NO134299B - - Google Patents

Description

The present invention relates to a process for the production of new 4-carbamoxymethyl-1-phthalazone derivatives with the general formula

where R means a hydrogen atom or a lower alkyl group, especially C i - Co, alkyl group: means a member selected from the group consisting of a hydrogen atom, a lower alkyl group which may be branched or a cyclic lower alkyl group, an alkenyl group, especially - alkenyl group, phenyl or tolyl group, benzyl or phenethyl, a di-lower-alkylamino-lower alkyl group, preferably C - C 1 - alkyl group with C 1 -

or C 2 alkylamino groups, a furfuryl group, a picolyl group and a pyridyl group

R^ means a member selected from the group consisting of a hydrogen atom, a lower alkyl group, especially C, - alkyl group, phenyl or tolyl group, a carbamoyl group, an N-lower alkylcarbamoyl group, preferably an N-alkylcarbamoyl group with C - alkyl group, a K.N -di-lower-alkylcarbamoyl group, preferably an N.N-dialkylcarbamoyl group with C1-C3 alkyl groups, a lower alkyl-sulfonyl group, especially with C1-C lower alkyl group and a phenylsulfonyl or tolylsulfonyl group

R4 means a hydrogen atom, a halogen atom such as Cl, Br,

I or F, preferably Cl or Br, a lower alkyl group, in particular a C 1 - C 3 alkyl group and a lower alkoxy group, preferably a C - C 4 alkoxy group5

R5 means a hydrogen atom, a halogen atom, such as Cl, Br, I or F, preferably Cl or Br, a lower alkyl group, especially a C₁ - C₃ alkyl group, an alkoxy group, preferably a C₁ - C₃ alkoxy group, an amino group, a lower alkanoylamino group, a lower alkoxycarbonyl group, preferably an alkoxycarbonyl group with a C₁ - C₁ alkoxy group and a carbamoyl group, and R.j and R.sup.2 can together with the nitrogen atom of the carbamoyl group form a pyrrolidine, piperidine, morpholine or 4-methyl-piperazine group, and

R 1 and R 2 may be present at any of the C-5, C-6, C-7 or C-8 positions of the phthalazone ring.

The above compounds can be prepared by any of the following methods:

a) a compound with the general formula

where R^, R4 and R^ have the same meaning as in formula

(IN),

is allowed to react with an isocyanate of formula

where R 2 has the same meaning as in formula (I) with the exception of a hydrogen atom.

or

b) the compound with the general formula (II) is converted using known methods into a compound with the general formula

formula

where . R^ and R^ have the same meaning as stated under formula (I), and where

X means an oxygen or sulfur atom,

Z means a lower alkyl group or an aryl group

which can be substituted,

and then compounds of formula (IV) are allowed to react with ammonia or an amine of formula

where R^ and R_ have the same meaning as indicated

in formula (I),

or

c) the compound of formula (II) is allowed to react with phosgene, after which the intermediate compound of formula

where , R^ and R^ have the same meaning as stated in formula (I),

may react with ammonia or the amine of formula (V), or

d) the compound of formula (II) is allowed to react with a derivative

■iav a carbamic acid of formula

where R-^ and R^ have the same meaning as stated in formula (I), and

Y means a halogen atom, an alkoxy-, aryloxy-,

alkylthio or arylthio group,

or

e) a compound with the general formula

where R^, R^, R^ and R^ have the same meaning as

given in formula (I),

is allowed to react with a hydrazine derivative of formula

where R^ has the same meaning as stated in formula (I).

Compounds according to the present invention can be prepared using any of the methods described above.

The compounds prepared by means of the methods described above are new, and in the experimental atherosclerosis caused by added cholesterol they show a profound effect with respect to preventing atherosclerosis by

inhibiting the deposition of cholesterol on the arterial walls. They also prevent the increase in coagulation ability and susceptibility to thrombosis caused by injection treatment of animals with cholesterol or adrenaline, i.e. they prevent the shortening of blood clotting time as well as the increase in adenosine diphosphate-induced platelet aggregation in animals. The compounds according to the invention are useful for treatment

of atherosclerotic and thrombotic diseases.

The starting material according to the invention, and which has formula (II),

can be produced either by means of known methods or by means of the new methods described below.

1) 4-Hydroxymethyl-1-phthalazone can be produced from 2-carboxy-acetophenone by the reaction sequence described below. This procedure is described in Ber. 40, 72 (1907) and Annual Report of the Department of Pharmacy, Kanazawa University, Vol. 12, 1-6 (1961). 2) The above described method 1) cannot be used for the substituted phthalazone derivatives due to the fact that the starting materials are usually unavailable. We have now found that a connection with formula

where R 1 , R 4 and R 1 have the same meaning as stated in formula (I), and where

Y' means an alkoxy group or a halogen atom,

can be easily reduced to the compound of formula (II) with sodium borohydride. (comp. Japanese patent application no. 58643/71). Compounds of formula (X) can be prepared using known methods, e.g. the method described in J. of Am. Chem. Soc, 68, 1316 (1946).

3) We have also found that the compound of formula (II) can be prepared by adding a compound of formula

where R. and R,- have the same meaning as stated in

formula (I),

react with hydrazine derivatives of formula (IX). Compounds of formula (XI) can be prepared using a Ber. 40, 72 (1907) described ar /.-log way or by means of the following reaction scheme.

The procedure for compound (XI) to compound (II) can be visualized using the following scheme.

This method is particularly applicable for the production of phthalazone compounds which are substituted at the N-2 position in the phthalazone nucleus.

Examples of compounds of formula (II) include 4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-2-methyl-1-phthalazone, 2-ethyl-4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-2 -phenyl-l-phthalazone, 4-hydroxymethyl-2-tolyl-l-phthalazone, 2-carbamoyl-4-hydroxymethyl-l-phthalazone? 4-hydroxymethyl-2-(N-methyl-carbamoyl)-1-phthalazone, 2-(N,N-dimethyl-carbamoyl)-4-hydroxymethyl-l-phthalazone, 4-hydroxymethyl-2-methylsulfonyl-l-phthalazone, 2-benzenesulfonyl-4-hydroxymethyl-1-phthalazone, and 4-hydroxymethyl-2-(p-toluenesulfonyl)-1-phthalazone. Furthermore, 4-hydroxymethyl-1-phthaliizone derivatives having one or two substituents such as chlorine atom,

a bromine atom, an alkyl, alkoxy, amine, acetylamino, alkoxycarbonyl and carbamoyl group at any of the C-5, C-6, C-7 and C-8 positions of the phthalazone nucleus , can also be used. E.g. 7-chloro-4-hydroxymethyl-l-phthalazone, 7-bromo-4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-7-methoxy-2-methyl-l-phthalazone, 4-hydroxymethyl-7-methoxy-2- phenyl-l-phthalazone, 5-acetylamino-4-hydroxymethyl-l-phthalazone, 8-acetylamino-4-hydroxymethyl-7-methoxy-l-phthalazone, 7-ethoxycarbonyl-4-hydroxymethyl-l-phthalazone, 8-amino- 7-chloro-4-hydroxymethyl-l-phthalazone, 6,7-dimethyl-4-hydroxymethyl-l-phthalazone, 4-hydroxymethyl-2,6,7-trimethyl-l-phthalazone, 7-chloro-4-hydroxymethyl- 2-(N-methylcarbamoyl)-1-phthalazone, 2-benzenesulfonyl-4-hydroxymethyl-7-methoxy-1-phthalazone, and 7-bromo-4-hydroxymethyl-2-(p-toluenesulfonyl)-1-phthalazone may be mentioned .

According to method e), the starting materials (VIII) can be prepared from previously described compounds with formula (XI) according to the following scheme.

As an example of the compound (VIII) can be mentioned, tu-carbamoxy-2-carbamoylacetophenone, 2-(N-methylcarbamoxy)-2-carbamoyl-acetophenone, tu-(N,N-dimethylcarbamoxy)-2-carbamoyl-acetophenone, uj- (N,N-tetramethylenecarbamoxy)-2-carbamoylacetophenone, and ε-(N,N-pentamethylenecarbamoxy)-2-carbamoylacetophenone.

Furthermore, the acetophenone derivatives described above, which have one or two substituents represented by R. or R.sub.3 in formula (I) in one of the C-3, C-4, C-5 or C-6 positions in the phthalazone cores can also be used.

In the embodiment according to method a) for the compound (I) react with an equimolar amount or an excess, especially between 1.2 and 2 mol, of isocyanate (II) in an inert solvent or diluent, such as benzene, toluene, chlorobenzene, acetonitrile , chloroform, dioxane, tetrahydrofuran or pyridine. The reaction is carried out at a temperature between room temperature and 150°C, especially below 100°C. At a temperature between 50 - 100°c, the reaction will usually be complete in 1 - 5 hours. At approx. room temperature, longer reaction time is preferred, e.g. between 5 and 24 hours. If necessary, a catalyst, such as tertiary amine, e.g. trimethylamine, triethylamine, an N-alkyl piperidine or pyridine are used.

Examples of the isocyanate (III) include methyl-, ethyl-, propyl-, isopropyl-, butyl-, amyl-, cyclohexyl-, allyl-, phenyl-, tolyl-, xylyl-, |3-dimethylaminoethyl-, y-diethylaminopropyl- , α- and (3-furfuryl-, α-, (3- and γ-picolyl-, α-, β- and γ-pyridyl isocyanate.

Instead of the isocyanate (III), compounds can be used which can be converted into the isocyanate of formula (III) under the reaction conditions, and if necessary, a catalyst which forms isocyanate in situ can be used. E.g. can acylazide with formula

where R has the same meaning as in formula (I),

except for one hydrogen atom,

or S-alkyl thiol carbamates represented by formula

where R 2 has the same meaning as stated in formula (I), with the exception of a hydrogen atom, and where "alkyl" means a lower alkyl group such as a methyl or ethyl group,

used with heating. S-alkyl thiocarbamates can also be used in the presence of a trialkylamine and a heavy metal salt,

such as solvate nitrate.

In accordance with the reaction according to the present invention of the compound of formula (II) with the compound of formula (III), the reaction also includes the reaction of the compound (II) with a compound which can be converted into the compound of formula (III) under the reaction conditions. Method a) can only be used for the production of compounds where R 1 means a hydrogen atom and where R 2 does not mean a hydrogen atom.

In the derivative form according to method b), a compound of formula (II) is converted into a compound of formula

(IV) by known methods with an ester of chlorocarbon or chloro-thiolcarbonic acid represented by the formula

where X and z have the same meaning as stated in formula

(IV).

In this method, 4-phenoxycarbonyloxymethyl-1-phthalazone derivatives are preferred, where X and Z mean respectively an oxygen atom and a phenyl group in formula (IV) due to economic considerations as well as the availability of the product. Instead of the phenyl group, one can also use the substituted phenyl group, e.g. the p-chlorophenyl and p-nitrophenyl group, as well as the a- and (3-naphthyl group. Other phthalazone derivatives, such as 4-alkylthiocarbonyloxymethyl-l-phthalazone, 4-alkylthiocarbonyloxymethyl-l-phthalazone and 4-arylthiocarbonyloxymethyl-l- phthalazone derivatives can be used if necessary Examples of compounds of formula (IV)

is 4-methoxycarbonyloxymethyl-l-phthalazone, 4-phenoxy-carbonyloxy-methyl-l-phthalazone, 4-(p-chlorophenoxy-carbonyloxyethyl)-1-

phthalazone, 4-methylthiocarbonyloxymethyl-1-phthalazone, 4-ethylthiocarbonyloxymethyl-1-phthalazone and 4-phenylthiocarbonyloxymethyl-1-phthalazone. Furthermore, the phthalazone derivatives described above can also be used, and which have one or two substituents represented by R4 or R5 in formula (I) in one of the C-5, C-6, C-7 and C-8 positions in the phthalazone nuclei and/or the substituent represented by R 1 in formula (I) in N-2 of the phthalazone nuclei.

The compound of formula (IV) is then allowed to react with ammonia or an amine of formula (V). Procedure b) can be visualized using the following reaction core:

The reaction of the compound *IV) with the amine can be carried out in

presence or absence of solvents or diluents, e.g. methanol, ethanol and propanol. In general, the reaction proceeds easily at a temperature between 0° and 100°C, even at approx. room temperature, and is complete within a few hours. Air ammonia, or the amine can be used in excess, and usually an amount of 1 - 10 mol of amine per moles of compound (IV) satisfactorily. Examples of amines of formula (V) are primary amines, such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, amyl-, allyl-, cyclohexyl-, benzyl-, (3-dimethylaminoethyl-, γ-diethylaminopropyl- , picolyl-, and furfurylaniine, and secondary amines such as dimethylamine, diethylamine, pyrrolidine, piperidine, N-methylpiperazine and morpholine.

In the embodiment according to method c), a compound of formula (II) is converted into an ester of the chlorocarbonic acid of formula (VI) by reaction with phosgene. The intermediate product of formula (VI) is then allowed to react with ammonia or an amine of formula (IV). Procedure b) can be reproduced using the following reaction scheme:

The method c) can be carried out in two independent steps, viz

by reaction with phosgene and by reaction with amine. As the intermediate product (VI) is unstable and difficult to purify, it is preferred to carry out the process in one step without isolating the product (VI). With the embodiment according to method b), a compound of formula (II) is dissolved or suspended in an inert solvent or diluent. such as an aromatic hydrocarbon, ether, and chlorinated hydrocarbon. Examples of solvents or diluents are benzene, toluene, xylene, ethyl ether, dioxane, chloroform and ethylene-

dichloride or their mixtures. A tertiary amine is preferably added to the solution or suspension, such as di-

methylaniline, diethylaniline, triethylamine, N-alkylpiperidine and pyridine as a dehydrochlorinating agent or catalyst.

As shown in the above reaction core, two moles of hydrochloric acid are produced, and it is therefore necessary to use at least

two moles of tertiary amine. In the reaction with amine, it is possible to replace the tertiary amine with the reactant amine. The amount of phosgene is usually between 1.0 - 1.2 mol per mol phthalazone,

but excess of amine (V) used does not prevent the reaction. The reaction is carried out at a temperature between -10 - 10°C,

and is completed in 1 - 20 hours.

In carrying out method d), the compound (II) is allowed to react with an equimolar amount or an excess, especially between 1.5 - 5 mol, of the compound (VII) in an inert solvent in the absence or presence of a catalyst. As the derivatives of carbamic acid are represented by formula (VII), unsubstituted, or N-monosubstituted or N.N-disubstituted carbamyl chloride, alkyl carbamate, aryl carbamate, alkyl thiol carbamate, and aryl thiol carbamate can be used. E.g. one can mention carbamyl chloride, and then as carbamyl chloride methylcarbamyl chloride, ethylcarbamyl chloride, dimethylcarbamyl chloride, N,N-pentamethylenecarbamyl chloride and phenylcarbamyl chloride; an alkyl carbamate,

such as methyl carbamate, methyl-N-methylcarbamate, methyl-N-isopropyl-carbamate, methyl-N,N-dimethylcarbamate and methyl-N,N-(ethylene-oxo-ethylene)carbamate5 an aryl carbamate, such as phenylcarbamate, phenyl-N-methylcarbamate and phenyl-N-phenyl-carbamate5 an alkylthiol carbamate, such as methyl-N-methylthiol carbamate, ethyl-N,N-dimethylthiol carbamate, and methyl-N-pyridylthiol carbamate; an aryl thiolcarbamate, such as phenyl-N-methylthiolcarbamate and phenyl-N,N-pentamethylene carbamate. As an example of a solvent or diluent, mention may be made of an inert organic solvent, such as ethyl ether, tetrahydrofuran, dioxane, hexane, chloroform, benzene, toluene, monochloro-, dichloro- and trichlorobenzene. If desired, a catalyst can be used in this process. When the compound (VII) is a carbamyl chloride, a dehydrochlorinating agent is preferably added, such as dimethylaniline, diethylaniline, N-methylpiperidine and pyridine. When the compound (VII) is a carbamate or thiol carbamate, sulfuric acid can be used,

an organic acid, e.g. benzenesulfonic acid or toluenesulfonic acid,

an ester exchange agent such as an organotin compound such as dimethyltin oxide, dibutyltin oxide, or dibutyltin diacetate, an alkali metal acetate such as sodium acetate, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide, an alkali metal phenoxide such as sodium phenoxide. In certain cases, and while the reaction is in progress, azeotrope distillation of the alcohol formed during the reaction will significantly improve the yield of the product (I). Method d) can be carried out at a temperature between 50 - 200°C, especially 60 - 150°C. In the embodiment according to method e), the compound (VIII) is allowed to react with the hydrazine derivative (IX) in a solvent or diluent. As regards the compound (IX), hydrazine and monosubstituted hydrazine can be used, e.g. methylhydrazine, ethylhydrazine, phenylhydrazine, semicarbazide, 4-methylsemicarbazide, 4,4-dimethylsemicarbazide, methylsulfonylhydrazine, benzenesulfonylhydrazine and p-toluenesulfonylhydrazine. Aqueous methanol, ethanol or propanol can be used as a solvent or diluent. The amount of hydrazine can be used in excess, e.g. 1-20 mol, especially 2-5 mol, of hydrazine per moles of phthalazone. The reaction can be carried out o o at a temperature between 50 - 200 C, especially at approx. 100 C. The reaction according to method e) can be reproduced using of the following form;

Regardless of which method is used in the production, the product can be separated and purified using conventional

tional methods which will be described later.

The invention shall be illustrated by the following examples.

EXAMPLE 1

To a solution of 5 g of 4-hydroxymethyl-1-phthalazone in 10 ml of dried pyridine, 2 g of methyl isocyanate were added. The solution was allowed to stand at room temperature. overnight, after which it was heated for 1 hour at 80°C in a water bath. The pyridine was distilled off under reduced pressure, and the residue was recrystallized in methanol, whereby 5 g of 4-(N-methylcarbamoxymethyl)-1-phthalazone with m.p. 2 30 - 232 C. The product had;

following formula

EXAMPLE 2

1.3 g of methyl isocyanate was added to a solution of 3 g of 7-bromo-4-hydroxymethyl-2-methyl-1-phthalazone in 60 ml of dried pyridine. The solution was allowed to stand overnight at room temperature and then it was heated for 30 minutes at 80°C. The reading was evaporated under reduced pressure, and the residue was recrystallized in ethyl acetate-petroleum ether, whereby 3 g of 7-bromo-4-(N-methylcarbamoxymethyl)-2-methyl-1-phthalazone with m.p. 181 - 183°C. The product has the following formula:

EXAMPLE 3

Three grams of 4-hydroxymethyl-1-phthalazone and 5 g of 3-pyridinecarboxylic acid were dissolved in 40 ml of anhydrous pyridine. The temperature of the reaction mixture slowly increases to approx. 100°C, and was held for 40 minutes at this temperature. The solution was then heated at 125°C under reflux for 8 hours. Pyridine was distilled off from the reaction mixture, and the resulting residue was recrystallized in acetone, whereby 2.8 g of 4-(N-p-pyridylcarbamoxymethyl)-1-phthalazone with m.p. 194 - 196°C. The product had the following structure.

EXAMPLE 4

4 g of 4-hydroxymethyl-1-phthalazone, 6 g of S-methyl-N-oc-furfurylthiol carbamate and 3 g of triethylamine were added to a mixed solution consisting of 40 ml of pyridine and 10 mg of acetonitrile. A solution of 5.2 g of solvent nitrate in 10 ml of acetonitrile was added to the solution while cooling and stirring. After the addition was complete, the reaction mixture was allowed to stand for 24 hours, after which it was heated for 2 hours to 100°C. After cooling, the reaction mixture was diluted with chloroform, and the precipitate was filtered. The residue thus obtained was recrystallized in ethanol and water, whereby 3 g of 4-(N-α-furfurylcarbamoxymethyl)-1-phthalazone with m.p. 182 - 184°C.

EXAMPLE 5- 27

In a similar way as in examples 1-4, products of formula (I) were obtained from compounds of formula (II) and isocyanate of formula (III) with 70 - 90% yield, and as shown in table I.

EXAMPLE 28

1) Preparation of 4-phenoxycarboxyloxymethyl-l-phthalazone To a solution of 5 g of 4-hydroxymethyl-l-phthalazone in 25 ml of pyridine, 6 g of phenylchloroformate were added upon cooling and with stirring. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then diluted with water. The resulting precipitate was filtered and recrystallized from ether to give 6 g of 4-phenoxycarbonyloxymethyl-1-phthalazone melting at 113-114°C.

2) Preparation of carbamate

To a solution of 6 g of 4-phenoxycarbonyloxymethyl-1-phthalazone as described above in 100 ml of methanol, 2 g of ammonia were introduced at room temperature. The solution was allowed to stand overnight and then methanol was distilled from it. The residue thus obtained was recrystallized from methanol to give 3.1 g of 4-carbamoxymethyl-1-phthalazone melting at 230-232°C.

EXAMPLE 2 9

To a stirred solution of methylamine in methanol which was prepared from 4 ml of 30% aqueous monomethylamine and 50 ml of methanol was added 2 g of 4-phenoxycarbonyloxymethyl-7-methoxy-2-methyl-1-phthalazone prepared in the same way as in example 28,1). The reaction mixture was allowed to stand overnight and the methanol was distilled off. The residue was taken up in chloroform and the chloroform extract was washed successively with 5% NaOH solution and water. The chloroform was distilled off and the residue thus obtained was recrystallized from methanol-ethyl acetate to give 0.7 g of 4-(N-methyl-carbamoxymethyl)-7-methoxy-2-methyl-1-phthalazone, mp 171 - 173 °C.

EXAMPLE 30

4 g of 4-methylthiocarbonyloxymethyl-1-phthalazone prepared from 4-hydroxymethyl-1-phthalazone and methylchlorothiol-formal in the same way as in example 28, 1), was dissolved in 20 ml of methanol. 1 g of dimethylamine was added to the solution while stirring. The reaction mixture was allowed to stand at room temperature for 3 hours and was then dried under reduced pressure. The residue was recrystallized from ethyl acetate-petroleum ether to give 0.6 g of 4-(N,N-dimethylcarbamoxymethyl)-1-phthalazone melting at 174-176°C.

EXAMPLE 31-5

In the same way as in examples 28-30, the products of formula (I) were obtained from the starting compounds represented by formula (IV) and ammonia or the amines represented by formula (V) in a 70-90% yield, which shown in Table II.

EXAMPLE 51

To a stirred solution of 3.4 g of 4-hydroxymethyl-1-phthalazone and 3.2 g of dimethylaniline in 100 ml of dried toluene, a solution of 2.2 g of phosgene in 20 ml of toluene was added dropwise at a temperature of 0 - 5 °C. After completion of the addition, the reaction mixture was stirred for 3 hours at 0 - 5 oC and 3 hours at approx.

10°C. While keeping the temperature of the mixture below 10°C

A further amount of ammonia was introduced. The mixture was kept below 10°C and then allowed to stand at room temperature for 3 hours. The mixture was washed with water, the toluene layer was separated and the aqueous phase was extracted with ethyl acetate. The combined toluene and ethyl acetate solution was dried and distilled under reduced pressure. The residue thus obtained was recrystallized from methanol to give 4-carbamoxymethyl-1-phthalazone which melted at 2 30 - 2 32 oC.

EXAMPLE 52

A solution of 9.2 g of 7-chloro-4-hydroxymethyl-2-methyl-1-phthalazone and 7 g of dimethylaniline in 300 ml of dried toluene was cooled to -5-0°C. 5.5 g of phosgene were added to the solution with stirring at -5 - 0°C. After the addition of phosgene was finished, the mixture was stirred at 0-5°C for 5 hours, and then 5 ml of 30% aqueous methylamine was added at 0-5°C with stirring. The reaction mixture was stirred for one hour and then allowed to stand at room temperature for 3 hours. The mixture was washed with water and the toluene solution was dried and distilled off. The residue was recrystallized from ethyl acetate to give 6.5 g of 7-chloro-4-(N-methyl-carbamoxymethyl)-2-methyl-1-phthalazone melting at 148-149 oC.

Analysis of the elements:

EXAMPLES 53 - 5 9 ..

In a similar manner to examples 51 - 52, the products of formula (I) were obtained from the starting compounds represented by formula (II) and the amines represented by formula (V)

in a 40 - 60% yield as shown in table III.

EXAMPLE 60

A mixture of 4 g of 7-chloro-4-hydroxymethyl-2-methyl-1-phthalazone,

3 g of dimethylaniline, 2 g of methylcarbamyl chloride and 40 ml of absolute ethyl ether were refluxed for 5 hours. The reaction mixture was washed sequentially with water, 3% HCl and water. The ethyl ether was dried and distilled from. The residue was recrystallized from ethyl acetate to give 2.2 g of 7-chloro-4-(N-methyl-carbamoxymethyl)-2-methyl-1-phthalazone melting at 148-149°C.

EXAMPLE 61

To a solution of 3 g of 4-hydroxymethyl-2-methyl-1-phthalazone and 1.3 g of methyl-N-methylcarbamate in 100 ml of n-heptane, 0.3 g of sodium methoxide was added. While the reaction mixture was gently boiling, heptane was gradually distilled off. The distillate was introduced into a Dean-Stark separator, through which methanol that had been separated was withdrawn and heptane was returned to the reaction flask. After the formation of methanol had subsided,

the volume of the reaction mixture was concentrated to approx. half of the original volume when distilled. The residue was diluted with ice water and heptane was separated and the aqueous layer was extracted with ether. The heptane solution and ether extract were combined and the solution was distilled from. The residue obtained

was recrystallized from ethyl acetate-petroleum ether to give 1.7 g of 4-(N-methyl-carbamoxymethyl)-2-methyl-1-phthalazone melting at 115-116°C.

EXAMPLE 62

A mixture of 3 g of 4-hydroxymethyl-7-methoxy-1-phthalazone, 10 g of phenyl-N-methyl carbamate, 0.5 g of sodium acetate and 20 ml of trichlorobenzene was heated for 5 hours at a temperature of 80 - 90°C

in a water bath. Low-boiling substances were distilled from under reduced pressure, the resulting residue was extracted with chloroform. The chloroform was washed with water and the solvents were distilled off. The residue was recrystallized from methanol to give 2.3 g of 4-(N-methyl-carbamoxymethyl)-7-methoxy-1-phthalazone melting at 219-220°C.

EXAMPLE 63

A mixture of 1 g of 7-chloro-4-hydroxymethyl-1-phthalazone, 3 g of phenylthiocarbamate, 0.2 g of sodium acetate and 15 ml of dioxane was heated for 3 hours at a temperature of 80-90°C. By distillation in vacuum, low-boiling substances were eliminated.

The resulting residue was extracted with chloroform and the chloroform extract was washed sequentially with 5% NaOH solution and water. Chloroform was distilled from and the residue was recrystallized from methanol to give 0.5 g of 7-chloro-4-carbamoxymethyl-1-phthalazone melting at 243-245°C.

Analysis of elements:

EXAMPLE 64

1) A solution of 3 g of tu-(N-methyl-carbamoxy)-2-carbamoylaceto-phenone and 4 ml of 85% hydrazine hydrate in 100 ml of methanol was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and cooled to room temperature.

The precipitated crystals were filtered and recrystallized from methanol to give 2.5 g of 4-(N=methylcarbamoxymethyl)-1-phthalazone melting at 230-232°C. 2) w-(N-methyl-carbamoxy)-2-carbamoylacetophenone, the starting compound in 1), was prepared by the following method. 2 g of 4-oxo-3,4-dihydroisocoumarin (m.p. 147 - 148°C) was added portionwise to 60 ml of concentrated ammonia while stirring. The mixture was stirred for a further 5 hours at room temperature and then dried under reduced pressure at below 50°C. The residue was recrystallized from acetone to give 1.6 g of Cu-oxy-2-carbamoylacetof enone melting at 151-153°C. 1 g of UJ-oxy-2-carbamoylacetophenone as prepared above and 0.4 g of methyl isocyanate were dissolved in 20 ml of pyridine. The reaction mixture was allowed to stand overnight and then heated to 40°C for one hour. After the pyridine was distilled off, the residue was recrystallized from methanol-ethyl acetate to give 0.7 g of o-(N-methyl-carbamoxy)-2-carbamoylacetophenone with m.p. 180 - 182°C.

EXAMPLE 65

A solution of 2 g of o-(N-methyl-carbamoxy)-2-carbamoyl-acetophenone as described in Example 64, 2) and 5 ml of phenylhydrazine in 20 ml of ethanol was refluxed for 3 hours in a water bath. The solvent was distilled off and the residue was recrystallized from ethanol-n-hexane to give 3 g of 4-(N-methyl-carbamoxymethyl)-2-phenyl-1-phthalazone melting at 136-138°C.

EXAMPLE 66-70

In the same way as in example 1 from the reaction of 4-hydroxymethyl-1-phthalazone and B-dimethylaminoethyl isocyanate, 4-[N-(p-dimethylaminoethyl)-carbamoxymethyl]-1-phthalazone with m.p. 148 - 150°C obtained (recrystallized from ethyl acetate) obtained in 75% yield, whose structure is shown below.

Similarly, 4-[n-((3-diethylaminoethyl)-carbamoxymethyl]-1-phthalazone melting at 116 - 120°C (recrystallized from an ethyl ether), 4-[N-(γ-dimethylaminopropyl)-carbamoxymethyl] -2-phenyl-1-phthalazone melting at 159 - 160°C (recrystallized from ethyl acetate), 7-bromo-4-[N-((3-dimethylaminoethyl)-carbamoxymethyl] -1-phthalazone melting at 184 - 186 °C (recrystallized from ethyl acetate), and 4-[N-(γ-dimethylaminopropyl)-carbamoxymethyl]-2-methyl-1-phthalazone-oxalate with melting point 158 - 169 oC (recrystallized from ethanol) obtained.

EXAMPLES 71 - 78

In the same way as in Example 28, the reaction result of 4-phenoxycarbonyloxymethyl-1-phthalazone and N-methylpiperazine was 4-[N,N-(ethylene-methylimino-ethylene)-carbamoxymethyl]-1-phthalazone which melts at 152 - 154°C (recrystallized from methanol) obtained in 80% yield, the structure of which is shown below.

In a similar manner, 4-[N-(γ-diethylaminopropyl)-carbamoxymethyl]-1-phthalazone with m.p. 133 - 135°C (recrystallized from ethyl acetate/petroleum ether), 4-[N-(γ-diethylaminopropyl)-carbamoxymethyl]-7-methoxy-1-phthalazone melting at 162 - 163°C. (recrystallized

lysed from ethyl acetate), 4-[N-((3-dimethylaminoethyl)-carbamoxymethyl]-7-methoxy-1-phthalazone melting at 159 - 160°C.

(recrystallized from ethyl acetate), 6,7-dimethyl-4-[N-(p-dimethylaminoethyl)-carbamoxymethyl]-1-phthalazone melting at 172-173°C.

(recrystallized from ethyl acetate), 6,7-dimethyl-4-[N,N-(ethylene-methylimino-ethylene)-carbamoxymethyl]-1-phthalazone melting at 208 - 210°C. (recrystallized from ethanol/n-hexane), 7-chloro-4-[n,N-(ethylene-methylimino-ethylene)-carbamoxymethyl]-1-phthalazone melting at 171 - 172°C. (recrystallized from ethanol/n-

hexane), and 5-acetylamino-4-[N,N-(ethylenemethyliminoethylene)-carbamoxymethyl]-1-phthalazone melting at 243 - 245°C (recrystallized from ethanol/n-hexane) is obtained.

EXAMPLE 79-80

In the same manner as in Example 52, from the reaction of 4-hydroxymethyl-2-methyl-1-phthalazone and 3-dimethylaminoethylamine, 4-[N-((3-dimethylaminoethyl)-carbamoxymethyl]-2-methyl-1-phthalazo was obtained. n-oxalate melting at 193 - 195°C (recrystallized from ethanol) was obtained in 54% yield.In a similar manner, 4-[N-((3-dimethylaminoethyl)-carbamoxymethyl]-2-phenyl-1-phthalazone which melts at 155 - 157°C (recrystallized from ethyl acetate) is obtained.

Biological effect

After oral administration of 10 mg/kg of the compound of the present invention to a rabbit, the intensity of platelet aggregation caused by adenine diphosphate was measured by Born's method (Born, J. Physiol. 162, 67 (1962), see also O'Brien.

J. Clin. Path. 15, 452 (1962), Lancet, 1, 779 (1968).

A rabbit was injected with adrenaline (Lug/kg) 3 hours later

oral administration of the test. 5 minutes after the injection, 4.5 ml of blood was taken from the carotid artery and then diluted with 0.5 ml of a 3.8% solution of sodium citrate. After centrifugation of the blood at 1000 g for 30 minutes, 0.9 ml of the aliquots were taken from the top layer. The aliquots were

-5 -4

each added 0.1 ml of 3 x 10 molar and 10 molar los-

nings of adenosine diphosphate. Consequently, they were molar concentrations

— 6 — 5

of ADP in the serum or 3 x IO and 10 . The intensity of platelet aggregation was measured using a platelet aggregation meter (Model 169, Evans Elect. Ltd. England). The intensities of the ADP-induced platelet aggregation are shown as a percentage of the pre-injected amount.

As shown in table IV, compounds according to the present invention show lower values for ADP-induced platelet aggregation, and consequently an increase in the coagulation ability and the risk of thrombosis is prevented.

Claims (1)

Analogy method for the preparation of therapeutic active phthalazone derivatives of the general formula I where means a hydrogen atom or a lower alkyl group, R 2 means a hydrogen atom, a lower alkyl group which may be branched or cyclic, or a lower alkenyl, phenyl, tolyl, benzyl, phenethyl, di-lower-alkylamino-alkyl-, furfuryl, picolyl or pyridyl group, R^ means a hydrogen atom, a lower alkyl-, phenyl, or tolyl-, carbamoyl-, N-lower-alkylcarbamoyl-, N,N -di-lower alkylcarbamoyl, lower alkylsulfonyl or phenylsulfonyl group or tolylsulfonyl group, R^ means a hydrogen or halogen atom, a lower alkyl or lower alkoxy group, R^ means hydrogen or halogen atom, or a lower alkyl, alkoxy, amino, acetyl or benzoylamino, lower alkoxycarbonyl or carbamoyl group and R^ and R^ together with the nitrogen atom of the carbamoyl group can form a pyrrolidine, piperidine, morpholine or 4-methyl piperazine group, and R^ and R^ may be present at any of the C-5, C-6, C-7, or C-8 positions of the phthalazone core, characterized in that a) a compound of the general formula II where R^, R^ and R^ have the same meaning as stated under formula I, is allowed to react with an i cyanate of formula where R^ has the same meaning as stated in formula I with the exception of the hydrogen atom, or b) the compound of the general formula II is converted by known methods into a compound of the general formula where R_, R. oe R- have the same meaning as stated 3' 4 o in formula I, and where X means an oxygen or sulfur atom, Z means a lower alkyl group or an aryl group which may be substituted, after which the compound IV is allowed to react with ammonia or an amine of formula where and R2 have the same meaning as stated in formula I, or c) the compound of the general formula II is allowed to react with phosgene to a compound of the general formula where R^5 and R,, have the same meaning as stated in formula I, after which the intermediate compound of formula VI is allowed to react with ammonia or amine of formula V, or d) the compound of general formula II is allowed to react with a derivative of carbamic acid of formula where and R^ have the same meaning as stated in formula I, and where Y means a halogen atom, an alkoxy, aryloxy, alkylthio or arylthio group, or e) a compound of the general formula where R-p R2, R^ and R^ have the same meaning as stated in formula I, is allowed to react with a hydrazine derivative of formula where R^ has the same meaning as stated in formula I.