CS207771B2 - Method of preparation of the 9-aminodibenzopyrans - Google Patents

Description

The present invention relates to a process for the preparation of 1-hydroxy-3-substituted tetrahydro and hexahydro-dibenzo [b, d] pyranes having an amino or amine derivative at the 9-position, which are useful as analgesic agents, antidepressants, anxiety agents, hypotensive agents and as intermediates. From these 9-amino derivatives, pharmaceutical preparations are prepared which are used for the treatment of hypertension.

A number of dibenzopyran compounds have recently been found useful for the treatment of depression, pain and anxiety. U.S. Patent Nos. 3,928,598, 3,344,673, and 3,953,603 disclose various hexahydrodibenzo [b, d] pyran-9-ones which are useful as described above. Particular attention is focused on dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexanydro-9H-dibenzo [b, d] pyran-9-one, now called nabilone.

Some modifications of the known dibenzopyran compounds have been made to find new compounds with increased pharmacological usefulness or totally new uses. Only a few new modifications have incorporated a nitrogen atom into the dibsopyran molecule. U.S. Patent No. 3,886,184 discloses certain 1-amino-3-alkyl-9-alkyl-dibenzo [b, d] pyrans.

U.S. Patent No. 3,676,462 claims a series of 1-aminoalkyl- and 3-aminoalkyldibenzo [b, d] pyran. Similarly, a nitrogen atom has been introduced into ring C of certain dibenzo [b, d) pyranes. U.S. Patent No. 3,878,219 claims dibenzo [b, d] pyranes having a nitrogen atom at the 9-position. U.S. Patent No. 3,883,948 claims similar nitrogen-containing heterocycles in which ring C is a five-membered six-membered.

The invention relates to a process for the preparation of dibenzo [b, d] pyranes of the general formula I

where

R ¹ is hydrogen or C 1 -C 4 alkanoyl,

R ² is alkyl of 5-10 carbon atoms,

R ³ is hydrogen or methyl and Z is a substituent selected from the group consisting of

A 'A' X 'where

R ⁴ is hydroxyl,

R ⁵ is hydrogen, hydroxyl, C 1 -C 4 alkyl, CH ₂ (alkynyl) wherein C 2 -C 4 alkynyl, C 1 -C 7 alkanoyl, C 1 -C 7 alkanoyloxy, C 1 phenylalkyl up to 2 carbon atoms in the alkyl, phenylalkanoyl having 1 to 2 carbon atoms in the alkanoyl group, - (CH ₂ ) n -OH, - (CH ₂ -O-alkanoyl having 1 to 2 carbon atoms in the alkanoyl group, or -C- (CH 2) n) —COOH,

Where n is 2, 3 or 4,

R ⁶ is hydrogen, alkyl of ¹ 1 to 4 carbon atoms, (CH2jalkinyl, where the alkynyl contains 2-4 carbon atoms, alkanoyl of 1-7 carbon atoms, or

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of piperidine or morpholine,

R ⁷ is hydrogen or C 1 -C 7 alkanoyl;

R ⁸ is C 1 -C 7 alkanoyl and their non-toxic pharmaceutical acid salts and quaternary ammonium salts, characterized in that the compound of formula II

where

R ¹ is hydrogen and

R ² and R ³ are as defined above, is reacted with an amine of formula III

HNR ⁴ (Illj, where

R ⁴ is as defined above to give a compound of formula I wherein

Z is a group of formula IV (IV) and this compound of formula I wherein Z is a group of formula IV and R ⁴ is hydroxyl is hydrogenated to give a compound of formula I wherein Z is a group of formula VI

R.

R '(VI) and R ⁵ and R ⁶ are hydrogen and the compound thus obtained is reacted with an acylating agent to give a compound of formula I wherein Z is a group of formula VI, R ⁵ is a hydrogen atom and R ⁶ is an alkanoyl; 1-7 carbon atoms, fenylalkanoyl having 1-2 carbon atoms in the alkanoyl or -C (CH _{2) n} -COOH, for

wherein n is 2, 3 or 4, and optionally the compound so obtained wherein R ⁵ is hydrogen, R ⁶ is C 1 -C 4 alkanoyl or C 1 -C 2 phenylalkanoyl is reacted with a reducing agent and a compound of formula (I) wherein R ⁵ is hydrogen and R ® is C 1 -C 4 alkyl or C 1 -C 2 -phenylalkyl and optionally reacted with an acylating agent, and to give a compound of formula I wherein Z is a group of formula VI, R ⁵ is C 1 -C 7 alkanoyl or C 1 -C 2 phenylalkanoyl and R ⁶ is C 1 -C 4 alkyl or C 1 -C 4 phenylalkyl Optical isomers and epimers of the compound of formula (I) are optionally isolated, and the compound of formula (I) is isolated in the form of the free base or its non-toxic pharmaceutically acceptable acid addition salt or quaternary ammonium salt.

A preferred group of compounds of the invention are those of the above formula wherein

R ¹ is a hydrogen atom,

R ³ is methyl,

Z is a group of formula

AND

N

Λ where

R ^{4 is} as defined above.

Another preferred group of compounds of the above formula are those wherein

R ¹ is hydrogen or C 1 -C 4 alkanoyl,

R ³ is methyl and

Z is a group of the formula wherein

R ⁵ and R ^B is as defined above, preferably hydrogen, alkyl, alkenyl, or alkanoyl having 1 to 7 carbon atoms.

Another preferred group of compounds of the invention are those of the above formula wherein

R ¹ is hydrogen and

Z is a group of formula ff

Λ where

R ⁵ is hydrogen and

R ⁸ is C 1 -C 7 alkanoyl, in particular C 1 -C 2 alkanoyl.

A group of compounds particularly useful as intermediates in the preparation of other compounds of the invention are those of the above formula wherein Z is

And where

R ⁵ and R ⁶ are hydrogen atoms.

The invention also relates to pharmaceutical compositions comprising one or more biologically active compounds of the aforementioned general formula in combination with a suitable pharmaceutical carrier, diluent or excipient The pharmaceutical compositions with the compounds of the invention are particularly suitable for treating mammals by shepertension.

The compositions may also be used to treat anxiety, depression and similar central nervous system irregularities. The compositions may also be used to treat glaucoma.

The compounds of the invention are used to treat hypertension by administering to a mammal with hypertension an amount sufficient to lower the blood pressure of a hypotensive active compound of the above formula. A preferred method of treatment is to administer a dose effective to lower the blood pressure of a compound of the above formula wherein R ⁶ and R ⁷ are C 1 -C 7 alkanoyl, especially C 1 -C 2 alkanoyl.

In the above formula representing 9-aminoidibenzo [b, di] pyranes prepared according to the invention, R 1 is hydrogen and C 1 -C 4 alkanoyl. As used herein, the term "C 1 -C 4 alkanoyl" refers to C 1 -C 4 acyl radicals. Examples of such C 1 -C 4 alkanoyl groups are formyl, acetyl, propionyl, n-butyryl and isobutyryl.

R ² je'definováno as alkyl having 5 to 10 carbon atoms. These * terms have the meaning assigned to them in the chemical literature relating to dibenzopyrans. Examples of C 5 -C 10 alkyl are both straight and branched chain alkyl groups such as n-pentyl, n-hexyl, 1,1-dimethylheptyl, 1,2-dimethylheptyl, 1-ethyloctyl, 1,1-dimethyloctyl, 2,3-trimethylheptyl, 1-propylhexyl, isooctyl, n-decyl and the like.

As mentioned in the above general formula of the compounds of the invention, Z may be an imino group of the formula

R ⁴

AND

Wherein R ⁴ is hydroxyl. It is understood that the compounds of the invention with this definition for Z are oximes.

The term Z is similarly defined as a group of the formula

wherein R ⁵ and R ⁸ are C 1 -C 4 alkyls such as methyl, ethyl, n-propyl, isopropyl and n-butyl.

Examples of CHc (alkynyl) groups are substituents such as 2-propynyl, 2-bynynyl and 1-me207771 thyl-2-propynyl. R ⁵ and R ⁶ are further defined as C 1 -C 7 alkanoyls. This definition refers to acyl radicals of carboxylic acids having 1 to 7 carbon atoms. These groups may be unbranched or branched by an acyl chain. Typical examples of these groups are formyl, acetyl propionyl, isobutyryl, pentanoyl, isohexanoyl, 3-ethylpentanoyl, 2-methylhexanoyl, 1,2-dimethylpentanoyl and the like.

Preferred alkanoyl groups are C 1 -C 4 alkanoyl, preferably C 1 -C 2 alkanoyl. R ⁵ also includes C 1 -C 2 phenylalkyl, such as benzyl and 2-phenylethyl, as well as C 1 -C 2 phenylalkanoyl, such as benzoyl and phenylacetyl. R ⁵ may further be a group of the formula - (CH 2) _n -OH, wherein n is 2, 3 or 4.

These groups include 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl groups. The hydroxy group of such moieties can be acylated with alkanoyl of 1-2 carbon atoms, and thereby providing substituents such as acetoxymethyl and the like. When R ⁵ defines the group -CO (CH 2] _n COOH, such groups include 3- (hydroxycarbonyl] propionyl, 4- (hydroxycarbonyl) butyryl and 5- (hydroxycarbonyl) pentanoyl.

Many of these compounds of the invention are amines which are basic and readily form acid salts and quaternary ammonium salts. For example, the 9-amino, 9-alkylamino or 9-alkylamino-di-benzo [b, d] pyran of the invention may exist in base form or alternatively as a salt. The non-toxic pharmaceutically acceptable salts of the invention are those which do not add toxicity to the basic amine, and these salts can be used pharmaceutically in the same manner as the free bases.

The acid salts of the invention are prepared by standard procedures such as the reaction of a basic amine with an organic or inorganic acid. The acids commonly used to form non-toxic pharmaceutically acceptable salts are mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, as well as sulfamic acid, nitric acid and nitrous acid. Useful organic acids are acetic acid, oxalic acid, lactic acid, ascorbic acid, maleic acid, fumaric acid, succinic acid, p-toluenesulfonic acid, benzoic acid, nrethanesulfonic acid, adipic acid and the like.

Likewise, the basic amines of the invention are tertiary amines which readily form quaternary ammonium salts, which are also pharmaceutically acceptable. These tertiary amines are quaternized by reaction with an alkylating agent such as methyl iodide, ethyl bromide, n-butyl chloride, isopropyl iodide, allyl bromide, dimethylsulfate and the like.

It is understood that salts of compounds such as ainides and oximes are not normally formed because the nitrogen atom is not sufficiently basic and quaternary ammonium salts are formed only when both R ⁵ and R ⁶ in the above formula are groups such as alkyl, alkenyl, phenylalkyl and the like.

The 9-aminodibenzo [b, d] pyrans prepared according to the invention can be prepared by any of the above methods. Conventionally, an oxime derivative is first prepared, which is then reduced to give the N-unsubstituted 9-aminodibenzopyran derivative, which is then further converted to the corresponding derivative in a conventional manner such as alkylation or acylation.

The starting materials used in the synthesis of oximes are hydroxylamines and alkoxyamines such as methoxyamine and the 9-ketodibenzo [b, d] pyran derivative. These dibenzo [b, d] pyran-9-one starting materials are represented by formula II

where

R ^1, R ² and R ³ are as defined above.

The compounds of formula II which are preferably used in the preparation of the oximes of the invention are those of the above formula wherein R ¹ is hydrogen. These compounds include the following list of representative starting materials:

1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, 1-hydroxy-3-n- octyl-6,6-dimethyl-B, 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, 1-hydroxy-3- (1,2-dimethylheptyl) - 6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one,

-hydroxy-3- (1,2-dimethyl-1-heptenyl) - (hydroxyethyl-1-hydroxy-10,110a-hexahydro-9H-dibenzo [b, d] pyran-9-one, 1-hydroxy-3) - (1-ethylhexyl) -6,6-dimethyl6,6a, 7,8,10,10a-hexahydro-9H-dibenzofb, d] pyran-9-one, 1-hydroxy-3- (1,1-dimethylmethylheptyl); 6a, 7,8,10,10a-hexahydro-9H-dibenzo-b, d] pyran-9-one, 1-hydroxy-3- (1,2,3-trimethyl-2-pentenyl) -6, G -dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one and related compounds.

Since the ketones of formula II are dibenzo [b, d] pyranes that are fully saturated in the C ring, there are stereochemical isomers at carbon 6a and 10a. More specifically, the starting ketones and the corresponding 9-aminodibenzo [b, d] pyranes of formula I may exist as the 6a, 10acis-isomers and? A, 10a-trans-isomers. Each of these isomers forms a racemic or dl-pair. For example, a 6α, 10α-cis derivative may have both a 6α-hydrogen atom and a 10α-hydrogen atom oriented above the plane of the ring, or alternatively both hydrogen atoms may be oriented below the plane of the ring. However, the two isomers may form a cis-dl-racemic mixture. Similarly, the 6α-trans-isomer may be a compound in which the Ga-hydrogen atom may be above the plane of the ring, while the 10α-hydrogen atom may be oriented below the plane, or alternatively the 6α-hydrogen atom may be oriented below the plane of the circle. and the 10α-hydrogen atom may be oriented above the plane. Again, the two isomers form a trans-dl-pair. Normally, the preparation of the compounds of the invention involves the use of a racemic mixture of both the 6α, 10α-cis-hexahydrodibenzo [b, d] pyranone that is the dl-cis isomer, or alternatively the racemic mixture of the 6α, 10α-trans-isomer b, d] pyranone. It will be understood, however, that the compounds of the invention may also be prepared from optically active d- or 1-cis ketones or dl- or 1-trans-ketones to give the corresponding 9-aminodibenzo [b, d] pyran with the same stereochemistry as the starting material. ketone. Since all individual stereochemical isomers at positions 6a and 10a possess useful pharmacological activity, it is often preferred to use a mixture of dl-cis- and dl-trans-hexahydrodibenzo [b, d] pyran-9-ones as a starting material. It is particularly advantageous to use these racemic mixtures as they are readily available synthetically. Examples of these preferred starting materials are:

dl-trans-1-hydroxy-3- (1,2-dimethyl-6,6α, 7,8,10,10α-hexahydro-9H-dibenzo [b, d] pyran-9-one, dl-trans-1 hydroxy-3- (n-octyl) -6,6-dimethyl-6,6 (3,7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, dl-cis -1-hydroxy-3- (n-decyl) -6,6a, 7,8,10,10a-hexahydro-9H-dibemzo-b, d] pyran-9-one and dl-cis-1-hydroxy-3- (1,2-dimethylhexyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzoyl, d] pyran-9-one.

The various dibeinzopyranone starting materials of formula II are compounds known or readily prepared by known methods. For example, a large number of dl-cis- and dl-trans-hexahydrodibenzo (b, dj pyran-9-one) is described in U.S. Patent Nos. 3,928,598, 3,944,673, and 3,953,603. Preparation of dl-cis- and dl-trans The hexahydro-dibenzo [b, d] pyran-9-ones are further described in U.S. Patent Nos. 3,507,885 and 3,636,058. The synthesis of various starting materials useful in the preparation of the compounds of the invention is further described in Archer et al. 3. Synthetic Approaches to 9-Ketocannabinoids, Total Synthesis of Nabilone, J. Org, Chem., 42, No. 13, pp. 2277-2284 (1977).

As mentioned, oximes of formula I (R ⁴ is hydroxyl) can be prepared by reacting hexahydrodibenzo [b, d] pyran-9-one with hydroxylamine. In preparing the oximes of the invention, dibenzo [b, d] pyran-9-ion and hydroxylamine are reacted in approximately equimolar amounts, and the reaction is preferably carried out in a suitable solvent such as methanol, ethanol, water or a mixture of these solvents. The reaction is generally complete after about 30 minutes to 4 hours when the reaction is carried out at a temperature of from 25 to 100 ° C. The oxime product is preferably isolated by simply diluting the reaction mixture with water or a defective acid, and then extracting the oxime into a water immiscible solvent such as diethyl ether, benzene, chloroform, dichloromethane, ethyl acetate and the like. oxime in the form of an oil or solid, which can then generally be crystallized from solvents such as n-hexane and petroleum ether. An example of an oxime is:

1-hydroxy-3-n-pentyl-6,6-dimethyl-9-hydroxyimidio-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

The oximes thus prepared are useful as pharmacologically active compounds and are also valuable as intermediates.

The 9-unsubstituted aminodibenzo [b, d] pyranes prepared according to the present invention, i.e. hexahydrodihenzopyranes with an NHz group at the 9-position, can be prepared by reducing the above-mentioned 9-hydroxyiminoderivatives or further by reducing the 9-hydroxyamino compounds. For example, another reduction of the 9-hydroxy amino derivative can be carried out by reaction with zinc in acetic acid or sodium in liquid ammonia, as well as by catalytic hydrogenation. However, a preferred method is a simple reduction of the 9-hydroxyimino derivative by any of the available methods. For example, by reacting the compound, i. ko is 1-hydroxy-3- (1,2-dimethylheptyl) -9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-d: benzo [b, d] pyran with hydrogen in the presence of a catalyst such as Raney nickel, a complete reduction is performed to give the primary amine, for example 1-hydroxy-3- (1,2-dimethylheptyl] -9-amino-6a, 7,8,9,10,10'a-hexahydro This hydrogelation is typically carried out in a solvent such as methanol and liquid ammonia and is normally completed within 4 to 8 hours when carried out at an elevated temperature of from 80 to 120 ° C. The product, the primary amine, can be isolated by poisoning the reaction mixture by evaporation of the reaction mixture and evaporation of the solvent Further purification of the amine is optionally carried out by conventional methods such as crystallization, acid salt formation, chromatography, and the like.

The primary 9-aminohexahydrodibenzoj b, d] -pyranes formed in this way, although acting on the central nervous system of animals, are particularly important intermediates for the preparation of other compounds of the invention.

Alkylation of the primary 9-amino group, for example, provides the corresponding N-alkyl- and N, N-dialkylaminoiminohexahydrodibeinzo [b, d] pyrans. The corresponding N-acyl and N, N-diacyl are prepared by acylation ^. the mercapto [b, d] pyranes of the invention.

Alkylation of the 9-amino-hexahydrodibenzopyran can be carried out by reaction of the amino derivative with an alkylating agent by known methods. The term "alkylating agent" includes, in addition to reagents containing a (C 1 -C 4) alkyl group, those reagents having a (C 2 -C 4) alkynyl, C 1 -C 2 phenylalkyl, as well as - (CH 2), - OH. Typical examples of such alkylating agents are alkyl halides such as methyl iodide, ethyl bromide, propyl bromide, isobutyl iodide, 3-butenyl bromide, 2-propenyl bromide,

2-hydroxyethyl iodide, alkyl sulfates such as dimethylisulfate, diisopropylsulfate, diallylsulfate and di (3-butynyl) sulfate. Other alkylating agents include tosylates such as benzyl tosylate, 2-phenylethyl tosylate, tert-butyl tosylate, 3-butenyltosylate, 2-butinyltosylate and the like.

For the monoalkylation of primary 9-aminohexahydrodibenzo [b, d] pyran, the reagents are used in approximately equimolar amounts. An excess of the alkylating agent is used to carry out the dialkylation when R ⁵ and R ⁶ in the above formula are alkyl, alkenyl, alkynyl, hydroxyalkyl or phenylalkyl. The reaction is preferably carried out in the presence of a suitable base which acts as an acid binding agent. Commonly used bases are triethylamine, benzylamine, sodium hydroxide, pyridine, sodium methoxide, sodium carbonate and the like bases. The reaction is preferably carried out in a non-reactive organic solvent such as an ether, for example diethyl ether, diisopropyl ether, methyl ether and dioxane. Other commonly used solvents include alcohols such as methanol, ethanol, isopropainol, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic solvents such as benzene, toluene, xylene and the like. The reaction is conveniently carried out for 2 to 20 hours at 30 to 150 ° C. C. The alkylation reaction product, 9-alkylamino- or dialkylaminodibenzo [b, d] pyrain, is readily isolated by simply removing the solvent from the reaction mixture and washing the product with water or dilute acid. The product thus obtained can then be further purified by chromatography or crystallization. Alternatively, the 9-amino derivative can be isolated in the form of a salt that is well crystalline and can be isolated by filtration. In particular, the reaction mixture containing the alkylated or dialkylated amine can be acidified by the addition of an acid such as hydrochloric acid or succinic acid, and thus the amine is converted to the acid salt. In the case of N, N-dialkylamine prepared according to the procedure described above, i.e. those compounds wherein R ⁵ and R ⁶ are selected from substituents including alkyl, alkenyl, alkynyl, phenylalkyl and the like, these compounds are converted to the quaternary ammonium salt by further reaction a β alkylating agent such as methyl bromide, allyl iodide or propargyl bromide. These quaternary ammonium salts are well crystalline solids that readily recrystallize.

It is understood that if 9-aminodibenzopyran is monoalkylated according to the above process to give a compound of the invention wherein R ⁵ is alkyl, alkenyl, alkynyl, hydroxyalkyl or phenylalkyl and R ⁶ is hydrogen, then further alkylation is performed by reaction with an alkylating agent above in the manner described. This alkylation reaction can prepare the dialkylated 9-aminodibenzo [b, d] pyranes of the invention wherein the alkyl groups are different, i.e., where R ⁵ and R ⁶ are independently alkyl, alkenyl, alkynyl, hydroxyalkyl, phenylalkyl and the like.

By any of the above acylation reactions, it is understood that acylation may continue to take place on the 1-hydroxy group of dibenzopyran to give varying amounts of 1-acyloxy-9-acylaminodiphenyl [b, d] pyran depending on the excess acylating agent used, the reaction temperature, Alternatively, the 1,9-diacylated derivative may be separated from the 9-acylamino derivative by methods such as chromatography or alternatively the 1,9-diacylated derivative may be reacted with a mild base such as acidic sodium bicarbonate to effect complete reaction. hydrolysis of the 1-acyloxy group to produce exclusively 9-acylaminodibenzo [b, d] pyran. As already mentioned, protecting the 1-hydroxy group from chemical modification prevents unwanted side reactions at this site.

As already mentioned, the 9-amino- and 9-acylamino-hexahydro-dibenzo [b, d] pyranes prepared according to the present invention can be alkylated by normal alkylation reactions and 9-alkylamino- and 9-N-alkylacylamino-hexahydro-dibenzo [b; d] pyrans can be prepared. The alkylamino derivatives can be further alkylated to give the corresponding 9-dialkylamino derivatives. An alternative method of preparing 9-alkylamino- and 9-dialkylaminohexahydrodibenzo [b, d] pyranes is to reduce 9-acylamino- or 9-diacylaminoibexahydrodibenzo [b, d] pyran.

For example, by reaction of an acylamino compound such as 1-hydroxy-3-thi-pentyl-6,6-dimethyl-9-benzoylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran with a reducing agent such as diborane or lithium aluminum hydride, the corresponding N-alkylamine, for example the 9-benzylamino derivative, is prepared from the amide.

This reduction is normally carried out in a solvent such as diethyl ether or tetrahydrofuran at 0 to 80 ° C. Isolation and purification of the product is accomplished by standard procedures. The 9-alkylaminodibenzopyrans thus formed can be acylated or further alkylated in the normal manner. For example, by reacting a compound such as 1-hydroxy-3- (2-hexenyl) -9-butylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, with phenylacetyl bromide in the presence of triethylamine is followed by acylation of the amino group to give 1-hydroxy-3- (2-hexenyl) -9- (N-phenylacetyl) butylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d pyran.

As is known to those skilled in the art, compounds of the invention which are fully saturated in ring C and which do not have exocyclic double bonds are compounds of the above formula wherein:

Z is a group of formula

they may exist in the form of epimers. For example, when the oxime of the invention is fully reduced and 9-aminohexahydrodibenzo [b, d] pyrain is prepared, the compound is a mixture of the 9α-amino and 9β-amino derivatives. Separation of the epimeric mixture may optionally be accomplished by fractional crystallization, column chromatography, gas chromatography, high pressure liquid chromatography, and the like. In general, any isomer separation can be used to obtain the end products. For example, if it is desired to prepare an optically active amide such as · d or 1-trans-hydroxy-3- (1,1-dimethylheptyl j-6,6-dimethyl-9a- ₁ -9, or U-acetamido-6a 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, the oxime of the corresponding 'active' d- or 1-trans-1-hydroxy-3- (1,1- dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran-9-one The oxime is then fully reduced to give an epiuier mixture of d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,6-dimethyl-9-amino-6a, 7,8,9,10,10ia-hexahydro-6H-dibenzo [b, d The epimeric amines are then acylated, for example by reaction with acetic anhydride, and an epimeric mixture of the corresponding acetamides is prepared, separating the resulting acetamides to prepare optically active d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl). -6,6-dimethyl-9α (α9,3) acetamido-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b, d] pyranes. preferably named commonly adopted nomenclature rules for absolute stereochemical configuration using R and S terminology, as suggested by Fletcher et al., Nomenclature of Organic Compounds, Advances in Chemistry Serles, 126, American Chemical Society, 1974. According to this nomenclature, an optically active compound according to the invention called 6nR, 9R, 10nR-6a, 10a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamide, 6,8,9,10,10a -hexahydro-6H-dibenzo [b, d] pyr-an. For simplicity, the nomenclature is not used for the compounds below, but it is to be understood that the present invention includes these optically active isomers and racemic mixtures.

The 9-aminodibeino [b, d] pyran derivatives of the invention defined by the above formula are novel chemical compounds that have valuable pharmacological activity and many of them are useful as intermediates in the synthesis of pharmacologically active compounds. Accordingly, a further feature of the present invention are pharmacological formulations comprising at least one biologically active compound in association with one or more suitable diluents, carriers or excipients. Other pharmacologically active agents may be added to these pharmacological formulations with the compounds of the invention. Particularly preferred pharmacological formulations of the invention are useful for the treatment of hypertension. Particularly preferred are those containing the 9-amide derivative of the invention as the active ingredient.

The formulations according to the invention are formulated for appropriate application. For oral administration, the compound of the invention is admixed with a carrier and diluent such as dextrose, lactose, mannitol, cocoa butter, ethyl lactate, m-ethylcellulose, calcium silicate, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, potassium benzoate and the like. These preparations may be formulated as tablets or gelatin capsules. Alternatively, the compositions may be dissolved in liquids such as a 10% aqueous glucose solution, isotonic sodium chloride solution, sterile water and the like and may be administered intravenously or by injection. These solutions may optionally be lyophilized and stored in sterile ampoules for reconstitution by the addition of sterile water.

A particularly preferred formulation useful for treating hypertension in humans comprises a compound such as dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9, 10,10a-hexahydro-6H-dibenzo [b] d] pyranine in an amount of from 0.01 mg to about 1.0 mg in combination with a carrier such as sucrose or starch in an amount of about 500 mg. which can be administered to high pressure individuals in an amount of from 1 to 4 tablets per day.

As already mentioned, the compounds of the invention have different uses. Representative compounds of the invention exhibit activity in one or more standard assays and exhibit analgesic, anti-gliaucoma, anti-depressant and anti-anxiety as well as hypotensive effects. The most potent compounds are the 9-amino derivatives (for example, R ⁶ and R ⁷ in the above formulas are alkanoyls), although the other compounds of the invention are also pharmacologically useful. For example, dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b d] pyran exhibits an ED 50 of 2 mg / kg in the analgesic activity test when administered subcutaneously Similarly dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyamino-6 _R a, 7,8,9,10,10a-hexahydro-6H-DIBE: of benzo [b, d] pyran demonstrated in mice, minimum effective dose (MED) of only 5.0 mg / kg. Moreover, in the septal lesion rat assay, dl -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl 1-9- (N-ethyl) acetamido-6a, 7,8,9,10,10a-hexahyd (ro-6H) -dibenzo [b, d] pyran shows a MED of 10.0 mg / kg in the dog blood pressure lowering test dl-trains-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran exhibits an intravenous MED of 0.5 g / kg intravenously.

As can be seen from the above discussion on biological activity, many of the compounds of the invention are useful for the treatment of hypertension, anxiety, depression, pain, glautooma and related diseases. Thus, the compounds can be used to treat animals and humans with these difficulties. The present invention also relates to a method of treating hypertension in a mammal, characterized in that an effective dose of the hypotensive drug of the invention is administered to an individual with hypertension and the need for treatment induced or developing hypertension. A particularly preferred method for treating hypertension of the invention is to administer a compound of the invention having an amino group at the 9-position (i.e., R ⁵ is C 1 -C 7 alkanoyl).

The lipotensively active compounds of the invention can be administered by any route including oral, subcutaneous, intramuscular and intravenous.

Typical doses useful for treating humans vary and depend on the particular condition to be treated and the size and age of the patient. Typically, they range from about 0.001 to about 23 mg total daily dose per patient. Preferred daily dosages used to treat hypertension are, for example, from 0.1 to 10 mg per person. A typical treatment for hypertension includes, for example, administration of 5 mg / d dl-1-hydroxy-3- (1,2-dimethylheptyl) -9- (2,6-d ^: oxo-piperidino) -6a, 7,8,9,10, 10α-hexahydro-6H-dibenzo [b, d] pyran. A preferred treatment involves administration of about. 2 mg / day dl-trans-1-hydroxy-3- (1,1-diethylheptyl) -B, 6-dimethyl-9-zetetamido-6a, 7,8,9,10,10a-hex-ahydro-6H -dibenzo [b, d] pyran.

The preparation of the 9-aminodibenzopyrines according to the invention is described in more detail in the following examples. It is to be understood that the examples are formulated only to illustrate the invention, and the methods commonly used in their preparation do not in any way limit the invention to certain compounds and certain methods described.

Example 1 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dlbenzo [b, d] pyran

A solution of 4.0 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran-9-one and 1.155 g of hydroxylamine hydrochloride were dissolved in 60 ml of ethanol and 10 ml of water. While stirring, 4.4 ml of 5 N sodium hydroxide solution are added in one portion. The reaction mixture is then heated to boiling for 30 minutes with stirring. After cooling the reaction mixture to room temperature, 100 g of ice are added and acidified to pH 2.5 by addition of concentrated hydrochloric acid. The aqueous acidic reaction mixture was then extracted several times with diethyl ether. The ether extracts were combined, washed with 5% aqueous sodium bicarbonate solution, water and then dried. Evaporation of the solvent under reduced pressure gave 2.0 g of the product as an oil. The oil was recrystallized from 50 mL of n-hexane to give 3.8 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7.8, 9,10,10a-hexahydro-6H-dibenzo [b, d] pyraine as a white powder. Mp 143-145 ° C.

For O24H37NO3 calculated:

74.38% C, 9.62 ·% H, 3.61% N, found:

H, 9.37; N, 3.78. M / e: calc. 387, found 387.

The procedure was repeated using 7.5 g of optically active (-) - trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a7,8,9,10,10a-hexahydro-6H -benzo [b, d] pyran-9-one as the starting ketone. The product was isolated as described above to give 5 g of an oil.

m / e: calcd 387, found 387, [ _a] CHUU _{= 4} . ₄₀₎ ia] ^C /, ^Luli - 4-34,6.

The syn- and anti-isomers of the optically active oxime are separated by high-pressure liquid chromatography ehromatographic purification.

son-trans-i! hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hyd207771 roxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, [a [Α] D ^{: 1:} + 34.8 °

WE? ¹ - + 137.3 °.

anti-traus-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-d ^; benzoib, d] pyran,

MY ^: - ^ - 26.8 °,

K- ¹ --- 71.9 °.

Example 2 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran

A solution of 1.93 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzofib d.) pyran in 100 ml of methanol and 25 ml of liquid anhydrous ammonia containing 1.0 g of Raney nickel are stirred and heated at 100 ° C for 6 hours under a hydrogen atmosphere at 70 MPa.

The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated by evaporation of the solvent under reduced pressure to give a solid. The solid was dissolved in 300 mL of diethyl ether and washed with 50 mL of 1 N hydrochloric acid, 50 mL of 5% aqueous sodium bicarbonate, and water. The ether solution was then dried and concentrated to dryness in vacuo. 500 mg of a white solid are obtained. The solid was recrystallized from diethyl ether and hexane to give 1.85 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9 10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C 24 H 39 NO 2 calculated:

77.16% G, 10.52% H, 3.75% N, found:

77.77% G, 10.08% II, 3.27% N. m / e: calcd. 373, found 373.

Example 3 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyranhydrogenomaleinate

Solution 340 mg dl-trans-1-hydroxy-3- (1,1-dimethylhsptyl) -6,6-dimethyl-5-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b d) pyran in 50 ml diethyl ether containing 164 mg of maleic acid was stirred and heated to boiling for 10 minutes. The product precipitates out of solution and is filtered off. There was obtained dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b] d) pyran hydrogen maleate as a white solid, mp 15 ° -159 ° C.

For C28H43NO6 calculated:

% C, 68.68;% H, 8.85;% N, 2.86.

68.51% C, 8.57% H, 2.66 N / N. Example 4 dl-trans-1-hydroxy-3- (1,1-dimethylhsptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran

To a stirred solution of 750 mg dl-trans-1-liydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo (b, d) pyran in 10 ml of methanol was added simultaneously with 1.5 ml of triethylamine and 1.0 ml of acetic anhydride, the reaction mixture was stirred at 24 ° C for 12 hours and then 50 ml of water was added. The ether extracts were combined, washed with water and 10% aqueous sodium bicarbonate solution and dried, and the solvent was evaporated under reduced pressure to give 840 mg of foam, which was then applied to a column packed with 30 g of silica gel [Woelm activity I] and eluted. Thin layer fractions containing the desired product were combined and concentrated in vacuo to give 735 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido -6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For G26H41NO3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

% C, 75.51;% 9.75;% 3.43; m / e: 415;

Example 5

Following the procedure of Example 4, 5.98 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a -hexahydro-6H-dibenzo [b, d] pyran was treated with 8.0 mL of acetic anhydride and 12 mL of triethylamine in 100 mL of methanol. Normal processing. 3.97 g of product are obtained in the form of a white solid. The product is then chromatographed on a column packed with 240 g of silica gel [Wo207771 elm activity I]. The appropriate fractions are collected carefully and the solvent is removed to give 1.06 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9of-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran. A sample of this axial isomer was recrystallized from 20 mL of n-hexane. Mp 195-197 ° C. :

For G26H41.NO3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

H, 10.05; N, 3.12.

Further chromatography and collection of the appropriate fractions gave 2.16 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9/3-acetamido-6a, 7,8 g. 9,10,10a-Liexahydro-6H-dibenzo [b, d] pyran, mp 200-202 ° C.

For C20H41NO3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

74.95% C, 9.58% H, 3.31% N. Example 6 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-propionamido _: 6a, 7,8,9,10,10a-hexahydro-ΘΗ-dbenzo [b, d] pyran

Solution 373 mg dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b d) pyran in 20 ml of methanol containing 1.3 grams of propionic anhydride and 2.5 ml of triethylamine was stirred at room temperature for 48 hours, then the reaction mixture was diluted with 25 ml of water and stirred for 2 hours at room temperature. The ethereal extracts were combined, washed with water, 2 N hydrochloric acid, 10% aqueous sodium bicarbonate solution and dried, and the solvent was removed under reduced pressure to give a foam. It was then further purified by chromatography on 20 g of silica gel eluting with diethyl ether, collecting 10 ml fractions, fractions 5 to 30 were combined, and the solvent was evaporated to give 434 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) - 6,6-dimethyl-9-propionamido-6a, 7,8,9,10,10a-hexahydro-6 H-dibenzo [b, d] pyran.

For C27H43NO3 calculated:

% C, 75.48;% H, 10.09;% N, 3.26.

C, 75.23; H, 9.84; N, 3.26. M / e: calcd. 429, found 429.

Example 7 dl-trans-1-acetoxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b , d] pyran

Solution containing 373 g dl-trans-1-hydroxy-3- (1,1-dimethylliptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [ b, d] pyran, 10 ml acetic anhydride and 10 ml pyridine were stirred at room temperature for 48 hours. The reaction mixture was cooled and the methanol was evaporated. The residue was dissolved in diethyl ether, washed with water, 1N hydrochloric acid and brine. The ether solution was dried, the solvent was evaporated and the product was obtained as a white foam. The foam thus formed is purified by chromatography on a 11a column packed with silica gel with 20 g silica gel [Woelm, activity I], eluting with diethyl ether. Evaporation of the solvent from the appropriate fractions gave 420 mg of dl-trans-1-acetoxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hex N-hydro-6H-dibenzo [b, d] pyran.

For C28H43NO1 calculated:

% C, 73.49;% H, 9.47;% N = 3.06.

H, 9.36; N, 3.28. M / e: calc. 457, found 457.

Example 8 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-formamldo-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b , d] pyran

A solution of acetic anhydride (15 ml) and 98% formic acid (7.5 ml) was stirred and refluxed for 15 minutes. The mixture was cooled to room temperature and then 2.5 g of sodium acetate and 373 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7 were added. 8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran. The reaction mixture was stirred at room temperature for 4 hours and then added to a methanol solution containing sodium carbonate and water. After stirring for 1 hour, the solvent was evaporated under reduced pressure. The aqueous phase was extracted with diethyl ether and the ether extracts were combined, washed with water and dried. Evaporation of the solvent gave 410 mg of the product as a white solid. The product thus obtained was purified by chromatography on 20 g of silica gel to give 276 mg of dl-trans-1207771

hydroxy-3- (1,1-dimethylheptyl) -6,0-dimethyl-G-formamido-6-methyl-10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C 25 H 39 NO 3 calculated:

% C, 74.77;% H, 9.79;% N, 3.49.

74.61% C, 9.53% H, 3.64% N. m / e: calcd. 401, found 401.

Exemplary) dl-trans-1-hydroxy-3- (1,1-diinethylheptyl) -6,6-dimethyl-9- (3-hydroxycarbonyl) propionamido-6a, 7,8,9,10 10a-hexahydro-6H-dibenzo [b, d] pyran

Solution 372 mg dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo [b, d 1 pyran in 20 ml methanol containing 1.0 g anhydride. of succinic acid and 2.5 ml of triethylamine are stirred at room temperature for 72 hours. The reaction mixture was then diluted with 50 mL of water and the organic solvent was evaporated. The aqueous phase was extracted with diethyl ether and the ether extracts were combined, washed with water, 2N hydrochloric acid, again with water and 10% aqueous bicarbonate. sodium. After drying the solution, the solvent was evaporated under reduced pressure to give the product as a foam. The foam was applied to a column packed with 20 g of silica gel (Woelm activity II) and eluted with ethyl acetate. (1,1-dimethylheptyl) -6,6-dimethyl-9- (3-hydroxycarbonyl) propionamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C23H43NO5 calculated:

% H, 9.15;% N, 2.96.

% C, 70.98;% H, 9.35;% N, 2.97. Found: 473.

Example 10 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-benzamido-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b, d] pyran

To a solution of 373 mg dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-Liexahydro-6H-dibenzo [ b, d] Pyran in 20 ml of methanol is added in one portion a solution of 2.26 g of benzoic anhydride in 2.5 ml of triethylamine. The reaction mixture was stirred at room temperature for 60 hours and then diluted with 20 mL of water and stirred for an additional two hours. The organic solvent was evaporated and the aqueous phase was extracted with diethyl ether. The ether extracts were combined, washed with water, 2N hydrochloric acid, again and finally with 10% aqueous sodium bicarbonate. The organic phase was dried and the solvent was evaporated. The product is obtained in the form of a foam. The foam was chromatographed on 20 grams of silica gel activity I eluting with 1: 1 ether-hexane. The appropriate fractions were combined and the solvent was evaporated. 525 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-benzamido-6a, 7,8,9,10,10a-hexahydro-6H- are obtained. dibenzo [b, d] pyran.

For C30H13NO3 calculated:

% C, 77.95;% H, 9.07;% N, 2.93.

77.75% Cl, 9.30% II, 2.91% N. m / e: Calcd. 477, Found 477.

Example 1 1 dl-trans-3-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro- 6H • di-benzo [b, d] pyran

To a stirred solution of 2.0 g dl-trans-1-hydroxy-3- (1,2-dimethyletheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran-9-one in 40 ml of ethanol containing 10 ml of water is added 560 mg of hydroxylamine hydrochloride at once and then 2 ml of 5 N sodium hydroxide. The reaction mixture was stirred and heated to boiling for 90 minutes. The reaction mixture was cooled and the ethanol was evaporated. The aqueous phase is extracted with diethyl ether, the ether extracts are combined, washed with water and dried. Evaporation of the solvent under reduced pressure gave 2.3 g of the product as an oil. This oil was purified by chromatography on 100 g of silica gel and eluted with diethyl ether. Appropriate fractions were collected and the solvent was evaporated to give 1.46 g of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10 10a-hexahydro-6H-dibenzo [b, d] pyran.

For C 24 H 37 NO 3 calculated:

% C, 74.38;% H, 9.62;% N, 3.61.

% C, 74.13;% H, 9.30;% N, 3.33. M / e: calc. 387, found 387.

Example 12

Following the procedure of Example 11, 7.44 g of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran-9-one is reacted with 2.1 g of hydroxylamine hydrochloride and 8 ml of 5 N sodium hydroxide in 100 ml of ethanol containing 25 ml of water. Normal treatment of the foam which crystallizes from 75 mL of hexane gives 7.43 g of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7.8, 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, mp 162-164 ° C.

For C24I-I37NO3 calculated:

% C, 74.38;% H, 9.62;% N, 3.61.

H, 9.41; N, 3.78.

EXAMPLE 13 dl-trans-1-hydroxy-3- (1,2-dimethylheptyl 3 -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [a] b, d] pyran

A solution of 1.12 g of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran in 100 ml of methanol containing 25 ml of liquid ammonia and 1.0 g of Raney nickel was stirred at 100 [deg.] C. under nitrogen at 70 MPa for 8 hours. The reaction mixture is then filtered, concentrated to a volume of about 50 ml and diluted with 25 ml of a 10% sodium bicarbonate solution. The aqueous mixture was extracted with diethyl ether. The ether extracts were combined, washed with water, dried and evaporated to give 861 mg of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7.8, 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C 24 H 39 NO 2 calculated:

% C, 77.16;% H, 10.52;% N, 3.75.

77.54% C, 10.52% H, 3.94% N. m / e: calcd. 373, found 373.

Example 14

Following the procedure of Example 13, 3.87 g of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro -6H-dibenzo [b, d] pyran hydrogenates the reaction with hydrogen (70 MPa) in the presence

2.0 g of Raney nickel in 100 ml of methanol containing 25 ml of liquid ammonia. 3.38 g of dl-cis-1-hydroxy-3- (1,1-dimethyl-24-heptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10ahexahydro-6H-dibenzo were obtained. [b, d] pyran.

For C 24 H 39 NO 2 calculated:

% C, 77.16;% H, 10.52;% N, 3.75.

% H, 10.44;% 3.70; m / e: calc. 373, found 373.

Example 15 dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-acetamido-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b, d] pyran

A solution of 960 mg dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b d) pyran in 40 ml of methanol containing 5 ml of triethylamine and 5 ml of acetic anhydride was stirred at room temperature for 24 hours, then the methanol was evaporated and the solution was diluted with 50 ml of 10% sodium bicarbonate solution and stirred for two more hours. The ethereal extracts were combined, dried and evaporated to give the product as a foam The foam was chromatographed on 50 g of silica gel, eluting first with 600 ml of chloroform, 1000 ml of 0.5% methanol in chloroform, then 2000 ml of 1% methanol in chloroform and finally 500 ml of 2% methanol in chloroform, 20 ml fractions were collected, fractions 61-95 were combined and evaporated to dryness to give 354 mg dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6 -dimethyl-9/1-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, mp 140-145 ° C.

For C 26 H 11 NO 3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

H, 9.93; N, 3.53.

Fractions 101 to 150 were combined, the solvent was evaporated, yielding 591 mg of dl-trans- (1,2-dimethylheptyl) -6,6-dimethyl-9α-acetamido-6a, 7,8,9,10,10a-hexahydro -6H-dibenzo [b, d] pyran.

For C26H41NO3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

C, 74.89; H, 9.65; N, 3.61. M / e: calc. 415, found 415.

Example 16

Following the procedure of Example 15, 1.18 g of dl-cis-1-hydroxy-3- (1,1-dimethyheptyl) -hexahydro-6H-dibenzo [b, d] pyran was acylated by treatment with acetic anhydride and triethylamine in methanol. Chromatography gave 545 mg of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9,3-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, mp 107-120 ° C, and 494 mg dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9α-acetamido-6a, 7.8 9,10,10a-bexahydro-6H-dibenzo [b, d] pyran, mp 164-168 ° C.

Example 17 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dlmethyl-9- (N, N-dimethyl-N-propargyl) ammonium-6a, 7,8,9,10 10α-hexahydro-6H-dibenzo [b, d] pyranbromide

A solution of 600 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-dimethylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo (b d) pyran in 25 ml of ethanol containing 1.5 ml of propargyl bromide was stirred and heated to boiling for 48 hours, then the reaction mixture was cooled to room temperature and concentrated in vacuo to a volume of 5 ml. The precipitate was filtered off to give 625 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (N, N-dimethyl-N-propargyl) ammonium-6a, 7 8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyranbromide, mp 104-107 ° C.

For C29Hd7BrNO2 calculated:

% C, 66.39;% H, 8.76;% N, 2.77.

15.77% Br, found:

% C, 65.45;% H, 8.42;% N, 2.66.

14.94% Br.

Example 18

6aR, 10aR, trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R (and 9S) acetamido-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo [b, d] pyr

Using the procedure of Example 1, 7.5 g of 6aR, 10aR, trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10, 10a-hexahydro-6H were used. -dibenzo [b, d] pyran-9-one is reacted with 2.1 g of hydroxylamine to give the corresponding optically active oxime, which is reduced by reaction with hydrogen in the presence of Raney nickel to give 1.49 g of 6aR, 10aR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R (a 9S) amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d A solution containing the latter compound in 35 ml of methanol containing 10 ml of triethylamine is stirred at 25 ° C and 5 ml of acetic anhydride is added dropwise over 10 minutes, the reaction mixture is stirred at room temperature for 72 hours and the solvent is then evaporated under reduced pressure. The residual oil was then diluted with 50 ml of diethyl ether containing 10 ml of water, the aqueous ethereal solution was stirred at room temperature for two hours, the organic phase was separated, washed with aqueous bicarbonate solution. The solvent was evaporated to give 1.52 g of a white foam. The product thus obtained is chromatographed twice on 100 g of silica gel of activity I, eluting with 600 ml of chloroform, 1000 ml of 0.5% methanol in chloroform and finally 1% methanol in chloroform. Fractions of 20 ml are collected. Fractions consisting of one component according to thin layer chromatography were combined and concentrated in vacuo to give 287 mg of 6aR, 10aR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C 26 H 11 NO 3 calculated:

% C, 75.14;% H, 9.94;% N, 3.37.

% H, 9.77;% N, 3.12. M / e: calc. 415, found 415.

[.Alpha.] ^{D @ 20} = + 29.9 DEG.

Other chromatographically separated fractions contained 591 mg of 6aR, 10aR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9S-acetamido-6a, 7,8,9,10,10a-hexahydro -6H-dibenzo [b, d] pyran.

For C26H41NO3 calculated:

75.14 ° C, 9.94% II, 3.37% N, found:

H, 9.99; N, 3.18. M / e: calc. 415, found 415.

_[ α _] D 25 = -236.5 °.

Example 19

A parenteral preparation suitable for injection is prepared by dissolving 25 mg of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9- (N-ethyl) acetamido-6a, 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran v

250 ml of 0.9% aqueous sodium chloride solution and adjusting the pH of the solution to 6-7.

Example 20

An aqueous suspension suitable for oral administration of 2B cl is prepared by mixing 10 mg of finely divided dl-trans-1-hydroxy-3- (1-ethyl-2-hexenyl) -9-hydroxyimino-6a, 7,8,9,10,10a- hexahydro-6H-dibenzo [b, d] pyran with 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, 5 mg of saccharin sodium and 0.025 ml of vanilla tincture.

Claims (6)

A process for the preparation of 9-aminodibenzopyranes of the general formula I wherein R ¹ is hydrogen or C 1 -C 4 alkanoyl, R ² is alkyl of 5-10 carbon atoms, R ³ is hydrogen or methyl and Z is a substituent selected from the group consisting of wherein R ⁴ is hydroxyl, R ⁵ is hydrogen, hydroxyl, C 1 -C 4 alkyl, CH 2 (alkynyl) wherein C 2 -C 4 alkynyl, C 1 -C 7 alkanoyl, C 1 -C 7 alkanoyloxy, C 1 -C 7 phenylalkyl 2 carbon atoms in the alkyl fenylalkanoyl having 1-2 carbon atoms in the alkanoyl, - (CH2 I _n -OH, - (CH2) _n-O - alkanoyl having 1-2 carbon atoms in the alkanoyl or a group -C- (CH2) " COOH, II o where n is 2, 3 or 4, R ⁶ is hydrogen, alkyl of 1 to 4 carbon atoms, CH ₂ (alkynyl) wherein alkynyl of 2 to 4 carbon atoms, alkanoyl of 1 to 7 carbon atoms, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of piperidine, morpholine, R ⁷ is hydrogen or C 1 -C 7 alkanoyl, Y N O L E Z U R ⁸ is C 1 -C 7 alkanoyl, and non-toxic pharmaceutically acceptable acid salts and quaternary ammonium salts thereof, characterized in that the compound of formula II wherein: R ¹ is hydrogen and R ² and R ³ are as defined above, is reacted with an amine of formula III H ² NR ⁴ (III), wherein R ⁴ is as defined above, to give a compound of formula I wherein Z is a group of formula IV R * / i. A '(iv) and hydrogenating a compound of formula I wherein Z is a group of formula IV and R ⁴ is hydroxyl to give a compound of formula I wherein Z is a group of formula VI and R ⁵ and R ⁶ are hydrogen and the thus obtained the compound is reacted with an acylating agent to give a compound of formula I wherein Z is VI, R ⁵ is hydrogen and R ⁶ is C 1 -C 7 alkanoyl, C 1 -C 2 phenylalkanoyl or a group —C (CH2) n COOH, o wherein n is 2, 3 or 4, and optionally the compound so obtained, wherein R ⁵ is hydrogen, R ⁶ is C 1 -C 4 alkanoyl or C 1 -C 2 phenylalkanoyl, is reacted with a reducing agent and to give a compound of formula I wherein R ⁵ is hydrogen and R ⁶ is C 1 -C 4 alkyl or C 1 -C 2 phenylalkyl and optionally reacted with an acylating agent to give a compound of the formula of formula I wherein Z is a group of formula VI, R ⁵ is C 1 -C 7 alkanoyl or C 1 -C 2 phenylalkanoyl and R ⁶ is C 1 -C 4 alkyl or C 1 -C 2 phenylalkyl and optionally isolating the optical isomers and epimers of a compound of formula (I) and isolating a compound of formula (I) in the form of the free base or a non-toxic pharmaceutically acceptable acid salt or quaternary ammonium salt. 2. The process of item 1, for the preparation of 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a-7,8,9,10,10a-hexahydro-6H-dibenzo [b d) pyran, characterized by reacting 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [ b, d] pyran-9-one with hydroxylamine. 3. The process of item 1, for preparing 1-hydroxy-3- (1,1-dimethylheptyl) 6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [ b, d] pyran, characterized in that 1-hydroxy-3- (1,1-dimethylheptyl-6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-) is reacted. 6H-dibenzo [b, d] pyran with acetic anhydride. 4. The method of item 1, for preparing 1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d) pyran, characterized by reacting 1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a -hexahydro-6H-dibenzo [b, d] pyran with acetic anhydride. 5. The process of item 1, for preparing dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydroxybenzoates. dr-6H-dibenzo [b, d] pyran, characterized by reacting dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran with acetic anhydride. 6. The process of item 1, for preparing 6aR, 10aR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R-acetamido-6a, 7,8,9,10, 10α-Hexahydro-6H-dibenzo [b, d] pyran, characterized by reacting 6αR, 10αR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R-amino -6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran with acetic anhydride.