, which comprises alkylating the compound of Claim 1 wherein R is hydrogen, in the presence of an acid acceptor, with an alkylating agent R°Z ; wherein R is 3-chloro-2-butenyl ; benzyl; acetonyl; C^-C^ alkyl; C3~C-. alkenyl; C^-C^ alkynyl; C^-Cg cycloalkylmethyl ; Cfi-CR cycloalkenylmethyl ; exo-7-norcarylmethyl 1-adamantylmethyl; or 2-adamantylmethyl -Br; -I , or -OS (.0 R~ is CH phenyl or p_-tolyl ; and - i - 44042/3 ; RCZ can also be R9OS(0)2OR9, where R9 is C^-C^ alk li and thereafter optionally converting the free base to a salt by reaction with a pharmaceutically suitable acid.

20. . Method of making a compound of Claim 1 having formula wherein thr? hydrogens in the ¾a and l^a positions are in ans relationship to each other; n is zero or one; X is the anion of a pharmaceutically suitable acid; and cl R is 3-chloro-2-butenyl ; benzyl; p¾«rre'fc¾¾i-l,· C1~C5 alkv1'" C3~C5 al'kenyl; C.J-C-. alkynyl; C^-Cg cycloalkylmethyl ; Cg~Cg cycloalkenylmethyl , exo-7-norcarylroethyl ; 1-adamantylmethyl; or 2-adamantylmethyl ; 44042/3 which comprises acylating the compound of Claim 1 wherein R is hydrogen with an acylating agent of the formula 0 QCR wherein 4 , R xs 2-chloro-l-propenyl ; phenyl; benzyl; phonothyl; hydrogen; C1~C4 alkyl; ^-C^ alkenyl; C^- ^ alkynyl; styryl; C^-C^ cycloalkyl; methylcyclopropyl ; cycloalkenyl ; exo-7-norcaryl ; 1-adamantyl; or 2-adamantyl; 0 Q is -CI, -Br, C-^C^ alkoxy; R -C-0-; 0 0 5 II RJ_C-0-; or R 0-C-0-; if R is different from R and is C-^-C^ alkyl, provided that when R is hydrogen, R is methyl; R6 is C.-C, alkyl; _ ii9 - 44042/2 wherein R is as defined, above, then reducing the carbonyl group of the amide to a methyl= ene group with a metal hydride, then oDtionally converting the resulting free base to a salt by reaction with a pharmaceutically suitable- acid .