DK142984B - METHOD OF ANALOGUE FOR THE PREPARATION OF BENZOBICYCLOAL CANAMIN OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS - Google Patents

Description

(11} PRESENTATION 142984 C 07 C 87/458 DENMARK, 5 ”ln, c | 1 5 V. '91 c 07 c 93/00 C 07 C 135/02 § (21) Reputation No. 5920/71 (22) Filed Dec. 2, 1971 (24) Running day Dec. 2, 1971 (44) The application presented and the writ of publication published on 9 · Hl3 ·! '· 19 ^ 1

DIRECTORATE OF

PATENT AND TRADEMARKET A (30) prior, a notice from the

Dec 5 1970, 94985, US

(71) AMERICAN HOME PRODUCTS CORPORATION, 685 Third Avenue, New York, N.Y. 10017, US.

(72) Inventor: Meier Exra Friday, 157 Cedar Hollow Road, Paoli, Pennsylvania, US: John Richard Potoski, 652 Arch Street, Spring City, Pennsylvania = vania, US.

(74) Plenipotentiary in the proceedings:

The engineering firm Budde, Schou & Co._ (54) Analogous process for the preparation of benzobicycloalkanamines or pharmaceutically acceptable acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel benzobicycloalkanamines or pharmaceutically acceptable acid addition salts thereof. The compounds of the present invention exhibit analgesic and / or anti-inflammatory effects in standard pharmacological tests on animals.

The benzobicycloalkanamines prepared by the process of the invention have the general formula R1 R (i> 2 142984 where R is hydrogen, alkyl of 1-4 carbon atoms, alkyloxy of 1-4 carbon atoms, hydroxy, acyloxy of 2-8 carbon atoms or halogen, X means R 2 R 4 -N 2 or -N-> 0 é 5 R 1 represents alkyl of 1-4 carbon atoms or when X means R 2

V

R 1 can also mean hydroxymethyl or alkenyl of 3 to 5 carbon atoms, R 1 is hydrogen, alkyl of 1 to 4 carbon atoms or phenalkyl of 3 to 10 carbon atoms, R is hydrogen, alkyl of 1 to 4 carbon atoms, or alkenyl of 3 carbon atoms, R4 is alkyl of 1-4 carbon Π atoms, R is alkyl of 1-4 carbon atoms, and n is 3, 4 or 5, or are acid addition salts thereof.

The process of the invention is characterized in that a) an imino compound of the general formula R

C

wherein R is hydroxy, alkoxy of 1-4 carbon atoms or has the same 2 g of 2 e 7

meaning R, although R ° does not have the same meaning as R when R

7 means alkoxycarbonyl of 2-5 carbon atoms, R means alkoxycarbonyl of 2-5 carbon atoms, alkyl of 1-4 carbon atoms, alkenyl of 3-5 carbon atoms or hydroxymethyl, and R, R and n have the meanings previously defined, reduced or b) a compound of the general formula. - <CV X.

R-y ^ XCH

I I It W

where x + y is equal to n-2, Y means r2 or ^ C = NR6 \ r4 / 2 3 6 7 and R, R, R, R, R and n are as previously defined, reduced, reduced, and if desired alkylates or alkenylates a formed compound of 3 the general formula (I) wherein R represents hydrogen to form 3 a compound of the general formula (I) wherein R represents alkyl of 1-4 carbon atoms or alkenyl of 3-5 carbon atoms and / or a compound wherein R is hydrogen and R is alkyl of 1-4 carbon atoms, or alkenyl of 3-5 carbon atoms is alkylated or phenalkylated to form a corresponding compound wherein R is alkyl of 1-4 carbon atoms or phenalkyl having 7-10 carbon atoms, 23 and / or a compound wherein R and R are alkyl of 1-4 carbon atoms are oxidized in a manner known per se to form the corresponding N-oxide, and / or a compound of general formula (I) wherein R is alkyloxy of 1-4 carbon atoms or acyloxy of 2-8 carbon atoms is converted on its own known manner for a compound of general formula (I) wherein R is hydroxy and / or a compound of general formula (I) wherein R is hydroxy is converted in a manner known per se into a compound of general formula formula (I) wherein R is acyloxy of 2-8 carbon atoms and / or a free base of general formula (I) is converted to a pharmaceutically acceptable acid addition salt.

Generally, the compounds of general formula (I) in the form of acid addition salts have high melting point physical properties, are white crystalline solids and are substantially soluble in water and polar organic solvents such as lower aliphatic. alcohols and the like. By IR and NMR spectroscopy of the compounds prepared by the method of the invention, the data obtained confirm the above molecular structure. Taken together, the above physical properties together with the microanalytical data obtained, the nature of the starting materials and the method of synthesis positively confirm the structure of the compounds.

Many of the compounds of general formula (I) exhibit an analgesic effect in animals, as established by standard pharmacological tests. The analgesic effect of the compounds can be demonstrated by a modified test method described by D'Amour and Smith in Journal of Pharmacology 72:74 (1941), which is a recognized test for analgesics. In this test, the compound is administered orally, intraperitoneally or intramuscularly, and the time required for a response to a high-intensity light beam response to the tail is measured. The compounds of this invention generally exhibit analgesic activity in rats at a dose of 3.15 mg to 125 mg per day. kg of body weight by oral or intraperitoneal administration and from 0.16 to 10.0 mg per day. kg body weight by intramuscular administration. In the following 4142984 Table I, test data and results obtained by the method described above are given.

Compound Analgesic effect 123 Administration R R _R__R n path Dose A / T ** H Methyl Η H 5 i.p. 25 2/5

Methyl Ethyl Η Η 4 i.p. 50 5/6

Acetoxy Methyl Η H 4 i.p. 10 5/10

Acetoxy Methyl Η H 5 i.m. 1.25 3/6

Fluoromethyl Η H 5 i.p. 25 2/5

Methoxy Allyl Η H 4 p.o. 12.5 6/10

Methoxy n-Propyl Η H 4 i.p. 50 5/5

Hydroxy Ethyl Η H 3 i.p. 6.25 4/6

Methoxy Methyl Phenethyl H 3 i.p. 50 7/10

Methoxy Methyl H Allyl 4 i.p. 50 3/5

Hydroxy Methyl Methyl Methyl 5 p.o. 12.5 7/10 + Methoxy. Methyl Methyl Methyl 5 p.o. 12.5 7/10 + / r2

This compound is an N-oxide, i.e.-N

0ν 0

XMG / kg

Relationship between number of rats with analgesic effect and number of experimental rats.

i.p. - intraperitoneal i.m. - intramuscular p.o. - everywhere

According to the invention, the following compounds are preferred because of their particularly advantageous analgesic effect.

6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H - benzocyclonone-12-amine 12-Amino-6,7,8,9,10, 11-hexahydro-5-methyl-5,1-methano-5H-benzocyclonone-3-ol 5-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,1-methanol 5H-benzo-cyclonone-12-amine 12-Amino-6,7,8,9,10,11-hexahydro-5-ethyl-5,10-methano-5H-benzocyclonone-3-ol 13-Amino -5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano - benzocyclodecen-3-ol.

The compounds listed in the following table are administered to rats in the manner set forth in the table, and the analgesic potency of the compounds is measured by the method previously described. The ED ^ q values are determined.

Table ED50

Compound Administration (mg / kg body weight) 6,7,8,9,10,11-hexahydro-3-methoxy-intraperitoneal 25 -5-methyl-5,10-methano-5H-benzoal cyclonone-12-amine 12-amino-6,7,8,9,10,11-hexahydro-intraperitoneal 7.5 -5-methyl-5,10-methano-5H-benzo-intramuscular 1,8 cyclonon-3-ol oral 23 5 ethyl 6,7,8,9,10,11-hexahydro-intraperitoneal 3,5 -3-methoxy-5,10-methano-5H-benzo-intramuscular 13.5 cyclonone-12-amine oral 11 12-amino 6,7,8,9,10,11-hexahydro-intraperitoneal 3,5 -5-ethyl-5,10-methano-5H-benzo-intramuscular 0.25 cyelononen-3-ol oral 12 3-methoxy-5 methyl 5,6,7,8,9,10, intraperitoneal 4,5 11,12-octahydro-5,11-methano-intramuscular 15-benzoeyclodeene-13-amine oral 9 13-amino-5-methyl-5,6 , 7,8,9,10, - Intraperitoneal 1.1 11.12-Octahydro-5,11-methano-intramuscular 0.47 -benzocyelodecen-3-ol oral 9 6 142984

Other preferred compounds of general formula (I) are those where n is 3. These compounds generally have analgesic effect in warm-blooded animals and also have anti-inflammatory effect in animals, as confirmed by standard pharmacological tests. The anti-inflammatory effect of the compounds can be demonstrated by the test method described by Winter et al in Proceedings of the Society of Experimental Biology and Medicine, 111: 554 (1962) and by Buttle et al Nature 179: 629 (1957), which is a widely recognized test for anti-inflammatory agents. In this test, the compound is administered orally in the form of a solution or suspension in distilled water to a group of six rats. After 1 hour, edema is induced in the rat by infecting the leg with a 1% carrageenin solution. The paw voucher is measured immediately after infection and after 5 hours. The ability of the compounds to reduce the volume of edema thus induced compared to a similar number of control animals is an expression of the anti-inflammatory effect. The above-mentioned compounds generally exhibit anti-inflammatory action in rats at a dose of from 50 mg to 100 mg per day. kg body weight.

In process a), the imino compounds of general formula (II) can be reduced by standard reduction methods, e.g. with hydrogen using catalysts such as Raney nickel or platinum oxide, with boron and aluminum hydrides and the complex metal hydrides derived therefrom, or with an alkali metal, preferably sodium in an alkanol, e.g. ethanol or isopropanol. When the reduction of an oxime amino compound is catalytically carried out, reaction 2 proceeds stepwise, the imine of formula (II) wherein R is hydrogen can be isolated as an intermediate which can then be reduced to the desired primary amine. Examples of methods for implementing the various optional finishes, e.g. the hydrolysis of a compound wherein R is alkoxy to form a compound wherein R is hydroxy is set forth below.

2 3

A primary amine wherein both R and R are hydrogen may 2 e.g. is converted to a secondary amine wherein R is hydrogen and R 3 is alkyl or alkenyl, by reaction with a halogen compound of the general formula

Hal-R

3 '3' 7 where Hal represents chlorine or bromine and R is alkyl or alkenyl, preferably in the presence of an organic base. A secondary amine wherein R 3 is hydrogen and R is alkyl or alkenyl can be alkylated or phenalkylated to form a tertiary amine. For example, the secondary amine may be reacted with a halogenated formate ester and then reduced to form the tertiary amine wherein R is methyl.

The halogen formate ester can also be reacted in a similar manner with the primary amine in which both R and R are hydrogen to form an N-methyl secondary amine. Other tertiary amines may be prepared by acylating the secondary amine to form a compound which corresponds to the compound of formula (I), but wherein R is acyl and the acylated amine is reduced. Oxidation of di-alkyl tertiary amines to form the corresponding N-oxides is conveniently carried out by treatment with an organic peracid.

In process b), the benzobicycloalkanamines are prepared by reducing a compound of formula (V), after which the previously described post-treatments can be carried out to prepare other compounds of general formula (I). The reduction can be carried out using standard methods in which the olefinic bond can be catalytically reduced or by means of borohydride reducing agents such as sodium borohydride and aluminum chloride in diethylene glycol dimethyl ether, sodium borohydride and boron trifluoride in diethylene glycol dimethyl ether, diborane in tetrahydro-2 -butylboron in tetrahydrofuran. Any imino substituents present will simultaneously be reduced to the corresponding amines and alkoxycarbonyl substituents will be reduced to the corresponding alcohol.

The imino compounds of general formula (II) generally have physical properties such as water insolubility, but solubility at elevated temperature in polar organic solvents such as lower aliphatic alcohols and the like.

IR and NMR spectroscopic analysis of the imino compounds of general formula (II) prepared by the procedure described below confirms the previously described molecular structure. Taken together, the physical properties, nature of the starting materials and the synthesis method positively confirm the structure of the compounds of general formula (II).

8 142984

The imino compounds of general formula (II) can be prepared by reacting a tricyclic ketone of general formula (III) (m) 7 wherein R, R and n are as previously defined, with a compound of formula h2nr6 wherein R previously stated meaning.

As general physical properties of the compounds of general formula (III), it can be stated that they are high boiling liquids which are practically insoluble in water but soluble in conventional organic solvents such as di (lower) alkyl ethers, di (lower) alkyl ketones , lower aliphatic alcohols, chloroform and the like. The IR and NMR analysis data of the compounds prepared by the procedure described below confirm the previously stated molecular structure. The physical properties together with the nature of the starting materials and the synthesis method positively confirm the structure of the compounds of general formula (III).

The tricyclic ketones of the general formula (III) can be prepared by cyclizing a halogen, alkylsulfonyl or phenesulfonyl or tetrahydropyranyloxyalkyltetralone of the general formula

r8 Rs <? h2VY

j ° (iv) 9 1429 84.

8 wherein n is as previously defined, R is hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, acyloxy of 2-8 carbon atoms or halogen, R means alkoxycarbonyl of 2-5 carbon atoms, alkyl of 1 -4 carbon atoms or alkenyl having 3-5 carbon atoms, Y means halogen, preferably chlorine or bromine, lower alkylsulfonyl, phenensulfonyl or tetrahydropyranyloxy, and optionally converting a compound of formula (III) wherein R is alkoxy to a corresponding compound wherein R means hydroxy, e.g. by acid hydrolysis. The cyclization is preferably carried out with a strong base, e.g. sodium hydride or an alkali metal oxide.

As general physical properties of the compounds of general formula (IV), it can be stated that they are high boiling liquids which are practically insoluble in water, but soluble in conventional organic solvents such as di (lower) alkyl ethers, di (lower) alkyl ketones, lower aliphatic alcohols, chloroform and the like. IR and NMR spectroscopic analysis of the compounds prepared according to the method described below confirms the previously mentioned molecular structure. The physical properties as well as the nature of the starting materials and the synthesis method positively confirm the structure of the compounds.

The compounds of general formula (IV) are used as intermediates in the preparation of the amines of general formula (I).

The compounds of general formula (IV) can be prepared by alkylating a tetralone of general formula 8

Where R8 and R9 have the previously stated meaning, preferably in the presence of a strong base, e.g. sodium hydride or an alkali metal alkoxide, with a compound of the general formula

X - (CH) - Y

wherein Y and n are as previously defined and X is halogen, preferably chlorine or bromine, lower alkylsulfonyl or phenylsulfonyl, and optionally, when Y is tetrahydropyranyloxy, by hydrolyzing the product, preferably with aqueous mineral acid, and converting the resulting one. alcohol for another compound of general formula (IV), e.g. by treatment with a lower alkylsulfonyl or phenesulfonyl halide, e.g. the chloride, preferably in pyridine.

For the purposes of the above general formulas, alkyl of 1-4 carbon atoms is meant straight-chain and branched groups of 1-4 carbon atoms, e.g. methyl, ethyl, n-propyl, b-butyl and 1-butyl. By alkenyl having 3-5 carbon atoms is meant groups, including straight and branched groups, having 3-5 carbon atoms, e.g. allyl, 2-butenyl, 3-methyl-2-butenyl, 2-methyl-2-butenyl and 2-pentenyl. Phenalkyl means an alkyl group, as defined above, substituted at an end position with a phenyl group, e.g. benzyl or phenethyl. Phensulfonyl means a phenyl or substituted phenylsulfonic acid group, e.g. phenylsulfonyl or p-toluenesulfonyl. Acyloxy means either an aliphatic or an aromatic carboxylic acid group which, if aliphatic, contains from 2 to 8 carbon atoms either in straight chain, branched or cyclic to a carbocyclic ring, e.g. acetyloxy, propionyloxy, butyryloxy, i-butyryloxy, cyclohexanoyloxy or cyclopentanoyloxy. If the acyloxy group is aromatic, it may contain an unsubstituted aromatic core or an aromatic core substituted with lower alkyl, e.g. benzoyl, o-, m- or p-toluyl.

The process of the invention and the preparation of starting materials are further illustrated in Scheme A below, wherein the compounds are provided with Roman numerals for identification. In Scheme A, the reaction sequence is illustrated in the preparation of specific primary amines of formula (I), namely 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone -12-amine (XI), 12-amino-6,7,8,9,10, 11-hexahydro-5-methyl-5> 10-methano-5H-benzocyclonone-3-ol (XIV) and 12-amine amino-6,7,8,9, 10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyelonone; 3-ol acetate (XV), specific secondary amines of formula (i), namely N -allyl-6,7,8, - 9,10,11-hexahydro-1-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-amine (X) and N, 5-dimethyl-6, 7,8,9,10,11-hexahydro-3-methoxy-5,10-methyl-11H-benzocyclonone-12-amine (Xa), a specific example of a compound of formula (II), viz. 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one oxime (IX), a specific compound of formula (III) ), namely 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one (VIII) and a specific compound of formula (IV) ), namely l- (4 (chlorobutyl) -1-methyl-7-methoxy-2-tetralone (VII).

Referring now to Scheme A. The starting materials 1-alkyl or 1-alkenyl-2-tetralones can be prepared from commercially available 2-tetralones by a well-known alkylation reaction described by Stork and Schulenberg in the Journal of the American Chemical Society, 84, 284 (1962). The tetralones are treated with pyrrolidine in an inert solvent such as benzene and then reacted with the corresponding alkyl or alkenyl halide in an inert solvent, e.g. benzene or dioxane, at elevated temperature, conveniently at the reflux temperature of the solvent used. Substitution of an appropriate carbonylation reagent in this reaction will, if desired, allow the preparation of alkoxycarbonyl-substituted tetralones. The alkyl or alkenyl tetralones can also be prepared from a corresponding commercially available 1-tetralone which can be treated as described by Howell and Taylor in the Journal of the Chemical Society, 1958, 1249 with a Grignard reagent prepared from the corresponding alkyl or alkenyl halide, and the resulting 1-substituted dihydronaphthalene is oxidized with peracid.

Syntheses of non-commercially available tetralones are described in the literature. Eg. For example, the synthesis of α-tetralone is described in Organic Synthesis, Collective Volume IV, page 898, the synthesis of β-tetra- lone is described in the same work on page 903, and a general synthesis of β-tetralone is described in the description of Dutch patent no. 67.09534.

In the first step, portion addition, in the cold, is made by a strong base, e.g. a suspension of sodium hydride in benzene, to a stirred solution of 1-methyl-7-methoxy-2-tetralone (VI) and 1-bromo-4-chlorobutane, in dimethylformamide, then stirred at room temperature to form a compound WE YOU. Compound VII is converted to the tetralone VIII containing a bridge by treatment with a strong base, e.g. sodium hydride, in an inert solvent, preferably dimethylformamide. The tetralone VIII thus prepared containing a bridge is then used as an intermediate either for the production of oxime IX or, if desired, for the preparation of the secondary amine Xa.

12 142984

Schedule_A H C CH0CH0CH0CH0C1 CEU d d d d

H, CO> s. XX H ^ CO. X O

| | Br (CH 2) 4 Cl 2 | IN

S5H>

vi VII

Oh

Ψ

RjC H ^ C

kAJ - / «fVL kjk> -7

IX VIII

Reduction 1. ILCNEL

? 2 \ f \ l 2. Reduction E3G \ / - \ EA y- \ H, C (> X NHq \ H, CO X NHCK, \ "0317 χχχ> Π Xa

H ^ C

h3c0 nhch2ch = ch2 \ TTJl _ _y

X

13 142984

Schedule A (continued)

XI

HBr

Nf hoxQ ^^^)

XIV

1. Carbobenzoxy chloride 2. Acetic anhydride 5. Reduction

Y

XV

14 142984

To prepare Oxime IX, the tetralone VIII containing a bridge is treated with hydroxylamine under basic conditions. Oxime IX can be isolated in conventional manner and used as an intermediate for the preparation of the primary amine XI. To prepare the amine XI, oxime IX is treated either with hydrogen in the presence of a catalyst, preferably Raney nickel, and ammonium hydroxide, at moderate pressure, preferably 2.8-3.5 atm, or with hydride reducing agents, e.g. lithium aluminum hydride, diborane at elevated temperature or an alkali metal, preferably sodium in an alkanol, e.g. ethanol or isopropanol. When catalytic reduction is used, the reaction proceeds stepwise and the corresponding imine of formula (II) can be isolated as an intermediate which can then be reduced to the desired primary amine. The amine XI is isolated by conventional means. To prepare the amine Xa, the tetralone VIII containing a bridge is treated with excess methylamine. The substitution is carried out under removal of water, conveniently in the presence of calcium oxide, at elevated temperature, preferably 180 ° C to 180 ° C. When the amine has a boiling point below the desired temperature, the reaction is conveniently carried out in a sealed pressure vessel. The intermediate imine thus prepared can be reduced as obtained directly from the substitution reaction. The amine Xa is formed by treating this imine with either hydrogen in the presence of a catalyst, preferably platinum oxide, at moderate pressure, preferably 2.8-3.5 atm, or with hydride reducing agents, e.g. lithium aluminum hydride or sodium borohydride, diborane at elevated temperature or an alkali metal, preferably sodium in an alkanol, e.g. ethanol or isopropanol. The primary amine XI can also be converted to the secondary amine X by well known substitution reactions. An appropriate method is treatment with one mole equivalent of allyl bromide. The substitution is carried out in the presence of an organic acid acceptor, preferably diisopropylethylamine in an organic solvent at a temperature of ca. 60 ° C to 140 ° G. Benzene and xylene are particularly useful solvents, but it is clear to an organic chemist that any solvent can be used that does not interfere with the course of the reaction. It is convenient to use the reflux temperature of the solvent used. The secondary amine X is isolated by conventional means.

If desired, the secondary amine X can be methylated to form the N-methyl tertiary amine XII. A preferred methylation method is to first carbethoxylate the secondary amine by treatment with ethyl chloroformate in an inert organic solvent, e.g. methyl chloride or chloroform. To obtain good results, a weak inorganic base, e.g. sodium bicarbonate or potassium carbonate, for the reaction mixture. The temperature of the carbethoxylation reaction is not critical and, for convenience, room temperature is used. It is clear to an organic chemist that for use in this reaction, other haloformate esters will be equivalent to ethyl chloroformate. The earbethoxylated amine is then reacted with a reducing agent, preferably lithium aluminum hydride, in an inert solvent, preferably ether or tetrahydrofuran, to form the N-methylated tertiary amine XII which is isolated in known manner.

A preferred method of preparation for the tertiary amine XIII is to first acylate the secondary amine X with acetyl chloride in a basic organic solvent, preferably pyridine, at elevated temperature, suitably the reflux temperature of the solvent used. The acylated amine is then reacted with a reducing agent; preferably lithium aluminum hydride, in an inert solvent, preferably in tetrahydrofuran, to form the tertiary amine XIII which is isolated by standard methods.

The primary amine XI, which contains an alkyloxy substituent; ent, can be hydrolyzed to the phenol compound XIV. A particularly useful device; The second is to treat the primary amine with 48 $ * aqueous hydrogen bromide acid at elevated temperature, suitably reflux temperature. The crystalline product is isolated by standard methods. It is obvious to an organic chemist that the hydrolysis can be carried out on the tetra-ion VIII containing the bridge link, and that the phenol compound thus formed will then be completely equivalent to all other compounds which do not contain such a substituent. , in all subsequent reactions.

The phenolamine compound XIV can be acylated to form the acyl derivative XV. An organic chemist is aware that in order to acylate the phenol function, a primary or secondary amine must first be reacted with a suitable protecting group. Carbobenzoxychloride is particularly suitable for this purpose. The protected derivative is then treated with acetic anhydride and, in the case of the carbobenzoxy group, the protective group is conveniently removed by hydrogenolysis. It is obvious that any corresponding acylating agent may be used in place of acetic anhydride. The acylation reaction can also be carried out by exposing the phenolamine, appropriately distributed on an inert carrier, suitable potassium cranide powder, to a corresponding liquid acrylic strip agent in a vapor state at a temperature slightly above room temperature, conveniently 40-70 ° C.

Although Scheme A specifically illustrates the use of 1-methyl-7-methoxy-2-tetralone, it is clear that the methods will be equally applicable to tetralones carrying at the 1 and 7 positions other substituents which falls within the scope of the invention. It is also to be understood that the chain length of the polymethylene compound may be varied to produce ring systems of various sizes encompassed by the invention. Furthermore, it is clear that, in addition to α-dihalo-polymethylene, a corresponding polymethylene compound of the desired chain length can be used which, as substituents in the end positions, carries suitable cleavage groups, e.g. alkylsulfonyl or phenesulfonyl, or such a cleavage group and a group, e.g. tetrahydropyranyloxy, which can be easily converted to a cleavage group, by the initial cycloalkylation process. The use of other strong bases, e.g. alkali metal alkoxides, in suitable solvents instead of the sodium hydride used, are also obvious. Furthermore, it is clear that if the α, U7-disubstituted polymethylene does not carry a tetrahydropyranyl substituent, the entire cycloalkylation can be carried out without isolation of the intermediate, similar to compound VII. Furthermore, it is possible to use anhydrous ammonia instead of methylamine in the imination of compound VIII, and the reduction will then give compound XI. In addition, other alkyl and phenalkylamines may be used in place of methylamine to form secondary amino analogs of compound Xa. Other alkyl halides or alkenyl halides may be used in place of allyl bromide in the treatment of compound XI to form the secondary amines herein. Similarly, other alkanoyl or phenalkanoyl halides can be used in the preparation of the present tertiary amines.

The amine oxides of formula (I) are prepared by oxidation, conveniently with an organic peracid, of the dialkyl tertiary amines of formula (I) herein.

Reduction of the imino compounds of the alkoxycarbonyl series of formula (II) to the hydroxyalkylamines of formula (I) can be made by the same reduction methods used above to prepare the amines of formula (I).

Of course, no catalytic reduction involving the use of ammonia or primary amines should be used.

Optionally, a corresponding benzobicyclic alkoxycarbonyl ketone may be treated with an appropriate ketone protecting agent, e.g. ethylene glycol, upon which the alkoxycarbonyl group can be reduced to a hydroxymethyl group, after which the keto group is restored. This compound can then be converted to the hydroxymethylimino compound of formula (II) using the methods described above. Optionally, the hydroxyl group may be removed by standard methods, e.g. tosylation and reduction with lithium aluminum hydride. The various other substituted amines of formula (I) may be prepared from corresponding primary or secondary amines of formula (I) by post-treatments similar to those described above in the preparation of the differently substituted amines of formula (I).

It is to be understood that the benzobicyclic ketones of formula (III) appear in the form of racemic mixtures and that reduction of both imino compounds of formula (II) will lead to the amines of formula (I) in the form of diastereomers wherein the amine function may occur in synelle antiforms in relation to the benzene ring. The separation of the diastereomeric pairs and their resolution into enantiomers can, if desired, be carried out in known manner. The diastereomers, enantiomers and mixtures thereof all fall within the scope of the invention.

The synthesis of the amines and imines of formula (V) can be accomplished by methods similar to those described by Wiesner, Chau and Demerson in Tetra (Hedron Letters, 1965, page 2893).

The present compounds of formula (i) can be isolated in the form of pharmaceutically acceptable acid addition salts during the preparation, or the salts can be prepared by dissolving the specific compound of formula (i) in an organic solvent and treating them with an alcoholic solution of the same. selected acceptable acid in accordance with conventional methods for preparing acid addition salts from basic compounds. Examples of such useful acids include hydrochloric, hydrobromic, tartaric, phosphoric, maleic, citric, acetic, benzoic or other pharmacologically acceptable acids.

The compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, the route of administration chosen and the general pharmacological practice. The compounds can e.g. orally administered in the form of tablets or capsules containing such excipients as starch, milk, sucrose and the like. They can be administered orally in the form of solutions or they can be injected parenterally, e.g. intramuscularly. For parenteral administration, they may be used in the form of sterile solutions or suspensions containing other solvents, e.g. enough salt or glucose to make the solution isotonic.

18 142984

Dosage of the subject of pharmacology; active compounds vary depending on the mode of administration and the specific compound selected. Furthermore, it depends on the individual being treated. Usually, the treatment is started with a small dose that is substantially less than the optimal dose of the compound. Thereafter, the dose is increased by small amounts until the optimal effect is reached under the circumstances. Usually, to produce the same effect, greater amounts of active agent will be required for oral administration than for parenteral administration. Generally, the compounds of this invention are administered at a concentration which usually produces effective results without causing any harmful side effect.

The preparation of starting materials and the process according to the invention are explained in more detail in the following examples.

Example 1 1- (4-Chlorobutyl) -1-methyl-7-methoxy-2-tetralone 57 g of 1-methyl-7-methoxy-2-tetralone, 200 g of tetramethylene chloro bromide and 250 ml of dimethylformamide are placed in a 2 liter reaction vessel 4, the sora is provided with a reflux condenser with a drying tube, a mechanical stirrer, nitrogen delivery plug, thermometer and a soft rubber stopper. After cooling this solution to 10 ° C, a sodium hydride suspension prepared from ea is slowly added. 8 g of sodium hydride liberated from mineral oil by washing with benzene and 100 ml of benzene in 10 ml portions through the rubber stopper using a syringe. The temperature is kept between 12 and 20 ° C during the 1.5 hour addition period. The reaction mixture is then allowed to reach room temperature, stirred for 3 1/2 hours and poured into 1.5 liters of ice water. The layers are isolated, the aqueous phase is extracted with ether, the combined organic phases are washed with saturated brine, dried over sodium sulfate, and the organic solvents are removed under reduced pressure. Distillation of the residue gives 62.5 g of the intended product with b.p. 155-185 ° C (about 0.5 mm Hg).

IR analysis: 5.85, 7 * 95µ · 19 142984

Example 2 1- (5-Bromopentyl) -1-methyl-2-tetralone

Analogous to the method used in Example 1 in the preparation of 1- (4-chlorobutyl) -1-methyl-7-methoxy-2-tetralone is prepared from 20.0 g, 0.125 mol, 1-methyl-2-tetralone, 115 g, 0.5 mole, 1,5-dibromopentane and 6.06 g, 0.1575 mole sodium hydride in a 54.5 # rs dis * persion in mineral oil in 100 ml of dimethylformamide, 19.8 g (54 #) of the intended connection with kp. 155-175 ° C (o, 3 mm Hg).

IR analysis: 3.45, 5> 85µ ·

Example 3 1- (5-Bromopentyl) -1-methyl-7-methoxy-2-tetralone

Analogous to the process used in Example 1 in the preparation of 1- (4-chlorobutyl) -1-methyl-7-methoxy-2-tetralone is prepared from 150 g, 0.788 mol, 1-methyl-7-methoxy-1 2-tetralone, 707 g, 3.06 mole, 1,5-dibrompentane and 37.1 g, 0.842 mole, sodium hydride in the form of a 54.5 # dispersion in mineral oil in 600 ml of dimethylformamide, 182 g (68, 1 #) of the intended product with b.p. l85-198 ° C (1.0 mm Hg).

IR analysis: 3.5, 5.80, 7.9µ

Example 4 1- (4-Chlorobutyl) -1-ethyl-7-methoxy-2-tetralone A. Analogous to the method used in Example 1 in the preparation of 1- (4-chlorobutyl) -1-methyl-7- methoxy-2-tetralone is prepared from 35 g of 1-ethyl-7-methoxy-2-tetralone 37 »4 g of the intended product with b.p. 160-173 ° C (0.4 mm Hg).

IR analysis: 5.83, 8.0µ.

B. 2.3 g of pure sodium beads is dissolved under mechanical stirring under Ng in 50 ml of absolute ethanol. After cooling to 20-25 ° C, 20.5 g of 1-ethyl-7-methoxy-2-tetralone is added in 5 ° ml of dry ethanol over 30 minutes. After stirring for 30 minutes, this solution is added dropwise to a stirred solution of 44.0 g of 1,4-dirMorbutane in 60 ml of dry ethanol, keeping the temperature at 10-15 C. After stirring for 4 hours at this temperature, the reaction mixture is allowed to allowed to warm to 20-25 ° C, stirring continued for an additional 12 hours. After rapidly cooling to below room temperature, the precipitated solids are removed by filtration using diatomaceous earth. The filtrate is concentrated under reduced pressure, the resulting residue is partitioned between ether and water, the ether layer is washed with brine, dried, concentrated under reduced pressure and distilled under vacuum to give 16 g of the intended compound with b.p. l65-175 ° C (0.2 mm Hg).

142984 20

Example 5 6,7,8,9,10,11-Hexahydro-5-methoxy-5-methyl-5,10-methano-5H-henzinypl n-n-xxien-12-one

To a 2-liter reaction vessel equipped with mechanical stirrer, drip funnel, reflux with drying tube, thermometer, nitrogen supply plug and a soft rubber stopper are added 15 g, 0.27 mol, sodium hydride in the form of a 50 $ dispersion in mineral oil, which is then wash with benzene to remove the mineral oil. Then 750 ml of dimethylformamide is added and 62.5 Si 0.22 mol, 1- (4-chlorobutyl) -1-methyl-7-methoxy-2-tetralone in 150 ml of dimethylformamide is added dropwise with vigorous stirring while the temperature is kept between 50 and 55 ° C · The reaction mixture is stirred and heated to 80-85 ° C for 2.5 hours, stirred at room temperature overnight and poured into 2.0 liters of ice water. After acidification with concentrated hydrochloric acid, the separated oil is extracted with ether. The extract is washed with saturated brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue distilled to give 52.5 g of the intended compound with b.p.

150-155 ° C (0.25 mm Hg).

IR analysis: 5.8, 8.0µ.

Example 6 5,6,7,8,9,10-Hexahydro-5-methoxy-5-methyl-5,9-methano-benzocyclooctene-11-one

Analogous to the procedure described in Example 5 for the preparation of 6,7,8,9,10, H-hexahydro-5-methoxy-5-methyl-5,10-metha-no-5H-benzoeyeloocten-12-one is prepared from from 1- (5-bromopropyl) -1-methyl-7-methoxy-2-tetralone the intended product in 74 $ yield, bp. 118-121 ° C (0.05 mm Hg). A sample is converted to the semicarbazone, m.p. 225-225 ° C.

Analysis for C% H% N $

Calculated 66.87 7 * 57 14.62. Pound 66.75 7.51 14.74 21 142984

Example 7 5-Methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-5H-benzocyclodecene -_- 13-one

Analogous to the procedure used in Example 5 for the preparation of 6,7,8,9,10,11-hexahydro-3-nithoxy-5-methyl-5,10-methanol-5H-benzocyclonone-12-one from 19.8 g, 0.0675 mole, 1-methyl-1- (5-bromopentyl) -2-tetralone and 3.57 g, 0.08 l mole, sodium hydride in the form of a 5 s dispersion in mineral oil in 250 ml of dimethylformamide, 6.2 g ($ 40.4) of the intended product, b.p. 126-135 ° C (0.3 mm Hg).

IR analysis: 3.45, 5.9d ·

Example 3 5-Methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methano-5H-benzo-cyclo-decen-13-one A. Analogous to the Example 5 describes the process for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-metha-no-5H-benzocyclonone-12-one prepared from 90, 0 g, 0.265 mole, 1-methyl-1- (5-bromopentyl) -7-methoxy-2-tetralane and 12, S7 g, 0.292 mole, sodium hydride in the form of a 5 µg 5 dispersion in mineral oil in 750 42.7 g (62.4 $) of the intended compound, m.p. 150-175 ° C (0.5 mm Hg).

IR analysis: 3.0, 3.4, 5.9, δ, ΟΙμ ..

B. 5.28 g of anhydrous sodium hydride in 50 ml are added to a stirred mixture of 184 g of 1,5-dibromopentane and 32 g of 1-methyl-7-methoxy-2-tetra-lone in 300 ml of dry benzene. Stirring is continued for 12 hours at 25 ° C and at reflux temperature for an additional 15 hours. The mixture is cooled, 5.8 g of sodium hydride is added to 50 ml of benzene, stirring is continued at 25 ° C for 10 hours and at reflux temperature for an additional 12 hours. After cooling, excess base is neutralized with concentrated hydrochloric acid and the precipitated inorganic solids are removed by filtration. The filtrate is washed with brine, dried over sodium sulfate, concentrated and vacuum distilled to give 21 g of an oil of bp. 160-190 ° C (0.5 mm Hg) containing 6.5 g (27 $) of the intended compound by vapor phase chromatography (J>% OVI, C200-225-2-250).

22 142984

Example g.

5-ethyl-6,7,8,9,10, ll-hexahydro-3-methoxy-5 * 10-methano-5H-benzocyclo-_nonen-12-on_

Analogous to the procedure described in Example 5 for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-metha-no-5H-benzocyclonone-12-one from 37 * 4 g of 1- (4-chlorobutyl) -1-ethyl-7-methoxy-2-tetralone, 22.2 g of the intended compound with b.p. 138-142 ° C (0.35 mm Hg).

IR analysis: 5 * 85 * 8.0µ.

Example 10 6.7> 8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one oxime A-0.2 g 6.7 * 8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one, 0.5 g of hydroxylamine hydrochloride, 6 ml of sodium hydroxide and 2 ml of ethanol are heated. for reflux for A hours. The reaction mixture is cooled and diluted with water. The above liquid is decanted from the separated oil. The oil is washed several times with water and then treated with 2-propanol from which the intended product crystallizes, m.p. 174-176 ° C.

Analysis for c16 H21 NO2: C

Calculated 74 * 1 8.16 5 * 40

Pound 74.38 8.10 4.98 IR Analysis: 3 * 2, 6.2, 8.1µ.

B. 14 g, 0.2 mol, hydroxylamine hydrochloride in 250 ml methanol are mixed with 165 g, 0.2 mol, sodium acetate in 200 ml of methanol. After standing for 1 hour, the solution is filtered and 10 g, 0.04 mol, 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclo are added. nonene-12-one. The solution is heated under reflux for 5 hours concentrated to a volume of approx. 200 ml. On cooling, filtration, washing with methanol and drying 8.0 g of the intended product are obtained with m.p. 174-176 ° C.

C. 20.0 g, 0.082 mol, 6.7 * 8,9.10, 11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyelonone-12-one and 28, 5 g * 0.410 mol, hydroxylamine hydrochloride in 150 ml of pyridine is stirred at reflux for 24 hours. The mixture is cooled and concentrated. The residue is extracted with 750 ml of ether in several portions, and the extracts are washed first with water and then with dilute hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and the residue is crystallized by boiling isopropanol to give 6.0 g of the intended product, m.p. l67-171 ° C. An additional 1.08 g of product is isolated. The total yield is 33>%.

Example n 5-Methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-5H-benzocyclodecene-13-one oxime

Analogous to the process described in Example 10, Method C, for the preparation of 6,7,8,9 AO, 11-hexahydro-5 * -methoxy-5-methyl-5,10- -methano-5H-benzoyl cyclone-12 on-oxime is prepared from 5.9 g, 0.0171 mole, 5-methyl-5,6,7,8,9,10,11,12-octahydro-5, U-methano-5H-benzocyclodehyde. 15-one and 8.55 g, 0.125 mol, hydroxylamine hydrochloride in 20 ml of pyridine 1.27 g of the intended product, m.p. 122-127 ° C after recrystallization from isopropanol.

IR analysis: 5A5, 5A5, 6.1µ.

Example .12 .................

5> 6,7,8,9,10-hexahydro-5-methoxy-5-methyl-5,9-methano-benzocycloocten -_- 11-one-oxim_,

Analogous to the process described in Example 10, Method A, for the preparation of 6,7,8,9,10,11-hexahydro-5-methoxy-5-methyl-5,10- -methano-5H-benzocyclonone-12- on-oxime is prepared from 0.5 g of 5,6,7,8,9,10-hexahydro-5-methoxy-5-methyl-5,9-methanobenzocyelooctane-11-one and 6.5 g of hydroxylamine hydrochloride, 3.9 g of product after trituration with hexane, m.p. 158-L42 ° C. Recrystallization of a mixture of isopropanol and water gives the intended compound with m.p. 146-148 ° C. Analysis for Ο- ^ Η- ^ ΝΟ, ^: C% E% N #

Calculated 73 M 7.8l 5.71

Pound 73 Al 8.05 5.61 24 U2984

Example 13 5-Methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methano-5H-benzo-cyclodecene-13-one oxime

Analogous to the process described in Example 10, Method C, in the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10- -methano-5H-benzocyclonone-12 on-oxime is prepared from 42.6 g, 0.165 mol, 5-methyl-3-methDD -5,6,7,8,9,10,11,12-octahydro-5,11-itethano-5H-benzo - cyclodecen-13-one and 57.3 g, 0.824 mol, hydroxylamine hydrochloride in 300 ml of pyridine, 18.9 g $ 42, of the intended product, m.p. 152-158¾.

Analysis for C ^H- ^NgOg: C $ E% Nf0

Calculated 74.69 8.48 5.12

Pound 75.25 8.64 4.72

Example 14 5-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzoylcyclo-nenone-12-one oxime

Analogous to the method described in Example 10, Method C, for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12 on-oxime is prepared from 3.5 g of 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-one and 20 ml hydroxylamine hydrochloride 3.5 g of the intended compound in the form of a brown oil which crystallizes on standing.

IR analysis: 3.2, 6.0µ.

Crystallization of the crude solid from a mixture of ethanol and water gives an intentional compound of m.p. LL6-ll4 ° C.

Analysis for C ^ HHg ^NOg:

Cfo H $ N $

Calculated 74.69 8.48 5.12

Pound 75.20 8.93 4.84 25 142984

Example 15 6.7, 8.9> 10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclo-nonen-12-amine ______ A. 15 g, 0.058 mol, 6.7 , 8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one oxime, 3 tsp. Raney nickel, 100 ml of ethanol and 50 ml of concentrated ammonium hydroxide are shaken with hydrogen at a pressure of 3.16 atm and 45 ° C. The catalyst is removed by filtration and the filtrate is concentrated to remove the solvent. The residue is distilled under reduced pressure to give 11 g of the intended product with b.p. l40-l42 ° C (0.2 mm Hg). The hydrochloride has m.p. 298-299 ° C.

Analysis for C16H24C1N0: C # H # N #

Calcd 68.21 8.58 4.96

Pound 67.96 8.63 4.92 B. Distilled 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-amine in Treat 200 ml of dry ether with dry hydrogen chloride in ether until the solution is acidic. The precipitated salt is isolated, washed with ether and dried to give 32 g of product m.p. 257-267 ° C.

This product is dissolved in 1000 ml of water and 180 ml of methanol. By adding 2 ml of concentrated hydrochloric acid, concentration at atmospheric pressure to 500 ml, isolating the precipitate obtained by cooling, washing and drying, 20.0 g of product are obtained with m.p. 302-305 ° C. For IR and · NMR spectroscopic studies, this product is assigned a configuration with the amine group in the anti-configuration.

Concentrating the mother liquor from the isolation of the anti-product gives 2 g of product with m.p. 262-273 ° C. Additional concentration to approx. 65 ml, clarification and cooling gives 5.9 g of crystals with m.p. 231-236 ° C, which is isolated by an additional 50 ml of cold water. The recrystallization is done by dissolving in a mixture of acetone and methanol in a ratio of 2: 1, concentrating to half the volume and adding acetone to a volume similar to the original. Repeating the concentration-dilution process three additional times followed by cooling gives 4.5 g of product with m.p. 232-240 ° C.

Analysis for C ^ gHHClNO: C # H # N # Cl #

Calcd 68.21 8.58 4.96 12.54

Pound 68.40 8.72 5.02 12.04 On the basis of IR and NMR spectra, this product is added to a configuration where the amine group has the syn configuration.

26 U2984

Example 16

Anti-5-methyl-5,6,7,8,9,10,11,12-oetahydro-5,11-methano-benzocylo-decene-13-amine 2.5 g 5-methyl-5,6,7,8 9,10,11,12-octahydro-5,11-methano-5H-benzocyclodecene-13-one oxime, 2 g of Raney nickel, 4 ml of ammonium hydroxide and 50 ml of ethanol are shaken with hydrogen at a pressure of 5 16 atm. After cessation of hydrogen uptake, approx. 0.49 atm versus 0.98 atm theoretically, the solution is taken out, filtered and concentrated. As the residue, a pink oil is obtained which is combined with fresh Raney nickel, ammonium hydroxide and ethanol and hydrogenated at 3.52 atm and 50-60 ° C. After completion, the solution is worked up as described above. The residue, which is a colorless oil, is converted to the hydrochloride, filtered, washed and dried. The salt is recrystallized from water to give 1.15 g of the intended compound as the hydrochloride with m.p. greater than 335 ° C. Analysis for C- gHH ^ ^ClN:

Gfo E% Nfo

Calculated 72.29 9.10 5.27

Found '72.12 9.45 5.28

Example 17

Anti-6,7,8,9,10,11-hexahydro-5-methyl-5,10-rae thano-5H-benzenocyclonone-12-amine 2.5 g 6,7,8,9,10, 11-Hexahydro-5-methyl-5,10-methano-5H-benzo-cyclonone-12-one oxime, 6 g of Raney nickel catalyst in 25 ml of concentrated ammonium hydroxide and 50 ml of ethanol are shaken with hydrogen at a pressure of 3 , 52 atm and 45 ° C. After cessation of hydrogen uptake, the catalyst is filtered off, the filtrate is concentrated and the residue is converted to the hydrochloride salt, 2.8 g. On recrystallization of water the desired compound is obtained as the hydrochloride with m.p. greater than 315 ° C.

Analysis for C- NN ^OIN:

Gfo Efo Nfo

Calcd 71.62 8.8l 5.55

Found 71.62 8.8l 5.86 27 142986

Example 18 5-Ethyl-6,7, 8,9> 10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclo-nonen-12-amine A. Analogous to that of Example 15, Method A process described for the preparation of 5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11 - methano-benzocyclodecene-13-amine is prepared from 4.0 g of 5-ethyl - -6,7,8,9,10,11-hexahydro-5-methoxy-5,10-methano-5H-benzocycloneone - 12-amine approx. 3.5 g of the intended product which is converted to the solid hydrochloride salt with m.p. 226 ~ 231 ° C.

From IR and NMR resonance spectra, this product is added to the amine group in anti-configuration.

Analysis for C ^H ^NOCl: E% N #

Calculated 69.01 8.86 4.73

Pound 68.76 8.94 4.72 B. Analogous to the procedure described in Example 15, Method A, for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl * - 5,10-Methano-5H-benzocyclonone-12-amine is obtained from 5-ethyl - 6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclonone · -> · -12-on-oxime the distilled intended product, which, by gas or orange o * graph and mass spectral analysis, turns out to be an approx. 8-1 mixture of See epimeric amines. By dissolving 70 g of this mixture in 1100 ml of aqueous hydrochloric acid, filtering the solution through diatomaceous earth and standing for 1 day at room temperature and for 2 days at 10 ° C, 64 g of anti-5-ethyl-6,7,8 are obtained. 9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzo-cyclonone-12-amine hydrochloride hydrate, m.p. 253 "256 ° C.

Analysis for CjjH ^NO-HCl.HgO

Calculated 65.05 8.99 4.46

Pound 65.26 9.01 4.50 C. The filtrate recovered under B above is basified with aqueous sodium hydroxide, extracted with ether and the ether extracts are dried and concentrated to an oil. This oil is chromatographed on 300 g of silica gel. Elution with a solution of 3 parts of benzene and 1 part of chloroform gives 3.0 g of pure syn-5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methanol. benzocyclononen-5H-12-amine. Conversion of the amine to the hydrochloride in ether gives a crystalline salt, m.p. L82-L85 ° C.

Analysis for C ^ HHgNOCl: C% E% N #

Calculated 69.01 8.86 4.73

Found 68.73 8.91 4.75 28 1Λ298Λ

Example 19 5.6.7.8.9. 7,8,9,10,11 ~ hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-amine is prepared from 4.2 g of 5.6.7.8.9.10-hexahydro-3 -methoxy-5-methyl-5,9-methano-benzocyclooctene-11-one oxime 2.7 g of the intended compound with b.p. 125-129 ° C (0.1 mm Hg).

A sample is converted to the hydrochloride which crystallizes from a mixture of ethanol and ether, m.p. 262-264 ° C.

Analysis for C ^ HHgClNO: C% Η% N

Calculated 67.27 8.28 5.23

Found 67.16 8.48 5.14. B. Analogous to the method described in Example 15, Method A, in the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone 12-amine is obtained from 5,6,7,8,9,10-hexa-hydroxy-5-thoxy-5-methyl-SilO-methano-SH-benzocyclooctene-11-one oxime the distilled intended product which, gas chromatography and mass spectroscopy are found to be a 3-2 mixture of amino epimers. By repeated recrystallization of the hydrochloride of 27 g of the epimeramino mixture of a mixture of ethanol and ether, 16.3 g of product are obtained with m.p. 270-272 ° C, which is added to the vision configuration.

Analysis for C ^H ^ gNOCl: C C E E% N N.

Calculated 67.27 8.28 5.23

Found 67.17 8.48 5.14 C. Concentrating the combined mother liquor from B gives a residue which is crystallized by acetonitrile and then recrystallized from ethanol and ether respectively to give a product of m.p. 300-302 ° C added to the anti-configuration.

Analysis for C-jH HHOCl:

Cfo Efo

Calculated 67.27 8.28 5.23

Found 67.14 8.24 5 * 24 29 142984

Example 20

Anti-3-methoxy-5-methyl-5,6,7,8,9 »10,11,12-octahydro-5,11-methano-_-benzocyclodecene-13-amine

Analogous to the procedure described in Example 16 for the preparation of 5-methyl-5,6,7,8,9,10,11,12-octahydro-5, H-methano-benzo-cyclodecene-13-amine is prepared from 18 5 g of 3-methoxy-5-methyl-5,6,7> 8-9,10,11,12-octahydro-5,11-methanobenzocyclodecene-13-one oxime 3 tsp. Raney nickel, 100 ml ethanol and 50 ml concentrated ammonium hydroxide after distillation 11.1 g of the intended product with b.p. 1400-145 ° C, 1.2 mm Hg, which is converted to the hydrochloride which is recrystallized from water, m.p. 311-312 ° C.

Analysis for C ^ HggClNQ: H # N #

Calculated 69.13 8.86 4.73

Found 69.17 9 * 16 4.70

Example 21

Syn-6,7 * 8,9,10,11-hexahydro-3-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone-12-amine. - 2 * 5 g syn-6.7 * 8.9 * 10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-amine hydrochloride, 50 ml saturated aqueous sodium hydrogen carbonate solution, 50 ml of methylene chloride and 3 ml of ethyl chloroformate are stirred at room temperature for 4 hours. The organic layer is isolated, washed first with aqueous sodium carbonate and then with hydrochloric acid and sodium chloride, dried and concentrated to give 2.6 g of oil. This oil is added to a mixture of 1 g of lithium aluminum hydride in tetrahydrofuran and the resulting mixture is refluxed overnight.

Add 2 ml of water and filter the mixture. Concentrating the filtrate gives 2.1 g of oil which is converted to 1.8 g of hydrochloride with m.p. 249-250 ° C after recrystallization from a mixture of ethanol and ether.

Analysis for C1 ^H₂gNOCl: C # H # N $

Calculated 69.01 8.86 4.73

Found 68.53 9.08 5.13

Example 22

Syn-6,7,8,9,10,11-hexahydro-3-methoxy-N, N, 5-trimethyl-5 * 10-methano-5H- __-benzocyclonone-12-amine

Analogous to the procedure described in Example 21 for the preparation of syn-6,7> 8,9i10,11-hexahydro-3-methoxy-N, 5-dimethyl-5 * 10 - methano-5H-benzocyclonone-12-amine is obtained. out ffa 1.2 g of syn-6,7,8,9,10,11-hexa-hydro-3-methoxy-F * 5-dimethyl-5 * 10-methano-5H-benzocyclonone-12-amine 0.90 g of the hydrochloride of the intended product, m.p. 200-202 ° C. Analysis for C- gHH ^NOCl:

Cfo E% E%

Calculated 69 * 76 9 * 11 4.52

Pound 69.28 9.12 4.69

Example 23

Anti-6,7,8,9,10,11-hexahydro-3-methoxy-N, N, 5-trimethyl-5 * 10-methano-5H- -benzooyolonone-12-amine

Analogous to the procedure described in Examples 21 and 22 for the preparation of syn-6,7 * 8,9 * 10,11-hexahydro-3-ethylethoxy-N, N, 5-trimethyl-5,10-methano-5 benzocyclonone-12-amine is prepared from 1 * 2 g of anti - 6,7,8,9,10 * 11-hexahydro-5-methoxy-5-ylethyl-5,10-methano-5H-benzo-cyclonone-12 -amine 1.0 g of the hydrochloride of the intended product, mp * 207-209 ° C.

Analysis for C 1/4 H2 O: C fo E% N #

Calculated 68 * 79 9.14 4.46

Pound 68.83 9 * 36 4.69

Example 24

The anti-5-ethyl-6,7 * 8,9 * 10, ll-hexahydro-3-methoxy-N-methyl-5 * 10-methano-5 H -_- benzoeyclononen-12 amin_

Analogous to the procedure described in Example 21 for the preparation of syn-6,7,8,9,10,11-hexahydro-3-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyelonone-12 amine is prepared from 8 * 0 g of anti-5-ethyl-6 * 7 * 8 * 9 * 10 * 11-hexahydro-3-methoxy-5 * 10-methano-5H-benzocyclonone-12-amine 5 * 5 g of the hydrochloride of the intended product, m.p. 282-284 ° C (dec.) After recrystallization from a mixture of ethanol and ether.

Analysis for C ^ gHH gNOCl:

Cfo Ef Ef

Calculated 69.76 9 * 11 4 * 52

Pound 69.29 9 * 22 4.6l 31 142986

Example 2¾

The anti-5-ethyl-6,7,8,9 * 10, ll-hexahydro-N, N-dimethyl-5-methoxy-5,10-metha-_no-5H-benzocyclononen-12 amln_

Analogous to the procedure described in Example 21 for the preparation of syn-6,7,8,9 * 10 * 11-hexahydrox-5-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone-12 amine is obtained from 4.0 g of anti-5-ethyl - 6,7 * 8,9,10,11-hexahydro-5-methoxy-N-methyl-5,10-methano-5H-benzocyclo-nonen-12 -amine 2.65 S of the hydrochloride of the intended product, m.p. after recrystallization of a mixture of ethanol and ether.

Example 26

Anti-3-methoxy-N, 5-dimethyl-5,6,7 * 8> 9 * 10,11,12-octahydro-5 * 11-methano-benzooyolodecene-15-amine

Analogous to the procedure described in Example 21 for the preparation of syn-6,7 * 8,9 * 10,11-hexahydro-5-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone -12-amine is obtained from 8.0 g of anti-5-methoxy-5-methyl-5,6,7,8,9 * 10,11,12-octahydro-5,11-methanobenzocyclodecene-15'-.

-amine 5 * 5 g of the hydrochloride of the intended product, m.p.

505-505 ° C (dec.) After recrystallization from a mixture of ethanol and ether.

Analysis for C- g g ^NOCl: 0 $ N #

Calculated 69.76 9 * 11 4.52

Pound 69.27 8.99 4.66

Example 27

The anti-5-methoxy-N, N, 5-trimethyl-5,6,7,8,9 * 10, ll, 12-octahydro-5H-methano-_benzocyclodecen-15-amine ......

Analogous to the procedure described in Example 21 for the preparation of syn-6,7,8,9,10,11-hexahydro-5-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone-12 amine is obtained from 4.0 g of anti-5-methoxy-N, 5-dimethyl-5,6,7,8,9,10,11,12-octahydro-5H-methanobenzocyclodecene-15-amine 2.0 g of the hydrochloride of the intended product, m.p. 195-198 ° C after recrystallization from a mixture of ethanol and ether. Analysis for C ^H ^ qNOCl. HgO: C # H # N #

Calculated 66.74 9 * 45 4.10

Pound 66.6l 9 * 59 5.96 32 142984

Example 28

Anti-5, 6,7,8,9,10-hexahydro-5-methoxy-N, 5-dimethyl-5,9-methanobenzocycloalkten-11-amine

Analogous to the process described in Example 21 for the preparation of syn-6,7, 8,9,10,11-hexahydro-5-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone-12 -amine is obtained from 1.5 g of anti-5,6,7,8,9,10 - hexahydro-5-methoxy-5-methyl-5,9-methano-benzocycloethylene-11-amine 1.2 g of the hydrochloride of the intended product with m.p. 266-267 ° C. Analysis for C- HHg ^NOCl: C% Η% N%

Calcd 68.19 8.58 4.97

Found 67.88 8.88 4.80

Example 29.

Syn-5-ethyl-6,7,8,9,10,11-hexahydro-5-methoxy-N-methyl-5,10-methano-5-H-benzocyclonone-12-amine

Analogous to the procedure described in Example 21 for the preparation of anti-6,7,8,9,10,11-hexahydro-5-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyelonone-12 amine is obtained from 1.2 g of syn-5-ethyl - 6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-amine 0.90 g of the hydrochloride of the intended compound, m.p. 284-285 ° 0 (dec.) After recrystallization of a mixture of ethanol and ether.

Analysis for C18H2NOCl. l / 4H 2 O: C fo E% W °

Calcd 68.77 9.14 4.46

Found 69.69 9.19 4.42

Example 30

Anti-N-allyl-6,7,8,9,10, ll-hexahydro ~ 5-methoxy-5-methyl-5,10-methano-5H -_- benzocyclononen-12 amin_

Anti-6,7,8,9,10,11-hexahydro-5-methoxy-5-methyl-5,10-methano-5H-benzoylelonone-12-amine, 0.85 g allyl bromide, 1.5 g diisopropyl -ethylamine and 10 ml of benzene are heated at reflux for 5 hours. The mixture is cooled, diluted with ether and filtered. The solvents are removed under reduced pressure and the residue distilled to give 1.5 g of the intended compound with b.p. 144-146 ° C (0.2 mm Hg). The distilled product is taken up in ether and treated with hydrogen chloride in ether in slight excess to give 1.5 g of the hydrochloride salt of the intended compound, m.p. 200-202 ° C. Analysis for C

Calculated 70.95 8.74 4.55

Found 70.50 8.77 4.46 33 142984

Example 31

Syn-N-allyl-5,6,7,8,9,10-hexahydro-; 5-methoxy-5-methyl-5,9-methanobenzo-_cycloocten-ll-amine ........

Analogous to the procedure described in Example 30 for the preparation of N-allyl-6,7,8,9,10,11-hexahydro-5-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12 amine is prepared from 1, g of syn - 5,6,7,8,9,10-hexahydro-5-methoxy-5-methyl-5,9-methane ° -benzocyclooctene-11-amine 1.5 g of the intended product with b.p. 148-155 ° C (0.3 mm Hg). A sample is converted to the hydrochloride.

Analysis for C ^ gHHggClNO: C% H # N $

Calculated 70.22 8.51 4.55

Pound 69.75 8.75 4.47

Example 32

Anti-6,7,8,9,10, ll-hexahydro-5-methoxy-5-methyl-N- (5-methyl-2-butenyl) -_- 5,10-methano-5H-benzocyclononen-12- amine 4.5 g 6,7,8,9,10,11-hexahydro-5-methoxy-5-methyl-5,10-methano-5H-benzoylclonone-12-amine, 4.5 g 5.5 dimethylallyl bromide, 5.75 g of diisopropylethylamine and 60 ml of xylene are heated at reflux for 4 hours. The mixture is cooled, diluted with ether and filtered. The solvent is removed under vacuum and the residue distilled to give 1.2 g of the intended product with b.p. l66-170 ° C / 0.2 mm Hg. A sample is converted to the hydrochloride and recrystallized from ethanol, m.p. 295-298 ° C.

Analysis for C ^ HHgClNO: C% E%

Calculated 69.01 8.86 4.75

Found 68.90 8.92 4.83 34 142984

Example 33

Syn-5,6,7,8,9,10-hexahydro-5-methoxy-5-methyl-N- (3-methyl-2-butenyl) -_- 5,9-methano-benzocyclooctene-11-amine 4 g of syn-5,6,7,8,9,10-hexahydro-5-methoxy-5-methyl-5,9-methano-benzocyelooethene-11-amine, 1.5 g of diisopropylethylamine and 0.7 g of 1-chloro-5-me thy1-2-butene is refluxed for 7 hours in xylene. The reaction mixture is cooled to room temperature, filtered and the filtrate is extracted with 2N hydrochloric acid. The aqueous extract is made basic and extracted with ether. The ether extract is then washed with water, dried over sodium sulfate, concentrated in vacuo and the residue distilled under reduced pressure to give 1.5 g of the intended product, b.p. 150-155 ° C / 0.5 mm Hg. Treatment of the product in ether with hydrogen chloride gives hydrochloride t with m.p. L66-L69 ° C.

Analysis for C ^H ^ qCINO:

Cfo Ufo Wfo

Calculated 71.51 9.00 4.17

Pound 71.58 9.09 4.20

Example 34

Anti-12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzo-cyolonone-5-ol

A solution of 1.19 g of anti-12-amino-6,7,8,9,10,11-hexahydro-5-methoxy-5-methyl-5,10-methano-5H-benzocyclonone in 15 ml of 48 $ The hydrogen bromide acid is refluxed for 30 minutes under nitrogen. The mixture is cooled, diluted with 50 ml of water, filtered and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ethanol and evaporated to dryness. Redissolving in 25 ml of ethanol, adding 50 ml of ether and standing in the cold gives crystals which are recrystallized from isopropanol to give the hydrobromide of the intended compound as the i-propanolate (0.72 g), m.p. 246-248 ° C.

Analysis for C1gH ^OBrNO₂:

Cfo Hfo W °

Calculated 58.10 8.07 5.76

Found 57.52 8.71 5.69 35 162984

Example 35

Anti-13-amino-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-benzo-cyclodecen-3-ol 3 g anti-3-methoxy-5 -Methyl-5,6,7,8,9,10,11,12-oetahydro-5,11 - methano-benzocyclodecene-13-amine is refluxed in 60 ml of 48 # aqueous hydrobromic acid for 1 hour. The mixture is poured into 100 g of ice and stirred. The precipitate is filtered off, washed with cold water, then with ether and dried. By recrystallization of water after treatment with activated charcoal, the intended compound is obtained in an amount of 1.85 S / m.p. 269-270 C.

Analysis for C ^H ^BrNO · 1 / 2H₂O: C% H

Calculated 57.18 7.52 5.97

Pound 57.22 7.61 4.14

Example 36

The anti-12-amino-6,7,8,9,10, H-hexahydro-5-ethyl-5,10-methano-5H-benzo-_cyelononen-5-ol_

A mixture of 2.0 g of ar ± i-5-ethyl-6,7,8,9,10 / 11-hexahydixr'3-nBf ± aiqr-5,110-methano-5H-benzocyclonone-12- amine and 75 ral 48 $ of hydrogen bromic acid are refluxed for 1/2 hour, then concentrated to a viscous oil. The oil is dissolved in water and treated with concentrated aqueous ammonia.

Filtration gives 1.7 g of a crude product with m.p. 170-191 ° C. Recrystallization of ethyl acetate gives the intended product, m.p. 201-204 ° C.

Analysis for C 16 H 25 NO: C%

Calculated 78.52 9.45 5.71

Found 77.95 9.68 5.88

Example 37

Syn-Il- (dimethylamino) -5,6,7,8,9,10-hexahydro-5-methyl-5,9-methano-____-benzocyclooctene-3-ol __ 1.2 g syn-5,6,7 8,9,10-Hexahydro-3-methoxy-N, N-5-trimethyl-5,9-methano-benzooyclooctene-11-amine prepared as described in Example 46 is refluxed for 1 hour under dry nitrogen in 13 ml of aqueous 48 % hydrogen bromic acid. Concentration of the solution gives a residue which, by crystallizing a mixture of ethanol and ether, gives the intended product in the form of the hydrobromide with m.p. 268-271 ° C.

Analysis for C- HHphNOBr: N * H #

Calculated 58.89 7.41 ^, 29

Found 58.80 7.52 4.22 36 142984

Example 38

Syn-11-amino-5,6,7,8,9,10-hexahydro-5-methyl-5,9-methanobenzoeyeloctene-3-ol

Analogous to the procedure described in Example 34 for the preparation of anti-12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-metha-no-5H-benzocyclonone-3-ol is obtained from 2.0 g of syn-5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,9-methanobenzocyclooctene-11-amine 2.3 g of hydrobromide -ethanolate of the intended compound, m.p. 277-280 ° C after recrystallization from a mixture of ethanol and ether.

Analysis for C ^H NOBr, 1 / 2CpH₂-OH:

Cf Hf Nf

Calculated 56.07 7.22 4.36

Pound 55.86 7.57 4.10

Example 39

Anti-ll-amino-5,6,7,8,9,10-hexahydro-5-methyl-5,9-methanobenzoeyelo-_ooten-3-ol_

Analogous to the procedure described in Example 34 for the preparation of anti-12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-ne-thano-5H-benzocyclonone-3-ol is obtained from 1.25 g of anti-5,6,7,8,9,10-hexa-hydro-3-methoxy-5-methyl-5,9-methanobenzocyclooctene-11-amine 1.05 g of the hydrobromide of the intended connection with m.p. 305-510 ° C (dec.) After recrystallization from a mixture of ethanol and ether.

Analysis for C

Cf Hf Nf

Calculated 56.38 6.76 4.70

Pound 56.01 6.79 4.63

Example 40

Syn-12-Amino-6,7,8,9,10, ll-hexahydro-5-methyl-5,10-methano-5H-benzocyclo-_nonen-3-ol ~ ____

Analogous to the procedure described in Example 34 for the preparation of anti-12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methanol-5H-benzoeyclonone-3-ol is obtained from 1.2 g of syn-6,7,8,9,10,11-hexa-hydro-3-methoxy-5-methyl-5,10-methano-5H-benzoeyclonone-12-amine 1.1 g of the hydrobromide salt of the intended compound, m.p. 130-134 ° C after recrystallization from acetonitrile.

Analysis for C 15 H 21 NO. HBr. l / 4 CH ^ CN

C f Hf Nf

Calculated 57.72 7.11 5.43

Found 57.47 7.00 5.57 37 142084

Example 4L

Syn-12-Amino-6,7 * 8,9 * 10, ll-hexahydro-5-ethyl-5 * 10-methano-5H-benzocyclo-_nonen-3-ol _________

Analogous to the procedure described in Example 34 for the preparation of anti-12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methanol-5H-benzocyclonone-3-ol is obtained from 1.0 g of syn-5-ethyl-6,7,8,9,10,11 - hexahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-amine 0.72 g of the hydrobromide of the intended product with m.p. 266-270 ° C after recrystallization of a mixture of ethanol and ether.

Analysis for C- gHHgjNOBr: C% H # N #

Calculated 58.89 7 * 41 4.29

Found 58.50β 7.47 4.10

Example 42

Anti-6,7,8,9,10,11-hexahydro-5-methoxy-N, 5-dimethyl-5,10-methano-5H -_-benzocyolonone-12-amine 3 g 6.7 * 8.9 10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one, 2 g of alumina and 10 ml of liquid methylamine are heated in a closed container at 180-190 ° C. 18 hours. After cooling the mixture, it is diluted with ether and filtered to isolate the hydrated calcium oxide. The filtrate is concentrated to an oil which is taken up in ethanol and shaken with hydrogen at a pressure of 3 * 16 atm in the presence of platinum dioxide catalyst. The catalyst is filtered off, carefully purified with ethanol and the combined filtrate concentrated in vacuo. The residue is distilled under reduced pressure to give 1.8 g of the intended product with kp. 138-144 ° C / 0.2 mm Hg. For analytical use, a sample is converted to the hydrochloride crystallized by ethanol, m.p. 295-298 ° C.

Analysis for OjyHpgOINO: C # N #

Calculated 69.01 8.86 4.73

Found 68.90 8.92 4.83

Example 43 5,6,7,8,9,10-Hexahydro-3-methoxy-5-methyl-N-phenethyl-5,9-methano-N-benzocyclooctene-11-amine

Analogous to the procedure described in Example 42 for the preparation of N, 5-dimethyl-6,7 * 8,9 * 10,11-hexahydro-3-methoxy-5 * 10-methano-5H-benzocyelonone-12-amine is prepared from 2.3 g of 5 * 6.7 * 8,9,10 - hexahydro-3-methoxy-5-methyl-5,9-methanobenzocyclooctene-11-one 1.80 g of the intended compound with b.p. 170-200 ° C / 0.5 mm Hg. A sample is converted to the hydrochloride.

38 142984

Analysis for C₂ ^H ^ qCCNO:

Cfo N% N%

Calculated 74.27, 8.12, 5.77

Pound 7 ^, 23 8.29 3.59

Example 44

Syn-5,6,7,8,9, lo-hexahydro-3-methoxy-N, 5-dimethyl-5,9-benzo-raethano -______ cyclooctene-ll-amin__

By analogy with the method used in Example 42, the position of anti-6,7,8,9,10,11-hexahydro-3-methoxy-N, 5-dimethyl-5,10-methano-5H-benzocyclonone-12-amine is prepared from 9.5 g of 5 6,7,8,9,10-Ie xahydro-5-methoxy-5- * methyl-5,9-methano-benzoeyclooctene-11-one 5.4 g of the intended product in the form of the hydrochloride, m.p. 232-236 ° C.

Analysis for C- HH ^CINO.

Cfa H% N / o

Calcd 68.19 8.58 4.97

Pound 67.83 8.45 4.91

Example 45

Syn-N-allyl-N, 5-dimethyl-5,6,7,8,9,10-hexahydro-5-methoxy-5,9-methano -_-benzocyclooctene-11-amine 5 g of syn-N-allyl -5,6,7,8,9,10-Hexahydro-3-methoxy-5-methyl-5,9- -methano-benzocyclooctene-11-amine, 3 ml of ethyl chloroformate, 50 ml of saturated aqueous sodium bicarbonate solution and 25 ml of methylene chloride are stirred. vigorously overnight at room temperature. The layers are separated, the methylene chloride is washed with 2N hydrochloric acid, dried over potassium carbonate and concentrated in vacuo. 3.3 g of residue are obtained, which is dissolved in 100 ml of tetrahydrofuran, stirred and refluxed under nitrogen with 1 g of lithium aluminum hydride for 20 hours. The mixture is cooled, 1.5 ml of water is added to decompose excess hydride, and aluminum salts are removed by filtration. The filtrate is dried and concentrated in vacuo, and the residue is distilled to give 1.4 g of the intended product with b.p. 130-135 ° C / 0.5 mm Hg. A portion is dissolved in ether, treated with hydrogen chloride, the crystals filtered off, recrystallized from ethyl acetate to give the hydrochloride with m.p. L64-L66 ° C.

Analysis for C- HHggClNO: C% H% Wo

Calculated 70.89 8.77 4.35

Found 71.06 9.07 4.53 39 142984

Example Αξ> 5,6,7,8,9 11 O-Hexahydro-3-methoxy-N, N, 5-trimethyl-5,9-methano-benzo-oyolo-octene-11-amine

Analogous to the procedure described in Example 45 for the preparation of N-allyl-N, 5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methano-benzocyclooctene-11 amine is prepared from 11.1 g of N, 5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methano-benzocyclooctene-11-amine 8.1 g of the intended connection with kp. 125-130 ° C / 0.3 mm Hg. The product dissolved in ether is converted by treatment with hydrogen chloride to a crystalline hydrochloride. Recrystallization of a mixture of ethanol and ether gives a product, A, with m.p. 180-190 ° C, which is recrystallized from a mixture of ethanol and ether to give a needle-shaped crystals product, m.p. 225-226 ° C.

Analysis for C ^ HHgClNO: C% N #

Calculated 69.01 8.86 4.74

Found 68.89 8.92 4.70 Based on IR and NMR spectroscopic data, the product is added to a structure such as the isomers where the amino grouping is placed in the anti-configuration.

The mother liquor from the crystallization of product A is concentrated and an additional portion of product is obtained with m.p. 218-223 C. Recrystallization of a mixture of ethanol and ether gives a product with hexagonal crystals, m.p. 221-223 ° C.

Analysis for C ^H ^CINO: C% B.% N #

Calculated 69.01 8.86 4.74

Found 68.89 8.64 4.74 On the basis of IR and NMR spectroscopic data, this product is added to a structure such as the isomers where the amino group is located in the syn configuration.

Example 47 N, 5-Dimethyl-N-phenethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5> 9-methano -_-benzoeyclooctene-11-amine

Analogous to the process described in Example 45 for the preparation of N-allyl-N, 5-dimethyl-5> 6,78,9,9,10-hexahydro-3-methoxy-5) 9-methano-benzocyclooctene-11-amine is prepared. from 3 * 8 g of 5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-N-phenethyl-5,9-methano-benzo-cyclooctene-11-amine 3> 1 g of the intended product with kp. l85-190 ° C / 0.3 mm Hg. Treatment of a portion of the product in acetone with one equivalent of fumaric acid gives the fumarate, which is recrystallized from acetone as a hydrate, m.p. 149-151 ° C.

Analysis for CggH- ^ NO ^. l / 4HgO:

0% H% NiS

Calculated 71.53 7.6L 2.98

Pound 71.58 7.73 2.98

Example 48 N, 5-Dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-N- (3-methyl-2-butenyl) -β- 5.9 "methano-benzocyclooctene-11 amin_

Analogous to the process described in Example 45 for the preparation of N-allyl ~ N, 5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methanobenzoeyclooctene-11-amine is obtained. from 3.8 g of 5,6,7,8,9,10-hexa-hydro-3-methoxy-5-methyl-N- (3-methyl-2-butenyl) -5,9-methano-benzocyelo oeten-II-amine 2.6 g of the intended product with b.p. 150-155 ° C / 0.4 mm Hg. Treatment of a portion of this product in acetone with fumaric acid gives the crystalline fumarate as a hydrate with m.p. 136-138 ° C. Analysis for Cg ^H- ^NO ^. l / 4HgO: C # Hfo N #

Calculated 69.19 8.24 3.22

Found 69.20 8.11 3.32

Example -49 N, 5-Dimethyl-6,7,8,9,10,11-hexahydro-3-methoxy-N- (3-methyl-2-butenyl) -5,10-methano-5H-benzocyclonone -12-amine 3.5 g 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-N- (3-methyl-2-butenyl) -3,10-methano-3H -benzocyclonone-12-amine, 6 g of ethyl chloro formate, 100 ml of saturated aqueous sodium hydrogen carbonate solution and 50 ml of methylene dichloride are stirred vigorously at room temperature for 24 hours. The layers are then separated, the organic layer is washed with 2N hydrochloric acid, dried over potassium carbonate and concentrated in vacuo. The residue weighing 3 g is dissolved in 50 ml of tetrahydrofuran and added to a suspension of aluminum hydride in 50 ml of tetrahydrofuran, stirred and heated at reflux for 18 hours. After cooling, 4.5 ml of water is added and the reaction mixture is stirred for 30 minutes and filtered. The filtrate is dried over anhydrous sodium sulfate and concentrated. The residue, which weighs 2 g, is treated with fumaric acid in acetone to give the fumarate of the intended compound in the form of hemihydrate, 1.8 g, m.p. 108-110 ° C.

Analysis for CggH37NO4. 1 / 2HgO: 0% Hfo Nfo

Calculated 69.02 8.47 3.08

Found 68.82 8.54 2.94 4i 142984

Example 50 12-Amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclonoene-3-Qlj acetate A. A mixture of 15.0 g of 12 -amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclonone-3-ol, 11.6 g of carbobenzyloxychloride and 100 ml of saturated aqueous sodium bicarbonate solution are stirred. 30 minutes. 100 ml of methylene chloride is added and the mixture is stirred for 1 hour. The organic layer is isolated, dried and concentrated. The residue is triturated with ethyl acetate and pentane, then filtered to give 24 g of crude product. Recrystallization of a mixture of ethyl acetate and cyclohexane gives 18.3 g of carbobenzyloxylated amine, m.p. 103-110 ° C.

B. A solution of 5.0 g of the carbobenzyloxylated amine prepared under A above, 10 ml of acetic anhydride and 50 ml of pyridine is allowed to stand overnight. The solution is diluted with water and extracted with ether. The ether extracts are washed with 2% hydrochloric acid, dried and concentrated to give 5.1 g of O-acetylated product, which is shown to be pure by thin layer chromatography.

C. A solution of 2.5 g of the O-acetyl product prepared above under B and 0.75 g of hydrogen chloride gas in 50 ml of tetrahydrofuran is hydrogenated in a Parr apparatus over 250 mg of 10 $ palladium on coal at a hydrogen pressure of 2, 8l atm. for 90 minutes. The catalyst is filtered off and by concentration of the filtrate 2.2 g of the intended product is obtained in the form of a viscous glassy mass. Crystallization of the vitreous product of a mixture of tetrahydrofuran and ether gives crystalline 12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclo-nonene-3 ol acetate hydrochloride with m.p. 268 ° C.

Analysis for C ^H ^NOgCl: C% H # N $

Calculated 65.90 7.81 4.52

Found 65.38 7.82 4.48

Example 51 12-Amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclo-nonen-3-ol-cyclopropane-carboxylate A. A solution of 2, 0 g of the carbobenzyloxylated amine prepared in Example 50 and 2.0 ml of cyclopropane carboxyl chloride in 10 ml of pyridine are allowed to stand overnight. The solution is diluted with water and extracted with ether. The ether extracts are washed with 2% hydrochloric acid, dried and concentrated to an oil. The oil is chromatographed on 70 g of alumina (Woelm activity III). Elution with ether gives 1.5 g of oil which is crystallized from a mixture of ethyl acetate and hexane to give 1.2 g of snip o-cyclopropane carboxylate derivative. 104-109 ° C.

B. Analogous to the method described in Example 50, C for the preparation of 12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclonone-3 -ol-aeetate is obtained from 1.0 g of the O-eyclopropane arboxylate derivative prepared above under A 0.45 g of the hydrochloride of the intended product with m.p. 255-257 ° C (dec.) By crystallization of a mixture of tetrahydrofuran and ether.

Analysis for C- Eb EbjgNOgCl. 1 / 4H20: 0% H% l]%

Calculated 67.04 7 * 85 4.12

Found 66.79 7> 68 4, 144

Example 52

Resolution of anti-5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-_-methano-5H-benzocyelonone-12-amine

A solution of 64.6 g, 0.249 mol, anti-5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-amine in 300 ml of methanol are added to a solution of 41.5 g of 0.275 mol, 1-tartaric acid in 1400 ml of methanol. The resulting solution is warmed, filtered and diluted to 2000 ml and left for 3 days. By filtration, 36.1 g of a salt, m.p. 200-203 ° C (decomposition) and 7§7ρ = -27 ° (1% in dimethylformamide). Recrystallization of the salt of methanol gives 29.1 g of substance with m.p. 212-214 ° C and /a.7D = -32.8 °. This salt is converted to the free base by treatment with aqueous sodium hydroxide and extraction of the aqueous mixture with ether, followed by drying with ether extracts over anhydrous magnesium sulfate. After removal of the desiccant and ether solvent, 176 g of resolved base are obtained. This is converted to hydrochloride hydrate salt with m.p. 115-119 ° C (dec.) And ~ - 4.1 ° (2% in methanol).

To recover the isomeric opposite-rotational capability, the mother liquor is concentrated from the first crystallizations described above, treated with aqueous sodium hydroxide and extracted with ether. After drying the ether extracts over anhydrous magnesium sulfate and concentrating the extracts, 41.5 g of base are obtained. This is dissolved in 500 ml of methanol and the solution is added to a solution of 26.4 g of d-tartaric acid in 1000 ml of methanol. This solution is diluted to ΐβΟΟ ml and allowed to stand for 5 days. Filtration gives 36.7 g of salt with m.p.

205-209 ° C (decomposition) and 7§7p = + 30.3 ° (1 $ in dimethylformamide).

Recrystallization of this salt from methanol gives 30.0 g of salt with m.p. 209-211 ° C (decomposition) and / §7D = +31> 9 ° · Conversion of this 43 1Λ 2 9 8 Λ salt to the free base in the same manner as described for the left-turning isomer above gives l6.8 g of base. This is converted to the hydrochloride hydrate salt with m.p. 115-H9 ° C (dec.) And / 57D = + 44.5 ° (2% in methanol).

Example 53

Preparation of plus and minus rotational isomers of anti-12-amino - 6,7,8,9,10,11-hexahydro-5-ethyl-5,10-roethano-5H-benzocyclonone-5-ol A. A mixture of 9.5 g of optically pure minus anti-5-ethyl-6,7,8,9,10,11-hexahydro-5-methoxy-5,10-methano-5H-benzocyclonone-12-amine and 80 ml 48 # Hydrogen bromic acid is heated at reflux temperature under a dry nitrogen atmosphere for 50 minutes. The resulting solution is concentrated to 40 ml, diluted to 150 ml with water and basified with concentrated ammonia water. After standing for 1 hour, the mixture is filtered to give 8.9 g of product with m.p. l85-191 ° C. Recrystallization of the product of ethyl acetate gives 7.5 g with m.p. 194-196 ° C and 1 & 7-Q = -51.3 ° (2 # in methanol).

B. In the treatment of 9.5 g of optically pure plus-turning anti-5-ethyl - 6,7,8,9,10,11-hexahydro-5-methoxy-5,10-methano-5H-benzocyclonone-12- amine with 48% hydrogen bromic acid as under A, 9.3 g of crude product is obtained with m.p. 178-190 ° C. Recrystallization of this product from ethyl acetate gives 7.0 g of product with m.p. 194-196 ° C and / 57D = + 52.0 ° (2% in methanol).

Example 54

Resolution of anti-5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,5,11-methanobenzocyclodecene-13-amine

A solution of 83 g of racemic anti-5,6,7,8,9,10,11,12-octa-hydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecene-13-amine prepared as described in Example 20 in 200 ml of methanol are added to a solution of 57 g of d-tartaric acid in 500 ml of methanol. The solution is diluted to 1 liter and allowed to stand for 2 days. Filtration gives 83.5 g of salt with m.p. 200-208 ° C (dec.). After three recrystallizations of this salt of methanol, 21 g of optically pure tartrate with m.p. 213-215 ° C. This is converted to optically pure base by treating the salt with dilute sodium hydroxide and extraction with ether. Exactly half of the dried ether extract (225 ml) is treated with 15 ml of ethanol and acidified with ethereal hydrochloric acid. By filtration 5.8 g of the hydrochloride of the plus-turning enantiomorph are obtained with m.p. 234-237 ° C.

44 142984

Analysis for C ^HggNNOCl: C% Ufa 11%

Calculated 69.01 8.86 4.73

Pound 68.90 9.10 4.42 B.

The mother liquor of the above tartrate crystallization is concentrated and the residue is transferred in base form by treatment with dilute aqueous sodium hydroxide and extraction with ether. Removal of the ether gives 58 g of base which is dissolved in methanol and treated with 38 g of 1-tartaric acid in methanol. The final solution has a volume of 800 ml. By filtration after 4 days, 41.3 g of tartrate are obtained with m.p. 204-209 ° C (dec.). After two recrystallizations of this salt, optically pure tartrate with m.p. 2l6-2l8 ° C. Upon conversion to the optically pure base and then to the hydrohloride as indicated under A, 6.0 g of hydrochloride of the minus-turning enantiomorph are obtained with m.p. 234-237 ° and -46.0 °.

Analysis for C ^ yHH gNOCl: C% H% 11%

Calculated 69.01 8.86 4.73

Found 68.63 9.10 4.35

Example 55 (+) - Syn-13-amino-5,6,7,8,9,10,11,12-alpha cahydro-5-methyl-5,11-methano-benzocyclodecen-3-ol

The other half of the ethereal solution of optically pure plus rotating base described in Example 54, A, is concentrated to give 6.5 g of base. This is treated with 100 ml of 48 $ hydrogen bromic acid and heated to reflux under dry nitrogen for 1/2 hour, then concentrated. The residual oil is crystallized by water to give 5.4 g of hydrobromide salt of the intended product, m.p. 268-272 ° C and / §7jp = + 4l, 4c Analysis for C-, EphNOBr. 1 / 4H? 0: C% H% 11%

Calculated 58.09 7.46 4.23

Found 58.20 7.61 4.23 45 1A 2 9 8 Λ (-) - Syn-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5, 11-methanol-benzocyclodecen-3-ol

Analogous to the process described for the preparation of the plus turning isomer is obtained from the ether solution of the negative turning base described in Example 54, B, 5.5 g of hydrobromide salt of the intended product with m.p. 269-271 ° C and = -4l, 7 °

Analysis for Cl6H24NOBr. 1 / 4H 2 O: C% N #

Calculated 58.09 7.46 4.23

Found 58.47 7.41 4.26

Example 56

Anti-β- (dimethylamino) -5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11 -_-methanobenzocyclodecen-5-ol

A solution of 5.0 g of anti-5,6,7,8,9,10,11,12-octahydro-3-methoxy-N, N, 5-trimethyl-5,11-ethanobenzocyclodecerr-13-aide -Hydrochlor ± d prepared as described in Example 27 in 80 ml of 48% urban hydrochloric acid is heated to reflux under dry nitrogen for 20 minutes, then concentrated. The residue is crystallized by a mixture of ethanol and ether to give 4.4 g of the hydrobromide of the intended product, m.p. 243-245 ° C. Analysis for C ^ gHHNNOBr:

Cfo H $ N%

Calculated 6l, 01 7.96 3 »95

Found 6l, 06 8.10 3 »85

Example 57 Phentyl-5,6,7,8,9,10,11,12-octahydro-3-methoxy-N, N, 5-trimethyl-5,11-metha-benzocyclodecene-13-amine-N-oxide

To a solution with a temperature of 0 ° C consisting of 1.5 g of anti-5,6,7,8,9,10,11,12-octahydro-3-methoxy-N, N, 5-trimethyl-5, 11-methanobenzocyclodecene-13-amine prepared zone described in Example 27 in 20 ml of dry tetrahydrofuran is added 1.0 g of m-chloroperbenzoic acid in 10 ml of tetrahydrofuran. The solution is stirred at 9-10¾ for 30 minutes. 2 ml of ethanol saturated with hydrogen diloride are added. After crystallization, 30 ml of ether is added and the mixture is filtered to give 1.7 g of the hydrochloride of the intended product, m.p. 170-173 ° 0 (dec.).

Analysis for Ο- ^ Η- ^ ΝΟ ^ Ι: 0%

Calculated 67.13 8.90 4.13

Found 66.6l9 »04 3.98

Example 5S

6.9.10.11- Tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclo-nonen-12-one.

Under a nitrogen atmosphere, a solution of 40 g (0.21 mol) of 1-methyl-7-methoxy-2-tetralone in 100 ml of t-butanol is added dropwise to a freshly prepared solution of potassium t-butoxide (9.8 g, 0.25 M potassium in 400 ml of t-butanol). The mixture is stirred at room temperature for 1 hour after the addition is completed, then it is transferred under nitrogen to a drip funnel and then dropwise added to a solution of 53 g (0.42 mol) of cis-1,4-dichloro-2-butene in t-butanol while stirring under nitrogen. After the addition of 1 g of potassium iodide, stirring is continued for approx. 18 hours at room temperature. Then, an additional amount of fresh potassium t-butoxide solution (15 g, 0.38 M potassium in 400 ml of t-butanol) is added dropwise and the mixture is refluxed for 6 hours after completion of addition. When the reflux period is over, stirring is continued at room temperature for approx. 16 hours. Then the reaction mixture is poured into ca. 4 liters of water and the organic phase is extracted with benzene. The benzene solution is washed twice with water, dried over magnesium sulfate and the solvent is evaporated in vacuo to give 57 g of a crude oil. Distillation of the crude oil gives 36 g of product with bp. 155-165 ° C / o, 5 mm, which crystallizes from hot heptane, m.p. 79-81 ° C.

Example 59 6.9.10.11- Tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclo-nonen-12-one oxime.

A clear solution of 23 g of sodium acetate in 15 ml of methanol is mixed with a clear solution of 19.5 g of hydroxylamine hydrochloride in 200 ml of methanol and the precipitate formed of sodium chloride is filtered off. To the mixture is added a solution of 13.5 g of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one in 50 ml of methanol. After the addition is complete, the mixture is refluxed for approx.

4 hours, after which it is left stirring for a further 16 hours. The solvents are evaporated in vacuo and the residue is slurried in water to give a solid which is filtered off, carefully treated with water and dried to give 14.2 g of product with m.p. 122-125 ° C.

Recrystallization from isopropanol gives 11.7 g of the desired compound, m.p. 124-126 ° C.

47

Example 60 14,784,9,8,9,10,11-Hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzo-cyclonone-123-amine.

5 g of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H - benzocyclonone-12-one oxime, 150 ml of ethanol, 30 ml of concentrated ammonium hydroxide and 2 teaspoons of Raney Nickel is shaken with hydrogen at pressure of 2.8 atm for 5 hours at room temperature.

The catalyst is filtered off and the solvents removed in vacuo. The residual oil is partitioned between ether and water. By separating the ether layer, drying over magnesium sulfate and removing the ether in vacuo, 4.5 g of crude product is obtained.

Treatment of an ether solution of the crude product with anhydrous hydrogen chloride gives 3.5 g of precipitate with m.p. 265-272 ° C. Recrystallization from hot water gives 1.6 g of the desired compound, m.p. 301-303 ° C.

Example 61 5-Ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-one.

Analogous to the procedure described in Example 58 for the preparation of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-one is obtained from 20.4 g of 1-ethyl-7-methoxy-2-tetralone and 25 g of cis-1,4-dichloro-2-butene, 17.8 g of the desired compound with bp 150-185 ° C / 0.4 mm.

Example 52 5-Ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-one oxime.

Analogous to the procedure described in Example 53 for the preparation of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methano-5H - benzocyclonone-12-one oxime is obtained from 16, 0 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-one and a clarified mixture of 25.5 g of sodium acetate and 22 g of hydroxylamine. hydrochloride in 200 ml of methanol, 10.3 g of the desired compound, m.p. 150-153 ° C.

Example 63 48

U298A

5a-ethyl-6,7,8,9,10, ll-hexahydro-3-methoxy-5,10-methano-5H-benzocyclo-nonene-123 amine.

Analogous to the process described in Example 60 for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclonone-12-amine is prepared. from 3.0 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methano-5H-benzocyclonone-12-one oxime 1.4 g of the hydrochloride salt of the above compound, mp. 247-250 ° C.

Claims (2)

49 U2984 Patent Claims. An analogous process for the preparation of benzobicycloalamines of the general formula r1 ........... wherein R is hydrogen, alkyl of 1-4 carbon atoms, alkyloxy of 1-4 carbon atoms, hydroxy, acyloxy of 2 -8 carbon atoms or halogen, X means R2? 4 -N ^ or -N-> 0 X * 3 R5 R1 means alkyl of 1-4 carbon atoms, or when X means - <B3 R "* may also mean hydroxymethyl or alkenyl having 3-5 carbon atoms, R 2 represents hydrogen, alkyl of 1-4 carbon atoms or phenalkyl of 3 to 7 carbon atoms, R means hydrogen, alkyl of 1-4 carbon atoms, or alkenyl of 3-5 carbon atoms, R 4 means alkyl of 1-4 carbon atoms, R means alkyl of 1-4 carbon atoms and n is 3, 4 or 5, or pharmaceutically acceptable acid addition salts thereof, characterized in that a) an imino compound of the general formula R7 ^ r- ^ V> = nR6 I If <CH2} n (II) - ^ 50 1Λ298Λ g where R means hydroxy, alkoxy of 1-4 carbon atoms or has the same 2 6 2 meaning as R, however, R does not have the same meaning as R when 7 7 R means alkoxycarbonyl of 2- 5 carbon atoms, R means alkoxy carbonyl of 2-5 carbon atoms, alkyl of 1-4 carbon atoms, alkenyl 2 of 3-5 carbon atoms or hydroxymethyl, and R, R and n have the meanings previously defined, reduced, or b) a compound with the general formula R7 - (CH2> x Rx ^^ Y \ LL i? i «<CH2> y where xfy is equal to n - 2, Y means R1 2 3 4 3 or J> C = NR5 R 2 And R, R, R, R, R and n are as previously defined, are reduced, and if desired, a compound of the general formula (I) wherein R is hydrogen is alkylated or alkenylated to form a compound with the general formula (I) wherein B? means alkyl of 1-4 carbon atoms or alkenyl of 3-5 carbon atoms and / or a compound wherein R is hydrogen and R is alkyl of 1-4 carbon atoms, or alkenyl of 3-5 carbon atoms is alkylated or phenalkylated to form of a corresponding compound, 2 wherein R is alkyl of 1-4 carbon atoms or phenalkyl of 3 to 7-10 carbon atoms, and / or a compound wherein R and R are 3 alkyl of 1-4 carbon atoms are oxidized on their own known manner for the formation of the corresponding N-oxide and / or a compound of the general formula (I) wherein R is alkyloxy of 1-4 carbon atoms or acyloxy of 2-8 carbon atoms is converted per se method for a compound of the general formula (I) wherein R is hydroxy and / or a compound of the general formula (I) wherein R is hydroxy is converted in a manner known per se into a compound of the general formula (I) wherein R is acyloxy of 2-8 carbon atoms, and / or a free base with the general formula (I) is converted to a pharmaceutically acceptable acid addition salt.