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

¢ 54) Process for the preparation of 9-iminodibenzopyran derivatives

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

R₃

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(II)

N

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OH

I'm X

Wherein R 1 represents alkyl radical of 5-10 carbon atoms, alkenyl 5-10 carbon atoms, Ra represents hydrogen atom or methyl radical, R> represents hydroxy or alkoxy with 1 ... 4 carbon atoms, analgesic and antidepressant substances.

Procedures for the preparation of aminodibenzo [b, d] pyranes are known, used as analgesic, antidepressant and tranquilizers (Offenlegungsschrift, no. 2437135).

The process according to the invention broadens the range of aminodibenzo [b, d] pyran derivatives in that a pyranon derivative of general formula II:

is treated with an amine of general formula III:

h₂n-r₃ (iu) wherein Ri, Ra and R3 have the above meanings, in approximately equimolar amounts, in the presence of NaOH, in a solvent selected from methanol, ethanol or their mixture, at reflux temperature, after which the obtained compounds can be transformed into pharmaceutically acceptable acid addition salts.

The following are 4 examples of the process according to the invention.

Example 1. Preparation of dl-trans-1-hydroxy-3 - (1,1-dimethylheptyl) -6,6-aimethyl-9-hydroxyimino-6a-7,8,9,10,10a-hexahydro-6H-dibenzo [ b, d] pira nuiui

A 4.0 g solution of dl-trans -1- hydroxy -3- (1,1- dimethylheptyl) -6,6- dimethyl -6a, 7,8,9,10, 10a-hexahydro-6Hdibenzo [b, d] pyran -3- one and 1.155 g of

PRICE OF LEI 13.43 hydroxylamine hydrochloride, dissolved in 60 ml ethanol and 10 ml water, was stirred while 4.4 ml of sodium hydroxide 5 Ν were added with stirring. The reaction mixture was then heated to reflux and stirred at this temperature for 30 min. After cooling the reaction mixture to room temperature, up to 100 g of ice was added, then acidified to pH = 2.5 by the addition of concentrated hydrochloric acid. The aqueous acid reaction mixture was then extracted several times with diethyl ether. The ethereal extracts were combined, washed with sodium bicarbonate solution 5 ° / o ȘI with water, and then anhydrized. Removal of the solvent by evaporation under reduced pressure gave 2.0 g of the product as an oil. The oil was crystallized from 50 ml of n-hexane to give 3.8 g of dl-trans-1-hydrox y-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyimino-6a compound , 7, 8, 9, 10,

10a- hexahydro-6H- dibenzo [b, d] pyran as a white powder, m.p. 143-145 ° C.

Analysis for Ca + îVNGs, in%:

- calculated; C, 74.38; H, 9.62;

N, 3.61;

- found; C, 74.61; H &lt;= 9.37; N, 3.78;

m / e; calculated: 387; found; 387. The process was repeated using 7.5 g of optically active (-) -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl6a, 7, 8, 9, 10, 10a -hexahydro -6H- dibenzo [b, d] pyran -9- as starting ketone. The isolation of the product was done as shown above and gave 5 g as oil;

m / e; calculated: 387; found: 387.

, .CHCb ", CHCb -4.0; /« / 3Q5 = + 34.6 °

Chromatographic purification of a sample from such a product, using the chromatographic process. liquid under high pressure, resulted in the separation of the sin and anion isomers of the optically active oxime.

Sih-trans-I-hydroxy-3- (1,1-dimethylheptyl) -6,6- dimethyl -9- hydroxyimino -6a, 7,8,9,10, 10a - hexahydro-6H- dibenzo [b, d ] piran;

= +³⁴’⁸° ^; ^/?65^cb -^: +¹³⁷’³ '·

Anti-French-1-hydroxy-3 - (1,1-dimethylheptyl) -6; ύ- dimethyl -9- hydroxyimino -6a, 7,8,9,10,10a-hexahydro-6H- dibenzo [b, d ] = -26.8 °; / «/

chloroform

365

-71,9°.

Example 2. Preparation of dl-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6- dimethyl-9-hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [ b, of the pyron

To a stirred solution of 2.0 g of dltrans -1- hydroxy -3- (1,2-dimethylheptyl) 6,6-dimethyl -6a, 7,8,9,10,10a-hexahydro-6Hdi-benzo [ b, d] pyran-9-one in 40 ml of ethanol, containing 10 ml of water, 560 mg of hydroxylamine hydrochloride was added, followed by the addition of 2 ml of 5 N sodium hydroxide. The reaction mixture was heated to at reflux and was stirred for 90 min. The reaction mixture was cooled and the ethanol was evaporated off. The aqueous layer was extracted with diethyl ether and the etheric extracts were combined, washed with water and then anhydrized. Evaporation removal, under reduced pressure, gives 2.3 g of product as an oil. The oil was purified by chromatography over 100 g of silica gel, eluting with diethyl ether. Similar fractions were collected and the solvent was evaporated to give 1.46 g of dl-trans -1- hydroxy -3- (1,2-dimethylheptyl) -6,6- dimethyl9-hydroxyimino -6a, 7 , 8,9,10,10a- hexahydro6H-dibenzo [b, d] pyran.

Analysis for CmH »NOj, in%:

- calculated: C - 74.38; H, 9.62; N, 3.61;

- found; C, 74.13; H = 9.50 N =.

3,39.

m / e; calculated: 387; found: 387.

Example 3. Preparation of dl-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl -9- hydroxyimino-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo jb , of the pyron

Following the procedure set forth in Example 2, 7.44 g of C 1 -C 1 -hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10, lOa were reacted. -hexahydro -6H- dibenzo [b, d] pyran -9- one with 2.1 g hydroxylamine hydrochloride and 8 ml of 5N sodium hydroxide solution, in 100 ral ethanol containing 25 ml water. Normal processing resulted in a horse slag crystallized from 75 ml of hexane to give 7.43 g of d-1-cis-hb droxy-3- (1,1-dimethylheptyl) -6.6-dimethyl9- compound. hydroxyimino -6a, 7, 8, 9, 10, lOa-hexahydro -6H- dibenzo [b, d] pyran. Melting point 162 ... 164 ° C.

Analysis for Cr.HuNCă, in%:

calculated: C, = 74.38; H, 9.62; N, 3.61;

- Found: C, 74.56; H, 9.41; N, 3.78.

Example 4. Preparation of 6aR, lOaRtrans -1- hydroxy-3- (1, l-dimethylheptyl) -6,6dimethyl -9R- (and 9S) -acetamido -6a, 7, 8, 9, 10, 10a - hexahydro-6H - dibenzo [b, d] pyran pyron:

. .CHCb / «/_D

Following the general procedure shown in Example 1, the compound in the amount of 7.5 g of 6aR, 1,0aR -trans- 1-hydroxy -3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7, 8, 9, 10 , 1 O-hexahydro-6H- [bd] pyran -9-one, was 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, lOaR -trans- 1 -hydroxy-3- (1,1-dimethylheptyl) -6. , 6- dimethyl -9R (and 9S) -amino -6a, 7, 8, 9, 10. 10a-hexahydro-6H-dibenzo [b, d] pyran. A solution of the latter compound, in 30 ml of methanol containing 10 ml of triethylamine, 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 10 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, 1000 ml of methanol 0.5® / e, in chloroform and finally with 2000 ml of methanol l® /₀ in chloroform. Fractions containing each 20 ml were collected. The fractions which showed, by thin layer chromatographic analysis, that they were composed of a component, were combined and the solvent was removed by evaporation under reduced pressure to obtain 287 mg of compound 6a'R, lOaRtrans-1 -hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl -9R- acetamido -6a, 7, 8, 9, 10, 10a-hexabydro -6H- dibenzo [b, d] pyran.

The analysis for CmIIjiNOî, in%:

- calculated: C = 75.14; H, 9.94;

N, 3.37;

- Found: C, 75.32; H, 9.77; N, 3.12.

m / e: calculated: 415; found 415.

Further chromatographic separation yielded fractions containing 591 mg of compound 6aR, lOaR-trans- 1-hydroxy -3- (1,1-dimethylheptyl) -6,6- dimethyl -9S- acetamido -6a, 7, 8.9, 10,10a-hexahydro-6H- dibenzo [b, d] pyran.

Analysis for C20II41NO3, in%:

- calculated: C = 75.14; H, 9.94;

N, 3.37.

- Found: C - 74.91; H, 9.99; N * = 3.18;

m / e: calculated '; 415; found: 415.

. .CHCb _ ""_no . , chloroform

1^Ά1Y) 64.9 tA / day - - 236.5,

The non-toxic, pharmaceutically acceptable salts of the compounds of formula I are salts that do not add substantial toxicity to the initial amine and, consequently, can be pharmaceutically used in a similar manner to the free amine bases. Acid addition salts are prepared by processes known as, for example, the reaction of the basic amine with an organic or inorganic acid. Acids commonly used to form non-toxic, pharmaceutically acceptable acid addition salts include mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric acid as well as sulfamic, nitric and nitric acid. Typical, commonly used organic acids include acetic, oxalic, lactic, ascorbic, maleic, fumaric, succinic ptoluensulfonic, benzoic, methanesulfonic, adipic and the like. The compounds of formula II introduced into the reaction may be: - 1-hydroxy-3- n.-pentyl-6,6-dimethyl-6,6a, 7,8,9,10, 1 O-hexahydro-9H-dibenzo [b, d] pyran-9-one;

- 1-hydroxy-3- n-octyl-6,6-dlmethyl-6,6, 6a, 7, 8, 10, 1 Oa-hexahydro -9H- dibenzo [b, d] pyran -9-one;

- 1-hydroxy-3- (1,2-dimethylheptyl)

6, 6a, 7, 8, 10 1 Oa-hexahydro -9H- dibenzo [ta, d] pyran -9-one;

- 1-hydroxy-3- (1,2-dimethyl -1-heptenyl) -6,6- dimethyl -6,6,6a, 7,8, 10 -hexahydro-9H-dibenzo [b, d] pyran -9one;

- 1-hydroxy -3- (1-ethylhexyl) -6,6- dimethyl -6,6a, 7,8,8, 10a-hexahydro -9Hdibenzo [b, d] pyran -9-one;

- 1-hydroxy-3- (1,1-dimethylheptyl) -6, 6a, 7, 8, 10, 1 O-hexahydro-9H- dibenzo [b, d] pyran -9-one;

- 1-hydroxy-3- (1,2,3-trimethyl -2pentenyl) -6,6- dimethyl-6,6, 7, 8, 10, 10-hexahydro-8H- dibenzo [b, d] pyran-9-one and related compounds.

It will be recognized that, since the ketones of general formula II are dibenzo [b, d] pyranes, which are completely saturated in the carbon ring, stereochemical isomers at carbon atoms 6a and 10a exist.

Specifically, the starting ketones and, consequently, the pyran 9-amino-dibenzo [bd] compounds of general formula I may exist as cis deletions at position 6a, 10a and as trans deletions at position 6a, 10a. Each of these spillovers constitutes a racemic mixture or a pair of Mr. (dextrogir levogir). For example, the derivative 6a, lOa-cis can have both the hydrogen atom at, 6a, and the hydrogen atom at 10a,

Ί .oriented above the plane of the ring or, in. alternatively, both hydrogen atoms may be oriented under the plane of the ring. These two isomers form a cis-dl raeemic 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 under the plane or, alternatively, the hydrogen atom at, 6a be oriented below the plane of the ring, and the hydrogen atom at, 10a be oriented above. These two isomers constitute a trans-dl pair mixture.

Normally, the preparation of the compounds according to the present invention comprises the use of a racemic mixture of either 6a, 10a-cis-hexahydrodibenzo [b, d] pyranone, i.e. a dl-cis isomer or, alternatively, a racemic mixture of the 6a, 10a- isomer. ircms i.e. dZ-trcms-hexahydrobenzo [b, d] pyranone. It should be noted, however, that the compounds of the present invention can also be obtained from an optically active d-cis or l-cis ketone or a d-trans or l-trans ketone, thereby giving the compound 9-iminodibenzo [b , d] corresponding pyran, having the same stereochemical integrity as it and the starting ketone. Since all of the individual stereochemical isomers at positions 6a and 10a appear to possess useful pharmacological activity, it is often preferable to use as a starting material a mixture of dl-cis and dl-trans-hexahydro-dibenzo. [b, d] piran -9- one. In particular, it is advisable to use such racemic mixtures, as they are readily available synthetically. Examples of such preferred starting materials include:

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

- dZ-trans -1- hydroxy -3- (n-octyl) 6,6-dimethyl -6, 6a, 7, 8, 10, 1-hexahydro-9H-dibenzo [b, d] pyran-9-one;

- dl-cis -1- hydroxy -3- (re-decyl) -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, 9, 10 10a-hexahydro-9H- dibenzo [b, d] pyran-9-one;

- dl-cis -1- hydroxy-3- (1,2-dimethylhexyl) 6,6-dimethyl-6,6, 7a, 8, 10, 10a-hexahydro-9H-dibenzo [b, d] pyran-9- one.

As noted above, oximes and alkoxy-oximes of general formula I (for example, where R 1 is hydroxy or alkoxys with 1 ... 4 carbon atoms) can be prepared by reacting hexahydro-dibenzo [b, d] pyran- 9-one with hydroxylamine or alkoxyamine as per s

for example, methoxyamine and ethoxyamine. Such amines are generally available as an acid addition salt and may be used by adding a base to the reaction mixture to release the free amine in situ or by neutralizing the salt before using the free amine in the reaction. In the preparation of oximes and O^_of the alkyl oximes of the present invention, the dibenzo [b, d] -pyran-9-one compound and hydroxy lamina or alkoxyamine are typically reacted in approximate equimolar amounts, and the reaction is best conducted in a solvent common to those two substances such as, for example, methanol, ethanol, water or a mixture of such solvents, in general, the reaction is substantially complete after about 0.5 to 4 hours, when carried out at a temperature of about 25 to about about 100 ° C. The oxime or O-alkyl oxime product is conveniently isolated by simply diluting the reaction mixture with water or aqueous acid and extracting the oxime with a water-immiscible solvent, such as, for example, diethyl ether, benzene, chloroform, dichloromethane, acetate. ethyl and the like. Evaporation of the solvent from the organic extracts normally leaves behind the oxime product as an oil or solid, which in general can then be crystallized, if desired, from solvents such as, for example, n-hexane and petroleum ether. . Examples of oxime derivatives thus prepared include:

- 1-hydroxy-3-n-pentyl-6,6-dimethyl9-hydroxyimino -6a, 6, 8, 9 L -a-hexahydro-6H-dibenzo [b, d] pyran;

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

- dl-trans -1- hydroxy -3- (1,2-dimethylheptyl) -9-ethoxyimino-6a, 7, 8, 9, 10, lOa-hexahydro-6H- dibenzo_ [b, d] pyran;

- dl-cis -1- hydroxy -3- (1,1- dimethyloctyl) -6,6- dimethyl -9- isobutoxyimino-6a, 8, 9, 10, lOa-hexahydro-6H- dibenzo [b, d] - pyran.

The oxime derivatives, thus formed, are useful as pharmacological substances, apart from the fact that they are valuable as intermediates. For example, reducing such compounds provides hydroxyamines and alkoxyamines derivatives. In addition, the hydroxyimine compounds may be O-alkylated with C 1 -C 4 alkylating agents, such as isobutyl bromide, to produce the corresponding 9-alkoxyimino-dibenzo [b, d] pyran compounds. Furthermore, normal acylation of hydroxyimino compounds, for example, by reaction with an acylating agent, carboxylic acid C1, C7, produces the corresponding imino-hexahydrodibenzopyran derivatives.

70886

The present 9-imino-clibenzo [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 compounds. pharmacologically active. The pharmaceutical compositions containing at least one biologically active compound, obtained according to the present invention, in combination with one or more diluents are carriers or excipients thereof. Furthermore, other pharmacologically active substances may be incorporated into the composition, containing an active ingredient. A preferred pharmaceutical composition according to the present invention is useful in the treatment of hypertension. Preferred compositions are those containing the derivative 9-amido compound as active ingredient.

The compositions have a form which slightly favors the particular route of administration desired for each particular case. For oral administration, the compound obtained according to the present invention is mixed with carriers and diluents such as, for example, dextrose, lactose, mannitol, coconut butter, ethyl lactate , methyl cellulose, calcium silicate, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, potassium benzoate and related excipients. Such compositions may be prepared in tablet form or may be introduced into gelatin capsules. The mixtures may alternatively be dissolved in liquids such as, for example, 10% aqueous glucose solution, physiological serum, sterilized water or the like, and administered as intravenous injections. Such solutions can, if necessary, be lyophilized and stored in sterile vials, ready for transformation into solution by adding sterilized water. A preferred composition, useful for treating hypertension in human beings, contains a compound such as, for example, dl-trans -1- hydroxy3- (1,1-dimethyl-hexahydro) -6H-dibenzo [b, d] pyran, in an amount of from about 0.01 to about 1.0 mg, in combination with a carrier such as, for example, sucrose or starch, in an amount of 500 mg. Such compositions can be transformed into tablets that can be administered to a patient with hypertension, at a dose of about 1 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-depressant activity. anxiety.

For example, compound dl-trans -1- hydroxy -3- (1,1-dimethylheptyl) -9- hydroxyimino -6a, 7, 8, 9, 10, 10a-hexahydro-6Hdibenzo [b, d] pyran showed DEso (= 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, compound dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6- dimethyl -9- hydroxyimino -6a, 7, 8, 9, 10, 1-hexahydro-6H- dibenzo [b , d] pyran caused a reaction in mouse behavior at a minimum effective dose (DME) of only 5.0 mg / kg body weight. Moreover, when tested, by the sample of rat septal lesion, the compound dl-trans -1-hydroxy -3- (1,1-dimethylheptyl) -6,6- dimethyl -9-acetamido -6a, 7, 8, 9 , 10, IVO-hexahydro-6H- dibenzo [b, d] pyran, administered intravenously, demonstrates a minimum effective dose (DME) of 0.5 μg / kg body weight. Many of the compounds obtained according to the present invention are useful in the treatment of hypertension, anxiety and related diseases. The compounds can thus be used for testing animals and people suffering from the same diseases. For the treatment of hypertension in mammals, an effective dose is administered for the treatment of hypertension, of a hypotensive, active compound, a being suffering from hypertension and who needs treatment or a being suspected of having hypertension and who needs prophylactic treatment. The active hypotensive compounds of the present invention may be administered by any of the routes, including the oral, subcutaneous, intramuscular and intravenous routes. The usual doses, useful for the treatment of people, will of course vary, depending on the particular disease of the treated being, the size and age of the patient, but will usually vary from about 0.001 to about 20 mg daily total dose for each patient. Preferred daily dosages commonly used when treating hypertension will vary, for example, from about 0.1 to 10 mg per patient.

A suitable aqueous suspension for oral administration is prepared by mixing 10 mg of compound, finely divided, dl-trans-1-hydroxy-3- (1-ethyl -2-hexenyl) -9-hydroxyimino-6a, 7, 8, 9, 10, lOa-hexahydroxy6H- dibenzo [b, d] pyran with 500 mg acaca gum, 5 mg sodium benzoate, 1.0 g sorbitol solution, 5 mg sodium saccharin and 0.025 ml vanilla tincture.

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