CS207770B2 - Method of preparation of the aminodibenzopyrans - Google Patents

Description

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

_: Many compounds dibenzopyran was recently found to be useful for treating depression, pain and anxiety. U.S. Patent Nos. 3,928,593, 3,944,673, and 3,953,603 disclose various hexahydrodibenzo [b, d] pyran-9-ones useful as described above. Particular attention is focused on dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10ahexahydro-9H-dibenzo [b, d] pyran- 9-he, now called charged.

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 such modifications included a nitrogen atom in the dibenzopyran 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] pyranes. Similarly, a nitrogen atom has been introduced into ring C of certain dibenzo [b, d] pyranes. U.S. Patent No. 3,878,219 claims dibeinzo [b, d] pyranes having a nitrogen atom at the 9-position. 3 888 946 similarly claims nitrogen-containing heterocycles in which ring C is a five-membered six-membered ring.

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

Z is a substituent selected from the group consisting of

R * 'Ν'

A 'Λ where

R ⁴ is hydroxyl,

R ⁵ is hydrogen, hydroxyl, (C 1 -C 4) alkyl (CH (alkynyl) (C 1-4 alkynyl), C 2 -C 4 alkynyl, C 1 -C 7 alkanoyl, C 1 -C 7 alkanoyloxy, C 1 -C 2 phenylalkyl atoms in the alkyl fenylalkanoyl having 1-2 carbon atoms in the alkanoyl, - (CH2 _I: -OH, (CH2) _n-O-alkanoyl having 1-2 carbon atoms in the alkanoyl or a group -C- (CH2] n-COOH l | 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 or morpholine,

R ⁷ is hydrogen or C 1 -C 7 alkanoyl,

R ⁸ is C 1 -C 7 alkanoyl and their non-toxic pharmaceutically acceptable acid salts and the quaternary ammonium salts thereof, 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

H2NR ⁴

AND

N

A ov) and a compound of formula I, wherein Z is a group of formula IV and R ⁴ is hydroxyl, is reacted with an acylating agent to form a compound of formula I wherein

Z is a group of formula (VII) or (VIII)

(Vil)

V (Vln)

R ¹ , R ⁷ and R ⁸ are C 1 -C 4 alkanoyl groups and optionally hydrolyzed a compound of formula I to give a compound of formula I wherein Z is 0 of formula VII or VIII, R ¹ and R ⁷ are hydrogen atoms and R ⁸ is C 1 -C 4 alkanoyl, and optionally the optical isomers and epimers of the compound of Formula I are isolated, and the compound of Formula I is isolated as the free base or a non-toxic pharmaceutically acceptable acid salt or quaternary ammonium salt thereof.

The invention also relates to pharmaceutical compositions comprising one or more biologically active compounds of the above 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 with hypertension. 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 hypotensively 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.

where

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

Z is a group of formula IV

In the above formula representing the 9-amino-dibenzo [b, d] pyranes prepared according to the invention, R ¹ is hydrogen and C 1 -C 4 alkanoyl. The term "C 1 -C 4 alkanoyl" as used herein means acyl radicals of C 1 -C 4 carboxylic acids. Examples of such C 1 -C 4 alkanoyl groups are formyl, acetyl, propionyl, n-butyryl and isobutyryl.

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

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

N

And where

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

where

R ⁵ and R ⁶ are C 1 -C 4 alkyls such as methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of the (2-alkynyl) group are substituents such as 2-propynyl, 2-butynyl and 1-methyl-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 branched or unbranched chains of acyl groups. Typical examples of such 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. carbon atoms. 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 formula - (CH 2) n - OH, wherein n is 2, 3 or 4. These groups include 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl groups. Hydroxy8 group in these substituents may 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 (CHžJ _n COOH, such groups include 3- (hydroxykarbonyljpropionyl 4A ( 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-dialkylaminodibenzo [b, d] pyran of the present 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, methanesulfonic acid, adipic acid and the like.

Likewise, the basic amines of the invention, which are tertiary amines, 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 amides and oximes are not normally formed because the nitrogen atom ammonium salts are formed only when both R ⁵ and R ⁶ in the above formula are groups such as alkyl, 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 hydroxylamine 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

people

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-6,6α, 7,8,10,10α-hexahydro-9H-dibenzo [b, d] pyran-9-one, 1-hydroxy-3- n-octyl-6,6-dimethyl-6,6a, 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-dibenzoib, d] pyran-9-one,

-1-hydroxy-3- (1,2-dimethyl-1-heptenyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 -one, 1-hydroxy-3- (1-ethylhexyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-d: benzo [b, dlpyran-9-one, 1 -hydroxy-3- (1,1-dimethylheptyl) -6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, 1-hydroxy-3- ( 1,2,3-trimethyl-2-pentenyl-6,6a-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 exist stereochemical isomers at the 6a and 10a carbon atoms. More specifically, the starting ketones and the corresponding 9-aminodibenzo [b, d] pyranes of formula I may exist as the 6α, 10α-cis isomers and 6α, 10α-trans isomers. Each of these isomers forms a racemic or dl-pair. For example, the 6a, 10a-cis derivative may have both a 6a-hydrogen atom and a 10a-hydrogen atom oriented above the plane of the ring, or alternatively both hydrogen atoms may be oriented below the plane of the ring. The two isomers may form a cis-dl-racemic mixture. Similarly, the 6a, 10a-trans isomer may be a compound wherein the 6a-hydrogen atom may be above the plane of the ring, while the 10a-hydrogen atom may be oriented below the plane, or alternatively the 6a-hydrogen atom may be oriented below the plane of the ring and 10a-hydrogen atoms. can be oriented above the plane. Again, the two isomers form a trans-dl-pair. Normally, the preparation of compounds of the present invention involves the use of a racemic mixture of both the 6α, 10α-cis-hexahydrodibenzo [b, d] pyranone, i.e. the dl-cis isomer, or alternatively the racemic mixture of the 6α, 10α-trans-isomer, i.e. dl-trans- hexahydro-benzo [b, d] pyranone. However, it is understood that the compounds of the invention may also be prepared from optically active d- or 1-cis-ketones or d- or 1-trans-ketones to give the corresponding 9-aminodibenzo [b, d] pyran with the same stereochemistry as starting 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-one 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-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexabydro-9H-dibenzo [b, d] pyran-9- on, dl-trans-1-hydroxy-3- (n-octyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9- on, dl-cis-1-hydroxy-3- (n-decyl) -6,6a, 7,8,10,10a-hexahydro-9-dibenzo [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-dibenzo [b, d] pyran-9-one.

The various dibenzopyran 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, d] pyran-9-ones are described in U.S. Patent Nos. 3,928,598, 3,944,673 and 3,953,603. Preparation of dl-cis and dl-transhexahydrodibenzo ( 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., Cannabinoids 3. Synthetic Approaches 9-Ketocannabinoids Total Synthesis of Nabilone, J. Org. Chem., 42, No. 13, pp. 2277-2284 (1977).

As already mentioned, oximes and alkoxyoximes of formula I (i.e., where R ⁴ is hydroxyl or C 1 -C 4 alkoxy) can be treated at 207770 by reaction of hexahydrodibenzo [b, d] pyran-9-one with hydroxylamine or alkoxyamine, such as is methoxyamine and ethoxyamine. These amines are generally commercially available in the form of acid salts and can be used by adding a base to the reaction mixture to release the free amine in situ or to neutralize the salt prior to use of the free amine in the reaction. In the preparation of the oximes and O-alkoxy groups of the present invention, dibenzo [b, d] pyran-9-one and hydroxylamine or alkoxylamine 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 product, oxime or O-alkyloxime is preferably isolated by simply diluting the reaction mixture with water or aqueous acid and then extracting the oxime into a water-immiscible solvent such as diethyl ether, benzene, chloroform, dichloromethane, ethyl acetate and the like. normally the oxime product is obtained as an oil or solid, which can then generally be crystallized from solvents such as n-hexane and petroleum ether. Examples of oximes thus prepared are:

1-hydroxy-3-n-pentyl-6,6-dimethyl-9-hydroxiimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, 1-hydroxy-3- (1,2-Dimethyl-2-pentenyl) -9-methoxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, dl-trans-1-hydroxy-3- (1,2-dimethylbeptyl) -9-ethoxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran and dl-cis-1-hydroxy-3- (1, 1-diryl-octyl) -6,6-dimethyl-9-isobuthoxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzophb, d] pyran.

The oximes thus prepared are useful as pharmacologically active compounds and are also valuable as intermediates. For example, reduction of these compounds yields hydroxylamine derivatives and alkoxyamine derivatives. Further, the hydroxyimino compounds can be O-alkylated with a C 1 -C 4 alkylating agent such as isobutyl bromide to give the corresponding 9-alkoxyimododibenzo [b, d] pyrans. Further, by normal acylation of hydroxyimino compounds, for example by reaction with an acylating agent derived from a C 1 -C 7 carboxylic acid, the corresponding 9-alkanoyloxy-amino-hexahydro-dibenzopyran derivatives are prepared.

Like the hydroxyimino compounds mentioned above, the hydroxy amino derivatives can readily be acylated with an acylating agent derived from a C 1 -C 7 alkanoic acid to give the corresponding 9-alkanoyloxyaminodihenzopyranes of the present invention having 1 to 7 carbon atoms in the alkanoyloxy group.

The process for preparing the amides of the invention involves the acylation of oxime, i.e., 9-hydroxyiminohexahydrodibenzo [b, d] pyran, as described by Boar et al., J. Chem. Soc. Perkin 1237 (1975). According to this procedure, an oxime such as 1-hydroxy-3-isohexyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran is reacted with any commonly used acylation with a reagent, for example a C 1 -C 7 alkanoyl halide or C 1 -C 2 phenylalkanoyl halide in the alkanoyl moiety to prepare an acylated oxime, in particular 1-hydroxy-3-isohexyl-9-acyloxyimino-6a, 7,8,9,10 10α-hexahydro-6H-dibenzo [b, d] pyran. Further acylation of 9-acyloxyiminoderivátu provides triacylated tetrahydrodibenzopyran which occurs predominantly as ^Δ θ isomer, namely a l-acyloxy-3-substituted-9-diacylamino-6a, 7,10,10a-tetrahydro-6H-dibenzoyl-benzo [b , d] pyran. Slight hydrolysis of this triacylated derivative removes 1-acyl and one of the 9-amino acyl groups to prepare the 9-acylaminotetrahydrodibenzopyran of the invention.

The 9-alkylaminodibenzopyranes of the invention can be acylated as described for the acylation of primary 9-amino derivatives to give the corresponding 9-N-alkylacylaminohexahydrodibenzopyranes. For example, a compound such as dl-cis-1-hydroxy-3-n-pentyl-9-allylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran can be reacted with an acylating agent such as acetyl bromide to prepare the corresponding 9-N-alkyl acylamino derivative, namely dl-c18-1-hydroxy-3-n-pentyl-9-N-allylacetamido-6a, 7,8,9,10 10α-hexahydro-6H-dibenzo [b, d] pyran.

In an analogous manner, the 9-dialkylaminodibenzopyrans of the present invention are used as intermediates for the preparation of the preferred 9-acylamino derivatives of the invention. For example, dialkylated derivatives, such as cis-1-hydroxy-3- (2-heptenyl) -9-N-methylisopropylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, can be demethylated, for example by reaction with an alkyl haloformate, to produce a carbonate which, by alkaline hydrolysis and then acylation under normal acylation conditions, provides the corresponding 9-N-isopropyl-acylamino-hexahydrodibenzopyran.

Alternatively, the primary and secondary amines of the invention can be converted directly to the amide by reaction with a carboxylic acid in the presence of a suitable coupling reagent such as N, N-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), etc. By reaction of a primary amine such as d-cis207770

Í1

-1-hydroxy-3-isohexyl-9-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran with a carboxylic acid such as phenylacetic acid in the presence of DCC condensation is performed to give the corresponding 9-phenylacetamide. The product is readily isolated by simply filtering the reaction mixture and evaporating the solvent from the filtrate.

By any of the above acylation reactions, it is understood that the acylation may also proceed at the 1-hydroxy group of dibenzopyran, and different amounts of 1-acyloxy-9-acylaminodibenzo [b, d] pyran will be obtained depending on the excess acylating agent used, reaction temperature. Alternatively, the 1,9-acylated 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 sodium bicarbonate to effect complete reaction. hydrolysis of the 1-acyloxy group to produce exclusively 9-acylamino-dibenzo [b, d] pyran. As already mentioned, protecting the 1-hydroxy group from chemical modification prevents unwanted side reactions at this site.

As mentioned, the 9-amino- and 9-acylamino-hexahydro-dibenzo [b, d] pyranes prepared according to the 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-diacylaminohexahydrodibenzo [b, d] pyrane.

For example, by reaction of an acylamino compound such as 1-hydroxy-3-n-pentyl-6,6-dimethyl-9-benzoylamino-8a, 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 reaction 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 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 present invention that are fully saturated in ring C and which do not have exocyclic double bonds, that is, compounds of the above formula, wherein Z is a group of formula, may exist in the form of epimers. For example, when the oxime of the invention is fully reduced and the 9-aminohexahydro-dibenzoyl] pyran is prepared, the compound is a mixture of 9-amino and 9/3-amino derivative. 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 optically active amides such as d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9a or 9β-acetamido-6a, 7 , 8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, oxime corresponding to the optically active d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6 is prepared first 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 epimeric mixture of d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,0-dimethyl-9-amino-6a, 7,8,9,10 10a-hexahydro-6H-dibenzo [b] d] pyran. The epimeric amines are then acylated, for example by reaction with acetic anhydride, and an epimeric mixture of the corresponding acetamides is prepared. Separation of the acetamides thus formed affords optically active d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9α- (α 9β) -acetamido-6α, 7.8, These optically active compounds are preferably named by commonly accepted nomenclature rules for absolute stereochemical configuration using R and S terminology as suggested by Fletcher et al. Nomenclature of Organic Compounds, Advances in Chemistry Series, 126, American Chemical Society, 1974. According to this nomenclature, a typical optically active compound of the invention is called 6aR, 9R, 10aR-6a, 10-trans-1-hydroxy-3- 1-dimethylheptyl-6,6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran For the sake of simplicity, the following nomenclature is not used for the compounds listed below, but it is to be understood that the invention encompasses these optically active isomers and racemic mixtures.

The 9-aminodibenzo [b, d] pyran derivatives according to the invention defined by the above formula are novel chemical compounds which 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 invention is the pharmacological formulations contained

Comprising at least one biologically active compound in association with one or more suitable diluents, carriers or excipients. Other pharmacologically active agents can be added to these pharmacological formulations with the compounds of the invention. Particularly preferred pharmacological formulations of the present invention are useful for the treatment of hypertension. Particularly preferred are those containing the 9-amino derivative of the present invention as the active ingredient.

The formulations of the invention are formulated to suit the particular application. For oral administration, the compound of the invention is mixed with a carrier and diluent such as dextrose, lactose, mannitol, cocoa butter, ethyl lactate, methylcellulose, 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] pyran 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. tablets that 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-glaucoma, anti-depressant and anti-anxiety as well as a hypotensive effect. The most active compounds are the 9-amide derivatives (for example, R ⁶ and R ⁷ in the above formulas are alkanoyls), although the other compounds of the invention are also useful pharmacologically. 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 in mice. Similarly dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d ] pyran shows a minimum effective dose (MED) of only 5.0 mg / kg in mice. In addition, in the injured rat test dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (N-ethyl) acetamido-6a, 7,8,9,10,10a -hexahydro-6H-dibenzo [b, d] pyran shows a MED of 10.0 mg / kg. In the blood pressure lowering test in dogs dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-he: xahydro -6 H-dibenzo [b, d] pyran exhibits an intravenous MED of 0.5 µg / kg when administered.

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, glaucoma and related diseases. Thus, the compounds can be used to treat animals and humans with these difficulties. The invention also relates to a method of treating hypertension in a mammal which comprises administering an effective dose of a hypotensive drug of the invention to an individual with hypertension and in need of treatment induced or developing hypertension. A particularly preferred method for treating hypertension according to the invention is to administer a compound of the invention having an amido group at the 9-position (i.e., R ⁵ is a C 1 -C 7 alkanoyl),

Hypotensively active compounds of the invention may 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 0.001 to about 20 mg of 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-dioxopiperidino) -6a, 7,8,9,10,10a-hexahydro- 6H-dibenzo (b, d] pyran. Preferred treatment includes administration of about 2 mg 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.

The preparation of the 9-aminodibenzopyrans 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 present 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-dibenzo [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 a

1.155 g of hydroxylamine hydrochloride are 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 adding 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-hexaliydro-6H-dibenzo [b, d] pyran as a white powder, mp 143-145 ° C.

For C21H37NO3 calculated:

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

% C, 74.61; 9.37% H, 3.78% N. 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-6a, 7,8,9,10,10a-hexahydro 6H-dibenzo [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, [< ^{HCb &gt; +410} _]

Ι «0Γ = +34.6.

Chromatographic purification of a sample of this product by high pressure liquid chromatography separates the syn- and anti-isomers of the optically active oxime.

syn-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b, d] pyran, = + 34.8 ° ~ + 137.3 °.

anti-trans-1-hydroxy-3- (1,1-dimethylhephyl) -6,6-dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, [ ^α ] ^{( HHGH} = -26.8 °

Example 2 dl-traus-1-acetoxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (Ν, Ν-diacetylamino) -6α, 7,10,10α-tetrahydro-6H-dibenzo [ b, d] pyran

A solution of 2.59 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] pyran in 25 ml of acetic anhydride and 75 ml of pyridine was stirred and refluxed for 24 hours under nitrogen. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure to give an oily residue. ml of diethyl ether and 50 ml of water and stirred for one hour The mixture was filtered and the organic phase was separated The ethereal solution was washed with 1 N hydrochloric acid, water, saturated sodium chloride solution and dried. This was then chromatographed on 100 g of silica gel [Woelm, activity I] eluting with 1: 1 hexane-ether to give the fractions containing the main product and concentrate in vacuo to give 3.12 g of predominantly dl-1-acetoxy-3- ( 1,1-dimethylheptyl) -6,6-dimethyl-9- (Ν, Ν-diacetylamino) -6a, 7,8,9,10,10a-hexahydro-6H-dibe nzo [b, d] pyran with a small amount Δ ^{9 of the} compound.

m / e: calcd. 497, found 497. Example 3 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (acetamido) -6a, 7,10,10a- Tetrahydro-6H-dibenzo [b, d] pyran

Prepare a solution from 5.4 g of dl-trans-1-acetoxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (Ν, Ν-diacetylamino) -6a, 7,10,10a- tetrahydro-6H-dibenzo [b, d] pyran in 150 ml of methanol containing 50 ml of a 20% aqueous potassium carbonate solution. The reaction mixture was stirred at 24 ° C for two hours and then evaporated in vacuo. The resulting oil was suspended in 100 mL of water and the aqueous mixture was extracted with diethyl ether. The ether extracts were combined, diluted with 20 mL of ethyl acetate and washed with 2 N hydrochloric acid, 10% aqueous sodium bicarbonate, and dried. Evaporation of the solvent gave 1.54 g of solid which was crystallized from hexane to give 1.33 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- ( acetamido) -6a, 7,10,10a-tetrahydro-6H-dibenzo [b, d] pyran, mp 186-188 ° C.

For C 11 H 11 NGi calculated:

H, 9.07; N, 3.07.

14.05% O, found:

% C, 73.74;% H, 8.79;% N, 3.16.

13.90% O.

m / e: calcd: 413, found: 413.

Example 4 dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-hydroximino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran

To a stirred solution of 2.0 g dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dlmethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzoyb, d ] Pyran-9-one in 40 ml of ethanol containing 10 ml of water was 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 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 10α-hexahydro-6H-dibenzo [b, d] pyran.

For C 24 H 37 NO 3 calculated:

% C, 74.38;% H, 9.62;% N, 3.61; found:

% C, 74.13; H, 9.50; N, 3.39. M / e: calc. 387, found 387.

Example 5

Following the procedure of Example 4, 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, yields 7.43 g of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dlmethyl-9-hydroxyimino-6a, 7.8, 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, mp 162-164 ° C.

For C 24 H 37 NO 3 calculated:

% C, 74.38;% H, 9.62;% N, 3.61; found:

74.56% C, 9.41% H, 3.78% N. Example 6 trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-acetoxethyl) ) acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran

A solution of 500 mg of trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (2-hydroxyethyl) amino-6a, 7,8,9,10,10a-hexahydro-6H The dibenzo [b, d] pyranhydride chloride prepared as described in Example 4 in 25 ml of methanol containing 1.5 ml of triethylamine and 1.5 ml of acetic anhydride is stirred at 25 ° C for 48 hours. The reaction mixture was then diluted with 50 ml of chloroform and the diluted solution was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated to give trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-acetoxyethyl) acetamido-6a, 7.8 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

For C30H47NO5 calculated:

% C, 71.82;% H, 9.44;% N, 2.79; found:

% C, 69.46;% H, 8.72;% N, 2.56. m / e: calcd 501, found 501.

Example 7 trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-hydroxyethyl) acetamido-6a, 7,8,9,10,10a-hexahydro-6H -dibenzo [b, djpyran

A solution of 500 mg of trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-acetoxyethyl) acetamido-6a, 7,8,9,10,10-α-hexahydro- The 6H-dibenzo [b, d] pyran of Example 6 was dissolved in a solution of 40 mL of methanol and 10 mL of water containing 138 mg of potassium carbonate and stirred at 25 ° C for 90 minutes before diluting with 150 mL of saturated aqueous sodium chloride solution. The aqueous phase was extracted several times with diethyl ether, and the ether extracts were combined, washed with water, dried and the solvent was evaporated under reduced pressure to give 500 mg of the product as a white solid, thus crystallizing from cyclohexane / hexane / ethyl acetate to give 395 mg. teans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-hydroxyethyl) acetamido-6a, 7,8,9,10,10a-hexahydro-6H- 148 DEG-158 DEG C. m / e: 459.

For C28H15NO4 calculated:

% C, 73.16;% H, 9.87;% N, 3.05;

found:

H, 9.84; N, 3.15. Example d1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (N, N-dimethyl-N-propargyl) 207770 ammonium-6a, 7,8,9,10 10α-hexahydro-6H-dibenzo [b, d] pyranbromide

A solution of 600 mg 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. The reaction mixture was then cooled to room temperature and concentrated in vacuo to a volume of 5 mL. The mixture was diluted with diethyl ether and hexane and the product precipitated. 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, m.p. 104-107 ° C.

For C29H47B1'NO2 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 9

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] pyran

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 treated with 2.1 g of hydroxylamine to give the corresponding optically active oxime. The oxime thus formed is reduced by treatment with hydrogen in the presence of Raney nickel to give 1.49 g of a mixture of 6aR, 10aR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9R (and 9S). 1-Amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran.

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 was stirred at room temperature for 72 hours and then the solvent was evaporated under reduced pressure. The residual oil is then diluted with 50 ml of diethyl ether containing 10 ml of water. The aqueous ether solution was stirred at room temperature for two hours, the organic phase was separated, washed with aqueous sodium hydrogen carbonate solution and dried.

Evaporation of the solvent gave 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 a single component according to chromatography on a thin layer were combined and evaporated under reduced pressure 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 C26H41NO3 calculated:

H, 9.94; N, 3.37. found:

% C, 75.32;% H, 9.77;% N, 3.12. m / e: calcd 415, found 415.

-1.2 °, [ ^α ] ^{D 15} + 29.9 °.

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 i

calculated:

% C, 75.14;% H, 9.94;% N, 3.37; found:

74.91% C, 9.99% H, 3.18% N. The m / e calcd 415, found 415. | «// ^and -64.9 °,

-236.5 °.

Example 10

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, 7,8 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran in 250 ml of 0.9% aqueous sodium chloride solution and adjusting the pH of the solution to 6-7.

Example 11

An aqueous suspension suitable for oral administration 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. -6-PI-dibenzo [b, d] pyran and 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 (2)

OBJECT OF THE INVENTION 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 alkyl, phenylalkanoyl of 1 to 2 carbon atoms in alkanoyl, - (CH 2) n -OH, - (CH 2 -O-alkanoyl of 1 to 2 carbon atoms in alkanoyl, or -C- (CH ₂ ) n - COOH, Where n is 2, 3 or 4, R ⁶ is hydrogen, alkyl of 1 to 4 carbon atoms, CH 2 (alkynyl of 2 to 4 carbon atoms, alkanoyl of 1 to 7 carbon atoms, 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 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 ⁴ H 2 NR (III) wherein R ⁴ is as defined above to form a compound of formula I wherein Z is a group of formula IV, R * i ^x . N ' Nv) and a compound of formula I wherein Z is a group of formula IV and R ⁴ is hydroxyl is reacted with an acylating agent to form a compound of formula I wherein Z is a group of formula VII or VIII R‘‘ (Vil) R ^and - R (VID) R ¹ , R ⁷ and R ⁸ are C 1 -C 4 alkanoyl groups and optionally hydrolyzed a compound of formula I to give a compound of formula I wherein Z is a group of formula VII or VIII, R ¹ and R ⁷ are hydrogen atoms and R ⁸ is C 1 -C 4 alkanoyl, and optionally the optical isomers and epimers of the compound of Formula I are isolated, and the compound of Formula I is isolated as the free base or a non-toxic pharmaceutically acceptable acid salt or quaternary ammonium salt thereof. 2. The process of item 1, for preparing 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-liydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo [b, d] pyran-9-one with hydroxylamine.