NO753165L - - Google Patents

Description

Aminobenzazocines and methods for their preparation.

The present invention relates to N-alkylated 8-amines

-2,6-methano-3_benzazocines that can be used as strong pain relievers, as well as intermediates and processes that can

■used for the production of said compounds.

Said N-alkylated-8-aminated-2,6-methano-3-benzazo-enes according to the present invention are 1,2,3,^,5>6-hexa-hydro-3-Q-8-RR'N- 5-X-6-Y-ll-Z-ll-Z»-2,6-methano-3-benzazocines with the following formula:

where:

Q is propyl, isobutyl, neOpentyl, allyl, 2-methyl-2-propenyl,

2-chloro-2-propenyl, cis-3~chloro-2-propenyl, cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl ,

R is hydrogen or methyl,

R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

sec-butyl, benzyl or cyclopropylmethyl,

X is hydrogen, methyl or ethyl,

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl,

Z is hydrogen, methyl, ethyl or. hydroxy, and

Z' is hydrogen, methyl or ethyl,

or acid addition salts of the above compound.,

In addition to the fact that they can be used as strong painkillers, some of the above-mentioned compounds of formula I can also be used as intermediates or starting compounds for the production of other compounds of formula I.

New intermediates which can be used for the preparation of the above compounds are 1,2,3,4,5,6-hexahydro-3~Q1 - 8-nitro-5-X-6-Y-ll-Z-ll-Z' -2j6-methano-3-benzazocines with the following formula:

where:

Q! is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl, . 2-methyl-2-propenyl, 2-chloro-2-propenyl,• cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl , cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl, X is hydrogen, methyl or ethyl,

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl,

Z is hydrogen, methyl, ethyl or hydroxy, and'

Z' is hydrogen, methyl or ethyl,

or addition salts of the above compounds.

One can reduce a 1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-ll-Z-ll-Z'-2,6-methano- 3-benzazocine of formula II by means of a method which can reduce the 8-nitro or 8-amino group without thereby reducing or converting the molecule' otherwise, whereby a corresponding 1,2,3-4,5,6 -hexahydro-3-Q'-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine (formula I or V).'

Furthermore, one can nitrate a 1,2,3,4,5,6-hexahydro-3_Q1 - 5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine, whereby one obtains prepared a corresponding 1,2,3,4,5,6-hexahydro-3-Q'-8-nitro~5-X-6-Y-ll-Z-ll-Z'-2,6-methano-3 ~benzazocine of formula II.

Other intermediates which can be used for the preparation of compounds of formula I are the following: 1,2,3,4,5,6,7,8,9,10"decahydro-3-Q'-8-hydroxyimino-5-X -6-Y-ll-Z-ll-Z'-2,6-methano-3~benzazocines with the formula:

where Q', X, Y, Z and Z<1> are as defined for formula II, and acid addition salts of these compounds. 1,2 ,3,4 , 5,6-,7,8,9 }10-decahydro-3-Q'-8-0kso-5-X-6-Y-11-Z-ll-Z'-2 ,6-methano-3-benzazocines of the formula: where Q', X, Y, Z and Z'' are as defined for formula II, as well as acid addition salts thereof. 1,2,3,4,5,6-hexahydro-3-Q°-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3- benzazocines of the formula: where Q° is hydrogen or benzyl' and R, R', X, Y, Z and Z' are as defined in formula I, as well as acid addition salts of these compounds. 1,2,3,4,5,6-hexahydro-3-Q"-8-RR'N-5-X-6-Y-ll-Z-ll-Z'-2,6-methano-3_benzazocines with the formula: where Q" is formyl, acetyl or Q* where Qx is propionyl, isobutyryl, pivaloyl,'.acryloyl, 2-methylacryloyl, 2-chloroacryloyl, . cis-3-chloroacryloyljcis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl, propioyl, cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl, and R, R'}X, Y, Z and Z' are as defined for formula I, as well as acid addition salts of these connections. 1,2J3345536-hexahydro-3-Q"-8-nitro-5-X-6-Y-ll-Z-ll-Z 2,6-methano-3-benzazocines of the formula: where Q", X, Y, Z and Z' are as defined for formula VI. 1,2,3,4,5,6-hexahydro-3-Q'-8-RR"N-5-X-6-Y-ll-Z-ll-Z 2,6-methano-3-benzazocines with the formula: where Q', X, Y, Z and Z' are as defined for formula II, R is hydrogen or methyl and R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or cyclopeopanecarbonyl, as well as acid addition salts of these compounds . 1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-ll-Z-ll-Z'-2,6-methano-3- benzazocines with the formula:

or Q", X, Y, Z and Z' are as defined for formula VI; -R is hydrogen or methyl; and R" is formyl, acetyl, propionyl,

butyryl, isobutyryl, benzoyl or cyclopropane carbonyl.

Mon. can'. dehydrate and rearrange a 1,2 ,3 ,4 ,5, 6 , 7 , 8 ,9 ,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-ll-Z-ll-Z '-2,6-methano-3-benzazocine with formula IV, whereby a corresponding 1,2,3,4,5,6-hexahydro-3-Q'-8-amino-5-X-6- Y-11-Z-11-Z'-2,6-methaneb-3-benzazoline.

Compounds of formula IV are prepared from the corresponding compounds of formula III, by using hydroxylamine or an acid addition salt of such compounds, e.g. hydr.oxylamine hydrochloride.

One can reduce a 1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methano- 3-benzazocine by a Birch-type reduction, whereby a corresponding 1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5- X-6-Y-ll-Z-ll-Z '-. 2,6-methano-3-benzazocine of formula III.

Furthermore, one can selectively hydrolyze et'1, 2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-ll-Z-ll-Z'-2 ,6-methano-3-benzazocine of formula IX by a method which effectively removes R" without thereby removing Q", whereby a corresponding 1,2,3,4,5,6-hexahydro-3- Q"-8-RHN-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine.

One can also reduce a 1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-ll-Z-ll-Z'-2,6-methano -3-benzazocine of formula VII by a method which effectively reduces 8-nitro to 8-amino without otherwise converting or reducing the molecule, whereby a corresponding 1, 2,3,4,5,'6-hexahydro- 3-Q"-8-aminob-5-X-6-Y-11-Z-11-Z'-2,6-methano-3_benzazocine.

One can also reduce a 1,2 , 3,4 , 5 ,6-hexahydro-3_QX-' 8-RR'N-5-X-6-Y-ll-Z-ll-Z'-2,6-methano -3-benzazocine of formula VI by a method which effectively reduces 3~Q to 3~Q without otherwise reducing or converting the molecule, whereby a corresponding 1,2,3,4,5,6-hexahydro- 3-Q-RR'N-5-X-6-Y-11-Z-ll-Z'-2,6-methano-3-benzazocine of formula I.

Compounds of formulas I-IX may each exist as one or more optical isomers or as a mixture thereof.

The symbols

and C*'Z' represent bonds that are oriented

below the paper plane if the plane in the tetralin group is considered to lie in the paper plane. When Z is methyl, ethyl or hydroxy, so indicated

the bond to be equatorial (eq) with respect to the tetralin moiety and trans with respect to Y. When Z is hydroxy, the 11-carbon atom is SR in chirality and the compound is in the so-called a-series of benzomorphanes-, as indicated by May and co-authors (see Nathan B. Eddy and Everette L. May, Synthetic Analgesics, Part IIB and Parts IIA and IIB, Pergamon Press, Oxford, 1966, pages II7-137). When Z' is methyl or ethyl, it is said to be axial (ax) with respect to the tetralin group and cis with respect to Y. When X is methyl or ethyl, it is said to be equatorial with respect to the hexahydrobenzazocine group or moiety and trans with respect to Y.

Compounds of the formulas I-VI and VIII are amino bases and react with organic and inorganic acids to form acid addition salts. Because of the basic amino groups, the free base formulas will react with organic and inorganic acids, and acid addition salts are formed. The acid addition salts can be prepared from any organic or inorganic acid. They can be produced in the usual way, e.g. either by directly mixing the base with the acid, or when this is not appropriate, by dissolving either or both compounds, be it the base or the acid separately in water or in an organic solvent, and then mixing the two solutions, or by dissolving both the base and the acid together in one solvent.

The resulting acid addition salt can be isolated by filtration, if it is insoluble in the reaction medium, or by evaporating the reaction medium so that the acid addition salt is obtained as a residue. The acid groups or the anions in these salt forms are in themselves neither new nor critical, and one can. thus, use any acid anion or acid-like compound capable of forming salts with bases.

Representative acids for forming said acid addition salts include formic acid, acetic acid, isobutyric acid, o-mercaptopropionic acid, trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, succinic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucinic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharinic acid, ascorbic acid , penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridi"ncarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid," isethionic acid, ■berizenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanesulfonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid

acid, phosphoric acid, arsenic acid and the like. The aforementioned acid addition salts can be used as sources for the production of the free bases by reaction with a stronger base. Thus, if one or more properties such as solubility, molecular weight, physical appearance, toxicity or the like give the base or the acid addition salt a form that makes it unsuitable for the purpose for which one wishes to use the compound, then it can easily be converted into another more suitable form. For pharmaceutical purposes, acid addition salts of relatively non-toxic and pharmaceutically acceptable acids are preferably used, e.g. hydrochloric acid, lactic acid, tartaric acid and the like.

Both the free bases and the acid addition salts can be crystallized

as crystalline solvates with crystallization solvent •

in different amounts and forms, eg..as the hydrate, sesqui-hydrate or ethanolate.

Different methods that can be used in practice

for the preparation of the present compounds will. now be described in more detail.

The method comprising reducing a 1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-ll-Z-ll-Z'-2, 6-methano-3-benzazocine of formula II can be made by any method which effectively reduces 8-nitro to 8-amino without thereby reducing or converting the molecule, e.g. by using iron and aqueous hydrochloric acid. As an auxiliary solvent, one can e.g. use ethanol. You can also use a buffering agent,

eg sodium acetate. The reduction speed can be regulated by heating or cooling. The process comprising reducing 1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-ll-Z-11-Z'-2,6- methano-3-benzazocines of formula VII, are carried out in a similar manner.

The process comprising dehydrating and rearranging 1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z -11-Z'-2,6-methano-3-benzazocine of formula IV is carried out

as an aromatization process and is thus carried out by any method which effectively dehydrates the oxime without thereby dehydrating or converting the molecule, e.g. using hydrochloric acid

and acetic anhydride. As a solvent, one can e.g. use acetic acid. The rate of aromatization can be regulated by heating or cooling. The use of hydrochloric acid and acetic anhydride on compounds of formula IV gives the corresponding compounds of formula VIII where R is hydrogen and R" is acetyl, and the corresponding compounds of formula IX where R is hydrogen and Q" and R" are both acetyl, and these can be isolated or they can be hydrolysed without isolation to remove acetyl.

Said 8-nitro-reductions and said 8-hydroxyimino-dehydration-rearrangement-hydrolysis reactions are alternative methods and give only the corresponding compounds of formulas I, V and -VI where R and R' are both hydrogen, "which can be used as intermediates for the production of the other compounds

of formula I, V and VI, where R is methyl and/or. R' is methyl,

ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, benzyl or cyclopropylmethyl, by an alkylation which is either carried out in a single step, e.g. by using a suitable ester of an inorganic acid or a strong organic acid, or by a multi-step process, e.g. by an acylation and reduction. A single-step alkylation is carried out, e.g. using dimethyl sulfate, ethyl iodide, propyl bromide, isopropyl bromide, butyl methane sulfonate, isobutyl bromide, sec-butyl bromide, benzyl chloride or cyclopropyl methyl bromide. Dimethylation is preferably carried out by catalytic hydrogenating methylation using formaldehyde and palladium on carbon as a catalyst, or alternatively by a so-called reductive methylation using formaldehyde and formic acid. Monobenzyl-

ring is preferably carried out by reductive benzylation using benzaldehyde and . sodium borohydride. In said multi-stage alkylation, the acylation step in said acylation-reduction sequence can give the corresponding compounds with the formulas VIII. and IX by e.g. uses formic acetic anhydride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyryl chloride, benzoyl chloride or cyclopropane carbonyl chloride. The reduction step in said acylation-reduction sequence can e.g. is carried out using diborane or lithium aluminum hydride, and results in a simultaneous reduction of Q<x>in compounds of formula IX to the corresponding group Q in compounds of formula I.

A third alternative process for preparing compounds of formula I is a process which involves reducing the corresponding 1,2,3,4,5,6-hexahydro-3-Q yt—8-RR'N-5-X- 6-Y-ll-Z-ll-Z'-236-methano-3-benzazocine with formula VI and this can be carried out by e.g. to use lithium aluminum hydride.

If one wishes to prepare a desired combination of Q, R and R' in compounds of formula I, this may necessitate the use of protective groups during said N-alkylation or N-acylation. Benzyl is. such a protecting group in compounds of formula VIII where Q' is benzyl, and can e.g. is removed by catalytic hydrogenation using palladium as a catalyst. Formyl and acetyl are such protective groups in compounds of formula VI where Q" is formyl or acetyl, and can, for example, be removed by hydrolysis.

In compounds of formula IX, R" can be selectively removed without removing Q" in a process which involves selectively hydrolyzing a 1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N- 5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine with formula IX, and this can e.g. is done by using diluted hydrochloric acid. The speed with regard to said selective hydrolysis can be regulated by heating or cooling.

The process involving a nitration of a 152,354,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3~benzazocine.as that a 1,2,3 34,5 >6-hexahydro-3-Q ' -8-nitro-5-X-6-Y-ll-Z-ll-Z '.-2 ,.6- methano-3-benzazocine with formula II, can be carried out by any method which effectively replaces nitro for hydrogen in the 8-position of the aromatic ring without simultaneously converting the molecule, and this can e.g. is carried out using nitric acid. A solvent is also preferably used, e.g. acetic acid. The rate of nitration can be regulated by heating or cooling the solution. 1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-ll-Z-ll-Z'-2,6-methano-3-benzazocines with formula VII can be similarly prepared by nitrating 1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-ll-Z-11-Z' - 2 ,6- methano-3_benz.azocins .

The process comprising reducing a 1,2,3,4,5}6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2/6 -methano-3-benzazocine is carried out by a reduction of the so-called Birch type (The Merck Index, 8th ed., Merck & Co., Rahway,

N.J., 1968, pp. Il4'6), e.g. using sodium and liquid ammonia. One can e.g. use an auxiliary solvent, e.g. a mixture of tetrahydrofuran and isopropyl alcohol. - 1,2,3,4,5,6,7,10-octahydro-3-Q'-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methano -3-benzazocine is an intermediate product and can be easily hydrolysed, e.g. using dilute hydrochloric acid, to a 1, 2 , 3 , 4 , 5 , ^ 6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-ll- Z-II-Z'-2,6-methano-3-benzazocine of formula II. If Q' is benzylic or allylic, then this can be removed by reduction, or replaced by one of the methods described below.

If one in compounds with formulas VI, VII and IX

wishes to introduce Q" by acylation of the corresponding compounds of formula V where Q° is hydrogen, compounds' of formula II

where Q' is hydrogen and compounds of formula VIII where Q' is hydrogen, respectively, one can e.g. use formic acetic anhydride, acetic anhydride, propionyl chloride, isobutyryl chloride, pivaloyl chloride, 2-methylacryloyl chloride, 2-chloroacryloyl chloride, cis-3-chloroacryloyl chloride, cis-3-chlorocrotonoyl chloride, trans-3-chlorocrotonoyl chloride, propioyl chloride, cyclopeopanecarbonyl chloride or 2,2 -dichlorocyclopropanecarbonyl chloride. Alternatively, Q" can be incorporated into compounds of formula VII by first acylating the corresponding 1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2, 6-methano-3-benzazocine and then nitrating the resulting 1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-ll-Z-ll-Z'-2 ,6-methano-3"benz.azocine as described above.

Thus ■Q can be built into compounds of formula I

by an acylation-reduction sequence through a suitable group Q<x>, as this can be done in connection with formula VI, VII or ,IX as described above, or alternatively by an alkylation of the corresponding compounds with formulas II, III

and VIII, where Q' is hydrogen, i.e. on the corresponding 1,2,3,4-5, 6-hexahydro-5-X-6-Y-ll-Z-ll-Z ' - 2 , 6-methano-3-benzaz'ocines before said 8-nitration or the corresponding 1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methano-3-benzazocines before Birch's reduction , e.g. using propyl bromide, isobutyl bromide, neopentyl bromide, allyl chloride, 2-methyl-2-propenyl chloride, 2-chloro-2-propenyl chloride, cis-3-chloro-2-propenyl chloride, cis-3-chloro-2-butenyl chloride, trans -3-chloro-2-butenyl chloride, propargyl bromide, cyclopropyl methyl bromide or (2,2-dichlorocyclopropyl) methyl bromide.

Some of the above-mentioned 1,2,3,4,5,6-hexahydro-3"Q'-5-X-6-Y-ll-Z-ll-Z'-2, 6-methano-3-benz 'azociher, 1,2,3,4,5 , 6-brexa-hydro-3-Q'-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methano -3-benzazocines, 1, 2 ,3 , 4 , 5, 6-hexahydro-3-Q"-5-X-6-Y-ll-Z -'ll-Z '-2', 6- ' methano- 3-benzazocines and 1,2,3,4,5,6-hexahydro-3-Q"-8-methoxy-5- X-6-Y-11-Z-11-Z'-2,6-methano- 3-benzazocines are known, and those that are not known can be prepared from the corresponding 1,2,3,4,5,-6-hexahydro-5-X-6-Y-ll-Z-ll-Z'-2 ,6-methano-3~benzazocines and 1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-ll-Z-ll,Z'-2,6-methano- 3-benzazocines by the methods described above Some of the aforementioned 1,2,3,4,5,6-hexahydro-5-X-6-Y-ll-Z-ll-Z'-2,6- methano-3-benzazocines and 1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methoxy-3-benzazocines are known, and those that are not known can, for example, be prepared from the corresponding 1,2,3,4,5,6-hexahydro-3-methyl-5-X-6-Y-ll-Z-ll -Z'-2,6-methano-3"benzazocines and 1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy y-5-X-6-Y-11-Z-11-Z'-2,6-methano-3_benzazocines, e.g. by a cyanogen rig with cyanogen bromide, after which the resulting 1,2,3,4,5,6-hexahydro-3-cyano-5-X-6-Y-ll-Z-ll-Z'-2,6- methano-3"benzazocines and 1,2,3,4,5,6-hexahydro-3-cyano-8-methoxy-5-X-6-Y-ll-Z-ll-Z'-2,6-methano -3-benzazocines These 1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy-5-X-6-Y-ll-Z-ll-Z *-2,6-methano -3-benzazocines which are not known can be prepared from the corresponding 1,2,3,4,5,6-hexahydro-3-methyl-8-hydroxy-5-X-6-Y-ll-Z-ll-Z '-2,6-methano-3_benzazocines by O-methylation, eg using diazomethane.

The various combinations of X, Y, Z and Z' as substituents in said 1,2,3,4,5,6-hexahydro-5-X-6-Y-ll-Z-ll-Z1 - 2,6- methano-3-benzazocines and 1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z '-2 , 6-methano-3~t >enzazocines are known and can be produced by known methods. See e.g. Eddy and May (reference given above), Parfitt and Walters (J. Med.. Chem., vol. 14, no. 7, 1971, pages 565-568), May et al. (J.- Med.. Chem., vol. 12, no. 2, 1969, pages 405-4.08), US Patent 3-320,265, British Patents 1,299,699 and 1,299,700 and Dutch Patent Application 73/14758.

The following examples illustrate the invention. The structures of the compounds appear from the reaction types. Confirmation of the structures is done by elemental analysis, ultra-violet spectra, infrared spectra, nuclear magnetic resonance spectra and/or mass spectra. Development of the reactions and the homogeneous composition of the products was determined by thin-layer chromatography and/or gas-liquid -chromatography Melting and boiling points or stated ranges for said properties are uncorrected unless otherwise stated.

Example 1

A. A solution of 3-(cyclopropylmethyl)-1,2,'3}4,5,6-hexahydro-cis-6j11-dimethyl-2,6-methane-3-benzazocine (Example 1 in US Patent 3- 38.2. 249 3 ll3o g) in 50 ml of acetic acid was added, while stirring and cooling at 2.5 - 5°C, to a solution of fuming nitric acid of 155 ml. as well as 90 ml of acetic acid. The temperature was allowed to rise slowly to room temperature. After standing overnight, the solution was purged with an air stream, then partially evaporated at 55-60°C under reduced pressure to 148 g of a yellow liquid to which was added a solution of 85 g of sodium hydroxide in water. The resulting solution in chloroform was washed with water, dried and concentrated to give 11.6 g of a red syrup. A solution of the red syrup in ether was then filtered. Addition of hydrochloric acid in ether to the filtrate and recrystallization of 10.3 g of product from ethanol, gave white crystals of .3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2,6-methano-3-benzazocine hydrochloride (7.2 g, m.p. 283-284°C). The free base was obtained as an orange syrup from the salt by

using sodium hydroxide, and is the compound of formula II where Q' is cyclopropylmethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. 13.2 g of iron powder was added in portions to a solution of 3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2 , 6-methano-3-benzazocin (the free base product of part A from this example) (11.6 g), in 35 ml of water, 60 ml of ethanol and 3 3 66 ml of concentrated hydrochloric acid, and the mixture was boiled under reflux. 5 g of sodium bicarbonate was added and the resulting mixture was filtered, after which the filtrate was concentrated under reduced pressure. Ether and ethanol were added to the remaining yellow syrup, and the resulting mixture was filtered. after which the filtrate was concentrated. Hydrogen chloride: was added a solution of 5 3 47 of the resulting red syrup in ethanol (total preparation of said product was 10.4 g). Recrystallization of the product (m.p. 303-306°C) from methanol to ether gave white crystals of 8-amino-3-(cyclopropylmethyl)- - 1,2,3,4,5,6-hexahydro-cis- 6,11-dimethyl-2,6-methanoT3-benzazocine dihydrochloride (2.71 g3 m.p. 314-316°C), and the free base of this compound is the compound of formula I where Q is cyclopropylmethyl. R is hydrogen, R' is hydrogen, X is hydrogen,

Y is methyl, Z is hydrogen and Z' is methyl.

C. A solution of 1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine (the free base is the compound described as 5,9 ~dimethyl-6,7-benzomorphane picrate and hydrochloride in J. Org. Chem., 24, 117 (1959), total 40.4 g) in 320 ml of acetic acid, was added a solution of 600 ml of 90 # nitric acid and 400 ml acetic acid while cooling at 4-6°C and stirring. It

resulting mixture was warmed to room temperature, poured over 4500 ml of ice water, acidified with 35% sodium hydroxide solution and then extracted with ether. The ether extracts were dried and concentrated to give 40.0 g of a syrup. Hydrogen chloride was added to a solution of the syrup in acetone. Recrystallization of 27.5 g of the product (m.p. 252-255°C)' from ethanol gave a white powder of 16.9 g of 1,2,3,4,5,6-hexahydro-6(eq ),11(ax)-dimethyl-8-nitro- .

2, 6-methano-3-benzazocine hydrochloride (2.66-268°C). The free base

of this compound is the compound of formula II where Q' is hydrogen, X is hydrogen, Y is methyl,. Z is hydrogen and Z' is methyl. D. Acylation of 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocine (the free base of the product from part C in this example) with cyclopropanecarbonyl chloride, gives 1,2,3,4,5,6-hexahydro-3~cyclopropanecarbonyl-8-nitro-6(eq), ll(ax)-dimethyl-2,6-methano- 3-benzazocine, i.e. the compound of formula VII wherein Q" is cyclopropanecarbonyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

E. Reduction of 1,2,3,4,5,6-hexahydro-3-cyclopropane-carbonyl-8-nitro-6(eq),11(ax)-dimethyl-2,6-methano-3~benzazocine ( the product from part D. of this example) using iron and hydrochloric acid gives 1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-amino-6(eq),11(ax)-dimethyl -2,6-methano-3-benzazocine, i.e. the compound of formula VI wherein Q" is cyclopropanecarbonyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

F. Reduction of 1, 2, 3, 4, 5, 6-hexahydro~3-cyclopropane-carbonyl-8-araino-6 (eq),11(ax)-dimethyl-2, 6-methano-3_benzazoc -in

(the product from part E in this example) using lithium aluminum hydride j gives 8-amino-3-(cyclopropylmethyl)-1,2 ,3 ,4 ,5 3 6-hexahydro-cis-6,11-dimethyl-2 ,6-methano-3-benzazocine which. is identical to the free base from part B in this example.

G. A solution of 3-(cyclopropylmethyl)-1,2,3,4.,5,6-hexahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3_benzazo- one (the free base from part A in Example 20 of US Patent 3-372.165>

50.0' g), 500 ml of tetrahydrofuran and 500 ml of isopropyl alcohol were added, while stirring approx. 1.5 liters of liquid ammonia under boiling with reflux. 69.5 g of sodium were then added in small pieces of approx..l g with stirring over the course of 1/2 hour. After the blue color of the solution had disappeared (which takes about 1 hour or so), 200 ml of methanol was added, the condenser was then removed and the ammonia left to evaporate overnight. The remaining cloudy solution was diluted with water and extracted with three 300 mL portions of ether. The ether extracts were washed with water and sodium chloride solution, dried and concentrated to give 2-(cyclopropylmethyl)-1,2,3,4,5,6,7jl0-octahydro-8-methoxy-6(eq),11(ax)- dimethyl-2,6-methano-3-benzazocine (45.4 g) and the product was divided into a 10 g and a 20 g portion, and one of the portions was converted to the hydrochloride salt using ether with hydrogen chloride, and then the product hydrolyzed. Three recrystallizations of the combined salt portions from benzene-methanol gave white, fine crystals of 3-(cyclopropylmethyl)-1,2,3>4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl -8-oxo-2,6-methano-3-benzazocine hydrochloride' (ca. 8.5 g, m.p. 206-208°C), and the free base is the compound of formula III where Q' is cyclopropylmethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

H. A mixture of 3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8-9,10-decahydro-6,11-cis-dimethyl-8-oxo-2,6-methano -3-benzazocine hydrochloride (the product from part G in this example, 1.0 g), 0.24 g of hydroxylamine hydrochloride, • 5 ml of ethanol and 5 ml of pyridine were refluxed for 3 hours, then diluted with water , made basic with sodium bicarbonate and extracted with chloroform. The chloroform extracts were dried and concentrated. Recrystallization of the residue from ethanol gives 3~(cyclopropylmethyl)-1,2,3,4,5,6,7}8,9,10-.decahydro-6,11-cis-dlmethyl-2,6-methano-3 -benzazocin-8-one-oxime, i.e. the compound of formula IV where Q' is cyclopropylmethyl,

X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl. On a larger scale, the product was obtained as white crystals with m.p. 190-193°C. I. 1.0 g of acetic anhydride was added to a solution of 3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl- 2,6-methano-3-benzazocine-8-oxime (the product from part H in this example, 2.2 g) in 20 ml of acetic acid. Gaseous hydrogen chloride was bubbled through the solution which was then refluxed for 1 hour and then evaporated for the solvent. 2N dilute hydrochloric acid was added to the residue and the mixture was heated on a steam bath for 2 hours, basified with aqueous ammonia and extracted with chloroform. The chloroform extracts were dried and concentrated. Ether added hydrogen chloride was added to a solution of the residue in methanol, giving 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2 ,6-methano-3-benzazocine and an infrared spectrum of this product showed that it was identical to the product from part B in this example.-

Example 2

A. A solution of 1,2,3,4,5,6-hexahydro-8-methoxy-cis-6,11-dimethyl-2,6-methano-3-benzazocine (described as 2'-methoxy-5, 9-dimethyl-6,7-benzomorphan in J. Org. Chem, 25, 986 (1960), 9.25

g), 130 ml of tetrahydrofuran and 130 ml of isopropyl alcohol were added while stirring approx. 400 ml of liquid ammonia with boiling below

backflow. Sodium was then added for approx. 15 pieces under continuous stirring during 1/2 hour.. After further stirring and after the blue color of the solution had disappeared, which took approx. 4 hours, 40 ml of methanol was added and the mixture was warmed to room temperature and allowed to stand overnight. The remaining colorless cloudy solution was diluted with 600 ml of water', and. then extracted with two 400 ml portions of ether. The ether extracts were washed with saturated sodium chloride solution, dried and concentrated to give 9.3 g of 1,2,3,4,5,6,7,10-octahydro-8'-methoxy-6(eq),11(ax)- dimethyl-2,6-methano-3-benzazocine as a tan oil. 8 ml of concentrated hydrochloric acid was added to a solution of 21 g of 1,2,3,4,5,6,7,10-octahydro-'8-methoxy-6(eq) ,11(ax)-dimethyl-2,6- methano-3-benzazocin in 50 ml of acetone, and the mixture was kept at 0<Q>C for 5 days. The crystalline product was collected in two portions. Each portion was separated, recrystallized from acetone and water, and the products combined, yielding white crystals of

1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-"3-benzazocin-8-one hydrochloride (11 g, 198-201°C in m.p.), and the free base of this product is the compound of formula III where Q' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A solution of 132,334,5,6,7,8,9,10-dehydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-one hydrochloride (the product from part A in this example, 2.0 g), 0.6 g of hydroxylamine hydrochloride, 10 ml of pyridine and 20 ml. ethanol was refluxed (2 h) and then concentrated. The product was triturated with isopropyl alcohol and dried to give white crystals of 1,2,3,4,5,6,7,8,9,-10-decahydro-6,11-cis-dimethyl-2,'6-methaneb -3-benzazocin-8-one-oxime hydrochloride (1.8' g, m.p. 237-240°C), and the free base of this product is the compound of formula IV where Q' is hydrogen,

X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

C. Gaseous hydrogen chloride was bubbled through a mixture of 1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-'methano-3-benzazocine -8-one-oxime hydrochloride (the product from part B

in this example, 4.0 g), 2.0 g of acetic anhydride and 15 ml of acetic acid. The resulting red solution was heated to reflux, the hydrogen chloride stream was stopped and the solution refluxed for 3 hours and then concentrated.

A resolution of the remaining red. syrup in 50 ml of 6N dilute hydrochloric acid was heated on a steam bath for 1 hour and then concentrated.

Recrystallization of the resulting purple crystals from aqueous alcohol gave pale pink crystals of 8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine -dihydro chloride hydrate (4 g, m.p. above 280°C, and the free base of this product is the compound of formula V where Q° is hydrogen, R is' hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

D. A mixture of 8-amino-1 32,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methane-3-benzazocine dihydrochloride hydrate' (the product from part C of this example , 2 g), 3 g of cyclopropanecarbonyl chloride, 20 ml of a saturated sodium bicarbonate solution and 30 ml of chloro-

form, was stirred at 0°C for 1 hour and then at room temperature for 1 hour. The chloroform layer was washed with a saturated sodium bicarbonate solution and concentrated to give 3.2 g of a yellow oil of N-(3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq ),11(ax)-dimethyl-2,6-

methano-3-benzazocin-8-yl)cyclopropanecarboxamide (3.2 g) and this is the compound of formula IX where Q" is cyclopropanecarbonyl,

R is hydrogen. R" is cyclopropanecarbonyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

E. A solution of N-(3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine -8-yl)cyclopropanecarboxamide (the product from part D in this example 3.8 g) in 30 ml of tetrahydrofuran was added to a solution of 50 ml of diborane in tetrahydrofuran (1 molar as BH^) while cooling at 0°C, after which the mixture was heated to boiling under reflux for 2 hours. 100 ml of 5N dilute hydrochloric acid was added and the clear solution was concentrated under reduced pressure. The aqueous residue was washed with ether, basified with sodium hydroxide solution (35%) and extracted with chloroform. The chloroform extracts were dried and concentrated to ∼3.2 g of a red oil. A similar reduction of N-(3~(cyclopropanecarbonyl)-1,2,3-4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3~benzazocine -8-yl)cyclopropanecarboxamide (5.8 g) also gave 5 g of a red oil. Recrystallization of the red oil from isopropyl acetate gave white crystals of 3-(cyclopropylmethyl)-8-(cyclopropylmethylamino)-1,2,3,4,5}6-hexahydro-cis-6,11-dimethyl-2,6-methano -3.-benzazocine hydrochloride (m.p. 229-232°C), and the free base of this product is the compound of formula I, where Q is cyclopropylmethyl, R is hydrogen, R' is cyclopropylmethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

Example 3~

A. 10 ml of formic acid was added dropwise while cooling to 0°C with 20 ml of acetic anhydride, and the resulting solution was heated to 50°C for approx. a quarter. A solution of 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methane-3-benzazocine (the free base of the product from part B in this example, 6.7 g) in 20 ml of formic acid was added dropwise while cooling to the former solution. The resulting mixture was refrigerated overnight and then the solvent was evaporated. The residue was basified with sodium bicarbonate and then with concentrated aqueous ammonia and then extracted with ether. The ether extracts were dried and then purified from ether to give N-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6 -methano-3-benzazocin-8-yl)-formamide (5 g), and this is the compound of formula VIII where Q! is cyclopropylmethyl, R is hydrogen, R" is formyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl. B. A mixture of N-(3_(cyclopropylmethyl)-1,2,3,4, 5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-formamide (the product from part Ai of this example, 5 g) and a solution of diborane in tetrahydrofuran (1M as. BH^-, 80 ml) was refluxed for 3 hrs., acidified with dilute 6N hydrochloric acid and then purified from tetrahydrofuran. The aqueous residue was washed with ether, basified with sodium hydroxide and extracted with ether. The ether extracts were dried and cleared of ether. To ether added hydrogen chloride was added a solution of the product in 3.5 g of ethanol, and this gave white crystals of 3-(cyclopropylmethyl)-1,2,3>4,5 ,6-hexahydro-cis-6,11-dimethyl-8-(methylamino)-2,6-methano-3-benzazocine dihydrochloride ethanolate hydrate (m.p. above 250°C), and the free base of this product is the compound of formula I where Q is cyclopropylmethyl, R is hydrogen, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

Example 4•

A. A mixture of 8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine dihydrochloride hydrate (the product from part C of Example 2 ,.total 10 g), 20 ml of acetic anhydride and 100 ml of pyridine were heated on a steam bath for 4 h and then the solvents were evaporated, giving N-(3-acetyl-1,2,3,4,5-6-hexahydro -6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-acetamide, i.e. the compound of formula IX wherein Q" is acetyl,

R is hydrogen, R" is acetyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A mixture of the entire product from part A of this example and dilute hydrochloric acid (2N) and ethanol in equal parts was heated on a steam bath for 2 hours, evaporated ethanol, cooled and made basic with ammonia and then extracted•with ether . The ether extracts were then dried. The product was crystallized from the ether solution and recrystallized from ethyl acetate to give white crystals of 3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2, 6-methano-3_benzazocine (m.p. 208-209°C), and this is the compound of formula VI'where Q" is acetyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is hydrogen C. A mixture of 20 g of 3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-cis-6 j11-dimethyl-2,6-methano-3 -.benzazocine (the product of part B in this example), 25 ml of 35-40% formalin, 180 ml of ethanol and a catalytic amount of 10% palladium-on-carbon were hydrogenated in a Parr apparatus at 55°C and then filtered. The filtrate was concentrated and the residue dissolved in ether. The ether solution was dried and evaporated to ether to give 17.7 g of an oil of 3-acetyl-1,2,3,4,5,6-hexahydro-6 (eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, i.e. this is the compound of formula VI where Q" is acetyl, R is methyl, R' is methyl,. X is hydrogen, Y' is methyl, Z is hydrogen and Z' is methyl. D. A mixture of 17 g of 3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3 -benzazocine (the product from part C in this example) and 200 ml of concentrated hydrochloric acid were boiled for 30 h under reflux and then concentrated. A mixture of the residue and water was basified with concentrated aqueous ammonia and then extracted with chloroform. The chloroform extracts were dried and concentrated. The picrate salt of the product was recrystallized from aqueous ethanol and freed from picric acid. The oxalate salt of. the product was recrystallized three times from absolute ethanol and then freed from the oxalic acid, yielding an oil of 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino )-2,6-methano-3-benzazocine, i.e.' the compound of formula V where Q° is hydrogen, R is methyl, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

E. 4 ml of cyclopropanecarbonyl chloride was added dropwise while stirring and cooling to ice temperature to a mixture of 3.5 g of 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8 -(dimethylamino)-2,6-methano-3-benzazocinoxalate (the oxalate salt of the product from part D

in this example), 100 ml of chloroform and 100 ml of a 1N sodium hydroxide solution. Stirring was continued at room temperature for 3 h, after which the mixture was basified with sodium hydroxide. The chloroform layer was washed with a saturated sodium bicarbonate solution, dried and evaporated for chloroform, yielding 4 g of 3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax) -dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, i.e. the compound of formula VI where Q" is cyclopropanecarbonyl, R is methyl, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

F. A solution of 4 g of 3-(cyclopropanecarbonyl)-1,2;3,4-5,6-hexahydro.-6 (eq),11(ax)-dimethyl-8-(dimethylamino)-2,6- methano-3-benzazocine (the product from part E in this example) in 20 ml of tetrahydrofuran was added dropwise with stirring to a suspension of 2 g of lithium aluminum hydride in 70 ml of tetrahydrofuran. The mixture was refluxed for 3 h and then cooled. A saturated sodium-potassium tartrate solution was added and the tetrahydrofuran layer was decanted and concentrated. A solution of the residue in ether was washed with water, dried and concentrated. Treatment of the residue with hydrogen chloride and two recrystallizations of the product

from ethanol gave a white powder of 3-cyclopropylmethyl-8-dimethyl-amino-cis-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine dihydrochloride (m.p. 243-246°C). The free base of this product is the compound of formula I where Q is cyclopropylmethyl, R' is methyl, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

G. A mixture of 14.2 g of 1,2,3,4,5,6-hexahydro-6(eq), 11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocine hydrochloride

i (the product from part C of Example 1), 9.5 g of sodium bicarbonate, 5.8 ml of benzyl chloride and 90 ml of N,N-dimethylformamide were refluxed for 4 hours, then filtered, after which the filtrate was concentrated centered. A solution of the remaining syrup in ether was filtered and acidified with ether to which hydrogen chloride was added. Two recrystallizations of the product of 18.2 g from ethanol gave a white powder of 1,2,3,4,5,6-hexahydro-3-benzyl-6(eq),11(ax)-dimethyl-8- nitro-3-benzazocine hydrochloride (257-2.58°C )'. The free base of this product is the compound of formula II where Q' is benzyl,

X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

H. A reduction of 1, 2 , 3 , 4 , 5 , 6-hexahydro-3.-benzyl-6 ( eq ) , 11(ax)-dimethyl-8-nitro-3-benzazocine hydrochloride (the product of part G in this example) using iron and hydrochloric acid gives 8-amino-' 3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6- methano-3-benzazocine, i.e. it is the compound of formula V where Q° is benzyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl..

I. A reductive methylation of 8-amino-3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine ( the product from part H in this example) using formaldehyde and formic acid gives 3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-

(Dimethylamino)-2,6-methano-3-benzazocine, i.e.' the compound of formula V where Q° is benzyl, R is methyl,. R.' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

J. Debenzylation of 3~benzyl-1,2,3,4,5,6-hexahydro-6(eq), 11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine ( the product from part I of this example) by catalytic hydrogenation using palladium as a catalyst gives 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-( dimethylamino)-2,6-methano-3-benzazocine, which is identical to the product from part D in this example.

K. Acylation of 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methane-3-benzazocine (the product of part D in this example) with cyclopropanecarbonyl chloride gives ,3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6- methano-3_benzazocine which is identical to the product from part E in this example.

Example 3

A. 8 ml of isobutyryl chloride was added dropwise to a solution of 4 g of 8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine (the free base of the product from part C in ex. 2) and chloroform. 50 ml of a saturated sodium bicarbonate solution was added and the mixture was refluxed for 2 hours. The chloroform layer was washed with saturated sodium bicarbonate solution, dried and concentrated to give a red oil of N-('3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11 (ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)isobutyramide, i.e. the compound of formula IX where Q" is isobutyryl, R is hydrogen, R" is isobutyryl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl..

B. A solution of 5 g of N-(3-isoburyryl-1,2,3,4,5,6-hexa-hydro-6(eq),11(ax)-dimethyl-2,6-methano~3- benzazocin-8-yl)iso-butyramide (the product from part A in this example), 200 ml of 6N dilute hydrochloric acid and 100 ml of ethanol were heated on a steam bath for 3 h, the ethanol was evaporated, after which the solution was washed with ether, acidified with sodium hydroxide and extracted with ether. The ether extracts were dried and concentrated, giving • 8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano- 3-benzazocine (approx. 4 g), i.e. the compound of formula VI where Q" is isobutyryl.., R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

C. A solution of 4 g of 8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine (the product from part B in this example) in 50 ml of tetrahydrofuran, a suspension of 2.5 g of lithium aluminum hydride in 100 ml of tetrahydrofuran was added with stirring. Stirring was continued and the mixture was refluxed for 3 hours and then cooled. A saturated sodium potassium bitartrate solution was added and the tetrahydrofuran layer was quenched and concentrated. Ether added hydrogen chloride was added to a solution of the residue in ethanol. Recrystallization of the resulting solid from ethanol and ether and then from aqueous ethanol containing concentrated hydrochloric acid gave as a white powder 8-amino-1,2,3,4,5,6-hexahydro-3-isobutyl-cis-6,11 -dimethyl-2,6-methano-3-benzazocine dihydrochloride (m.p. above 300°C).' The free base of this product is the compound of formula I where

Q is isobutyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

Example 6

A. A mixture of 3 g of 8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benz.azocine (the free base of the product

from part C of Example 2), 80 ml of chloroform, 80 ml of a saturated sodium bicarbonate solution and 5 nil of propionyl chloride were stirred at room temperature for 2 hours. The chloroform layer was dried and concentrated, giving as a red oil N-(3-propionyl-1,2,3-4,5,6-hexa-hydro-6(eq),11(ax)-dimethyl-2,6 -methano-3-benzazocin-8-yl)-propionamide, (4.2 g), and this is the compound of formula IX where Q" is propionyl, R is hydrogen, R" is propionyl, X is hydrogen, Y is methyl , Z is hydrogen and Z\ is methyl. B. A mixture of the whole product from part A in this example 50 ml of ethanol and 25 ml of 5N dilute hydrochloric acid was heated on a

steam bath for 1 hour and then diluted with water. The resulting mixture was washed with ether, basified with ammonia and extracted with ether. The ether extracts were washed with sodium chloride solution, dried and concentrated, and 8-amino-1,2,3,4,5,6-hexahydro-6(eq),11(ax)- was obtained as a red oil dimeth yl ^-propionyl^ , 6-methano-3~benzazocine (3 g), i.e. the compound of formula VI where Q" is propionyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

C A dissolution of the product from part B in this example

in tetrahydrofuran, a suspension of 0.6 g of lithium aluminum hydride was added with stirring for approx. 50 ml tetrahydrofuran. The mixture

was stirred under reflux for 1 hour and then cooled. A saturated potassium sodium tartrate solution was added and the mixture was filtered. The filtrate was concentrated. Treatment of the red oil remaining therein with hydrogen chloride and recrystallization of the product from methanol and ether gave as a white powder 8-amino-cis-6,11-dimethyl-l j 2, 3,,'4 , 5, 6-hexahydro~3 -propyl-2,6-methane-3-benzazocine dihydrochloride sesquihydrate (m.p. 202-207°C). The free base of this product is the compound of formula I where Q is propyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is hydrogen.

Example 7

A solution of 4.4 g of 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine (the free base of the product from part B in example 1), 3.2 g of benzaldehyde and 100 ml of ethanol were boiled under reflux for 2.5 hours and then cooled. 1.0 g of sodium borohydride was added and the resulting solution stirred at room temperature for 2 hours and then concentrated. The residue was diluted with 6% hydrochloric acid, washed with ether, basified with sodium hydroxide and extracted with ether. The ether extracts were washed with sodium chloride solution, dried and concentrated. Treatment of the remaining red oil of 5.2. g with hydrogen chloride and recrystallization of the product'. from ethanol, gave as a white powder 3-(cyclopropylmethyl)-1,2,3,4,5,6-hexa-hydro-cis-6,11-dimethyl-8-benzylamino-2,6-methano- 3-benzazocine dihydrochloride (m.p. 233-237°C). The free base of this product is the compound of formula I where Q is cyclopropylmethyl, R is hydrogen, R' is benzyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

Example 8

A, A mixture of 5.12 g of 1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine-8 -one hydrochloride (the product from part A in Example 2), 2.42 g of allyl bromide, 3.36 g of sodium bicarbonate and approx. 50 ml of N,N-dimethylformamide was heated to 140°C under stirring and nitrogen for 1 hour and then concentrated. The residue was mixed with water, ether and a saturated sodium bicarbonate solution. The ether layer was dried, treated with charcoal and then concentrated. An addition of ether plus hydrogen chloride to a solution of the residue in ethanol and a recrystallization of the product from ethanol and ether gave 4 g of 3-allyl-1,2,3,4,5,6,7,8,9 ,10-decahydro-6 (eq),11 (ax)-dimethyl-2,6-methano-3-benzazocin-8-one-hydrochloride, and the free base of this product is the formula III.where Q' is allyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A mixture of 1.7 g of 3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6 -methano-3-benzazocin-8-one hydrochloride (the product from part A in this example), 0.4 g of hydroxylamine hydrochloride, approx. 10 ml of pyridine' and approx. 20 ml of ethanol were boiled under reflux for 2 hours and then concentrated. A recrystallization of the residue from ethanol gave 3-allyl-1,2,3>A,5,6,7,8,9,10-deca-hydro-6(eq),11(ax)-dimethyl-2,6 -methano-3-benzazocin-8-one-oxime hydrochloride, and the free base of this product is the compound

■with formula IV where Q' is allyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

C. A refluxing mixture of 2.1 g of 3-allyl-1,2,3,4,5,6,7,8,9310-decahydro-6(eq),11(ax)-dimethyl-2, 6-methano-3-benzazocin-8-one-oxime hydrochloride (the product from part B

in this example), 0.7 g of acetic anhydride and approx. 30 ml of acetic acid was saturated with gaseous hydrogen chloride. The resulting red solution was refluxed for 2 h, then concentrated. A mixture of the residue and 40 ml of dilute 2N hydrochloric acid was heated for 1 hour on a steam bath and then concentrated. Crystallization of the residue from ethanol and recrystallization of the product from ethanol gave as a white powder 8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-3-(2- propenyl)-2,6-rnetano-3-benzazocin-dihydrochloride

(m.p. above 270°C). The free base of this product is the compound of formula I where Q is allyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z<1> is methyl.

Example 9

A. 20 ml of acetic anhydride and 10 ml of pyridine were added to a suspension of 3 g of 8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexa-hydro-cis-6,11-dimethyl -2,6-methano-3-benzazocine dihydrochloride (the product from part B of Example 1). in 100 ml of chloroform at approx. 0°C. The resulting solution was further stirred for 1 hour under cooling, washed with sodium bicarbonate solution, dried and concentrated to give as a red oil N-(3_(cyclopropylmethyl)-1,2,3,4,5,6- hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl,)acetamide, i.e. the compound of formula VIII where Q' is cyclopropylmethyl, R is hydrogen, R" is acetyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl. B. 0.5 g of lithium aluminum hydride was added to a soln. -ation of about 3 g of N-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3- benzazocil-8-yl)acetamide (the product from part A in this example) in 50 ml of tetrahydrofuran. The suspension was refluxed for about 2 hours and then cooled. A saturated sodium potassium tartrate solution was added, the mixture was then filtered, and the filtrate was concentrated. An ether solution of the residue was washed with water, dried and concentrated. Distillation of the remaining red oil gave as a yellow viscous oil 3_(cyclopropylmethyl)-8-(ethylamino)-1,2,3,4,5 , 6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine.

(700 mg, boiling point 155-160°C/0.03 mm Hg). This is the compound of formula I where Q is cyclopropylmethyl, R is hydrogen, R' is ethyl, X' is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

Example 10

A. A mixture of 4 g of -8-amino-3-(cyclopropylmethyl)-1,2,3}N,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin- dihydrochloride (the product from Part Bi Example 1), 4 ml of propionic anhydride, 8 ml of pyridine and 80 ml of chloroform were stirred overnight at room temperature. The resulting solution was washed with a sodium bicarbonate solution, dried and concentrated to give as a yellow oil N-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq), 11(ax)-dimethyl-2,6-methano-3_benzazocin-8-yl)-propionamide, a total of 3.8 g. This is the compound of formula VIII where Q' is cyclopropylmethyl, R is hydrogen, R" is propionyl, X

is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl. B. 0.75 g of lithium aluminum hydride was slowly added while cooling at 0°C to a solution of 3.8 g of N-(3-(cyclopropylmethyl)-1,2,3-,4,5,6-hexahydro-6 (eq) , 11(ax)-dimethyl-2,6-methano-3~benzazocin-8-yl)propionamide (the product from part A of this ex.) in 70 ml of tetrahydrofuran, and the resulting mixture was refluxed in about. 1 hour. Saturated sodium potassium tartrate solution was added, the suspension was filtered off and the filtrate was concentrated. Distillation of the remaining oil gave as a light brown to amber oil 3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-(propylamino)-2, 6-methano-3-benzazocine (2.0 g, bp. 155-160°C/0.05 mm). This is the compound of formula I where Q is cyclopropylmethyl, R' is hydrogen, R' is

propyl, X is hydrogen, Y is methyl, Z' is hydrogen and Z' is methyl.

■ Example 11

A. A mixture of 4 g of 8-amino-3-(cyclopropylmethyl)-.1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin- dihydrochloride (the product from part B in ex. 1), 4 ml of butyric anhydride, 5 ml of pyridine and 80 ml of chloroform were stirred at 0°C for approx. 2 hours. The resulting solution was washed with sodium bicarbonate solution and concentrated to give N-(3-cyclopropylmethyl)-1,2,3,4,5j6-hexahydro-6(eq),11(ax)-dimethyl as a yellow oil -2,6-methano-3_benzazocin-8-yl)butyramide, total 3.5 g- This is the compound with formula VIII where Q' is cyclopropylmethyl, R is hydrogen, R' is butyryl, X is hydrogen, Y is methyl, Z is hydrogen and Z<1> is methyl.

B. 0.75 g of lithium aluminum hydride was added while cooling at 0°C to a solution of 3.5 g of N-(3~(cyclopropylmethyl)-1,2,3,4,-5,6-hexahydro-6(eq ),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-butyramide (the product from part A in this example) in 100 ml tetrahydrofuran,. and the resulting mixture was refluxed for approx. 3 hours and then cooled. A saturated sodium-potassium tartrate solution was added, the suspension was filtered, after which the filtrate was concentrated. Distillation of the remaining oil gave an amber viscous liquid of 8-(butylamino)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6- methano-3-benzazocine (2.0 g, bp. 161-165°C/0.07 mm). This is the compound of formula I where Q is cyclopropylmethyl, R is hydrogen, R' is butyl, X is hydrogen, Y is methyl, Z is hydrogen and Z<1> is methyl.

Example 12

A. 250 g of benzyl chloride was added dropwise to a solution of 262 g of 3,4-diethylpyridine (Beilstein's Handbuch der Organischen Chemie, Vierte Auflage, 'Julius Springer, Berlin, 1935, P-253) in 700 ml of isopropyl alcohol. The resulting solution was refluxed for 12 hours and then concentrated under a vacuum pump. 250 ml of benzene was added to the residue and the solution was again concentrated. The procedure was repeated with two further portions of 250 ml and 500 ml of benzene. The rest now began to crystallize. 225.0 ml of benzene was added, and a thick suspension of 1-b.enzyl-3,4-diethylpyridinium chloride was obtained.

B. A Grignard reagent prepared from 85.5 g of magnesium, 407.g of benzyl chloride and 3020 ml of ether was added to the suspension product from part A in this example. Reflux boiling was maintained by the heat of reaction during the addition, and still,

by applying heat after the addition for approx. 1.5 hours. The reaction mixture was cooled in ice water containing 453 g of ammonium chloride, and the whole was made basic with aqueous ammonia. The ether layer was washed with water, purified from ether, which gave 712 g of 1,2-dibenzyl-3,4-diethyl-1,2-dihydropyridine.

C. A solution of 52 g of sodium borohydride in 260 ml of water

was added a solution of the entire product from part B in this example in 2 liters of ethanol. The mixture was stirred for 335 hours and left overnight at room temperature and then filtered. Water and ether were added to the filtrate. The ether layer was washed with water,

dried and concentrated. A vacuum distillation a-v the residue of 714 g gave two fractions of 408.2 g and 109.5 g respectively, which were only. partially reduced. Dry sodium borohydride was therefore added

42 g to a solution of most of the combined fractions, i.e. 515 g, in 1 liter abs. ethanol. The mixture was stirred at room temperature for 6 hours and then concentrated. Water and ether were added to the residue. The ether layer was washed with water, dried and concentrated. As the product still appears to be incompletely reduced, 40 g of dry sodium borohydride was added to a solution of the product in 1 liter of N,N-dimethylformamide. The mixture was allowed to stand overnight, diluted with 2 L of water and extracted with ether. The ether extracts were washed with water, dried and concentrated. Vacuum distillation of the residue gave as a yellow liquid 1,2-dibenzyl-3,4-diethyl-1,2,5j6-tetrahydropyridine (fraction II, bp. 148°C/0.2 mm - 170°C/0.1 mm , 203 g; fraction III, bp 154-17'8°C/0 .1 mm, most at 17.4°C, 172 g). D. A mixture of 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (fraction III from part C of this example), 1350 ml of 48% hydrobromic acid and 50 ml of acetic acid was boiled under reflux for 22 h. and then concentrated. The residue was treated with 35% sodium hydroxide solution and extracted with benzene while heating and stirring. The benzene extract was washed with water, dried and concentrated. Vacuum distillation of the residue of 155 g gave an orange syrup (fraction I: bp. l40°C/0.3 mm - l64°C/0.05 mm, 54.5 g; fraction II, b.p. 150-184< o>C/0.05 mm, '72.3 g) • .25 g of oxalic acid was added to a solution of fraction I of the orange syrup in ethanol (250 ml), and of 9.4 g of the oxalate salt (cf. p. 213-215°C). 32 g of oxalic acid was added to fraction II in 250 ml of ethanol, and here too the oxalate salt of 24.9 g (m.p. 216-221.5°C) was obtained. A mixture of 29.9 g of the combined oxalate salts, 400 ml of 10% sodium hydroxide solution and toluene was then stirred and then filtered. Concentration of the toluene layer gave the free base as a yellow syrup, weight 22.6 g. Treatment of the free base with hydrogen chloride gave the hydrochloride salt as a white solid, 23.8 g, m.p. 202-205°C. Recrystallization of 2.5 g of the hydrochloride salt from ethyl acetate gave cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methano-3-b'enzazocine hydrochloride (m.p. 210-212.5°C) . E. A mixture of 8.9 g of cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methane-3-benzazocine hydrochloride (the hydrochloride salt of the product from part .D of this example), 100 ml of ethanol and 0.4 g of 10% palladium-on-carbon were hydrogenated while heating to 50°C in a Parr apparatus, after which the entire solution was filtered. Concentration of the filtrate and treatment of the residue with ether gave 6.0 g of a white solid, m.p. 204-211°C. Recrystallization of a portion of the product (all but 2.65 g) of the white solid first from isopropyl alcohol-ether and then from isopropyl alcohol gave cis-6,11-diethyl-1,2,3,4,5, 6-hexahydro-2,6-methano-3-benzazocine hydrochloride (m.p. 208.5-211°C, approx. 3 g)• This hydrochloride salt was combined with two corresponding preparations, of 14, 5 g and 15.4 g. The combined hydrochloride salts were shaken with aqueous sodium hydroxide and toluene, after which the toluene layer was concentrated. Vacuum distillation of the residue gave the free base in three fractions (fraction I: bp. 78-90°C/0.03 mm,

3.29 g; fraction II: boiling point. 90-98°C/0.03mm, 14.32g; fraction III: boiling point. 98°C/0.03 mm, 9.69 gj.

F. 70 ml of 90% nitric acid was added in the course of 1 hour to a solution of 22.66 g of cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano- 3_benzazocine (the free base of the product from part E in this example) in 75 ml of acetic acid, cooled to 0°C, after which the mixture was left overnight at room temperature. 200 g of ice and 50 ml of water as well as 125 ml of 35% sodium hydroxide solution were added. The resulting oil solidified, giving two yields of a nitrate salt (31.3 g, m.p. 210-214°C, 0.8 g, m.p. 225-230°C). 21.8 g of the nitrate salt was triturated with sodium hydroxide solution (35$), water and ether. The ether layer was washed with water, dried and concentrated. Ether added hydrogen chloride was added to a solution of the resulting red syrup (16.4 g) in 200 ml of ethanol. Recrystallization of the first yield (11.0 g, m.p. 285-286°C) from isopropyl alcohol gave two yields of cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8 -nitro-2,6-methano-3-benzazocine hydrochloride (1.7 g, m.p. 293~294<Q>C, 7.1 g, m.p. 288-289°C). The free base of this product is the compound of formula II where Q' is hydrogen, X is hydrogen, Y is ethyl, Z is hydrogen and Z' is ethyl.

G. A mixture of 3.11 g of cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocine hydrochloride (the product from part F in this example), 2.0 g of sodium bicarbonate, 25 ml of N,N-dimethylformamide and 1.60 g of cyclopropyl methyl bromide were refluxed for 1.5 hours and then filtered. The solid was washed with ethanol, after which the filtrate was concentrated. The residue was washed with water and ether. The ether layer was washed with water, treated with charcoal and then concentrated. Ether to hydrogen chloride was added a solution of 3.0 g of the residue in 15 ml of ethanol, which gave 2.4 g of crystalline 3-(cyclopropylmethyl)-6(eq), 11(ax)-diethyl-1,2, 3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocine hydrochloride (m.p. 243-245°C). The free base of this product is the compound of formula II, where Q'• is cyclopropylmethyl, X is hydrogen, Y is ethyl, Z is hydrogen and Z' is ethyl.

H. A mixture of 2.4 g of 3-(cyclopropylmethyl)-6(eq), 11(ax)-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6- methano-3-benzazocine hydrochloride (the product from part G in this example), 6 ml of water, 11 ml of ethanol and 2.3 g of iron filings and two drops of conc. hydrochloric acid was heated on a steam bath with stirring for 7 hours. 1.5 g of sodium bicarbonate was added and the mixture was filtered. The solid was washed with ethanol, after which the filtrate was concentrated. The residue was partitioned between water and chloroform, and the chloroform layer was concentrated. Treatment of 3.6 g of the resulting syrup with ether gave a yellow powder. Addition of ether with hydrogen chloride to a solution of the yellow powder in ethanol gave crystals in two yields (0.9 g, m.p. 237°C , 0.9 g, m.p. 225-234 C). A pooling and a recrystallization of the two yields from aqueous acetone also gave two portions of white crystals of 8-amino-3-(cyclopropylmethyl)-cis-6, 11-diethyl-1,2,3,4,5,6-hexa-hydro-2,6-methano-3-benzazocine dihydrochloride (m.p. 290-292 C and m.p. 287-290'° (C, total 1.04 g). The free base of this product is the compound of formula I where Q is cyclopropylmethyl, X is hydrogen, Y is ethyl, Z is hydrogen and Z' is ethyl.

As mentioned above, compounds of formula I are strong analgesics, which can be shown by standard pharmacological procedures which are easily performed as done in the pharmaceutical industry. Thus, results for a particular compound can be easily determined without too much experimentation.

All compounds of formula I from the examples were tested and found to be active in the so-called acetylcholine twist test, a primary test for all analgesics. In this test, the ability of the compounds to prevent an acetyl-choline-induced writhing or convulsions in jus is determined. The following is an adaptation of the method of Collier and collaborators (Brit. J. Pharmacol. Chemother., 32, 295 (1968)) by Anne K. Pierson. An intraperitoneal injection of 3.2 mg per kg body weight of acetylcholine causes writhing in mice and this is a contraction of the abdomen, sometimes a simple writhing followed by a stretch of the hind legs. The mice were dosed with the test compound plus a dilution liquid or only with the said dilution liquid (control liquid) for 20 min. before the injection with acetylcholine was made, and was then observed for 2 min. after the injection. During this 2 min. observation period, mice that were not subjected to writhing were considered protected, while mice that were subjected to writhing and convulsions two or more times were considered not protected. The mice were dosed orally (usually from 150 - 200 mg/kg) or subcutaneously (usually from 75-100 mg/kg body weight). 15 mice were used per dose level. The ED5q~ values for the active compounds were calculated by an analysis as indicated by CI. Bliss, The Statistics of Bioassay, Academic Press, New York, 1952) on results taken from four or more appropriate dose levels. The following subcutaneous ED₂Q values were determined for compounds of formula I from the above examples.

Claims (20)

1. Process for the preparation of a 2,6-methano-3-benzazocine of formula I where: Q is propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl, trans-3~chloro-2-butenyl, propargyl, cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl, R is hydrogen or methyl, R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, benzyl or cyclopropylmethyl, X is hydrogen, methyl or ethyl, Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl, Z is hydrogen, methyl, ethyl or hydroxy, and Z' is hydrogen, methyl or ethyl, or an acid addition salt of such a compound, characterized in that (a) a corresponding compound of formula II is reduced where Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl, cis-3-chloro-2- butenyl, trans-3-chloro^-2-butenyl, propargyl, cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl, X, Y, Z and Z' have the same meanings as given above, or (b) dehydrates and rearranges a corresponding compound of formula IV: where Q', •X, Y, Z and Z' have the same meaning as stated above, or -Q' in the formulas II and IV is the same as Q or is hydrogen or benzyl, whereby a corresponding' compound with formula I or V, where both R and R' are both hydrogen atoms, Q<Q> is hydrogen or benzyl, and X, Y, Z and Z' are as indicated above, and if one obtains a compound of formula V where Q° is hydrogen, this acylates compound so that the corresponding compound of formula "IX: where Q", X, Y, Z and Z' have the meaning as stated above, - R is hydrogen or methyl and R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or cyclopropanecarbonyl, or where Q" is Q and Q and R" are the same and where Q is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl, 2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl, propioyl, cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl, after which said compound with formula IX is reduced as follows that a corresponding compound of formula I is produced where Q and R' are the same and R is hydrogen, or selectively' hydrolyzes the compound of formula IX so that the corresponding compound of formula VI is produced: where Q" is formyl, acetyl or Q*, where Q* has the same meaning as above, and R, R', X, Y, Z and Z' have the same meaning as above, or where R and R' are hydrogen, after which this compound is reduced so that the corresponding compound with formula I is produced where R is hydrogen and R' is hydrogen; or if a compound of formula V where Q° is benzyl is produced, this compound is alkylated so that a corresponding compound of formula V is produced where R is methyl and R' is different from hydrogen, this compound is debenzylated to produce a corresponding compound of formula V where Q° is hydrogen, R is methyl and R' is different from hydrogen, acylate the latter compound so that a compound of formula IV is produced where Q" is Q, R is methyl and R' is different from hydrogen, reduces the latter compound whereby a compound of formula I is produced where R is methyl and R' is different from hydrogen, and if desired, alkylates said compound of formula I where both R and R' are hydrogen, so that the corresponding compound of formula I is produced where R' is methyl and/or R' is different from hydrogen, and if desired, converts the basic compound of formula I into an acid addition salt. 2. Process for the preparation of a 2,6-methano-3-benzazocine of formula I, where Q,. R, R', X, Y, Z and Z' have the same meaning as stated in claim 1, or an acid addition salt of such a compound, characterized by reducing a compound of formula VI where Q" is Q - and Q R , R', X, Y, Z and Z' have the same meaning as stated in claim 1, and if desired, alkylates a compound of formula I where both R and R' are hydrogen atoms, so that a corresponding compound of formula I in which R is methyl and/or R' is different from hydrogen, and if desired, converts this compound into an acid addition salt. 3- Method according to claim 1 or 2, characterized in that X is hydrogen and Z is hydrogen. 4. Process according to claim 3, characterized in that X is methyl and Z' is methyl. 5. Process, according to claim 1 or 2, characterized in that 8-amino-3-(cyclopropyl methyl )-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine or an acid addition salt of this compound. 6. 2,6-methano-3-benzazpcine which can be used for carrying out a method according to claim 1, characterized see that said compound has formula II, where Q', X, Y, Z and Z <1> have the same meaning as stated in claim 1, or an acid addition salt of such a compound'. 7. Connection according to claim 6, k arak. teris, ert in that X is hydrogen and Z is hydrogen. 8. Compound according to claim 7, characterized in that Y is methyl and Z' is methyl. 9. Process for the preparation of compounds according to claim 6, characterized in that one nitrates a 1,2, 3, 4,5,6-hexahydro-3-Q'-5-X-6-Y-11-.Z-11 -Z'-2,6-methano-3-benzazocine whereby a 1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-ll is produced -Z-11-Z '-2', 6-methano-3_benzazocine, and, if desired, converts this basic compound into an acid addition salt. 10. 2,6-méthano-3-benzazocine which can be used for carrying out a method according to claim 1, characterized in that said compound has formula IV, where Q', X, Y, Z and Z' have the same meaning as stated' in claim 1, or an acid addition salt of such a compound. 11. A 1,2,3,4,5,6,7,8,9,10-decahydro-3-Q,-8-oxo-5-X-6-Y-11-Z-11-Z2, 6-methano-3-benzazocine, characterized by formula III where Q', X, Y, Z and Z' have the same meaning as stated in claim 1, or an acid addition salt of such a compound. 12. Method for producing compounds according to claim 11, characterized in that 1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z is reduced -11-Z'-2,6-methano-3-benzazocine by a Birch-type reduction and, if desired, converting the basic compound prepared into an acid addition salt. 13- 1,2,3,4,5,6-hexahydro-3-Q <0-> 8-RR'N-5-X-6-Y-ll-Z-ll-Z'-2,6- methano-3-benzazocine, characterized by formula V, where Q°, R, R', X, Y, Z and Z' have the same meaning as stated in claim 1, or et. acid addition salt of such a compound. 14. 1,2,3,4,5,6-hexahydro-3-Q"-8-RR, N-5-X-6-Y-ll-Z-ll-Z'-2,6-methano- 3-benzazocines which can be used for carrying out a method according to claim 2, characterized in that the compound has formula VI, where Q", R, R', X, Y, Z and Z' have the same meaning as stated in claim 1, or an acid addition salt of such a compound. 15. Method ■ for the preparation of compounds according to claim 14, where R' is hydrogen, characterized in that one selectively hydrolyzes a 1,2,3,4,5,6-hexahydro-3-Q"-8- RR"N-5-X-6-Y-ll-Z-ll-Z'-2J 6-methano-3-benzazocine of formula IX .'by a method which effectively removes the group R" without removing the group Q", and if desired, converts the free base produced into an acid addition salt.. . 16. Process for the preparation of compounds according to claim 14, where R and R' are hydrogen atoms, characterized by reducing a 1,2,3,4,5,6-hexahydro-3~Q"-8-nitro-5- X-6-Y-ll-Z-ll-Z'-2,6-methano-3-benzazocine of formula VII: where Q", X, Y, Z and Z' have the same meaning as stated in clause <y> 1, by a method which effectively reduces 8-nitro to 8-amino without otherwise reducing or converting the molecule, and if desired , converts the produced free base into an acid addition salt. 17. 1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-ll-Z-ll-Z <»-> 2,6-methano- 3-benzazocines, characterized by formula VII, where. Q", X, Y, Z and Z <1> have the same meaning as stated' in claim 1. 18. 1,2,3,4,5,6-hexahydro-3-Q,-8-RR"N-5-X-6-Y-ll-Z-ll-Z"-2, 6-methano- 3-benzazocine, kara 'k te. rice. rt-ved formula VIII: where Q', R, X, Y, Z and Z' have the same meaning as stated in claim 1, R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or cyclopropanecarbonyl, or an acid addition salt of such a compound. 19. A 1,2,3,4-,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-ll-Z-ll- Z'-2,6-methano-3-benzazocine, characterized by formula IX, where Q"', R, R", X, Y, Z and Z' have the same meaning as stated in claims 1 and 18. 20. Hexahydro-3-Q-8-RR'N-5-X-6-Y-ll-Z-ll-Z,-2,6-methano-3-benzazocines, characterized by formula I, where Q, R , R', X, Y, Z and Z' have the same meaning as stated in claim 1, or an acid addition salt of such a compound.