Method of preparation of the dibenzopyrans

(54) A method for preparing 9-aminodibenzopyranes

The invention relates to a process for the preparation of 1-hydroxy-3-substituted tethahydro- and hexahydro-dibenzo [b, d] pranes with an amine group or an amino derivative at the 9-position, which are useful as analgesic agents, antidepressants, anti-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, 3,944,673, 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-dimethyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, now called nabilon.

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 dibenzipyran molecule.

U.S. Patent No. 3,886,184 discloses certain 1-amino-3-alkyl-9-alkyldibenzo [b, d] pyrans.

²

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 dibenzo [b, dlpyranes having a nitrogen atom at the 9-position. U.S. Patent No. 3,888,946 likewise claims 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,

<img file="CS207772B2_D0001.tif" />

207 7 7 2 where

R¹ is hydrogen or C 1 -C 4 alkanoyl,

R² is alkyl of 5 to 10 carbon atoms,

R³ is hydrogen or methyl; and

Z is a substituent selected from the group consisting of

<img file="CS207772B2_D0002.tif" />

<img file="CS207772B2_D0003.tif" />

<img file="CS207772B2_D0004.tif" />

r 'r⁵

R⁴ R^F

X^and where

Rt is hydroxyl,

R⁵ is hydrogen, hydroxyl, alkyl of 1 to 4 carbon atoms, CH2 (alkynyl) wherein alkynyl of 2 to 4 carbon atoms, alkanoyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenylalkyl of 1 to 2 atoms carbon in alkyl, phenylalkanoyl having 1 to 2 carbon atoms in alkanoyl, - (CH2-OH, - (CH2j)_n—O — C1 -C2 alkanoyl or —C— (CH2-COOH),

Where n is 2, 3 or 4,

R⁶ is hydrogen, alkyl of 1 to 4 carbon atoms, CH2 (alkynyl of 2 to 4 carbon atoms, alkanoyl of 1 to 7 carbon atoms, or

R⁵ and R⁶ together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group consisting of piperidine and morpholine,

R⁷ is hydrogen or alkanoyl of 1 to 7 carbon atoms,

R® is Can-C alk alkanoyl and non-toxic pharmaceutically acceptable acid salts and quaternary ammonium salts thereof, characterized in that the compound of formula II

<img file="CS207772B2_D0005.tif" />

where

R¹ is hydrogen and

R² and R³ as defined above, reacted with an amine reagent under reductive conditions to give a compound of formula I wherein Z is a group of formula VI

<img file="CS207772B2_D0006.tif" />

R⁵ is alkyl of 1 to 4 carbon atoms, CH2 (alkynyl is of 2 to 4 carbon atoms in alkynyl, phenylalkyl of 1 to 2 carbon atoms in alkyl, or - (CH2)_n—OH, where n is 2, 3 or 4,

R⁶ is hydrogen, C1-C4 alkyl, CH₂(C 2 -C 4 alkynyl) alkynyl, or

R⁵ and R⁶ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of piperidine and morpholine and optionally a compound of formula I wherein Z is a group of formula VI,

R⁵ is - (CH2)_n- ~ OH and

R⁶ is hydrogen, reacted with an acylating agent to give a compound of Formula I.

where

Z is a group of formula VI,

R⁵ is - (CH2)_n-O-alkanoyl of 1 to 2 carbon atoms in the alkanoyl group a

R⁶ is (C 1 -C 2) alkanoyl and optionally reacted with a strong base to give a compound of formula (VI),

R⁵ is - (CH 2) n -OH and

R⁶ optionally, the optical isomers and epimers of the compound of formula (I) are isolated and the compound of formula (I) is isolated in the form of the free base or a non-toxic pharmaceutically acceptable acid salt or quaternary ammonium salt thereof.

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

R^J is hydrogen and

Z is a group of formula

V &lt;R &lt;

And where

R^5; is hydrogen and

R^G is alkanoyl of 1 to 7 carbon atoms, especially alkanoyl of 1 to 2 carbon atoms.

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 for the treatment of hypertension by administering to a mammal with hypertension an amount sufficient for the treatment of hypertension

lowering 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 R⁶and R⁷ are alkanoyl having 1 to 7 carbon atoms, in particular alkanoyl having 1 to 2 carbon atoms.

In the above formula representing 9-aminodibenzo [b, d] pyranes prepared according to the invention, R is¹ a hydrogen atom and an alkanoyl of 1 to 4 carbon atoms. 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.

R² is defined as alkyl of 5 to 10 carbon atoms. Examples of C 5 -C 10 alkyls are both straight and branched chain alkyl groups such as n-pentyl, n-heptyl, 1,1-dimethylheptyl, 1,2-dimethylheptyl , 1-ethyloctyl, 1,1-dimethyoctyl,

1,2,3-trimethylheptyl, 1-propylhexyl, isooctyl, n-decyl and the like.

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

<img file="CS207772B2_D0007.tif" />

where R⁵ and R⁶ are alkyl of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-butyl.

Examples of the (alkynyl) group are substituents such as 2-propynyl, 2-butynyl and 1-methyl-2-propynyl.

Groups R⁵ and R⁶ 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 straight or branched chain acyl groups. Typical examples of these groups are formyl, acetyl, propionyl. isobutyryl, pentanoyl, isohexanoyl, 3-ethylpentanoyl, 2-methylbexanoyl, 1,2-dimethylpentanoylapod.

Preferred alkanoyl groups are C 1 -C 4 alkanoyl, preferably C 1 -C 2 alkanoyl. R⁵ 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. R⁵ can 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 in these substituents may be acylated with C 1 -C 2 alkanoyl to give substituents such as acetoxymethyl and the like.⁵ is defined as —CO (CH2) group_nCOOH, these groups include 3- (hydroxycarbonyl) propionyl, 4- (hydroxycarbonyl) butyl 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 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 are tertiary amines which readily form quaternary ammonium¹ 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, dimethyl sulfate and the like. It is understood that salts of compounds such as amides and oximes are not normally formed because ammonium salts are formed only when both R @ 1 and R @ 2 are formed⁵ tak R⁶ in the above formula there 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^: of these methods. Conventionally, an oxime derivative is first prepared, which is then reduced to give the N-unsubstituted 9-aminodibenzipyran 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

<img file="CS207772B2_D0008.tif" />

where R^L, R² and R³ have the meaning given above.

Compounds of formula II which are preferably used in the preparation of oximes of the invention are those of the above formula wherein

R¹ is a hydrogen atom.

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-octyl- 6,6-dimethyl6,6a, 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, 1-hydroxy-3- (1,2-dimethyl-1-heptenyl) 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-dibenzo [b, dj pyran-9-one, 1-hydroxy-3- (1,1-dimethylheptyl) 6.6a, 7,8,10,10a-hexabydro-9H-dibenzo [b, d] pyran-Q-one, 1-hydroxy-3- (1,3- (trimethyl-2-pentyl) -6,6-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 which 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, 10a-cis isomers and the 6a, 10a-trans isomers. Each of these isomers forms a racemic or dl-pair. For example, a 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 in which 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 invention using 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-hexahydrodibenzo [ 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 exhibit useful pharmacological activity, it is often preferred to use a mixture of dl-cis- and dl-transhexahydrodibenzo [b, d] pyran-9-ones as the starting material. It is particularly advantageous to use these racemic mixtures as they are readily available synthetically.

Examples of such preferred materials are:

dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) - [eta] &amp; lt; 6 &amp; gt; -dimethyl-e.ea.Z4.10.10a-hexahydro-1H-dibenzo [b, d] pyran-9-one, dl -trans-1-hydroxy-3- (n-octyl) -6,6-dimethyl-6,6a, 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-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 dibenzopyranone starting materials of formula II are compounds known or readily prepared by known methods. E.g. a large number of dl-cis and dl trans-hexahydrodibenzo [b, d] pyran-9-ones are disclosed in U.S. Patent Nos. 3,928,598, 3,944,673 and 3,953,603. Preparation of dl-cis- and dl-trans-hexahydro The 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. Cannabinoldes 3. Synthetic Approaches to 9-Ketocannabinoids. Total Synthesis of Nabilone ',

J. Org. Chem. 42, No. 13, pp. 2277-2284 (1977).

The method for preparing the 9-alkylamino- or dialkylamino-hexahydrodibenzo [b, d] pyranes according to the invention is the reductive alkylation of the ketone, i.e., the reaction of hexahydrodibenzo [b, d] pyran-9-one with a primary or secondary amine in the presence of a reducing agent. Commonly used amines include methylamine, diethylamine, 2-propenylamine, pyrrolidine, piperidine, morpholine, 3-butinylamine, N207772

-methyl-3-butenylamine, 3-hydroxypropylamine, benzylamine, N-methyl-2-phenylethylamine, N-isopropylisobutylamine, dimethylamine. etc.

The reaction was. generally performed by mixing approximately equimolar amounts of dibenzopyran-9-one and an amine in a solvent such as methanol or ethanol. Hydrogen and a suitable catalyst, such as sodium borohydride or sodium cyanoborohydride, are used as the reducing agent in order to completely reduce the intermediate imine formed. Thus, the corresponding alkyl or dialkylaminodibenzopyran according to the invention is prepared. This reductive alkylation is carried out at a temperature of from about 10 ° C to about 50 ° C and is normally complete within 12 to 72 hours. Amin. The reaction is isolated as the free base or alternatively as an acid salt. Further cleaning up. by chromatography or crystallization.

As mentioned above, the primary 9-aminohexahydrodibenzo [b, d] pyrans can be acylated with any of the acylating agents to prepare various 9-amido derivatives of the invention including compounds of the above formula wherein R is⁵ is alkanoyl of 1 to 7 carbon atoms. The reaction of 9-aminodibenzopyran with an acylating agent is carried out under relatively mild conditions to prepare 9-amidohexahydrobenzo [b, d] pyran (R).⁵is alkanoyl;⁶ is hydrogen). These "relatively mild conditions" include the use of an acylating agent and 9-aminodibenzopyran in approximately equimolar. amounts at 0 to 50 ° C.

Bases such as triethylamine or pyridine for the reaction are used in the reaction. acid binding. Commonly used acylating agents include halides, azides, anhydrides. including mixed anhydrides and. cyclic anhydrides such as. is succinylanhydride, glutaric anhydride and anhydride, adipic acids derived from C 1 -C 7 alkanoic acid and C 1 -C 2 phenylalkanoic acid in the alkyl moiety.

By using these cyclic anhydrides. to prepare amides according to the invention wherein the acyl group has the formula --CO (CH 2) n COOH. Preferred apylaonic agents include acid halides and acid anhydrides. Examples of such reagents are acetyl chloride, ipropipic anhydride, acid anhydride. formic, benzoyl chloride, phenylacetyl bromide, heptanoyl iodide ,. succinic anhydride and isobutyrylanhydride.

The acylation may be carried out in any organic solvent including alcohols such as methanol, ethanol, in halogenated hydrocarbons such as dichloromethane, and 1,2-dibromoethane, ethers such as. dilsopropyl ether, diethyl ether and tetrahydrofuran, as well as in aromatic solvents such as benzene and toluene.

Under "relatively mild conditions", the monoacylane, normally completed within about 4 to about an hour, yields 9-acylamino-hexahydrodibisopyrani, for example by the reaction of dl-cis-1-hyd10, roxy-3-n-octyl-9-amino-6a, 7, 8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran with about one equivalent of isobutyl chloride in benzene in the presence of about one equivalent of base, such as pyridine at 25 ° C for 4 hours monoacylation to give dl-cic-1-hydroxy-3-n-octyl-9-isobutyrylamido-6a, 7,8,9,10,10a-hexahydro-6H -dibenzo [b, d] pyrpyne.

The 9-acylaminodibenzo [b, d] pyran product is readily isolated simply by diluting the reaction mixture with water, and then extracting the product into a suitable water-immiscible solvent such as diethyl ether, chloroform, dichloromethane and the like. under reduced pressure, the corresponding 9-acylaminodibenzo [b, d] pyran is obtained, which is then further purified by conventional methods, such as chromatography and crystallization.

9-acylaminodibenzo-pyran, wherein the acyl group has the formula —CO (CH2)_nCOOHs are useful as intermediates and as pharmacologically active compounds. Conversion of these compounds to acid halides and reaction of these acid halides with a strong base such as sodium hydride leads to the cyclization to the above compounds. of the above formula wherein R⁵ and R⁶ forms a hetero, cyclic ring, such as 2,5-dioxopyrrolidine and 2,6-dioxopiperidine.

Any of the above-mentioned acylation reactions is understood to mean that the acylation may continue to occur. 1-hydroxy group of dibenzopyran, and a different amount of 1-acyloxy-9-acylamino-dibenzo [, b, d.] Pyran is obtained depending on the excess, the acylating agent used, the reaction temperature and the reaction time.

Alternatively, the 1,9-diacylated derivative can be separated from the 9-acylamino derivative by methods such as chromatography or alternatively. 1,9-diacylated. the derivative may be reacted with mild extinguish, such as sodium bicarbonate, to effect complete hydrolysis of the 1-acyloxy group and prepare exclusively 9-acylaminodibenzo [b, d] pyran. As mentioned, the protection of the 1-hydroxy group from chemical modification prevents unwanted side reactions at this site.

As already mentioned, 9-amino- and 9-acylamino-hexahydrodibenzo [b, d] pyranes prepared according to the present invention have been mentioned. can be alkylated by normal alkylation. reactions and prepare. with 9-alkylamino-. a. 9-N-alkylacylamino-hexahydro-dibenzo [b, d] p, yranes. Alkylamino derivatives can further be alkylated to give the corresponding 9-dialkylamino derivatives. Alternatively, the method of preparing 9-alkylamino-9 and 9-dialkylamino-hexahydro-dibenzoy b, d] pyranes is by reducing, 9-acylamino-T or 9-diacylamino-hexahydro-dibenzoyl b, d-pyrimidine.

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

Z is a group of the formula

<img file="CS207772B2_D0009.tif" />

they may exist in the form of epimers. For example, when the oxime of the invention is fully reduced and the 9-aminohexahydrodibenzo [b, d] pyran is prepared, the compound is a mixture of 9-amino-and 9/3-amino derivative. Separation of the epimeric mixture may optionally be performed 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, it is desirable to prepare optically active amides such as d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- or -9 / 3-acetamido- 6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran, the oxime corresponding to the optically active d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) is first prepared. 6,6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran-9-one. The 0xim is then fully reduced to give an epimeric mixture of d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10 10α-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. By separating the acetamides thus formed, optically active d- or 1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9of- (and 9/3) -acetamido-6a, 7, 8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyrans. 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, 10a-trans-1-hydroxy-3- (1,1-dimethylmethyl-heptyl) -6,6-dimethyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran. For simplicity, the nomenclature is not used for the compounds below, but it is to be understood that the invention includes these optically active isomers and racemic mixtures.

The 9-aminodibenzo [b, d] pyran derivatives of the present invention, defined by the above general formula, are novel chemical compounds having valuable pharmacological activity and many of them useful as intermediates in the synthesis of pharmacologically active compounds. Therefore, a further feature of the 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-amino derivative of the 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-acetamldo-6a, 7,8,9,10 10α-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. which can be administered to individuals at high pressure 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 9-amide derivatives (e.g.⁸ and R⁷ in the above formulas are alkanoyls) although 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 shows 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-hydroxy-amino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [ b, d] pyran exhibits a minimum effective dose (MED) of only 5.0 mg / kg in mice, and in addition, in the dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6- dimethyl 9- (N-ethyl) acetamido-6a, 7,8,9,10,10ahexahydro-6H-dibenzo [b, d] pyran shows a MED of 10.0 mg / kg. In the dog blood pressure lowering test dl-trans-1-hydroxy-3- (1,1-dimethylheptyl] -6,6-dimetbyl-9-acetamido-6a, 7,8,9,10,10a-hexahydro-6H dibenzo [b, d] 207772 pyran exhibits an intravenous MED of 0.5 (Ug / kg).

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.⁵ is an alkanoyl having 1 to 7 carbon atoms).

Hypotensively active compounds of the invention may be administered by any route including oral, subcutaneous, intramuscular and intravenous.

Typical dosages 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- (1,1-dimethylheptyl) -9- (2,6-dioxopiperidino) -6a, 7,8,9,10,10a-hexahydro- 6H-dibenzo (b, d) pyran. Preferred treatments include the administration of about 2 mg / day 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.

The preparation of the 9-amino-dibenzopyrans of the invention is described in more detail in the following examples. It is 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-dimethylamino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] pyran

A solution of 1.48 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 in 50 ml of methanol containing 3.24 g of dimethylaminohydrochloride, 3.03 g of triethylamine and 378 mg of sodium cyanohydride was stirred at room temperature for 6 hours. The reaction mixture is concentrated by evaporation of the solvent and the residue is dissolved with 50 ml of diethyl ether. The ethereal solution was washed with 0.5 N hydrochloric acid, water, 10% aqueous sodium bicarbonate and again with water. The solution was dried and the solvent was evaporated under reduced pressure to give an oily residue. This was then dissolved in 50 mL of hexane and diluted with 1.0 mL of a 6.5 N methanolic hydrochloric acid solution. The resulting precipitated solid consists of 1.67 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethylamino-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo [b, d] pyranhydrochloride.

For C26HUNO2Cl calculated:

% C, 71.28;% H, 10.12;% N, 3.20.

8.09% Cl, found:

% C, 70.60;% H, 9.78;^!8% N,

7.62% Cl.

m / e: calcd. 401, found: 401. Examples 2 to 5

By the general procedure described in Example 1, dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6α, 7,8,9,10,10α-hexahydro-6H-dibenzo [b] d) pyran-9-one is reacted with the appropriate amine to give the following compounds:

dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-isopropylamino-6a, 7,8,9,10,10a-hexahydro-6H-di-benzo [b, d] pyran hydrochloride.

For C 27 H 46 NO 2 Cl calculated:

% C, 71.73;% H, 10.26;

7.84% Cl, found:

% C, 71.44;% H, 10.00;% N, 3.28.

7.54% Cl.

m / e: calcd 415, found 415.

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

For C27H41NO2 calculated:

% C, 78.78;% H, 10.04;% N, 3.40.

% C, 78.55;% H, 9.83;% N, 3.39.

m / e: calcd 411, found 411.

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

For C28HuNO / Cl calculated:

% C, 72.78;% H, 9.60;% N, 3.03;

found:

% C, 71.01;% H, 9.54;

7.13% Cl.

m / e: calcd. 425, found 425.

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

For C31H45NO2 calculated:

% C, 80.30;% H, 9.78;% N, 3.01.

% C, 80.31;% H, 9.86;% N, 3.01.

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

To a solution of 1.48 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 in 50 ml of methanol was added in one portion 2.44 g of ethanolamine, stirred at room temperature for 30 minutes and then diluted with a solution of 1.5 ml of 6.5 N hydrochloric acid in 10 ml of methanol. The acidic mixture was stirred for 15 minutes and then 378 mg of sodium cyanoborohydride was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered and the solvent was evaporated to give a gum. The crude product was dissolved in 100 mL of diethyl ether, washed with 0.5 N hydrochloric acid, saturated sodium chloride solution and 10% sodium bicarbonate solution. The ether phase is dried, the solvent is evaporated and a white foam is obtained. The foam is dissolved in 50 ml of hexane, to which 1.0 ml of 6.5N methanolic hydrochloric acid is added. The crystalline solid was filtered off and identified as 1.82 g of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (2-hydroxyethyl) amino-6a, 7.8 9,10,10a-hexahydro-6H-dibenzo [b, d] pyran hydrochloride.

Why₂6HtíNO3Cl found :.

% C, 68.48;% H, 9.58;% N, 3.25;

7.51% Cl. ·.

m / e: calcd. 417, found 417.

Example 7 dl-1-hydroxyxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-piperidino-6a / 7,8,9,10,10a-hexahydro-6H-dibenzo (b, d] pyran

By the general procedure described in Example 6, 744 mg of dl-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 1.7 g of piperidine to give the corresponding imine, which is then reduced by reaction with 19 mg of sodium cyanoborohydride and 0.75 ml of 6.5 N hydrochloric acid. Normal work-up of the reaction mixture yielded the product as an oil which was then treated with methanolic hydrochloric acid to give 689 mg of crystalline dl-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dir methyl -9-piperidin-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [h, d] pyran hydrochloride.

For C 29 H 48 NO 2 Cl calculated:

% C, 72.85;% H, 10.12;% N / 2.93.

7.41% Cl ·, found:

% C, 72.70;% H, 10.12;% N, 3.14;

7.16% Cl.

m / e: calcd. 441, found 441; Example

The procedure of Example 6 is repeatedly desired. morpholine. Normal work-up yields an oily product. The oil was treated with hydrochloric acid in methanol to give 615 mg of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-morpholino-6a, 7,8,9, 10,10a-hexahydro-6H-dibenzo [b, d] pyran hydrochloride.

For C28H16NO3Cl calculated:

% C, 70.04;% H, 9.66;% N, 2.42.

7.38% Cl, found:

% C, 69.79;% H, 9.40;

7.15% Cl.

m / e: calculated 443, found 443, calculated:

C 68.77, H 9.77, N 3.08,

7.81% Cl.

Example 9 dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-propyn-1-yl) acetamido-6a, 7,8,9,1010a - hexahydro-6H-dlbenzo [b, d] pyran

To a stirred solution of 500 mg dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (2-propyn-1-yl) amino-6a, 7,8,9, 10,10a-Hexahydro-6H-dibenzo [b, d] pyran in 25 ml of methanol containing 1.5 ml of triethylamine was added dropwise over 5 minutes with 1.5 ml of acetic anhydride, after which the reaction mixture was stirred at 25 ° C for 2 days. The reaction solvent was then evaporated and the oil thus obtained was dissolved in diethyl ether and washed with aqueous sodium bicarbonate solution. The ethereal solution was dried and the solvent was evaporated to give 500 mg of the product as an oil. The oil was purified by chromatography on 25 g silica gel [Woelm, activity I] eluting with diethyl ether. Appropriate fractions were combined, concentrated to dryness in vacuo to give 430 mg of dl-trans-1-hydroxy-3- [1,1-dimethylheptyl] -6,6-dimethyl-9-N- (2-propyne-1- yl) acetamido-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, dj pyran.

For O29H44NO3 calculated:

% C, 76.50;% H, 9.40;% N, 3.19.

C, 75.60; H, 9.18; N, 3.28. M / e: calc. 453, found 453.

Exemplary dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (N, N-dimethyl-N-propargyl) 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-dimethyheptyl) -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 cooled to room temperature and concentrated in vacuo to a volume of 5 ml, diluted with diethyl ether and hexane. precipitates. The precipitate was filtered off to give 625 mg of -6,6-dimethyl-9- (Ν, Ν-dimethyl-N-propargyl) ammonium-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d ] pyranbromide, mp 104-107 degrees Celsius.

For C29H47BrNO2 calculated:

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

15,77 0/0 Br, found:

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

Example 11

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 reacted with 2.1 g of hydroxylamine to give the corresponding optically active oxime, and the oxime thus formed is reduced 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-dihenzo [b, dj] 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 ethereal solution was stirred at room temperature for two hours, the organic phase was separated, washed with aqueous sodium bicarbonate 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 one component according to thin layer chromatography 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 O26H41NO3 calculated:

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

% C, 75.32;% H, 9.77;% N, 3.12. M / e: calc. 415, found 415. (?)?

Γ &lt;₆Τ + 29.9 °.

Other chromatographic separated fractions contain 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.

Í9

For O26H41NO3 calculated:

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

H, 9.99; N, 3.18. M / e: Calcd. 415, Found: 415.

_MCHC13 _₆₄₎₉O_j [?] A -236.5 °.

Example 12

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

Example 13 '

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. -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.