Amino-dibenzopyrans, their preparation, formulations containing them and their use as pharmaceuticals

The present invention relates to a process for the preparation of 9-aminodibenzopyran derivatives of general formula I:

H _zRi. ISI^z / \

OH \ / \ / V (I). 10 / \ Z \ Z

-lî->

- diinctil-6,6a, 7, 8, 10, 10a-he.xahydro ~ 9H- dibenzo - [b, d] - pyran -9-one ( Patents, S: U, A "No. 3928598, 3 944 673 , 3 953 603).

Also known are processes for the preparation of debenzopyran substituted with amino group or heterocycle with nitrogen (Patents, US, No. 3886184; 3676462 ·; 3878219; 3888946). .

The process according to the invention broadens the range of aminobenzopyran derivatives by subjecting them to the hydrogenation of compounds of general formula II:

wherein R 1 represents an alkyl radical with ¹⁵

5 ... 10 carbon or alkenyl atoms with 5 ...

carbon atoms, R, represents a hydrogen atom or a methyl radical, R 1 represents an alkanoyl radical with 1-7 carbon atoms, phenyl-alkanoyl with 1 or 2 atoms ²⁰ '. o 'carbon or the group - C - - (CH₂)

-COOH in which, there are 2,3 or 4 compounds that can be used in analgesic drugs, anti-depressant and 25, anxiety.

Processes for the preparation of some dibenzopyranes used as analgesics and antidepressants such as, for example, l-lrans-1-hydroxy-3- (1, -1-dimethylethyl) -6,6-30 are known.

OH

I (ii)

Ii3 lia \ l / \

R, wherein R ,, R_of have the meanings mentioned above and R₄ is hydroxy, in the presence of Raney nickel, as a catalyst in a solvent selected from methanol or. liquid ammonia at a temperature between 80 and 120 ° C,

The price of LEI 31.33 .3 for 4 ... 8 h, to obtain compounds of formula I, 1% is hydrogen atom, after which the obtained compound reacts with an acylating agent in approximately equimolar amounts, at a contained temperature integers 0 and 50ⁿC, in the presence of an acid acceptor such as triethanolamine or pyridine, to obtain compounds of formula 1 wherein 1% represents an alkanoyl radical with 1 ... 7 carbon atoms, thiomanyl alkylines with 1 or 2 carbon atoms. of

or - C - (CH,) "- COOH wherein n is 2,3 or 4 and, if desired, the optical isomers and epimers are isolated, and the compounds of formula I are isolated as free bases or as pharmacologically acceptable addition salts, or quaternary ammonium salts.

Examples of carrying out the process according to the invention are given below.

Example 1. a) Preparation of dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7, 8, 9, 10, 1Oa-hcxahIdro-6H. -dibenzo [Z>, d \ -piran

A solution of 1.93 g dc compound dl-trans-1-hydroxy-3- (1,1-dimethylheptyl-9-hydroxyimino-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyrane in 100 ml methanol and 25 ml anhydrous ammonia solution containing 1.0 g Raney nickel, was stirred and heated at 100 ° C for 6 h under hydrogen at a pressure of 70.3 kg / cmA The reaction mixture is then cooled to room temperature and filtered. The filtrate was concentrated by evaporating the srib solvent under reduced pressure to obtain a solid mass. The solid was dissolved in 300 ml of diethyl ether and washed with 50 ml of IN hydrochloric acid, 50 ml of 5% sodium bicarbonate aqueous solution and then with water. The ethereal solution was anhydrized and concentrated to dryness by evaporation under reduced pressure to obtain 500 mg of solid mass. The solid thus formed was recrystallized from diethyl ether and hexane to give 1.85 g of rfWra, 9-l-hydroxy-3- (1,1-dimethylhcptyl) -6,6-dimethyl - 9-amino -6a , 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyran.

Analysis for: C₂₁H_;!"NO₂,% i:

- calculated: C = 77.16; H, 10.52;

N, 3.75;

- found: C = 77, 77; Ή = 10.08;

N, 3.27.

m / e: calculated: 373.; found 373.

b) Preparation of dl-trans-7-hydroxy-3- (1,1-dimethibheptyl} -6,6-dimethyldP-amino-6a, 7, 8, 9, 10, 1-Qa-hexahydre-6H maleate -dibenzo (ό, d \ -piran)

G 340 mg solution of d / - / yl-bidroxy- (1,1-dimethylheptyl) - 6; 6-dimethyl-9-amino-6a, 7, 8, 9, 10, 10a-hexahydro-6H- dibenzo [b, dț-pyran in 50 ml of diethyl ether containing 164 mg of malic acid, was stirred and heated under reflux for 10 min. The product precipitated from the solution and was collected by filtration to obtain the maleate compound dc rf / - / ra «sl-hydroxy-3- (i, 1-dimethylhepHl) -6,6-dimethyl-9-amino-6a , 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo fb, d] pyran as a white solid with mp 157-159 ° C.

Analysis for: C₂JH_4iNO_G,% :

- calculated: ^:C, 68.68; H, 8.85;

N, 2.86;

- Found: C, 68.51; H, 8.57;

N, 2.66.

c) Preparation of dl-trans-1-hydroxy-3- (1,7-dimethylheptiPj-6,6-dirnetyl-9-acetamido-6a, 7, 8, 9, 10, 10a-hexahydro-OH-dibenzo (6, dj-pyran. At a solution, under stirring, of 750 mg of dPtrans-1-hydroxy - 3 (1,! -dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7, 8, 9, 10, 1 O-hexahydro-6H-dibenzo [b, pyran, in 10 ml of methanol, 1.5 ml of triethylamine and 1.0 ml of acetic anhydride were added at once. The reaction mixture was stirred for 12 h at 240 ° C and then 50 ml of water was added. The aqueous reaction mixture was extracted with ethyl ether. The ethereal extracts were combined, washed with water and then with 10% aqueous sodium bicarbonate solution and dried. Removal of the solvent by evaporation under reduced pressure gave 840 mg of solid slag. The slag was then inserted into a column with 30 g of silica gel and eluted with ethyl acetate. The fractions which showed, by thin layer chromatography, that they contain the desired product, were combined and concentrated until they reached the cystic acid to obtain 735 mg of rfL / zem-l-hydroxy-3- (1,1-dimethylheptyl) - 6 , 6-dimethyl-9-acetanido-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyran,

Analysis for C₂₃H₄NO₃, in the% :

- calculated: C = 75.14; H, 9.94;

N, 3.37;

- Found: C, 75.51; H, 9.75;

N, 3.43.

me: theoretically 415; calculated 415.

Example 2. Compoundsid-trans-1-hydroxy-3- (1,1-dimethylheptyl-6,6-dimethyl 9 alpha (and 9 beta) -acetamido-6a, 7, 8, 9, 10, lOa-hcxahydro-, 6H-dibenzo [6, d] -pyran

Following the conditions set forth in Example 1 c), 5.98 g of compound dl-7r-ws-1-hydroxy-3- (1,1-dimethylheptyl) -6, -6-dimethyl-9-acetamido was reacted. 6a, 7, 8, 9, 10, 10a-hexahydro-6H-dihenzo [h, d] pyran, with 8.0 ml • of acetic anhydride and 12 ml of triethylamine in 100-ml ethanol. Normal processing was obtained as a result of 3.97 g of ί

product, as a white solid. The product was chromatographed on a column with 240 g of silica gel. Similar fractions were with. Careful. collected, and the solvent a^: was removed to give 1.06 g of dl-trans-1-hydroxy-3- (1,1-dimethylethyl) -6,6-dunetyl-9 alpha-acetainido-6a, 7, 8, 9, 10, lOa-hexalridro-6H-dibenzo [b, d] -pyran. A sample of this axial isomer was crystallized from 20ND-hexane. Melting point 195 ... 197^eC. Analysis for Ε_ίβΗ._ηΝ0_{; ι}, in the% :

- calculated: C = 75.14; H, 9.94;

N, 3.37;

Found: C, 75.37; H, 10.05;

N, 3.12.

Other chromatographs and the collection of similar fractions gave, after evaporation of the solvent, 2.16 g of dl-trans - \ - hydroxy-3- (1,1-dimethylhcptyl) -6,6-dimethyl-9-beta-acetamido-6a compound. , 7, 8, 9, 10, lOa-hexahydro-6-dibenzo [b, dj-pyran.

Melting point: 200 ... 202 ° C.

Analysis for C_2UH₄₁NO_B in the% :

- calculated: C. = 75.14; H, 9.94;

N, 3.37;

- found: C = 74.95; H, 9.58;

N, 3.31. '

Example 3. Preparation of d-irans-hydroxy-3- (1,1-dimethylheptyl} -6,6-dimethyl-9- propionamido-6a, 7, 8, 9,10, 10 a-hexahydro-6H-dibenzo. [ b, df-pyran

A solution of dc 373 mg of dl-trans- 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino -6a, 7, 8, 9, 10, 10a-hexahydyl- 6H-dibcnzo [b, d] pyran, in 20 ml of methanol containing 1,3. g of propionic anhydride and 2.5 ml of triethylamine was stirred at ambient temperature for 48 h. The reaction mixture was then diluted with 25 ml of water and the reaction mixture was then stirred again for 2 h at room temperature. room. The excess methanol was then evaporated off under reduced pressure, and the product was extracted from the aqueous mixture with diethyl ether. The ethereal extracts were combined, washed with water, 2N hydrochloric acid, 10% aqueous sodium bicarbonate solution and anhydrized. Removal of the solvent by evaporation under reduced pressure gave a slurry which was then purified by chromatography on a column with 20 g silica gel eluting with diethyl ether. Fractions with a volume of 10 ml were collected, and fractions 5 to 30 were combined and the solvent evaporated to give 434 mg of dl-trans-Λ-hydroxy-3- {I-J-dimefilheptyl-6, 6-'-dimethyl-9-pr0pionamÎ'do-6at,' 7, '8/9, 10, 10a'-hexahydr0-6. H-dibenzo [b, d] -, pirates ,, 'Analysis, for, C₂; li_MNQ₃'in the%.; ,

..— calculated; C, 75.48; Η = / 10.09; ,_; '- χ ,, 3 26;

Found: C, 73.23; H, 9.84;

N = 3.26, m / e: calculated 429; found 429.

EXAMPLES 4. Preparation of d-trans-acetoxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9 - acyls do-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzate j% d] pirantdui

A solution containing 373 mg of dl-trans-1-lidroxy-3- {1, 1-dimethylheptyl) -6,6-dimethyl -9-amino-6a, 7, 8, 9, 10, 10a-hexahydro-6H- dibenzo [b, dj-pyran, 10 ml acetic anhydride and 10 ml pyridine, was stirred at room temperature for 48 hours. The reaction mixture was cooled and the methanol was evaporated off. The residue was dissolved in diethyl ether, washed with water, 1N hydrochloric acid and sodium chloride solution. The ethereal solution was anhydrized and the solvent was evaporated to give the product as a white slag. The slag thus produced was purified on a chromatographic column with 20 g · silica gel and eluted with diethyl ether. Evaporation of the solvent from similar fractions gave 420 mg of dEbwis-i-acetoxy-3- (f, 1-dimethylreptil) - 6 , 6-dimethyl-9-acet anii do-6a, 7, 8, 9, 10, 10a-hexahydrr-6H-dibenzo- [b; dj-pyran.

Analysis for (% ¾ %% ¾ in%:

. - - - calculated: C = 73.49; H, 9.47; ', N = 3.06;

'- found: ϊ C =. 73.26; H == 9/36; .

. , N =._;3,28%, ..

m / e: calculated 457; found 45. . -.

EXAMPLE 5 Preparation of trans -hydroxy-3- (1, 1-d-imyl) & ptil} -6 ', 6-dimethyl-9-Jonnainido-Oa, 7, <V, 9, 10, O-hexahydro-GI-αibenzc -, [6, for the year

A solution of 15 ml of acetic anhydride and 7.5 ml of 98% formic acid was stirred and heated at reflux for 15 minutes. The mixture was cooled to room temperature and the amount of 2.5 g of sodium acetate and 373 mg of rfZ- / ju «-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9 was added. - amino-6a, 7, 8, 9, 10, - 1.0a-hexahydro-6H-dibenzo [b, dj-pyran. The reaction mixture was stirred for 4 h at room temperature and then added to a methanol solution containing sodium carbonate and water. The mixture was stirred for one hour, after which time the organic solvent was removed and evaporated under reduced pressure. The aqueous layer was extracted with diethyl ether and the etheric extracts were combined, washed with water and anhydrous. Removal of the solvent by evaporation gave -410 mg'de · product-as a white solid: 'The solid- thus formed was purified,' by c-prnatography 'on 20_j g silica gel .. for, for. supports 27.6 mg of, dl-trans-Pz. -hydro-xi- 3- (1,1-dimethylhcptyl) -6,6-dimethyl-9Î3

-formainyl-6a, 7, 8, 9, 10, lOa-hexahydro-6H-dibenzo fb, d] pyran.

Analysis for C₂₅H_3i)U.S. n% :

- calculated: C = '74, 77; H, 9.19;

N = 3 49 - found: C - - 74.61 *; H, 9.53;

N = - .3, -64.

m / e: calculated 401; found 4.0.

Example 6, Preparation of D-Trans-1-Hyroxy-3- (7, Pd-Imethylheptyl) -6,6-Dimelyl-9- (3-H4-Oxycarcaryniphenyl} -propio^andnamido-6a, 7, 8, 9, 10, 10a-hexahydro-6IPdihens-o [b, d] pyran

A solution of 372 mg dc compound dl-trance-b'hydrox.i-3- (1,1-dimethylheptyl) -6,6- dimethyl-9-amino-6a, 7, 8, 9, 10, 10a-hcxahydro -6Hdibenzo [b, d] -pyran in 20 ml methanol containing 1.0 g succinic anhydride and 2.5 ml triethylamine was stirred at room temperature for 72 h. The reaction mixture was then diluted with 50 ml water. , and the organic solvent was removed by evaporation. The aqueous layer was extracted with diethyl ether and the etheric extracts were combined, washed with water, 2N hydrochloric acid, again with water and with 10% sodium bicarbonate solution. After anhydrization of the solution, the solvent was removed by evaporation under reduced pressure to give a slurry product. Slag was introduced together with 20 g of silica gel in a column and evaluated with ethyl acetate. Fractions showing by thin layer chromatography, containing the major component, were combined and the solvent was evaporated to give 507 mg of dltrans-1-hydroxy-1,1-dimethylheptyl) - 6,6-. Ifmethyl-9- (3-hydroxycarbonyl) -propionamido -6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] pyran.

Analysis for C₂₈H₁₃NO₅, in the% :

- calculated: L = 71.10; H, 9.15;

N, 2.96;

found: C, 70.98; H, 9.35;

H = 2, -97.

m / e: calculated 473; found 473.

Example 7. Preparation of dPtrans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6- dimethyl-9-benzamido-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dP benzo [b , df-pir of the year

To a solution of 373 mg of dPirans-1-hydroxy-3- (1, 1-dimethyl, ptil) -6,6-dimethyl-9-amino-6a, 7. 8, 9, 10, 10a-hexahydro- 6H-dibenzo fb, dj-pyran in 20 ml methanol, a solution of 2.26 g benzoic anhydride in 2.5 ml triethylamine was added at once. The reaction mixture was stirred for 60 liters at room temperature and then diluted with 20 ml of water and further stirred for an additional 2 h. The organic solvent was removed by evaporation and the aqueous phase was extracted with aqueous ether. The ethereal extracts were combined, washed with water, 2N hydrochloric acid, again with water and finally with 10% aqueous sodium bicarbonate solution. The organic layer was anhydrized and the solvent was evaporated to give the product as a slag (sponge). The slag was chromatographed on a column with 20 g of silica gel eluting with a 50% diethyl ether mixture. Similar fractions were collected and the solvent was evaporated to give 525 mg of dl-bwis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-benzamido-6a, 7, 8, 9, 10, lOa-hexahydro-6-H-dibenzo zb, d] -pyran.

Analysis for%:

- calculated: C = 77.95 H = 9.07;

N, 2.93;

Found: C, 77.75; H, 9.30;

N, 2.91.

m / e „calculated: 477; found 477.

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

A solution of 1.12 g of dL / zuMS-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-9-dihydroxy imino-6a, 7, 8, 9, 10, 10a-hexahydro-6H -dibenzo- [b, d] -pyrane in 100 ml of methanol containing 25 ml of ammonia solution and 1.0 g of Raney nickel was stirred at 100^flC, -for 8 hours under the pressure of a hydrogen atmosphere of 7 kgf / cm⁸. The reaction mixture was then filtered and concentrated to a volume of dc about 50 ml and then diluted with 25 ml of 10% sodium bicarbonate solution. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were combined, washed with water, anhydrized, and the solvent was evaporated to give 861 kg of 1-zz-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl. -9-amino-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyran.

Analysis for C₂₄H3₉NO_?, in the% :

- calculated; C, 77.1-6; II = 10.52;

Ν = 375;

- Found: C, 77.54; H, 10.52;

N, 3.94.

m / e: calculated 373; found 373.

b) Preparation of dPtrans-1-hydroxy-3-11,2-dimethylheptyl) -6,6-dimethyl-9-beta (and 9 alpha) -acetamido-6a, 7, 8, 9, 10, 1 () a- hexahydro-6H-dibenzo (f>, d] pyran

A 960 mg solution of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6- dimethyl-9-aniino-6a, 7, 8, 9, 10, 10a-hcxahydro- 6H-dibenzo [b, pyran, in 40 ml of methanol, containing 5 ml of triethanolamine and 5 ml of acetic anhydride was stirred at room temperature for 24 h. The methanol was then removed by evaporation and again

82370' '

solution was diluted with 50 nil 10% sodium bicarbonate solution and further stirred for another 2 h. The aqueous mixture was extracted with rlietyl ether, and the etheric extracts were combined, anhydrous, and the solvent was evaporated off to obtain a product in the form of a slag. The slag was crucinographed on 50 g of silica gel, first eluting 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. Fractions containing each 20 ml of eluted solution were collected. Fractions 61 ... 95 were combined and evaporated to dryness to give 354 mg of dl-tran sl -hydroxy-3- (1,2-dimethylheptyl]) - 6,6-dimethyl-9-6e / -1-acetainido-6a, 7, 8, 9, 10, 10a-hexalihydro-6 IL-dihenzo [b, d] pyran with melting point 40-45^ofC.

Analysis for: C₂"H₄iNO₃, in the% :

- calculated C = 75.14; H, 9.94;

N, 3.73.

- Found: C, 74.91; H, 9.93;

N, 3.53%.

Fractions 101, 150 were collected and the solvent was evaporated to give 591 mg dl-trans - \ - hydroxy-3- (1,2-dimethylheptyl) -6,6- dimethyl-9 «//« -acetamido-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [h, d] pyran.

Example 9. a) Preparation of dl-cis-1-hydroxy xi-3- (1,1-dimethylheptyl) -pi, 6-dimethyl-9-amiηο-ϋα, 7,8, 9, 1 (), 1 Oci -hexahydro-eH-dibenzo [6, d} -pyrane

Following the process described in Example 8, the compound in the amount of 3.87 g of dl-cis1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a, 7, 8, 9, 10, lOa-hexahydro-6H-dibenzo [b, d] -pyrane was hydrogenated by reaction with hydrogen (at 70 kg / cm²) in the presence of dc 2.0 g Ranev nickel in 100 ml methanol containing 25 ml of ammonia solution, to obtain 3.38 g dc compound i / - cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-di methyl-9-amino-6a, 7, 8, 9, 10, 1 O-hexalihydro-6H-dibcnzc [b, d] -pyran.

Analysis for C_MH_3iNO₂, in the% : _: - calculated: C = 77.16; H, 10.52;

N = 3.75.

. - found:. C, 76.87; II = 10.44;

N, 3.70.

m / e: calculated 373; found 373.

b) Preparation of dl-cis-1-hydroxy xi-3- (1,1-di-methylheptyl) -6-dimethyl-9 beta (and 9 alpha) -acetamido-6a, 7, 8, 9, 10, 10a-he xahydro-6H-dibenzo [6, d] -pyran

1.18 g of iZ / -ris-1-hydroxy-3- (1,1-dimethylcyptyl) -hexalihydro-6H-dibenzo [b, d] -pyrane were acylated by reaction with acetic anhydride and triethylamine in methanol; to obtain, after chromatography, 545 mg of <7 / - "-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9 0 / - - acetaniido-6a, 7, 8,9 , 10,10a-hcxahidiO-6H-dibenzo [b, dj-pyran. Melting point 107 ,, 120 ° C; and 494 mg dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9 alpha-acetamido-6a, 7, 8, 9, 10, l -ahexahydro-6H-dibenzo [b, dj-pyran. Melting point

I64 ... 168 ° C.

Example 10. Preparation of Gali, 10aH-iran s-hydroxy-3- (7,7-diethylethylheptyl} -6,6-dimethyl-9 R (and 9 S} -acetamido-6a, 7, 8, 9, 10, 10a- he xahydro-6H-dibenzo [b, d] pyramyl

7.5 g 6aR, 10aR-ira-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyran-9-one, reacted with 2.1 g of hydroxylamine to obtain the corresponding optically active oxime. The oxime thus formed was reduced by reaction with hydrogen in the presence of Raney nickel, to obtain 1.49 g of a mixture of 6aR, 10aR-7nms-1-hydroxy-3- (1,1-diethylheptyl) -0 , 6-d-methyl-9 R (and 9 S) amino -6a, 7, 8, 9, 10, 10a-hexalihydro-6H-dibenzo [b, dj-pyran, A solution of the latter compound, in 30 ml of methanol containing 10 ml of triethylamine, it was stirred at 25 ° C, while 5 ml of acetic anhydride were gradually added within 10 minutes. The reaction mixture was then stirred at room temperature for 72 hours, after which the solvent was removed by evaporation under reduced pressure. The residual oil was immediately dissolved in 50 ml of diethyl ether> containing 0 ml of water. The aqueous ether solution was stirred for 2 h at room temperature, after which the organic layer was separated, washed with aqueous sodium bicarbonate solution and dried.

Evaporation of the solvent gave 1.52 g of white slag. The product thus formed was chromatographed twice on a column with 100 g of silica gel and eluted with 600 ml of chloroform, 1 000 ml of 0.5% methanol, in chloroform and finally with 2 000 ml of 1% methanol in chloroform. Fractions containing each were collected. 20 ml. The fractions which showed, by thin layer chromatographic analysis, that they were composed of a component, were combined and the solvent was evaporated off under reduced pressure to obtain 287 mg of_}compound 6aR, lOaR -7m-i'-l-hydroxy-3- (l, l-climimethylheptyl) -6,6-dimethyl 9R -acetamido-6a, 7, 8, 9, 10, lOa-hexalihydro-H-dibenzo , | b, dj piran,,

Analysis for C_(iH₄₁NO_:1,: in the% :

- calculated: C = 75.14; .II =, 9.94; .

N, 3.37; '...

83370 . Found: C, 75.32; Ή = 9.77;

N: = 3.12%.

m / e: calculated 415; found: 415.

[«]_DCHC1₃ = -1; h.W'll <% = 4-29.9 °.

Further chromatographic separation yielded fractions containing 591 mg of compound 6aR, IOaR - / - iOi.is-I-hydroxy-.3- (1,1-dimethyl heptyl) ~ 6,6-dimethyl-9S-acetamide0-6a , 7, 8, 9, 10, 10a-hexahydro-6H dibenzo / bd / pyran.

Analysis for C_MH₄₁NO₃, in the % :

- calculated: C = '75, 14; Ή = 9.94;

N, 3.37;

- Found: C, 74.91; 14 = 9.99;

N, 3.18.

m / e: calculated 415; found: 415. [aJ_DCHCl₃ = -64.9 °; [X] CHCl₃₆₅ = = —236,5·.

Some compounds of general formula I, prepared according to the examples dc above, in which IU is defined as an alkyl group C-, - C₁₍, and an alkenyl group C., - C_k. include both straight chain and branched alkyl groups such as "-pentyl, nhexyl, K-liyl", tyl, 1,1-dimethylheptyl, 1,2-diethylheptyl, 1-ethylcetyl, 1,1- dimethylcetyl, 1,2,3-trimethylheptyl, 1-propylhexyl-iseethyl, "-decyl and the like. The term & quot; C 1 -C, alkenyl, u, similarly refers to the straight and branched alkenyl chains in which it is. include 2-pentenyl, 3-hexenyl, 5-heptenyl,

1, 1-dimethyl-2-heptenyl, 1,2-dimethyl-1-heptenyl, 2,3-dimethyl-2-heptenyl, l-ethyl-2-octenyl, 2-ethyl-1-heptenyl, 2-decenyl, 1-nonenyl, 1-methyl-1-nonenyl and related alkenyl groups. Groups 1% and R₆ are defined as groups "alkanoyl C_it-C_ţ". Such definitions refer to the acyl radicals of carboxylic acids having 1 to 1 to 7 carbon atoms. Such groups may be straight or branched chain acyl groups. Typical C 1 -C 6 alkanoyl groups include formyl, .acetyl, propionyl, isobutyryl, pentanoyl, isolexanyl, 3-ethylpentanoyl, 2-methylhexanoyl, 1,2-diethylhexanyl and related groups. Preferred groups of alkanoyl are C 1 -C 6 alkanoyl_of and the most preferred are Cj - C alkanoyl_?. R-, and R_e also include groups (C 1 -C 6 alkyl phenyl such as benzyl and 2-phenethyl, as well as (C 1 -C alkanoyl)₂) -phenyl such as, for example, benzoyl and phenylacetyl. R₃ it may additionally be a group having the formula: - (CH 1) - OH, where n is 2, 3 or 4. Such groups include 2.-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl. The hydroxy group of such dc parts can be acylated with the alkanoyl group Cj - C₂, making by this means substituents such as acetoxymtyl and the like. When R. defines the -CO group (CH₂) "- COOH, such groups include 3-hydroxycarbonyl) -propionyl, 4- '{hydroxycarbonyl) -butyryl and 5- (hydroxycarbonyl-pentanooyl).

The compounds of the general formula I are basic in nature and readily form acid addition salts and quaternary ammonium salts. For example, 9-amino-, 9-alkylaniinosa or 9-dialkylamino-dibenzo [b, d] pyran may exist in the free base form or alternatively in the form of salt.

Non-toxic, pharmaceutically acceptable salts are salts that do not add substantial toxicity to the initial amine and can therefore be pharmaceutically used in a manner similar to the free amine bases. Acid addition salts are prepared by standard procedures such as, for example, reacting the basic amine with an organic or inorganic acid. Acids commonly used to form pharmaceutically acceptable non-toxic addition salts include mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric acid as well as sulfamic, nitric and nitric acid. Typical organic acids usable include acetic, oxalic, lactic, ascorbic, maleic, fumaric, succinic, jGtoluensuIfonic, benzoic, methanesulfonic, adipic and the like.

Similarly, basic amines which are tertiary amines readily form quaternary ammonium salts which are also pharmaceutically acceptable. Such tertiary amines are quaternized by the reaction with an alkylating agent such as methyl iodide, ethyl bromide, 7-biylyl chloride, isobutyl iodide, allyl bromide, dimethylsulfate.

The 9-amino-dibenzo [b, d] pyran compounds of formula (I) may exist as cis isomers at position 6a, 10a and as f / nH-sla isomers at position 6a, 10a. Each of these isomers constitutes a racemic mixture or a pair of mls (dextrogir, levogir). For example, the derivative 6a, IOa-cts may have both the hydrogen atom at 6a, and the hydrogen atom at 10a, oriented above the plane of the ring or alternatively, both hydrogen atoms may be oriented below the plane of the ring. These two isomers form a racemic cis-dl mixture. Similarly the trans isomer 6a, 10a may be a compound where the hydrogen atom at 6a is above the plane of the ring, while the hydrogen atom at 10a is oriented plane or alternatively the hydrogen atom at 6a is oriented below the plane of the ring. , and the hydrogen atom at 10a is oriented above. Again these 2 isomers constitute a trans-dl pair mixture.

Normally, the preparation of compounds of general formula I comprises the use of a racemic mixture of either 6a, 10a-cfs-hexahydrodibenzo [b, d] pyranone, i.e. a dl-cis isomer, or alternatively, a racemic mixture of isomer 6a, 10a-. ri «ws, that is (ZT-Ziim-hexahydrobenzo fb, d] pyranone.

i »

Must be noted. However, that the compounds of general formula 1 may also be obtained from an optically active ketone d-cis or l-cis or a ketone d trans or l-irans, thereby giving the 9-amino compound -dibenzo [b, d] -pyrane correspondingly, having the same stereochemical integrity as the starting DC ketone.

Examples of oxime and general formula II include:

hydroxy-3 - «- pentyl-6,6-dimethyl-9-hydroxyimin © -6a, 6, 7, 8, 9, 10a-hcxahydro-6H-dibenzo [b, d] -pyran;

-hydroxy-3- (1,2-dimethyl-2-pentenyl) -9-mctoxumino-6a, 7, 8,9, 10, 10a-hexahydro-6H-dibenzo lb, d] pyran;

-dl-trans-1-hydroxy-3- {1,2-dimethylheptyl) -9-ethoxyimino-6a, 7, 8, 9, 10, lOa-hexahydro-6H-dib.enzo (b, d] pyran and dl -cis-1-hydroxy-3- (1,1-methyloctyl) -6,6-dimethyl-9-isobufoxiim.ino-6a, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] pyran.

As mentioned above, the 9-amino-hexaliidrodibenzo-l'b, d] pyran compounds, mayors, may be acylated with any of the numerous acylating agents to obtain various 9-amido compounds derived from the present invention, including compounds of the formula dc above, where R., is alkanoyl C_x-C ;. Reaction of compound 9- (NH₂) -ih'-benzopyran with an acylating agent, under relatively mild conditions, it produces monomacylation to obtain the compound 9-amido-hexalihydrodibenzo [b, dj pyran (R. alkane alkyl, and R is hydrogen). Thus the expression "relatively mild conditions includes the use of the acylating agent. and 9-amino-dibenzopyran compound. in quantities. approximately equimolccularc. and performing the reaction at a temperature of about 0 to about. to 50^QC is usually used in the reaction as a base, for example triethylamine or - pyridine, as an acid acceptor. Commonly used acylating agents include: C, C acid halides₇ and alkanoic acid (CjC_of) -phenyl alkanoic acids, azides, anhydrides, including mixtures of anhydrides, as well as cyclic anhydrides such as, for example, succinic anhydride, glutaric anhydride and adipic anhydride. The use of such cyclic anhydrides produces the amides of the present invention, where the acyl group has the formula - CO (CH)₂) "COOH. Preferred acylating agents include acid halides and acid anhydrides. Examples of such reagents include acetyl chloride, anhydride, prionpionic, formylactic anhydride, benzoyl chloride, fcnilactyl bromide, heptanoyl iodide, succinic anhydride and isobutyric anhydride. Acylation •. .^fcan be conducted in any of the many organic solvents, if sc chlorinated, including alcohols such as methanol and cyanol, hydrocarbons, halogens such as dichloromethane, 1,2-dibrqmctan, etheric, for example, diisopropyl ether, diethyl ether and tetrahydrofuran as well as aromatic solvents such as benzene and toluene, under relatively mild conditions, monoacylation is usually terminated in a range of about 4 to about 72 h to obtain 9-acylainino-hexabidrodihenzopyran compound. For example, the reaction of the compound dl-cis-1-hydroxy-3-ΐί-octyl - 9-amino.-6a, 7, 8, 9, 10, 10a-hexalihydro-6H-dihenzo [b, d] -pyrane with ca. an equivalent of isobutyryl chloride in benzene, in the presence of about one equivalent of a slurry such as, for example, pyridine at about 25 ° C, for about 4 hours, causes mono-alkyne to obtain the compound hf-ris-l-hydroxy- 3-κ-cetyl-9-isobutyramido-6a, 7, 8, 9, 10, fOa-hcxalihydro-CI-I-dibenzo [b, d] -pyran. The 9-acylamino-dibenzo [b, d] -pyrane product is readily isolated by simply diluting the reaction mixture with water and then extracting the product there with a suitable solvent immiscible with water such as diethyl ether, chloroform, dichloromethane or the like. also. Removing the solvent from the extraction, for example by evaporation under reduced pressure, gives the corresponding compound 9-acylamino-dibenzo [b, d] pyran, a compound which can be further purified, if desired, by standard methods such as chromatography and crystallization.

The 9-acyloamino-dibcnzopyran compounds where the acyl group has the formula: CO (CH.) -COOH are useful both as intermediates and as pharmacological substances. The transformation of such compounds into acid halide compounds and the reaction of such acid halides with a strong base such as sodium hydride causes cyclization to produce compounds of the above formula, where R "and R₃ completes the heterocyclic ring. as for example 2,5-dioxopyrrolidine and 2,6-dioxopiperidine.

Complete acylation of 9-amino-9-acylamino-hcxahidrodibenzo / b, dj-pyran compounds causes peracillary. to produce l-acyloxy-9-diacylamino-hcxalihydro-dibenzo [b, d] pyran compounds. Such pyracylation can be carried out by reacting either 9-amino- or 9-acylamino-hexahydro-dibenzo compound | b, Mr. pyran with an excess of acylating agent, for example, dc at about 2 to 10 mol excess, as well as performing the reaction at a high temperature of about 60 to 150C. Peracylation is carried out in the presence of a strong base such as sodium hydride. As an illustration of the peracar, a compound such as, for example, h / -rri-1-hydroxy-3- (2-hexoxy) -9-acetamidc-6a, 7, 8, 9, 10, 1 -a-hexahydrr-6H-dibenzo [b, dj piran can¹ be reacted with an excess of 5 mol dc despropionyl bromide in the presence of sodium hydride

I got about 100^uC, for about 72 l to give i / Z-cis-1-propionoxy-3- (2-hexcnyl) -9- (N-propionyl) -acetamido-6a, 7, 8, 9, 10, 10a -hexahydro-6Ii-dibenzo [b, d] -piran. The triacylated hexahydro-dibenzopyran compounds of this invention can be readily hydrolyzed by reaction with an aqueous solution such as, for example, sodium hydroxide or potassium carbonate to obtain the derivative wtono-acylate compound, namely 9-acylamino-hexahydro-compound. dibenzo [b, dț-piran.

The diacylated compounds of the present invention, for example l-hydroxy-9-N, N-diaciaminohexahydro-fiH-dibenzo [b, d] pyranes, can be prepared by the selective protection of the 1-hydroxy-fcnol group of the 9-acylamido derivative compound and further acylation of the nitrogen atom from the 9-starch group. Cracks suitable for hydroxyl protection include the bands of the benzyl and the lower alkyl. Such groups are readily removed by reaction with sodium thioethylate in a solvent, such as dimethylformamide. For example, C 1 -C 6 -hydroxy-1-3 - "- pentiI-9-acetamido6a, 7, 8,9, 10, 10a-hexalridro-6H-dibenzo [b, d] pyran may be benzylated to group 1. -hydroxy by reaction with a benzyl chloride equivalent. The resulting benzyl ether can be acylated. in the 9-amido group under strong conditions, for example, by the reaction of propionyl bromide and with a strong sodium hydride base. The resulting compound, the diacylated derivative can be desbenzylated by hydrogenation or by sodium thioethylate reaction to give the compound dl-cis1-hydroxy-3-M-pentyl-9- (N-propionyl} -acetamido-6a, 7, 8, 9, 10, 10a-hexahidrc-6H-dibeiizo [b, d] -pyran.

As can be seen, the compounds of the invention which are completely saturated in the ring of carbon atoms and which have no exocyclic bonds, ie compounds having the above formula where Z is

Co R »

It can exist as a spinal cord. For example, when an oxime of the present invention is wholly reduced to yield 9-amino-hexahydro-dibenzo [b, d] pyran, such a compound is typically a mixture of 9 - «// n- derivatives. amino and 9-0cAr-anrino. Separation of the epimeric mixture can be achieved, if desired, by the fractional crystalline c, chromatographic column, gas liquid chromatography, high pressure liquid chromatography and related methods, in general, any separation of isomers is not attempted until the final product is obtained. For example, when it is desired to prepare an optically active amide as, for example.

piu, d or / -fr-i-hydroxy-3- (1,1-dinethylhepfil) -6,6-dimethyl-9 alpha or 9 beta-acetamide-6a, 7, 8, 9, 10, 10a-hexahyldiO -6H-dibenzo [b, dj-pyran, it is preferable to first prepare the oxime corresponding to the compound d- or Z- / dayZKS-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl- 6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, d] -pyran-9 ~, optically active. The following oxime is completely reduced to obtain an epimeric mixture of rf- or Z- / r- "-hydroxy-3- (1,1-dimethylheptyl) -6,6-dnnetyl-9-amino-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo [b, dj-pyran. The epimeric amines are then acylated, for example, by reaction with acetic anhydride to obtain an epimeric mixture of the corresponding acetamidchlor. Separation of the acetamides thus formed gives the compound d- or Z- fra? -Hydroxy-3- (II-dimethylheptyl) 6,6-dimethyl-9 alpha. (; i 9 ir #) - acetamido-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo fb, d] pyran, optically active. Such optically active compounds are preferably referred to, using the currently acceptable rules of the nomenclature regarding absolute stereochemical configuration, and thus introduces the terminology R and S as suggested by Fîetcher / Nomenclator e of Organic Comfonnds, Advauces in Chemistry Series, 126, American Accordingly, a typical optically active compound of this invention would therefore be called 6aR, 9R, lOaR - 6a, IOa- / Co "sl-hydroxy-3- (l, l-dtmeti] heptyl) -6,6-dimethyl-9-acetamido-6a,

7, 8, 9, 10, 10a-hcxahydro-6H-dibenzo [b, d] pyran.

The 9-amino-dibenzo [b, d] pyran derivatives defined by the general formula above are novel chemical compounds having useful pharmacological activity and, in addition, many compounds are used as intermediates in the synthesis of pharmacologically active compounds. The pharmaceutical compositions contain at least one biologically active compound, obtained according to the invention, in combination with one or more carriers or excipients thereof. Further, other pharmacologically active substances may be incorporated into the composition containing an active ingredient. A particularly preferred pharmaceutical composition is useful in the treatment of hypertension.

Thus, 25 mg of dl-trans- 1 -hydroxy-3- (1,2-dimethylcptyl) -6,6-dimethyl-9- (N-methyl) -acetamido-6a, 7, 8, 9, 10 is dissolved 10a-hexahydro-6H-dibenzo fb, d] -pyrane, in 250 ml of aqueous solution of chloride dc, 0.9%, yielding a solution H of 6 to 7.

A suitable aqueous suspension for oral administration is prepared by mixing 10 mg of the finely divided compound, dl4ransA-hydroxy-3- (1-ethyl-2-hexcnyl) -9-hydroxyinrino-6a, 7, 8, 9, 10, 10a-hexahidiOxi-6H-dibenzo fb, d] pyran with 500 mg dc acacia gum,

8t237 mg sodium benzoate, 1.0 g sorbitol solution, 5 mg sodium saccharin and 0.025 ml dc vanilla tincture.

The compositions present a form that slightly favors the particular route of administration desired for each particular case.

For oral administration, the compound of the present invention is mixed with carriers and diluents such as dextrose, lactose, mannitol, cocoa butter, dc ethyl lactate, methyl cellulose, calcium silicate, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, potassium benzoate and excipients. Such compositions may be prepared as dc tablets or may be introduced into gelatin capsules. The mixtures may alternatively be dissolved in liquids, such as 10% aqueous glucose solution, physiological serum, sterilized water or the like and administered as an intravenous injection. Such solutions can, if necessary, be lyophilized and stored in sterile vials, ready for transformation into solution by adding sterilized water.

.0 A particularly preferred composition useful for treating hypertension in human beings contains a compound, for example, dl-trans-1-hydroxy-3- (1, i-dimethyl-hexahydro-6H-dibenzo [b, d] - pyran, in an amount of about 0.01 mg to about 1.0 mg in combination with a carrier such as, for example, sucrose or starch in the amount of 500 mg. Such compositions can be transformed into tablets that can be administered to a patient, suffering from high blood pressure, in a dose of about I to 4 tablets per day.

As already emphasized, the compounds obtained according to the present invention have a variety of uses. Representative compounds of the present invention have demonstrated activity in one or more assays designed to indicate analgesic, antiglaucoma, antidepressant and anti-anxiety activity. For example, dl-lrans-1-hydroxy-3- (1,1-dimethylheptyl) -9-hydroxy imino-6a, 7, 8, 9, 10, 10a-hexahydro-6H.dibenzo fb, d | piran, showed an ED_3U (- effective dose for 50 mice) of 2 mg / kg body weight, in analgesic activity, when tested subcutaneously, in the sample of seizures in mice. Similarly, the compound dl-tert-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxianrino-6a, 7, fi, 9, IO, 10a-hcxahydro- 6I-dibenzo [b, d] pyran caused a reaction in mouse behavior at a minimum effective dose (MED) of only 5.0 mg / kg body weight. Moreover, when sc tests through the rat septal lesion sample, the compound dl-trans - \ - hydroxy-3- (1,1is

-dimethylheptyl) -6,6-diamethyl-9-ae-me-do-6a, 7, 8, 9, IO, 10-hexahydro-6H-dibenzo fb, pyran dj, administered intravenously, demonstrates a minimal effective dose (MED) 0.5 pg / kg body weight.

As sc can see from the above exposure regarding biological activity, many of the compounds of the present invention are useful in the treatment of hypertension, anxiety, glaucoma pain and related diseases. The compounds can also be used to treat animals and people suffering from the same diseases. There is a method of treating hypertension in mammals. administering an effective dose for the treatment of hypertension, of a hypertensive compound, active, of the present invention, to a being suffering from hypertension and how he needs treatment or a being suspected of having hypertension and who needs prophylactic treatment. A special preferred method of treating stress is the administration of a compound of the invention having an amide moiety at position 9 (ie 1% is alkanoyl C)._t - C.).

The active hypertensive compounds of the present invention can be administered by any of the routes, including, oral, subcutaneous, intramuscular and intravenous. The usual doses useful for the treatment of people, will of course vary, depending on the particular disease of the being treated, the size and age of the patient, but will usually vary from about 0.001 to about 20 mg total daily dose, for each patient . Preferred daily doses commonly used when treating hypertension, for example, will vary from about 0.1 to 10 mg per patient. Common treatment for hypertension will include, for example, administering a patient of approximately 5 ings per day of the compound r / Z -! - hydroxy-3- (1,2-dimethylheptyl) -9- (2,6-dioxopiperidino) - 6a, 7, fi, 9, 10, 10a-hcxalihydro-6H-di · ben / o fb, d] pyran. A preferred treatment consists of administering about 2 mg pc daily of the compound dl-trans-1-hydroxy-3- (1,1-dimethylheptylj-hp-diaethyl-O-acetainido -6a, 7, 8, 9, 10, 10a -hexahidiO-6H-dibenzo [b, d] pyran.

The process, according to the invention, therefore has the advantage of obtaining compounds with important pharmacological properties.