CS203756B1 - Tetracyclic compounds derived from narceonic acid and process for preparing thereof - Google Patents

Description

The invention relates to tetracyclic compounds derived from narceonic acids of the general formula I,

where

X denotes an oxygen atom or - N — R group in which

R is hydrogen, phenyl, optionally substituted with chlorine, bromine or nitro.

The compounds of the formula I which have not been described so far are pharmacologically valuable substances with potential bacteriostatic effects.

In the near field, reactions of aromatic keto acids with hydrazine derivatives to produce phthalazine derivatives have been discussed, for example, by Vaughan and Baird (J. Am. Chem. Soc. 68, 1314, 1946); from benzylidene phthalide by treatment with hydrazine gave Bromberg (Ber. 29, 1434, 1896) 1-benzyl-3,4-dihydrophthalazin-4-one; from narcein derivative, narceinic acid, prepared by Freund and Frankfortér (Ann. 277, 20, 1893) 1- (2‘-ethenyl) benzyl-3,4-dihydrophthalazin-4-one. The reaction of aromatic aldehydes with hydroxylamine has been studied, for example, by Brady sp. (J. Chem. Soc. 529, 1928), synthesizing ΙΗ-benzo (d) - (1,2) oxazine derivatives.

The process for the preparation of the tetracyclic compounds according to the invention of the general formula is carried out, for example, by first preparing the (E) - or (Z) -isomer of narceonic acid by reaction with hydrazine derivatives in a slightly basic medium, preferably in the presence of sodium acetate or pyridine. 1- (2'-ethenyl) benzyl-3,4-dihydrophthalazin-4-one derivative, optionally by reaction with hydroxylamine 4- (2'-ethenyl) benzyl-1H-benzo (d) - (1,2) oxazine derivative -l-one; the derivatives obtained are then acidified, preferably in a methanolic solution of hydrogen chloride, at a temperature. the reaction mixture is cyclized to the corresponding derivative with the desired meaning of substituent R.

.. Further details are given in the examples. ,

Example 1

Preparation of 5,6-dihydro-3,4,12-trimethoxy-8-mg-ethyl-10,11-methylenedioxy-8H-isoquinolo (2,3-a) phthalazin-5-one. .

1.0 g of narceonic acid is mixed with a solution of 4.0 ml of hydrazine hydrate in 30 ml of ethanol and the mixture is refluxed for 4 hours on a water bath. The precipitated crystals of 1- (6‘-ethenyl-2‘-methoxy-3‘, 4‘-methylenedioxy) benzyl-3,4-dlhydro-5,6-dimethoxyphthalazin-4-one are filtered off with suction and recrystallized from ethanol. Yield 0.32 g, mp 276-278 ° C. 0.20 g of this material is refluxed for 1 hour in 50 ml of 5% methanolic hydrogen chloride solution, the solution is concentrated to 10 ml, poured into cold water, adjusted to pH 6.9 with 1% ammonia solution and extracted. 3 x 10 ml chloroform. The combined extracts were concentrated to crystallize and the material was recrystallized from methanol. Yield 0.120 g of the desired compound, m.p. 179-181 ° C.

Example 1 a d 2

Preparation of 6-phenyl-5,6-dihydro-10,11-methylenedioxy-3,4,12-trimethoxy-8-methyl-8H-isoquinolo [2,3-a] phthalazin-5-one

A solution of 0.5 g of narceonic acid in 30 ml of ethanol is refluxed for 4 hours with 0.5 g of phenylhydrdzine and 0.5 g of sodium acetate. The precipitated material was recrystallized from ethanol to give 0.36 g of 1- (6'-ethenyl-2'-methoxy-3 ', 4'-methylenedioxy) benzyl-3-phenyl-3,4- dihydro-5,6-dimethoxyphthalazin-4-one having mp 185-186 ° C; 0.18 g of this material was refluxed in 25 ml of 5% methanolic hydrogen chloride solution for 30 minutes. The solution is concentrated to a volume of 10 ml and poured into 50 ml of 5% ammonia solution. The resulting orange solid was filtered off, dried and recrystallized from methanol. The yield of the desired compound is 0.15 g, mp 185.5 ° C. Example 1 a d 3

Preparation of 5,8-dihydro-3,4,12-trimethoxy-8-methyl-10,11-methylenedioxybenz (d) (1,2) oxazino (3,4-b) isoquinol-5-one

0.3 g of narceonic acid is refluxed with 0.5 g of hydroxylamine hydrochloride in a mixture of 20 ml of ethanol and 5 ml of pyridine for 20 hours. The crystals precipitated (0.21 g) were recrystallized from ethanol. Yield 0.19 g of 4- (6‘-ethenyl-3‘, 4‘-methylenedioxy-2‘-methoxy) benzyl-7,8-dihydro-1H-benzo. [d] (1,2) oxazin-1-one, mp 196-197 ° C. 0.18 g of this material was refluxed for 1 hour with 70 ml of 5% methanolic hydrogen chloride solution. The mixture is concentrated and the residue is poured into 50 ml of 10% ammonia solution, the precipitate is filtered off and recrystallized from ethanol. The yield of the desired compound is 0.13 g, mp 196-198 ° C.

Claims (3)

Tetracyclic compounds derived from narceonic acid of the general formula I, wherein X represents an oxygen atom or a group = N — R in which R is hydrogen, phenyl, optionally substituted with chlorine, bromine or nitro. 2. A process for the preparation of a compound of the formula I according to claim 1, wherein: X denotes the grouping = N — R, where R is hydrogen, phenyl optionally substituted with chlorine, bromine or a nitro group according to claim 1, characterized in that in position 3 an appropriately substituted 1- (6'-ethenyl-2-methoxy-3 ^<, 4'-methylenedioxy) Benzyl-3,4-dihydro-5,6-dimethoxyphthalazine is cyclized by treatment with methanolic hydrogen chloride solution at the boiling point of the reaction mixture. 3. A process for the preparation of a compound of formula (I) in which X is an oxygen atom according to claim 1, wherein [alpha] - (4-ethenyl-N-methylenedioxy (4-methoxy) benzyl-7,8) is used. -dimethoxy-1H-benzo (d) (1,2) -oxazin-1-one is cyclized by treatment with methanolic hydrogen chloride solution at the boiling point of the reaction mixture.