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:

/^Z\

OR, (I)

FU

- | \ r₃ \ z

Ts!

wherein R 1 represents an alkanoyl radical 15 with 1 to 4 carbon atoms, Fb represents an alkyl radical with 5-10 carbon atoms or an alkenyl radical with 5-10 carbon atoms, R 1 represents an atom of hydrogen or a methyl and Z radio is 20 selected from a group:

used in analgesic, antidepressant and anti-anxiety medicines.

Processes for the preparation of some dibenzopyranes, used as analgesics and antidepressants, are known, for example, di-irans-1-hydroxy - 3 - (1,1-dimethylheptyl) - 6,6 - dimethyl - 6,6a, 7, 8.10, 10a-hexahid.ro - 9H - di.benzo- (b, d) -plran9-one (Patents, US, No. 3928598; 3944673; 3953603).

Also known are processes for the preparation of dibenzopyran substituted with amino group or with heterocyclyl with nitrogen (US Pat. No. 3886184; 8878219; 3888946).

The process according to the invention broadens the range of aminodibenzopyran derivatives by. that a compound of the formula, gen eral II:

R₄

I

N II | I CR,^(II) \chain link ^R\ l 11 I / vvk

Rî R₅ \ z

No.1

Z \

And

Rs Rî \ z

N

I

Z \

<img file="RO82369A_D0001.tif" />

wherein Rs and Rs represent a C 1-4 alkanoyl radical, 4 carbon atoms, com 82369

LAW PRICE 13.49 ί

wherein H- is hydrogen, R? and R3 have the aforementioned meanings and Rt is hydroxy fluoride, reacts with anhydride of lower alkanoic acid and pyridine, under nitrogen atmosphere, at reflux temperature, for 24 hours, to prepare the compound, with the general formula I , and, if desired, the optical isomers and epimers are isolated and the compounds of formula I are isolated, on 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. Preparation of dl-trans-1-acetoxy-3- (1,1-dimethylheptyl-6,6-dimethyl-9-N, N-diacetylamino) -6a, 6,10,10atetrahydro-611-dibenzolb, d] pyran

A 2.59 g solution of di-trans-1-hydroxy-3- (1,1-di-methylheptiyl) -6,6-dimethyl-9-hydroxyimino-Ga, 7,8,9,10, 10a-hexahydro-6H - dibenzo [b, d] ph'ao in 25 ml of acetic anhydride and 75 ml of pyridine, was stirred under nitrogen and heated at reflux for 24 h. After cooling the reaction mixture to room temperature To the camshaft, the solvent was removed by evaporation under reduced pressure to obtain an oily residue. The residue was dissolved in 50 ml of diethyl ether and 50 thousand water and stirred for one hour. The mixture was filtered and the organic layer was separated. The ethereal solution was washed with 1 N hydrochloric acid, water, saturated sodium chloride solution and anhydrized. Removal of the solvent gave 3.57 g of a dark color oil which was then chromatographed on a column with 100 g of silica gel with a 50% diethyl hexane-ether mixture. Fractions containing the major fraction were combined and concentrated to the fullness to give 3.20 g of predominant compound, dl-trans1-acetoxy - 3 - (l, l-dimethylheptif) -6,6-dimethyl - 9 - (N , N-di, methylammO) -6a, 7.10, lOa-tetrahydro-6H-di, benzo- [b, d] -pijran, with a minor amount of / \⁹ compound.

M / s analysis: calculated 497; found 497.

Example 2. Preparation of dl-trans-1-hydroxy-3-fl, 1-dimethylheptyl) -6,6-dimethyl9- (acetamido) -6a, 7,1.0,10a-tetrahydro-6H-dibenzo - [b, d] -pyrrane

A solution of 5.4 g of dltrans - 1 - aceliOxi-g-ill-diimeJihTeJiJti was prepared¹) 6,6-diimetU-9 - (N, N-diacetylamino) -6a, 7,10,10a-tcbrahydro 6H - dibenzo [b, d] pyran in 150 ml methanol containing 50 ml of potassium carbonate solution 20 N.

The reaction mixture was stirred at 24³C, for 2 h, then concentrated to dryness by evaporation under reduced pressure. The oil thus formed was suspended in 100 ml of water, and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were combined, diluted with 20 ml of ebyl acetate and then washed with 2N hydrochloric acid, aqueous 10% sodium bicarbonate solution and anhydrous. Removal of the solvent afforded 1.54 g of the solid which was then crystallized from hexane to give 1.33 g of dctrans-1-hydroxy-3- (1,1-dimethylhopthyl) 6,6-dimethyl-9 compound. - (acetamides-Ga, 7,10,10atetrahydro - 6H - [b, d] pyran. Melting point 186 - 188 ° C.

Analysis of the penitentiary C ^ HnNCh, in%:

- calculated: C, 73.81; H, 9.07;

N, 3.07; O = 14.05;

Found: C, 73.74; H, 8.79;

N, 3.16; O = 13.90.

m / o: calculated 413; found 413.

Example 3. Preparation 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

A solution of 1,177 g of compound cii-1hydroxy - 3 - (1,1-dimethylheptill) - 6,6dime-thiyl - 9 - (acetamido) - 6a, 7,10,10atetrahydro - 6H - diibenzo- [b, d] - pyran in 100 ml 10% aqueous ethanol, containing 0.5 g palladium, suspended on coal, 5%, was stirred at 50³C, for 12 hours, under a hydrogen atmosphere at a pressure of 3.5 at. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated to dryness by evaporation under reduced pressure to give 1.06 g of d-irans-1-hydroxy-3- (1,1-dimethylhoptiyl) -6,6-dimethyl-9- (acatamido) - 6a, 7,8,9,10, 10a - hexahydro-6H-diben, zo- [b, d] -pyran.

In the compounds of formula I, prepared according to the examples above, the term "C 1 -C 6 alkanoyl" refers to an acyl radical of an oarboxylic acid having from 1 to 4 carbon atoms. Examples of such groups of affluanoyl C1-C1 include formyl, acetyl, propyl, n-butyryl and isobutyryl.

R 'is defined as a Cs-C10 alkyl group and a Cs-C10 alkenyl group. Examples of "C 1-6 alkyl groups" include both straight and branched alkyl groups such as, for example, "-pentyl, u-hepbiyl-, 7-hexyl, π-heptyl, 1,1-di methylheptyl, 1,2-dimethyl.hepfcil, 1-ethylethyl, 1,1-diimethylcetyl, 1,2,3-tnymethylheptyl, 1-propylhexyl, isoethyl, n-decyl and the like82369; The term "Cs-Cn alkenyl" similarly refers to "straight and branched alkenyl chains," which include 2 pihenylenyl. 3-hexenyl, 5-heptenyl, 1,1-dimethyl-2-heptcnyl, 1,2-diamethyl-1-heptenyl, 2,3-dimethyl-2-heptenyl, 1-ethyl-2-octenyl, 2-ethyl-heptenyl , .2-deceryl, 1-nonenyl, 1-ketyl 1-1-alkyl groups and related alkenyl groups.

. ; Compounds obtained, first the process according to. of the invention, are of a basic nature and • readily form acid addition salts and quaternary ammonium salts. For example, 5-amino; 9-alkyl'jamimo- or 9-dialch-il. amino-'dibenzo - [- b, d] pi'pan, may exist in the form ·, free base or, alternatively, salt.

... Toxic salts, pharmaceutically acceptable, 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. The acid addition salts are prepared by standard procedures, such as, for example. reaction of basic amine with an organic or inorganic acid. Acids commonly used to form pharmaceutically acceptable non-toxic acid addition salts, include mineral acids, such as, for example,; hydrochloric acid, hydrobromic, sulfuric acid, ·. phosphoric as well as -a'dul sulphamia, nitrate and nitric acid. Typical organic acids usable include acetic acid, oxalie, lactic acid, ascorbic acid, maleic acid, fumaric acid, succinic acid, p-toluene sulphate, benzoic, methanesulfonic acid, adipose and the like.

Similarly, basic amines, are tertiary amines · readily form quaternary ammonium salts which are also pharmaceutically acceptable. Such tertiary amines are quaternized by reaction with an alkylating agent, such as, for example, methyl iodide, ethyl bromide, n -butyl chloride, isobutyl iodide, allyl bromide, dimethylsulfate and the like. . • '. 9-am'oo-dibe compounds (nzo [bd] loaves of general uiln form (I), - there may be one cis isomers at position 6a, 10a and as trans isomers at position' 6a, '10a.' Each of these isomers constitutes a racemic mixture or a pair of ds (dsxtro & ir, levop / r). D (> for example, the derivative 6a, lOa-cis may-, have both the hydrogen atom at Ga, as well as 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. The same two isomers form a racemic cis-dl mixture. Similarly, the trans isomer 6a, 10a may be a compound, wherein the hydrogen atom at the daughter is above the plane of the ring, in. while the hydrogen atom at 10a is oriented. sui.) piano or alternatively the hydrogen atom at Ta is oriented below the plane, the ring and the hydrogen atom is • 10a oriented above. Again, these two isomers are a trans-dl pair mixture.

In the normal embodiment, the preparation of compounds of general formula I comprises the use of a racemic mixture of either phia, Oa-cis-hexahydrodibenzo - [b, d] pyranone, i.e., a dl-cis isomer, or alternatively a raoemic mixture of the isomer. Ga, lOa-trcms, ie di-treacle-hexate], hydrobenzo [b, dipsyranone. It should be noted, however, that compounds of general formula I may also be obtained from an optically active ketone d-cis or l-cis or a d-trans or l-trans ketone, thereby giving compound 9-. corresponding ami, no-dibenzol [ib, d] -pyrane. having the same stereochemical integrity as the starting ketone. .

Examples of oxime of formula II include:

- Hydroxy-3-n-pentiyl-6,6-dimethyl-9-hydroxy-1,in-6a, 6,8,9,10a-hexahid.ro-6H-cliben.zo [, b, d] pyran;

- 1-Hydroxyl - 3. - (1,2-Dimethyl-2-pentenyl) -9-methoxyimnio-6a, 7,8,9,10,10a dro-fi H-dibenzo {| b, d]; pyran ;

- di-tran? - 1-Hydroxy-3- (1,2-dimethylheptyl) -9-ethoxyImino-6a, 7,8,9,10,10ahexaKdro-6H-dibenzo [b, d] pyran and - di- cis-1-Hixyroxy-3- (1,1-dimethylocytl) -6,6-dimethyl-9-isobutoxyliimino6a, 8,9,10,10a-hexahydro-6H-dibenzo [b, d) pyran.

According to the invention, an oxime such as, for example, 1-hldnoxy-3-isohexyl-9-lihydroxyimino-phia, 7,8,9,10,10a-hexahydro6H-dAben2o [b, d] pyran, is reacted with any of the many acylating agents commonly used, for example, C 1 -C 6 -alanoanoyl halides? or (C 1 -C 10) -phenyl halogenide, to sit. obtains an acylated oxime, specifically the compound -hydroxy-3-isohexylȚ-acyloxyloimlino-6a, 7,8,9,10,10a-hexahydro-6H-dibe.nzo [ib, d} pyran. Acylation in the continuation of such compound 9 - ^ oiloxiimi'no derivative results in the compound tetrahydro-dibenzopyran triacylate - which appears to be the Δ isomer.⁸ Predominantly, namely: l-a; I-oxy-3-substituted-9-diac ILylamiiw-Ga, 7,10,10a-te-, tetrahydro-6H - dibenzo [b, d] pyran. The gentle hydrolysis of such a tr.i • acyl derivative determines the removal of the 1-acyl group and one of the allyl groups takes the position 9-amiino, to obtain compound 9 - allylaminoAebrahydro-dibenzopyran of this invention.

The 9-aminiodiibenzo [.b, d] pinan derivatives, defined by the general formula above, are compounds of chemistry having a pharmacologically useful acti232369 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 process of the present invention, in combination egg one or m, of many diluents, carriers or excipients thereof. Further, other pharmacologically active substances may be incorporated into the composition containing an additive ingredient. A particularly preferred pharmaceutical composition is the use in the treatment of hypertension.

Thus, 25 mg of di-trans-1-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethite-9- (N-ethyl) -®-ketamido6a, 7.8,9 are dissolved. , 10,10a-hexahydro-6H - dibenzo- [b, d] -pyrane, in 250 ml of 0.9% aqueous sodium chloride solution and bringing the pH of the solution between G and 7.

A suitable aqueous suspension for oral administration is prepared by mixing 10 mg of compound, finely divided, dlirans-1-hydroxy: - 3 - (1-ethyl-2-hexenyl) 9-hydroxyim.ino-Ga, 7.8,9 , 10,10a - hexahydroxy - GH - ddbenzo [b, d) pyran egg 500 mg of acaoia gum, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, 5 mg of sodium saccharin and 0.025 ml of vanilla tincture.

The compositions have 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, for example, dextrose, lactose, mannitol, cocoa butter, ethyl lactate, mietiyl oeululose, potassium silicate, potato amdian, microcrystalline cellulose, polyvinyl chloride. -pltroiliidone, 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 one or more liquids, for example, 10% aqueous glucose solution, physiological serum, sterilized water or the like and administered as intravenous injections. Such solutions can, if necessary, be freeze-dried and stored in sterile vials, ready for transformation into solution by adding sterilized water.

A particularly preferred composition useful for treating hypertension in human beings contains a compound such as, for example, dl-trans-1-hydroxy-3- (1,1-dimethyl-hexahydro-GH-dibenzo [b, d] pyran, in an amount of cherry 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 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 this invention have demonstrated activity in the urn or several tests designed to indicate analgesic, antiglaucoma, antidepressant and anti-anxiety activity. For example, dl-trans-1-hydroxy-3- (1,1-diethylheptyl) -9-hydroxylmino-6a, 7,8,9,10,10ahexahydro-GH -: libe: iso (b, d | pyran, showed an EDso (= 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, dl-trans-1-hydroxy-3 (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxdamino-Ga, 7,8,9,10,10a-hexahydro-6H-dibenzo compound [ 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 tested through the sample of rat lesion in the rat, does the compound excite it?^Jdroxy - 3 - (1, l-dimethylheptyl) -6,6-ddmethyl-9-acetamido - 6a, 7,8,9,10,10a - hexah hydro-6 Hd ibemzo [b, d jpi nan, administered intravenously, demonstrates a minimum effective dose (MED) of 0.5 μg / kg body weight.

As can be easily seen from the above exposition. As regards assets, biological father, many of the compounds of this invention, are useful in the treatment of hypertension, anxiety, glauoma pain and related diseases. The compounds can thus be used to treat - animals and humans suffer the same diseases by administering - an effective dose for the treatment of hypertension, a hypofensive compound, active, of this invention, to a child suffering from hypertension and in need of treatment. , or a being suspected of having hypertension and may need prophylactic treatment. A special preferred matte 4 for treating stress is the administration of a campus of the invention, having an amide portion, taking position 9 (ie Rs is aloano.il Ci-Cî).

The active hypotensive compounds of this invention can 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 vary, of course, depending on the pain illness of the treated being, the size and age of the patient, but will usually vary from about 0.001 to about 20 mg dose to-⁵daily for each patient. Preferred daily doses commonly used when treating hypertension, for example, will range from about 0.1 to 10 mg per patient. The usual treatment for hypertension will include, for example, administering to a patient approximately 5 mg daily of dI-hydroxy-3- (1,2-dim9thylhepfc-1) -9- (2,6 -dioQpiperidineO) - 6a, 7,8,9,10,10 a - hexa- 15 hydro - 6H - dibenzo [b, dlpiran. A preferred treatment consists of the administration of circsa 2 mg daily of the compound dZ-frcms-1-hydroxy - 3 - (1,1-dknetfheptyl) - 6,6-dimethylU9-ace'tamIdo-6a, 7,8,9, 20 10,10a-hexahydro-6H-dibenzo [b, d] pyranes.

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