NO744713L - - Google Patents

Description

The present invention relates to a method for the production of new benzopyran derivatives with the general formula

in which the symbol means a single or double bond,

one of R and R-. the groups are an unsubstituted or

1 -3

mono- or di-alkyl-substituted amino group or a heteromonocyclic group, optionally containing another heteroatom, such as N, O, S, and the other is hydrogen or an unsubstituted or mono-

or di-alkyl substituted amino group or a heteromonocyclic group as defined above 5

each of the R 2 and R 1 groups are the same or different and may be hydrogen, halogen, hydroxy, alkyl, alkoxy or trifluoromethyl;

X can be

in which R,- and R^ can be hydrogen or alkyl, as well as a pharmaceutically acceptable salt thereof, with the exception of the following compounds:

- 2-amino-6-oxo-6H-dibenzo[b,d]pyran

- 3-amino-6-oxo-6H-dibenzo[b,d]pyran j - 8-amino-6-oxo-6H-dibenzo[b,d]pyran

- 3-amino-8-methoxy-6-oxo-6H-dibenzoLb,d]pyran

- 3-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran - 9-methyl-3-dimethylamino-6-oxo-7,8,9,10-tetra -"hydro-6H-dibenzo[b,d]pyran - 3-dialkylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran.

The alkyl and/or alkoxy groups contain 1-6, preferably 1-4, carbon atoms and may be branched or unbranched groups.

When and/or is a heteromonocyclic group, optionally containing another heteroatom, the heteromonocyclic group is preferably 5-membered or 6-membered. It is preferably a pyrrolidin-1-yl group, a piperidino, piperazin-1-yl, morpholino or pyrrol-1-yl group.

Preferred compounds according to the invention are compounds of the formula (I), in which X is -oC-- and one of R1 and R3 is hydrogen and

the other an amino group which is unsubstituted or substituted by one or two alkyl groups, preferably methyl or ethyl, one of R 2 and R 1 is hydrogen or halogen, preferably chlorine or bromine, and the other is hydrogen.

Pharmaceutically acceptable salts are, for example, those with hydrochloric acid, citric acid and tartaric acid.

Examples of preferred compounds according to the invention are the following:

- 3-amino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran

- 3-methylamino-6-oxo-6H-dibenzo[b,d]pyran

- 3-methylamino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran

- 3-dimethylamino-6-oxo-6H-dibenzo[b,d]pyran

- 3-dimethylamino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran

- 3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran - 3-ethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran.'

The benzopyran derivatives according to the invention can be produced by a method which includes:

(a) reaction of a compound of formula (II)

wherein and R^ have the previously indicated meanings and

Ry is an alkyl group,

with a compound of formula (III)

wherein and R 2 have the previously stated meanings, and R is hydrogen or an alkyl group, to give a compound of formula (I), wherein X is and the symbol means a single bond, and if desired, the compound of formula (I) thus obtained may; dehydrogenated to give a compound of formula (i), wherein the symbol represents a double bond, and/or, if desired, a compound of formula (i) wherein X is can be reduced to a compound of formula (1) wherein X is - CH^-, and/or, if desired, I may be a compound of formula (I), in which X is

transform into'

one. compound of formula (I), "wherein X

wherein R 2 and R 3 are alkyl groups, by means of a Grignard reaction; (b) decarboxylation of a compound of formula (IV) wherein R 2 , R 1 and X have the previously stated meanings and the symbol means a single or double bond and wherein one of R 1 and R 1 is the group wherein R 1 is a alkyl group and R" is hydrogen or an alkyl group and the other is the group

or have one of the above

given meanings with respect to R^ and R^, so that a compound of formula (I) is obtained, in which at least one of the groups R^ and R^ is an unsubstituted or mono-alkyl-substituted amino group, which amino group, if desired, can be further alkylated;

(c) reduction of a compound of formula (V)

wherein R2, R. and X have the meanings given above,

symbol means a single or double bond, and

one of the R"^ and R"^ groups is a nitro group and the other is a nitro group or has one of the meanings given above with respect to

R1 and R3,

and, if desired, a thus obtained compound of formula (I), in which one or both of the groups R-^ and R^ are unsubstituted amino groups can be converted into a compound of formula (I), in which at least one of the groups R-^ and R ^ is a mono- or, di-alkyl substituted amino group$

(d) cyclization of a compound of formula (VI)

in which R^ and R^ have the previously stated meanings,

Rg is hydrogen, alkoxy or carboxy,

Rg is hydrogen or, when Rg is an alkoxy group, Rg is an alkyl group, and where one of the groups R'"^ and R" is a nitro group or an optionally substituted amino- or hetero-monocyclic group as defined above, and the other is hydrogen or a nitro group or an optionally substituted amino or heteromonocyclic group

as defined above,

to give a compound of formula (I), wherein X is

and the symbol represents a double bond, and when the reaction product Rt is a compound of formula (I), in which one or both of R"'^ and R" is nitro, the method according to (b) is used, and, if desired , a compound of formula (I) wherein X is reduced to a compound of formula (I) wherein X is -CH2-, and/or, if desired, a compound of formula (I) wherein X is converted to a compound of formula (I) wherein X is

wherein R 1 - and R 2 are alkyl groups, by means of

a Grignard reaction^

(e) oxidation of a compound of formula (VII)

wherein R"^, R2, R'"3 and R4 have the former

stated meanings,

to give a compound of formula (I), wherein X is

and the symbol means a double bond, and when the reaction product is a compound of formula (I) in which one or both of R"'^ and R" are nitro groups, the procedure according to method (b) is used, and, if desired, reducing a compound of formula (I) wherein X is

to a compound of formula (I)

wherein X is -CH„-, and/or, if desired, a compound is converted

compounds of formula (i), wherein X is

to a compound of formula (I), wherein X is

wherein and R^ are alkyl groups,

by means of a Grignard reaction;

and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.

The reaction between the compound of formula (II) and the compound of formula (III) is preferably carried out in the presence of dehydrating agents, for example zinc chloride or concentrated sulfuric acid, and in the presence or absence of deionizing agents.

When zinc chloride is used, suitable solvents are, for example, methanol or ethanol. The subsequent possible dehydrogenation is preferably carried out in a catalytic manner, for example using palladium on charcoal at high temperatures, for example in the range 200 - 400°C.

The eventual reduction of a compound of formula (I), wherein

X is

to a compound of formula (I), wherein X is -Ct^-,

is preferably carried out with LiAIH4, or with borane.

The eventual conversion of a compound of formula (I), wherein

X is

to a compound of formula (I), in which X is where R,- and R^ are alkyl groups, can for example be carried out by reacting a compound of formula (I), in which X is

with an excess of magnesium alkyl halide at the reflux temperature for the organic solvent1, which is, for example, anisole.

The decarboxylation of the compound of formula (IV) can be carried out at the reflux temperature, both in an alkaline medium with sodium or potassium hydrate in ethanol or methanol, as well as in an acidic medium, for example by treatment with a mixture consisting of glacial acetic acid and concentrated sulfuric acid.

The reduction of the compound of formula (V) is preferably carried out using Raney nickel or hydrazine hydrate. The optionally subsequent conversion of the compound of formula (I), in which one or both groups R^ and R^ are unsubstituted amino groups into a compound of formula (I), in which one or both of the groups R^ and R^ are mono- or di -alkyl substituted amino groups, can be carried out by conventional methods, for example by reaction with alkyl halides in an alkaline medium.

Cyclization of the compound of formula (VI) is carried out when Rg

is hydrogen or a carboxyl group and Rg is hydrogen, preferably by means of oxidizing agents, for example with chromic anhydride or hydrogen peroxide. An excess of hydrogen peroxide is preferably used in a warm, dilute sulfuric acid solution. When RQ is an alkoxy group and Rg is an alkyl group, on the other hand, the cyclization of the compound of formula (VI) is preferably carried out by a simultaneous de-etherification and hydrolysis reaction, for example by treatment with strong acids.

The oxidation of the compound of formula (VII) is preferably carried out with peracetic acid. E.g. the oxidation can be carried out in an organic solvent1, such as dichloromethane, at a temperature in the range 0 - 100°C using an oxidizing mixture consisting of acetic anhydride, concentrated sulfuric acid and concentrated hydrogen peroxide.

As previously stated, a compound of formula (I) can be converted into another compound of formula (I) by known methods. Thus, when one or both of the R2 and R^ groups are hydroxy groups, an etherification can optionally be carried out by reacting the corresponding salt, for example an alkali salt with reactive alkyl esters of strong acids, for example alkyl halides or dialkyl sulphates. When one or both of the R2 and R^ groups are alkoxy groups, these can be converted into hydroxy groups by treatment with strong acids, for example hydrobromic acid, or with a pyridine salt, for example pyridine hydrochloride. The eventual salt conversion step can also be carried out by conventional methods.

The compounds of formula (IV) and (V) can e.g. is prepared by method (a), by suitably varying the substituents in the starting materials. The other starting materials are known from the literature or can be produced by known methods.

E.g. the compounds of formula (VI) can be prepared according to Ulmann [see, e.g. Ann. 332, 38 (1904)], by reacting a compound of formula (VIII)

in which R"'3, R4 and Rg have the previously indicated meanings and

Z is halogen,

with a compound of formula (IX)

wherein R"1 J. , R c „, R o and Z have the previously indicated

meanings,

in the presence of metallic agents, especially copper powder, with a subsequent hydrolysis of the reaction product, for example with strong acids. In the compounds of formula (VIII) and (IX)

Z is preferably iodine.

The compound of formula (VII) can, for example, be prepared according to the method described in J. Amer. Soc. (1931), 53

2720.

The benzopyran derivatives as well as the pharmaceutical compositions containing them act on the central nervous system, especially as sedatives, anti-psychotics and anti-depressants.

The anti-depressant activity of the compounds of the invention was determined in mice by their effect in preventing reserpine-induced blepharospasm and hypothermia.

Reserpine was administered endoperitoneally in a dose of

2.5 mg/kg, and the investigated compounds were administered orally for 30 min. for the administration of reserpine. Determination of blepharospasm (determined point wise according to the technique described by Rubin B. et al in J. Pharmacol., 120, 125, 1957, and the body temperature was measured (using rectally inserted thermocouples) respectively one and four hours after administration of reserpine.

Furthermore, the compounds according to the present invention prove to be much less toxic than the usual anti-depressants, such as imipramine, amitriptyline and derivatives thereof, in particular they prove not to be affected by peripheral atropine effect.

The compounds according to the present invention are preferably administered orally.

Results from clinical trials with humans have substantiated the pharmacological data.

Suitable doses for oral administration for adults are preferably 10 - 50 mg/dose 1-4 times a day.

The compounds according to the present invention can be incorporated into suitable pharmaceutical compositions which are preferably tablets, pills or gelatin capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose $ as well as lubricants, for example silicon oxide, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols. Furthermore, they may contain binding agents, for example such as starch, gelatin, methyl cellulose, carboxymethyl cellulose, gum arabic, tragacanth, polyvinyl pyrrolidone, disintegrants, such as starch, alginic acids, alginates, sodium starch glycolate, effervescent mixtures, dyes, sweeteners, wetting agents, such as lecithin, polysorbates, lauryl sulfates and generally non-toxic and pharmacologically inactive ingredients used in pharmaceutical compositions. The pharmaceutical compositions can be prepared in a known manner, for example by mixing, granulation, tableting, dragee production or film coating processes.

The following examples illustrate the present invention.

EXAMPLE 1

A mixture consisting of cyclohexanone-2-carbethoxy (0.1 mol), p-dimethylaminophenol (0.1 mol) and ZnC^ (0.01 mol) in ethanol

(250 ml) was kept at the reflux temperature for 2 days.

Water (500 ml) was then added and the solution extracted

twice with chloroform (300 ml), which after evaporation gave 2-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6K-dibenzo[b,d]pyran (yield 70%).

By proceeding in a similar manner and using

suitable substituted phenols, the following compounds were obtained:

- 1-chloro-2-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6K-dibenzo [b,d]pyran; - l-methoxy-2-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran5-l-hydroxy-2-dimethylamino-6-oxo-7,8,9 ,10-tetrahydro-6H-dibenzo[b,d]pyr an5 - 3-chloro-2-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran-, - 4-chloro-2-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran.

EXAMPLE 2

A mixture consisting of cyclohexanone-2-carbethoxy (0.1 mol) 5-dimethylamino-m-methoxy-phenol (0.1 mol) and ZnCl2 (0.1 mol)

in ethanol (250 ml) was kept at the reflux temperature for 2 days. Water was then added (500 mL), and the solution was extracted twice with chloroform (300 mL), to give,

after evaporation, 1-methoxy-3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran (yield 70%).

In an analogous manner, starting from pure dimethylaminophenols, the following compounds are obtained: - 3-(pyrrolidin-1-yl)-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b, d]pyran; - 3-(pyrrol-1-yl)-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran5-3-piperidino-6-oxo-7,8,9,10 -tetrahydro-6H-dibenzo[b,d]pyran-5-1-chloro-3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 1-hydroxy-3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran$ - 2-methoxy-3-dimethylamino-6-oxo-7,8, 9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 2-chloro-3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran.

EXAMPLE 3

A mixture of cyclohexanone-2-carbethoxy (0.1 mol), o-dimethylaminophenol (0.1 mol) and ZnCl 2 (0.1 mol) in ethanol (250 mL) was kept at reflux temperature for 2 days.

Water (500 mL) was then added and the solution was extracted twice with chloroform (300 mL) to give, after evaporation, 4-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[ b,d]pyran (yield 70%).

In an analogous way, starting from pure dimethylaminophenols, the following compounds are obtained: - 1-chloro-4-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H- dibenzo [b,d]pyran; - 2-chloro-4-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran; - 3-chloro-4-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran; - 1-methoxy-4-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran.

EXAMPLE 4

A mixture of cyclohexanone-2-carbethoxy (0.1 mol) and N-carbethoxy-3-methylamino-phenol (0.1 mol) in concentrated H 2 SO 4 (15 mL) was stirred at room temperature for

2 days, then completely in water (600 ml). The product was

separated, i.e. N-carbethoxy-3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran was refluxed with an excess of INNaOH in ethanol (100 mL) in three hours.

After cooling, the solution was poured into water (500 ml), for

to give, after filtration, 3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran (yield = 75%, mp 204 - 205°). By following the same procedure, the following compounds were obtained:

- 3-ethylamino-6-oxo-7,8,9,10-tetrahydro-6B-dibenzo[b,d]pyran; - 2-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 4-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 2-methoxy-3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d] pyran-, - 4-methoxy-3-methylamino-6-oxo-7,8 ,9,10-tetrahydro-6H-dibenzo [b,d]pyran; - 1-hydroxy-3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran; - 4-chloro-3-methylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran.

EXAMPLE 5

A mixture, consisting of cyclohexanone-2-carbethoxy (0.1 mol) and N-carbethoxy-p-aminophenol (0.1 mol) in concentrated I^SO^

(15 ml) was kept under stirring at room temperature for two days, then poured into water (600 ml). The product was separated, i.e. N-carbethoxy-2-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran was treated with a mixture of sulfuric acid and acetic acid in equal parts. The mixture was refluxed for three hours, then poured into water (500 mL) and made alkaline with 1N NaOH to give, after filtration, 2-amino-6-oxo-7,8,9,10-tetrahyde. ro-6H-dibenzo[b ,d]pyran (yield = 70%). By walking

proceeding in the same way, and starting from pure aminophenols, the following compounds were obtained:

- 2-methoxy-3-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]

- 3-amino-4-methoxy-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyran; - 2-chloro-3-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 1-methoxy-3-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibezno[b,d]; pyran; - 3-amino-4-chloro-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 4-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 2-methoxy-4-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]-pyran; - 3-methoxy-4-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]-pyran; - 2-chloro-4-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 3-chloro-4-amino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran.

EXAMPLE 6

3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran

(8 g) was mixed with palladium on charcoal (10% - palladium:

3 g) and the mixture was heated for 10 minutes under nitrogen at a temperature above 300°C. After cooling and trituration, the resulting residue was extracted with stirring for 10 hours with hot ethanol to give, after filtration and evaporation of the solvent, 3-dimethylamino-6-oxo-6H-dibenzo[b,d]pyran (yield = 70%; mp 138 - 140°C).

By proceeding analogously, the following compounds were obtained:

- 3-methylamino-6-oxo-6H-dibenzo[b,d]pyran, m.p. 207 - 214°C; - 3-amino-2-chloro-6-oxo-6H-dibenzo[b,d]pyran; - 3-amino-2-methoxy-6-oxo-6H-dibenzo[b,d]pyran; - 3-methylamino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran; - 3-(pyrrolidin-1-yl)-6-oxo-6H-dibenzo[b,d]pyran; - 3-(pyrrol-1-yl)-6-oxo-6K-dibenzo[b,d]pyran; - 3-piperidino-6-oxo-6H-dibenzo[b,d]pyran; - 3-methylamino-2-methoxy-6-oxo-6H-dibenzo[b,d]pyran; - 3-dimethylamino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran;

- 3-amino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran.

EXAMPLE 7

A mixture consisting of 4<1->chloro-4-nitro-2-diphenic acid (0.02 mol) and H 2 O 2 (0.2 mol) in H 2 SO 4 O.5N (250 ml) was refluxed for 8 hours. After cooling, methanol (10 mL) was added,

and then the mixture was neutralized with 1N NaOH and extra-

again with ethyl acetate to give, after evaporation, 3-chloro-8-nitro-6-oxo-6H-dibenzo[b,d]pyran (yield = 60%).

Using the same method, the following compounds were obtained: - 3-hydroxy-8-nitro-6-oxo-6H-dibenzo[b,d]pyran;

- 3-methoxy-8-nitro-6-oxo-6H-dibenzo[b,d]pyran.

EXAMPLE 8

A solution consisting of 2'-methoxy-5-nitro-2-diphenyl-carboxylic acid (0.02 mol) in acetic acid (200 mL), concentrated H 2 SO 4 (100 mL) and water (50 mL) was refluxed for 12 h . After cooling, by addition of cold water, a precipitate formed which, after filtration, was crystallized from :toluene to give 9-nitro-6-oxo-6H-dibenzo[b,d]pyran (yield

= 55%).

By proceeding in the same way, the following compounds were obtained: - 3-nitro-6-oxo-6H-dibenzo[b,d]pyran; - 2-nitro-8-chloro-6-oxo-6H-dibenzo[b,d]pyran; - 3-nitro-8-chloro-6-oxo-6H-dibenzo[b,d]pyran;

- 3-nitro-8-methoxy-6-oxo-6H-dibenzo[b,d]pyran.

EXAMPLE 9

A solution of 3-chloro-8-nitro-6-oxo-6H-dibenzo[b,d]pyran

(0.01 mol) in toluene (100 mL) and ethanol (100 mL) was reduced with Raney nickel and hydrazine hydrate. Evaporation and crystallization from CHCl 2 gave 3-chloro-8-amino-6-oxo-6H-dibenzo[b,d]pyran (yield = 90%).

By proceeding in the same way, the following compounds were obtained: - 7-amino-6-oxo-6H-dibenzo[b,d]pyran; - 9-amino-6-oxo-6H-dibenzo[b,d]pyran; - 3-hydroxy-8-amino-6-oxo-6H-dibenzo[b,d]pyran; - 2-amino-8-chloro-6-oxo-6H-dibenzo[brd]pyran; - 3-amino-8-chloro-6-oxo-6H-dibenzo[b,d]pyran; - 3-amino-8-methoxy-6-oxo-6K-dibenzo[b,d]pyran.

EXAMPLE 10

A solution consisting of l-nitro-9-fluorenone (0.02 mol) in acetic acid (50 mL) and concentrated I^SO^ (30 mL) was treated at room temperature with stirring with peracetic acid (40%) (0.04 minor; 8th ral). After stirring for one hour at room temperature, the solution was neutralized with Na 2 CO 2 and extracted repeatedly with ether to give, after evaporation of the solvent, 7-nitro-6-oxo-6H-dibenzo[b,d]pyran ( yield = 80%).

EXAMPLE 11

To a solution of 3-dimethylamino-6-oxo-6H-dibenzo[b,d]

pyran (0.1 mol) in tetrahydrofuran (50 ml) was added an excess of. LiAlH 4 (0.3 mol) and the mixture was refluxed for 24 hours. After neutralization by addition of dilute sulfuric acid, the inorganic salts were filtered off, and tetrahydrofuran was evaporated under vacuum to give 3-dimethylamino-6H-dibenzo[b,d]pyran (yield = 50%).

By an analogous procedure, the following compounds were obtained

obtained:

- 3-amino-6H-dibenzo[b,d]pyran; - 3-amino-8-chloro-6H-dibenzo[b,d]pyran; - 3-methylamino-6H-dibenzo[b,d]pyran; - 3-methylamino-8-chloro-6H-dibenzo[b,d]pyran; - 3-dimethylamino-8-chloro-6H-dibenzo[b,d]pyran; - 3-amino-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; - 3-methylamino-7, 8,9,10-tetrahydro-6H.-dibenzo[b,d]pyran; - 3-dimethylamino-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran;

- 3-ethylamino-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran.

EXAMPLE 12

To a solution of methylmagnesium iodide (0.5 mol) in anisole

1,3-dimethylamino-6-oxo-6H-dibenzo[b,d]pyran (0.1 mol) was added and the mixture was heated at 80°C for 20 hours.

After neutralization of the reaction mixture by addn

of dilute sulfuric acid, anisole was removed in a stream of steam.

After extraction with diethyl ether and evaporation of the ether

3-dimethylamino-6,6-dimethyl-6H-dibenzo[b,d]pyran was obtained (yield = 55%).

By proceeding in an analogous manner, the following compounds were obtained: - 3-amino-6., 6-dimethyl-6H-dibenzo[b,d]pyran; - 3-amino-8-chloro-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-methylamino-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-methylamino-8-chloro-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-dimethylamino-8-chloro-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-amino-7,8,9,10-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-methylamino-7,8,9,10-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran; - 3-dimethylamino-7,8,9,10-tetrahydro-6,6-dimethyl-6H-dibenzo [b,d]pyran; - 3-ethylamino-7,8,9,10-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran.

Claims (1)

1. Process for the preparation of new benzopyran derivatives of the general formula (I) wherein the symbol means a single or double bond, one of the R-^ and R^ groups is an unsubstituted or mono- or di-alkyl-substituted amino group or a heteromonocyclic group, optionally containing another heteroatom, such as N, O, S, and the second is hydrogen or an unsubstituted or mono- or di-alkyl substituted amino group or a heteromonocyclic group as defined above; each of the R 2 and R 1 groups are the same or different and may be hydrogen, halogen, hydroxy, alkyl, alkoxy or trifluoromethyl; X may be wherein R^ and R^ may be hydrogen or alkyl, and a pharmaceutically acceptable salt thereof, with the exception of the following compounds: - 2-amino-6-oxo-6H-dibenzo[b,d]pyran - 3-amino-6-oxo-6H-dibenzo[b,d]pyran - 8-amino-6-oxo-6H-dibenzo[b,d]pyran - 3-amino-8-methoxy-6-oxo-6H-dibenzo[b,d]pyran - 3-amino-6-oxo-7 ,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran - 9-methyl-3-dimethylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran - 3-dialkylamino-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran; characterized in that said method comprises (a) reacting a compound of formula (II) in which R^ and R^ have the above meaning and 11<R>7 means an alkyl group, with a compound of formula (III) in which and R 2 have the previously stated meanings, and R is hydrogen or an alkyl group, to give a compound of formula (I), wherein X is the symbol denotes a single bond, and, if desired, the compound of formula (I) thus obtained may be dehydrogenated to give a compound of formula (I), wherein the symbol represents a double bond, and/or, if desired, a compound of formula (I) wherein X is is reduced to one compound of formula (I), wherein X is -CH„, and/or, if desired, may be a compound of formula (I), wherein X is converted into a compound of formula (I) wherein X is wherein R^ and R^ are alkyl groups, by means of a Grignard reaction •, (b) decarboxylation of a compound of formula (IV) wherein R 2 , R^ and X are as previously defined, , and the symbol means a single or double<I1>bond, and in which one of R' and R'-, is the group wherein R' is an alkyl group and R" is hydrogen or an alkyl group, and the other is the group or has one of the meanings given above with respect to R^ and R^, so that a compound of formula (I) is obtained, in which at least one of the groups R-^ and R^ is an unsubstituted or mono-alkyl-substituted amino group, which amino group, if desired, can be further alkylated; (c) reduction of a compound of formula (V) wherein R 2 , R 2 and X are as previously defined, the symbol means a single or double bond, and one of the R"^ and R"^ groups is a nitro group and the other is a nitro group or has one of the meanings given above with respect to R1 and R3, and, if desired, a thus obtained compound of formula (I), in which one or both of the groups R^ and R^ are unsubstituted amino groups, may be converted into a compound of formula (I) in which at least one of the groups R^ and R^ is mono- or di-alkyl substituted ■ amino group: (d) cyclization of a compound of formula (VI) in which R 2 and R . is Rg an alkyl group, and where one of the groups R'"^ and R"'2 is a nitro group or an optionally substituted amino- or hetero-monocyclic group as defined above, and the other is hydrogen or a nitro group or an optionally substituted amino - or heteromonocyclic group as defined above, to give a compound of formula (I), wherein X is and symbol represents, a double bond, and when the reaction product is a compound of formula (I) in which one or both of R"'^ and R"12 is nitro, the procedure according to (c) is used, and, if desired, reducing a compound of formula (I), wherein X is to a compound of formula (I), wherein X is -CH„-, and/or, if desired, a compound is converted by formula (I), wherein X is to a compound of formula (I), in which X is wherein R^ and R^ are alkyl groups, by means of a Grignard reaction; (e) oxidation of a compound of formula (VII) in which R'"^, <R>2, Rl" 3 °9 R4are the previously stated meanings, to give a compound of formula (I), wherein X is and the symbol means a double bond, and when the reaction product is a compound of formula (I) in which one or both of R"'^ and R"<13> are nitro groups, the method according to method (c) is used, and, if desired , a compound is reduced of formula (I), wherein X is to a compound of formula (I) in which X is -CF^ and/or, if desired, a for- bond of formula (I), wherein X is to a connection of formula (I), wherein X is wherein R^ and R^ are alkyl groups, using a Grignard reaction5 and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.