DE2208325A1 - - Google Patents

Description

MTENTAN ¹ VTfT ^

DR. E. WIEGAND DIPL-ING. W. NIEMANN DR. M. KÖHLER DIPL-ING. C GERNHARDT

MÖNCHEN HAMBURG

TELEPHONE: 55 5476 TELEGRAMS: CARPATENT

8000 MONKS 15,

NUSSBAUMSTRASSE 10

February 22, 1972

V. 41024 / 72- Ko / Ne

Masayuki Ishikawa, Tokyo (Japan), Michiro Inoue, Chofu-shi (Japan), Takashi Tsuchiya, Tokyo (Japan), Takio ßhimamoto, Tokyo (Japan).

New phthalazone derivatives and processes for their

Manufacturing

The invention relates to new 1-phthalazone derivatives for pharmaceutical use and processes for their manufacture.

In one aspect the invention resides in 4-carbamoxymethyl- '1-phthalazone derivatives of the general Formula:

j; CHoOCMR ₁ Ro

209842/1200

wherein R. is a hydrogen atom or an alkyl group, preferably an alkyl group with 1 to 6 carbon atoms, in particular an alkyl group with 1 to 3 carbon atoms, Rp a hydrogen atom, an alkyl group which can consist of a branched or cyclic alkyl group, preferably an alkyl group with 1 to 6 carbon atoms, an alkenyl group, preferably an alkenyl group with 2 to 5 carbon atoms, in particular an alkenyl group with 2 to 4 carbon atoms, an aryl group, preferably a phenyl or tolyl group, an aralkyl group, preferably a benzyl or phenethyl group, a dialkylaminoalkyl group, preferably an alkyl group with 1 to 5 carbon atoms, with C, - or Cp-alkylamino groups, a furfuryl group, a picolyl group or a pyridyl group, R ₂ . a hydrogen atom, an alkyl group, preferably an alkyl group with 1 to 6 carbon atoms, in particular an alkyl group with 1 to 3 carbon atoms, an aryl group, preferably a phenyl or tolyl group, a carbamoyl group, an N-alkylcarbamoyl group, preferably an N-alkylcarbamoyl group with a Alkyl group with 1 to 3 carbon atoms, a Ν, Ν-bialkylcarbamoyl group, preferably a Ν, ϊί-dialkylcarbarnoyl group, with an alkyl group with 1 to 3 carbon atoms, an alkylsulfonyl group, preferably an alkylsulfonyl group with an alkyl group with 1 to 5 carbon atoms, especially an alkyl group with 1 to 4 carbon atoms or an arylsulfonyl group, preferably an arylsulfonyl group with a phenyl or tolyl group, R ^, a hydrogen atom, a halogen atom such as Cl, Br, J or F, preferably Cl or Br, an alkyl group, preferably an alkyl group with 1 up to 6 carbon atoms, especially an alkyl group with 1 to 3 carbons material atoms

209 O A 2/1200

or an alkoxy group, preferably an alkoxy group with 1 to 4 carbon atoms, E ₁ - a hydrogen atom, a halogen atom such as Gl, Br, J or F, preferably Cl or Br, an alkyl group, preferably an alkyl group with CL- to C ^ - , in particular an alkyl group with C, - to C ₇ , an alkoxy group, preferably an alkoxy group with 1 to 4 carbon atoms, an amino group, an acylamino group, preferably an acylamino group with an acyl group with 1 to 3 carbon atoms, an alkoxycarbonyl group, preferably an alkoxycarbonyl group with a Alkoxy group with 1 to 3 carbon atoms or a carbamoyl group, where E. together with Ep can form a divalent alkylene group which can be interrupted by a heteroatom, preferably an oxygen or nitrogen atom, with the exception of N of NE Kp of the formula I .

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

a) Compounds of the general formula:

II

where E ^, E ^ and E ₁ - have the same meanings as in formula (I), with an isocyanate of the formula:

III

209842/1200

wherein R _{2 has} the same meaning as in formula (I), except for a hydrogen atom, reacted or

b) the compound of the general formula (II) is converted into compounds of the general by processes known per se Formula:

Il

CHpOC-X-Z

IV

converted, wherein R ₅ ,, R ^ and R ^ have the same meanings as in formula (I) and X is an oxygen or sulfur atom, Z is a lower alkyl group or an aryl group which may be substituted, and then the compounds of the formula (IV) with ammonia or an amine of the formula:

wherein R. and R _{2 have} the same meanings as in formula (I), reacted or

c) a compound of the formula (II) is reacted with phosgene and then the intermediate formed compound of the formula:

2098 ^ 2/1200

(I.

CH ₂ OC-Cl

VI

wherein R. ,, E and R ^ have the same meanings as in formula (I) possess, with ammonia or an amiii of the formula (V) implemented or

d) a compound of formula (II) is combined with a derivative of carbamic acid of formula

Y, VII

wherein R, and Rp have the same meanings as in formula (I) and Y have an halogen atom, an alkoxy group, an aryloxy group, an alkylthio group or an aryl » thio group means converted or

e) a combination of the general formula:

^R 4

0 O

f! II

^x - CONKp

¥ 111 ^R 5

209842/120

where R., Rp, R ^ and R, - have the same meanings as "in formula (I), with a hydrazine derivative of the formula:

NH ₂ NHR, IX

wherein R ₇ . has the same meaning as in formula (I), implemented.

The compounds according to the invention can according to can be prepared by the method given above. The compounds obtained by the above methods are new and shown in experimental atherosclerosis induced by cholesterol feeding they have a pronounced effect in preventing atherosclerosis by reducing the deposition of cholesterol at the Arterial wall was inhibited. They also prevented the increase in coagulability and thrombogenicity, induced by one-shot treatment of the animals with cholesterol or adrenaline, d. H. they prevented a shortening of the clotting times of the blood as well as an increase in the adenosine diphosphate induced Platelet aggregation in the animal. The present compounds according to the invention are valuable for treatment of atherosclerotic and thrombotic vision Diseases.

The starting materials of the invention represented by the formula (II) can per se known processes or the new processes given below.

1) 4-hydroxymethyl-i-phthalazone can be obtained from 2-carboxyacetophenone can be prepared by the reaction sequence given below. This procedure is in Ber., Volume 4-0, page 72 (1907) and Annual Report of Department of Pharmacy, Kanazawa University, Vol. 12, 1-6 (1961)

2 0 9 8 4 2/1200

described:

COCH

COCHpBr v? \ COCH ₂ OH

COOH

COOH

CH ₀ OII

2) The above procedure 1) cannot can be applied to substituted phthalazone derivatives, since the starting materials are generally inaccessible are. It has now been found that compounds of the formula:

COY ^f

wherein R ,, R ^ and R ₁ - have the same meanings as in formula (I) and Y ¹ denotes an alkoxy group or a halogen atom, can be reduced smoothly to the compounds of the formula (II) with sodium borohydride, for which reference is made to the Japanese patent application No. 58643/71

209842/1200

is shown. The compounds of the formula (X) can according to methods known per se, for example those in J. of Am. Chem. Soc, Vol. 68, 1316 (194-6) getting produced.

3) It was also found that compounds of the formula (II) by reacting a compound of the formula:

XI

wherein R ^ and R ^ have the same meanings as in formula (I) possess, with hydrazine derivatives of the formula (IX) can be produced. The compounds of the formula (XI) can be prepared in a manner analogous to that in Ber., Volume 4-0, page 72 (1907) or according to the following reaction scheme getting produced.:

COOII

COOCHo

COCl

COOCH,

CH ₂ N ₂ -CK

-COCH ₂ N ₂ H ₂ SO,
COOCHo

It

209842/1200

The production process from the compound (XI) to the compound (II) can be shown by the following scheme:

R,

0 +

C.

This process is particularly valuable for the production of phthalazone compounds used at IT-2 des Phthalazon Binges are substituted.

Examples of compounds corresponding to formula (II) include: 4-hydroxyraethyl-i-phthalazone, 4-hydroxymethyl-2-methyl-1-phthalazone, 2-ethyl-4-hydroxymethyl-1-phthalazon, 4-hydroxymethyl-2-phenyl-1-phthalazon, 4-hydroxymethyl-P-tolyl-1-phthalazon, 2-carbamoyl-4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-2- (N-methyl-carbamoyl) -1-phthalazone, 2- (li, N-dimethyl-carbaHioyl) -4-hydroxyinethyl-1-phthalazon, 4-hydroxymethyl-2-methylsulfoii7 / l-1-ph thalazon, 2-benzenesulfonyl-4-hydroxymethyl-1-ph.thalazon and 4-hydroxymethyl-2- (p-touenesulfonyl) -1-phthalazone. Furthermore, 4-hydroxymethyl-i-phthalazone perivate, the one or two substituents, for example chlorine atoms, bromine atoms, alkyl, alkoxy, amine, acetylamino, Alkoxycarbonyl or garbamoyl groups in one the position C-5, C-6, C-7 and C-8 in the phthalazone inlet have to be used. Examples include: 7-chloro-4-hydroxymethyl-1-phthalazone, 7-B3? Oia-4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-7-methoxy- ■ 2-sietϊlyl-

2098A2 / 1200

1-phthalazon, ^ -hydroxymethyl ^ -niethoxy ^ -phenyl-iphthalazon, ^ -Acetylamino- ^ hydroxymethyl-i-phthalazon, S-acetylamino - ^ - hydroxymethyl ^ -methoxy-i-phthalazon, 7-ethoxycarbonyl-4-hydroxymethyl-i-phthalazon, 8-amino-7-chloro-4-hydroxymethy1-1-phthalazon, 6,7-dimethyl-4-hydroxymethyl-1-phthalazone, 4-hydroxymethyl-2,6,7-trimethyl-1-phthalazone, 7-chloro-4-hydroxyiaethyl-2- (N-niethylcarbamoyl) -1-phthalazon, 2-benzenesulfonyl-4-hydroxymethyl-7-methoxy-1-phthalazone and 7-bromo-4-hydroxymethyl-2- (p-toluenesulfonyl) -1-phthalazone.

In process e), the starting compounds (VIII) can be prepared from the compounds of the abovementioned Formula (XI) can be prepared according to the following scheme:

iCarbaiuoy-C-CHpOH lation

CONH ₂

ι;

Il

CCH ₂ OCNR ₁ R ₂

CONH

(VIII)

As examples of the compounds (VIII) may be mentioned: ¹ V -Carbamoxy-2-carb amoylacetophenon, uj - (N-Methylcarbamoxy) -2-carbamoylacetophenon, CO - (N, N-Dimethylcarbamoxy) -2-carbamoylacetophenon, Cd - ( N, K-tetramethylene carbamoxy) -2-carbamoylacetophenone and O) - (N, N-pentamethylene carbamoxy) -2-carbamoylacetophenone. Furthermore, the acetophenone derivatives given above which contain one or two substituents corresponding to R 1 or R ₁ - according to formula (I) in one of the positions C-3, C-4, C-5 or C-6 of the phthalazone ring , can also be used.

2098 ^ 2/1200

In the embodiment of process a), the compound of formula (I) is used in an equimolar amount or an excess, in particular between 1.2 and 2 Hol, of the isocyanate (II) in an inert solvent or diluents such as benzene, toluene, chlorobenzene, acetonitrile, chloroform, dioxane, tetrahydrofuran or pyridine. The reaction is preferred at a temperature between room temperature and 150 ° C, in particular below 100 ° C carried out. The reaction is usually carried out at a temperature between 50 and 100 ° C Finished in 1 to 5 hours. In areas of room temperature, longer reaction times, for example 5 to 24 hours preferred. If necessary, a catalyst, for example a tertiary amine, such as trimethylamine, triethylamine, N-alkylpiperidines or Pyridine can be used.

Examples of the isocyanate (III) include methyl, ethyl, propyl, isopropyl, butyl, amyl, cyclohexyl, allyl, phenyl, tolyl, xylyl, β-dimethylaminoethyl 1- , γ-diethylaminopropyl -, α- and ß-furfuryl, α-, ß- and γ-picolyl, α-, ß- and γ-pyridyl isocyanates.

Instead of the isocyanates (III) it is also possible to use compounds which are in the isocyanate of the formula (III) under the Reaction conditions can be converted, and if necessary, a catalyst can be used Formation of the isocyanate can be used in situ. For example can acyl azides according to the formula

R ₂ CON ₃ ,

where R ~ has the same meaning as in formula (I), exclusively a hydrogen atom, or S-alkylthiol carbamates according to the formula:

209842/1200

Rp ^ HC-S-alkyl,

wherein Rp has the same meaning as in formula (I), exclusively of a hydrogen atom and with "alkyl" a lower alkyl group such as methyl or ethyl group is used with heating will. The S-alkylthiocarbamates can also be used in the presence a trialkylamine and a heavy metal salt such as Silver nitrate, can be used.

The inventive reaction of a compound of the formula (II) with a compound of the formula (III) comprises thus also the reaction of the compound (II) with a compound that> is capable of being converted into a compound of the formula (III) under the reaction conditions. Method a) can only be used to prepare compounds in which R. is a hydrogen atom and Rp not.

In the embodiment of process b), a compound of the formula (II) is converted into a compound of the formula (IV) by methods known per se with an ester of chlorocarboxylic acid or chlorothiolcarboxylic acid accordingly the formula:

O
Cl-CXZ

converted, in which X and Z have the same meanings as in formula (IV). In this process, 4-phenoxycarbonyloxymethyl-1-phthalazone derivatives, wherein X and Z represent an oxygen atom and a phenyl group, respectively, in the formula (IV), preferred because they are simple and economical are accessible. Instead of a phenyl group, substituted phenyl groups, for example

2098U / 1200

p-chlorophenyl, p-bromopiienyl or p-nitrophenyl groups or α- or β-naphthyl groups can be used. Other phthalazone derivatives such as 4-alkoxycarboiiyloxymethyl-1-phthalazone, ^ -alkylthiocarbonyloxymethyl-1-phthalazone and ^ arylthiocarbonyloxymethyl-i-phthalazone derivatives can also be used if necessary. Examples of compounds of the formula (IV) are ^ -Methoxycarb-onyloxymethyl-i-phthalazon, 4-phenoxycarbonyloxymethyl-i-plithalazon, 4- (p-Clilorpnenoxycarbonyloxymethyl) -1-phthaiazon, 4-M ethyl tiii ο car bony 1 oxymethyl- 1-phthalazon, ^ a'tliyltliiocarbonyloxymethyl-1-phthalazon and ^ -rhenyltriiocarbonyloxymethyl-i-phthalazon. Furthermore, the phthalazone deuuvates listed above, v / elche one or two substituents corresponding to R ₁ or R ₁ - even formula (I) in one of the positions C-5, C-6, C-7 or C-8 of the phthaiazone Ring and / or substituents corresponding to E ^ according to formula (I) on the N-2 of the phthalazone ent, can also be used.

The compound of the formula (IV) is then reacted with ammonia or an amine of the formula (V). The procedure b) can be represented by the following reaction scheme:

209842/1200

CH ₂ OK

Il

il

Cl-C-X-Z

CH ₂ OC-XZ

+ NHR ₁ R ₂

Il

CH ₂ OC-XZ

ti

CH ₂ OCNR ₁ R ₂

f + H-X-Z

The reaction of the compound (IV) with the amine can be carried out in the presence or absence of solvents or diluents, for example methanol, ethanol or Propanol. In general, the implementation is going smoothly at temperatures between 0 and 100 ° C and is complete within a few hours even at room temperature. ammonia or amine can be used in excess and usually amounts of 1 to 10 moles of amine each Moles of the compound (IV) are satisfactory. Examples of amines of the formula (V) are primary amines, such as methyl, Ethyl, propyl, isopropyl, butyl, amyl ', allyl, cyclo-

209842/1 200

hexyl, benzyl, ß- dimethylaminoethyl, γ-diethylaminopropyl, Picolyl and furfurylamine and secondary amines, such as dimethylamine, diethylamine, pyrrolidine, piperidine, N-methylpiperazine and liorpholine.

In the embodiment of the method c) is a Compound of formula (II) to form an ester of chlorocarbonic acid of the formula (VI) converted by reaction with phosgene. The intermediate of the formula (VI) is then reacted with ammonia or an Arain (V). That Method b) can be represented by the following reaction scheme will:

CHoOH

(II)

+ COCL

It

CHoOC-Cl

(VI)

+ HCl

ti

CM ₀ OC-Cl

j] t + NHR ₁ R ₂ ir \

(VI)

(V)

It

CH ₂ OCNR ₁ R ₂

+ HCl

(D

209842/1200

The process c) can be effected in two independent stages, namely the reaction with phosgene and the reaction with the amine. However, since the intermediate (VI) is labile and difficult to purify, it is preferred to carry out the process in one step without isolating the product (VI). In the embodiment of process b) is the compound according to (II) in an inert solvent or diluent, for example an aromatic hydrocarbon, an ether or a chlorinated hydrocarbon or dissolved suspended. Examples of solvents or diluents are benzene, toluene, xylene, ethyl ether, dioxane, Chloroform and ethylene dichloride or mixtures thereof. to the solution or suspension is a tertiary amine, for example Dimethylaniline, diethylaniline, triethylamine, N-alkylpipderidine and pyridine are preferred as hydrogen chloride splitting agents or catalyst added. As shown in the reaction scheme above, two moles Hydrochloric acid is formed, so it is necessary to use at least 2 moles of the tertiary amine. In the Reaction with the amine is also a replacement of the tertiary amine by the amine serving as a reactant possible. The amount of phosgene is usually 1.0 to 1.2 moles per mole of phthalazone, but an excess is a problem Application of the amine (V) does not cause the reaction. The reaction is carried out at a temperature between -10 to + 10 ° C and finishes in 1 to 20 hours.

In the embodiment of process d), the compound corresponding to (II) is used in an equimolar amount or an excess, in particular from 1.5 "to 5 mol, the compound (VII) reacted in an inert solvent in the absence or in the presence of a catalyst. As derivatives of carbamic acid according to the formula

42/1200

(VII) unsubstituted or IT-monosubstituted or Ν, Ν-disubstituted carbamyl chlorides, alkyl carbamates, aryl carbamates, alkyl thiol carbamates and aryl thiol carbamates can be used. Examples include carbamyl chlorides, such as carbamyl chloride, methyl carbamyl chloride, ethyl carbamyl chloride, dimethyl carbamyl chloride, N, 1J-P ent amethylene carbarnyl chloride and phenyl carbamyl chloride, as alkyl carbamyl chloride, for example methyl carbamate, methyl 1T-methylcarbamate, methyl 1-topropyl carbamate, methyl 1-topropyl carbamate -dimethylcarbamat and methyl ϊϊ, E- (ethyl enoxo-a thy len) carbamate as Aryicarbamate, for example phenyl carbamate, N-phenyl-methylcarbaniat and Plienyl-ri-phenylcarbaraat, thiocarbamates as alkyl, for example methyl-ii-metliylthiolcarbaraat, A thyl-KjIi-dimethylthiolcarbamate, and methyl-N-pyridylthiolcarbaiat, as arylthiolcarbamate, for example phenyl-li-niethyltliiolca3? oamat and phenyl-N, N-pentamethylene carbaruat "Examples of the solvent, or diluent are ethers, organic solvents, like Lioxane, hexane, chloroform, benzene, toluene, honochloro-, dichlorobenzene and trichlorobenzene. If necessary, a catalyst can be used in this process. If the compound (VII) consists of a carbamyl chloride, a hydrogen chloride splitting agent such as dimethyl aniline, diethyl aniline, N-methyl piperidine or pyridine is preferably added. If the compound (VII) is a carbamate or thiol carbamate, sulfuric acid, organic acids, for example benzenesulphonic acid or toluenesulphonic acid, ester interchangers, such as organotin compounds, such as dimethyltin oxide, dibutyltin oxide or dibutylsin diacetate, alkali acetates, such as sodium acetate, alkali metal oxides, or such as sodium acetate, alkali metal oxides Potassium tert-butoxide, alkali phenoxides, such as sodium phenoxide, can be used.

209842/1200

In some batches, the yield of the product (I) can be increased considerably as the reaction proceeds by azeotropic distillation of the alcohol formed during the reaction. The process d) may be at temperatures between 50 to 200 ° C, in particular from 60 to 150 ⁰ C is performed.

In the embodiment of method e), the Compound (VIII) with the hydrazine derivative (IX) in one Solvent or diluent reacted. Examples of compounds (IX) are hydrazine and monosubstituted ones Hydrazines, for example methylhydrazine, ethylhydrazine, Phenylhydrazine, semicarbazide, 4— methylsemicarbazide, 4,4— Dimethyl semicarbazide, methyl sulfonyl hydrazine, benzenesulf onylhydrazine and p-toluenesulfonylhydrazine. As a solvent or diluents are preferably used water, methanol, ethanol or propanol. the The amount of hydrazine can be in excess, for example 1 to 20 mol, in particular 2 to 5 mol of hydrazine 1 mole of the phthalazone can be used. The reaction can take place at temperatures between 50 and 200 ° C, in particular run at about 100 ° C. The reaction of process e) can be represented by the following scheme.

OO
C-CH ₂ OCNR ₁ R ₂

+ H,

(VIII)

(IX)

CHpOCNR ₁ R

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No matter which manufacturing process is used the product can be separated and purified using customary methods as described below will.

The following examples serve to further illustrate the invention without limiting it.

example 1

To a solution of 5 E 4-Hydroxryniethyl-i-phthalazon in 100 ml of dried pyridine were 2 g of methyl isocyanate admitted. The solution was left to stand at room temperature overnight and then to 80 ° C. for 1 hour heated in a water bath. The pyridine was distilled off under reduced pressure and the residue from methanol recrystallized to give 5 S ^ - (N-Hethylcarbamoxymethyl) -1-phthalazone with a melting point of 2JO to 232 ° C The product has the following formula:

0
CH ₀ OCNIICH ₃

Analysis: CHK

Calculated (%) (C ₁₁ H ₁₁ O ₃ N ₅ ) 56.65 4.75 18.02

Found (%): 56.26 4.70 18.06

209642/1200

Example 2

1.3 g of methyl isocyanate were added to a solution of 3 g of V-methyl-1-phthalazone in 60 ml of dried pyridine. The solution was left to stand overnight at room temperature and then heated to 80 ° C. for J> 0 minutes. The solution was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate / petroleum ether, 3 6 7-bromo-4- (N-methylearbamoxymethyl) -2-methyl-1-phthalazone with a melting point of 181 to 183 ° C. being obtained. The product has the following formula:

CH ₀ OCMTCH.

Analysis:

Calculated (%) Found (%):

C H N

N ₅ Br): 44.17, 3.68, 12.88

44.46 3.49 13.01 Example 3

3 g of 4-hydroxymethyl-1-phthalazone and 5 g of 3-pyridinecarboxylic acid azide were dissolved in 40 ml of anhydrous pyridine. The temperature of the reaction mixture became slow

increased to about 100 C and at this temperature during Held for 40 minutes. Then the solution was at 125 ° C

209842/1200

heated to reflux for 8 hours. That was pyridine distilled off from the reaction mixture and the obtained Recrystallized residue from acetone and 2.8 g of 4- (N-ß-pyridylcarbamoxymethyl) -1-phthalazone with a

Melting point from 194 to 196 the following structure:

C received. The product has

Elemental analysis:

Calculated (%) (C Found (%):

60 C. H N 60 , 80 4.08 18.91 4th , 42 4.27 19, üo 2O ₅ N ₄ ): example

4 g of 4-hydroxyinethyl-i-phthalazone, 6 g of S-Hethyl-H-oc-furfurylthiol carbamate and 3 g of triethylamine were added to a mixed solution of 40 ml of pyridine and 10 mg of acetonitrile added. A solution of 5 »2 g of silicon nitrate was added to the solution added in 10 ml of acetonitrile with cooling and stirring. When the addition was complete, the reaction mixture became Left to stand for 24 hours and then heated to 100 ° C. for 2 hours. After cooling down, that became The reaction mixture is diluted with chloroform and the precipitate is filtered. The chloroform was washed with water and then distilled off. The residue obtained in this way

209842/1200

was recrystallized from ethanol and water to give 3 g of 4- (N-a-furfurylcarbamoxymethyl) -1-phthalazone with a Melting point from 182 to 184 ° C.

Elemental analysis: CHN

Calculated (%) (C J3 U ₄ N): 60.19 4.38 14.04

Found (%): 60.03 4.25 14.34

Examples 5 to 27

In the same way as in Examples 1 to 4, the products of the formula (I) from the compounds of Formula (II) and an isocyanate of formula (III) obtained in yields of 70 to 90% as shown in Table I.

2098A2 / 1 200

CH ₂ OH

jl / + R ₂ NCO

(ID

(in)

Tabel

No. R,

CH-

6th ^C 6 ^H 5 3 H 7th H H 8th H 9 H 10 II 11 12th 13th

H H CH,
3 H H CH,
3 H 7- CH O CH ₅ H 7-CH ₃ O CH, H 7-ci CH,
3 H 7-C ₂ II ₅ COO CH,
3 H 7-H ₂ NCO CH ₇
3 H 5-CH ₇ COKH CH ₃ 7-ci 8-NE ₂ CH,
3

product

Melting point

(Recrystalli

sationclö-

solution)

115-116 ⁰ c

Ethyl acetate / Petroleum ether

Ethanol / n-hexane

219-220 ⁰ C methanol

171-173 ° C methanol / ethyl acetate

230-232 ⁰ C methanol

230-232 ⁰ C methanol

248-250 ⁰ C methanol

215-217 ° C acetone

228-230 ⁰ C methanol / acetone

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Table I (port setting)

R.

R,

H H CH.

H H H H H

H H

CH ₂ COMI 3

(CH _x ) ^ NCO

7-CH ₂ O 8-CH _x CONH CH 3

6-CH ₇ 3

6-CH,

H H H H H

H H H H

CH ₇ SO ₂ - H

CH ₅ C ₆ H ₄ SO ₂ -H

7-CH _;

7-CH-

7-Cl

7-Br

H H H H H H CH.

CH.

XC ₅ H ₇
Allyl

Cyclohexyl

ß-pico-

^C 6 ^H 5
CH,

CH-

CH,

product

Melting point

(Recrystalline

sation solution

solvent)

210-211 ⁰ C ethyl acetate

219-220 ⁰ C methanol

205-206 ⁰ C ethyl acetate

186-188 ⁰ C ethanol / water

203-205 ⁰ C ethanol / water

203-204 ° C methanol

193-195 ⁰ C ethanol / water

207-208 ⁰ C methanol / water

18O-182 ° C ethanol / water

223-224 ⁰ C methanol

214-215 ⁰ C acetone

252-253 ° C ethanol / n-hexane

170-171 ⁰ C ethanol

155-157 ⁰ C

Ethyl acetate /

n-hexane

209842/1200

Example 28

1) Production of 4-phenoxycarboxyloxymethyl-1-phthalazone

To a solution of 5 S 4-Hydroxymethy1-1-phthalazon 6 g of phenylchloroformate were added to 25 ml of pyridine Cooling and stirring added. The reaction mixture was left to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then diluted with water. The precipitate obtained was filtered and recrystallized from ether, so that 6 g of 4-phenoxycarbonyloxymethyl-1-phthalazone with a Melting point of 133 to 114 ° C were obtained.

2) manufacture; of the carbamate

To a solution of 6 g of the above-mentioned 4-phenoxycarbonyloxymethyl-1-phthalazone in 1OO ml Methanol was added to 2 g of ammonia at room temperature. The solution was left overnight and then that Methanol is distilled off. The residue obtained was recrystallized from methanol to give 3.1 S 4-carbamoxymethyl-1-phthalazone with a melting point of 230 to 232 ° C.

Elemental analysis : CH Ή

Calculated (%) (C ₁₀ H ₉ O ₃ N ₃ ): 54.79 4.14 19.17 Found O): 55.03 4.20 19.30

2 O 9 8 4 2/1200

Example 29

With stirring, 2 g of 4-phenoxycarbonyloxymethyl-7-methoxy-2-methyl-1-phthalazone were added to a solution of methylamine in methanol which had been prepared from 4 ml of a 30% strength aqueous Honomethylamine solution and 50 ml of methanol was prepared in the same way as in Example 28, 1). The reaction mixture was left to stand overnight and then the methanol was distilled off. The residue was taken up in chloroform and the chloroform extract was washed successively with tyitolx WaOH solution and water. The chloroform was distilled off and the residue obtained was recrystallized from methanol / ethyl acetate, yielding 0.7 g of 4- (N-methylcarbamoxymethyl) -7-methoxy-2-methyl-1-phthalazone with a melting point of 171 to 173 ° C

Elemental analysis:

(%) < ^C 1 3 ^H 15 .3P 59 C. H N Calculated 59 , 76 5.79 16.08 Found ( , 65 5.47 15.82 5W ^: example

4 g of that obtained from 4-hydroxymethyl-1-phthalazone and methylchlorothiol formate 4-methylthiocarbonyloxymethyl-i-phthalazone prepared in a manner similar to Example 28 were dissolved in 20 ml of methanol. To the solution, 1 g of dimethylamine was added with stirring. The reaction mixture was allowed to stand at room temperature for 3 hours and then dried under reduced pressure. The residue was recrystallized from ethyl acetate / petroleum ether and gave 0.6 g of 4- (N, N-dimethylcarbamoxymethyl) -1-phthalazone with a melting point of 174 to 176 ° C.

209842/1200

Elemental analysis: CHN

Calculated (%) (C ₁₂ H ₁₅ O ₅ N ₅ ): 58.29 5.30 17.00

Found (%): 58.21 5.36 17.22

Examples 31 "to 50

In a manner similar to that in Examples 28 bis, the products of the formula (I) were obtained from the starting compounds corresponding to the formula (IV) and ammonia or the amines corresponding to the formula (V) in yields of 70 to 90 % , as can be seen from the table II results.

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CH ₂ OC-XZ

(IV)

+ HIiR _n R

(V) (D

Table II

No. R,

X Z

31 H H 7-CI O O ^C 6 ^H 5 H 32 H H 7-Br O ^C 6 ^H 5 H 33 ^C 6 ^H 5 H 7-CH; O ^C 6 ^H 5 H

34 H 7-CH, 8-CH, CuNH OC ₅ H ₅ H

35 HH 7-CH, 0 OC ₆ H ₅ CH,

36 H H

7-Br

37 H 6-CH, 7-CH.

38 H H H

39 H H H

NS-

OC ₆ H ₅ H

S CH _x HR ₂ product (I) melting point (recrystallization solvent)

CH

Methanol

Methanol

166-168 ⁰ C methanol

21O-211 ° C ethyl acetate

216-218 ° C methanol

-Or,

Methanol / water

195-197 ⁰ C.

Ethyl acetate /

Petroleum ether

186-188 ⁰ C.

Ethanol /

n-hexane

Cyclo- 165-168 ° C hexyl ethanol / water

20Θ8Α2 / 1200

29 - 22Ö8325

Table II (continued)

No. B, R ₄ R ₅ XZ R Rp product (I) ^ Melting point

(Recrystallization solvent)

40 HH 7-Cl 0 C ₆ H ₅ H β-Pi-177-179 ° C

^ colyl methanol

41 HH 7-CH 0 0 C ₆ H _r H α-Fur- 203-205 ° C

^ · * Furyl methanol

42 HH 7-Cl S CH, - (CHp) ₄ - 192-193 ° C

^ Methanol /

water

43 H 6-CH ₅ 7-CH, 0 C ₆ H ₅ - (CHp) ₅ - 200-202 ⁰ C.

^ PP ethyl acetate

44 HH 7-Br SC _fi H _q - (CHp) ₉ -O- (CH ₀ ) _o - 1p "3-155 ° C

^ Methanol /

water

45 HH 7-CH O 0 ₅ C ₆ H ₅ H Iso-C IL 218-220 ⁰ C.

^ 'Methanol / ethyl acetate

46 II H 7-CH 0 0 C _n H ₁ -HC _r H _c -CH ₉ 226-227 ° C

^{5 p} op ^ methanol

47 HH 7-CH 0 0 C ₆ H ₅ - (CH ₂ ) ₅ - 214-216 ° C

- ^ methanol / - -. -. . Ethyl acetate

48 HHH 0 Cf-H ₁ - - (CH ₉ ) ^ - J ?. ⁵ "? ⁵⁸ ?, /

6p 2 ^y 5 atnylacetate /

Petroleum ether

49 II II H 0 C ₆ H ₅ - (CH ₂ ) ₂ -0- (CH ₂ ) ₂ -_ 207-209 ° C

Ethanol / water

50 CH ₅ C ₆ H ₄ SO ₂

HH 0 C ₆ H ₅ HH 168-169 ° C

^ Ethyl acetate /

n-hexanone

209 842/1200

Example 51

A solution of 3 »^ 6 4-hydroxymethyl-i-phthalazone and 3.2 g of dimethylaniline in 100 ml of dried toluene dropwise a solution of 2.2 g of phosgene in 20 ml of toluene "at a temperature of 0 to 5 ° C added. When the addition was complete, the Reaction mixture for 3 hours at 0 to 5 ° C and 3 hours stirred at about 10 ° C. The temperature of the mixture was then kept below 10 ° C and an excess Amount of ammonia introduced. The mixture was kept below 10 ° C and then at room temperature for 3 hours ditched. The mixture was washed with water, the toluene layer separated and the water phase extracted with ethyl acetate. The combined toluene and ethyl acetate solutions were dried and reduced under reduced pressure Distilled pressure. The residue obtained was recrystallized from methanol to give 4-carbamoxymethyl-1-phthalazone with a melting point of 230 to 232 ° C.

Example 32

A solution of 9 »2 g of 7-chloro-4-hydroxymethyl-2-methyl-1-phthalazone and 7 g of dimethylaniline in 3OO ml of dried Toluene was cooled to -5 to 0 ° C. In the solution were 5> 5 g of phosgene with stirring at -5 to 0 ° C introduced. After the addition of phosgene was completed, the mixture was kept at 0 to 5 ° C. for 5 hours stirred and then 5 ml of a 30 ^ strength aqueous methylamine solution added at 0 to 5 ° C under Rünrenz. That The reaction mixture was stirred for 1 hour and then for 3 hours left to stand at room temperature. The mixture was washed with water and the toluene solution was dried and distilled off. The residue was recrystallized from ethyl acetate

2098A2 / 1200

crystallized and gave 6.5 g of 7-chloro-4- (N-methylcarbamoxymethyl) -2-methyl-1-phthalazone with a melting point of 148 to 149 ° C.

Elemental analysis:

Calculated (%) (C ₁₂ H ₁₂ O ₇ N Cl): 51.15 4.26 14.92

Found (%): 50.89 4.35 14.79

Examples 55 to 59

In a manner similar to Examples 51 and. The products of the formula (I) were obtained from the starting compounds corresponding to the formula (II) and the amines corresponding to the formula (V) in a yield of 40 to 60 % , as can be seen from Table III.

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CHpOH

i) COCl ₂
U) NHR, R ₀ (V)

χ T

(ID

(D

No. R-

53 C ₆ H ₅ H

H H H H CH,

H H H H

Table III R ^

7-CH O H

7-Br 7-Cl 7-Br

7-CH ₇ OH

CH-CH-

CH,
CH,

° 6 ^H 5

Product (I)

Melting point

(Recrystallization

solution solution

middle)

136-138 ° C ethanol / n-hexane

171-173 ⁰ C methanol / ethyl acetate

209-211 ⁰ C methanol

208-209 ⁰ C methanol

236-238 ° C

Ethanol / water

β-pyridyl 222-224 ⁰ C methanol

158-159 C ethanol / n-hexane

209842/1200

Example 60

A mixture of 4 g of 7-chloro-4-hydroxymethyl-2-methyl-1-phthalazone, 3 g of dimethy aniline, 2 g of methyl carbamyl chloride and 40 ml of absolute ethyl ether was refluxed for 5 hours. The reaction mixture was successively with V / ater, 3% HCl solution and V / ater gev / ash. The ethyl ether was dried and distilled off. The residue was recrystallized from ethyl acetate, leaving 2.2 g of 7-chloro-4- (K-methylcarbamoxymethyl) -2-methyl-1-phthalazone having a melting point of 148 to 149 ° C were obtained.

Example 61

To a solution of 3 g of 4-hydroxymethyl-2-m.eth.yl-1-phthalazone and 1.3 g of methyl K-methyl carbamate in 100 ml 0.3 g of sodium methoxide was added to n-heptane. Under while gently heating the reaction mixture, the heptane was gradually distilled off. The distillate was initiated into a Dean-Stark-Palle, from which the separated Methanol was removed and the heptane returned to the reaction flask. after, the education of methanol had ceased, the volim en des The reaction mixture was concentrated to about half its original volume by distillation. The residue was diluted with ice water and the heptane separated off and the V / ace layer extracted with ether. The Hep t an Solution and the ether extract were combined and the solvent was distilled off. The residue obtained in this way was recrystallized from ethyl acetate / petroleum ether and gave 1.7 g of 4- (N-methylcarbamoxymethyl) -2-methyl-1-phthalazone with a melting point of 115 to 116 G.

2098A2 / 1200

Example 62

A mixture of 3 g of 4-hydroxymethyl-7-niethoxy-1-phthalazone, 10 g phenyl N-ynethyl carbamate, 0.5 g sodium acetate and 20 ml of trichlorobenzene was heated to a temperature of 80 to 90 ° C in a water bath for 5 hours heated. The low-boiling substances were under distilled off under reduced pressure and the residue obtained was extracted with chloroform. The chloroform solution was washed with water and the solvent was distilled off. The residue was recrystallized from methanol, where 2.3 g of 4- (N-I'ethylcarbamoxymethyl) -7-methoxy-1-phthalazone with a melting point of 219 to 220 ° C.

Elemental analysis: 12 ° 5 ^N 3 ^): 6th 44 C. 3 H N Calculated (%) (C ₂ H 43 , 17th 3 , 68 12.88 Found (%): example , 85 , 50 12.62

A mixture of 1 g of 7-chloro-4-hydroxyinethyl-1-phthalazori, 3 g of phenyl thiol carbamate, 0.2 g of sodium acetate and 15 nil Dioxane was heated to 80 to 90 ° C. for J hours. The low-boiling substances were removed by distillation in vacuo. The residue obtained was with Extracted chloroform and washed the chloroform extract successively with 5% NaOH solution and water. The chloroform was distilled off and the residue was recrystallized from methanol, giving 0.5 g of 7-chloro-4-carbamoxymethyl-1-phthalazone with a melting point of 243 to 245 ° C were obtained.

209842/1200

El em entaranalys e: I ₈ O ₅ N ₃ Cl): 47 , 55 5 , 15 16 , 56 Calculated (%) (C _1Q I 46 , 88 5 , 25 16 , 27 Found (%): example 64

1) A solution of 3 g u ;- (N-Hethylcarbamoxy) -2-carbamoylacetophenone and 4 ml of 85% hydrazine hydrate in 100 ml of methanol was refluxed for J hours. The reaction mixture was concentrated under reduced pressure and cooled to room temperature. The precipitated Crystals were filtered off and recrystallized from methanol and thereby 2.5 S 4- (IT-methylcarbamoxymethyl) -1-phthalazone with a melting point of 2JO to 232 "C.

2) <^ - (N-methylcarbaraoxy) -2-carbamoylacetophenone, the starting compound according to 1) was prepared by the following process:

2 g of 4-0xo-3,4 ~ dihydroisocoumarin (melting point 147 to 148 ° C) were proportionately to 60 ml of concentrated Ammonia added with stirring. The mixture continued Cooled for 5 hours at room temperature and then dried under reduced pressure at temperatures below 50 ° C. The residue was recrystallized from acetone and gave 1.6 g of cü-oxy-2-carbamoylacetophenone with a Melting point from 151 to 153 ° C. 1 g & J-oxy-2-carbamoylacetophenone and 0.4 g of ethyl isocyanate were in 20 ml Pyridine dissolved. The reaction mixture was left to stand overnight and then heated to 40 ° C for 1 hour. After the pyridine had been distilled off, the The residue was recrystallized from methanol / ethyl acetate and gave 0.7 g of ^ - (N-Methylcarbamorx ^ O ^ -carbanioylacetophenone with a melting point of 180 to 182 ° G.

209842/1200

Example 65

A solution of 2 g of o) - (N-methylcarbamoxy) -2-carbamoylacetophenone, as described in Example 64-, 2), and 5 nil phenylhydrazine in 20 ml of ethanol were refluxed for 3 hours on a v / water bath. The solvent was distilled off and the residue was recrystallized from ethanol / n-hexane, J g of 4- (N-methylcarbamoxymethyl) -2-phenyl-1-phthalazone having a melting point of 16 to 138 ° C. being obtained.

Examples 66 to 70

In the same V / eise as in Example 1 was in the implementation of Ύ-Hydroxyniethyl-1-phthalazon and ß-Dimethylaminoäthylisocyanat the 4 - ^ - (ß-Dimethylaminoäthyl) -carbamoxymethy.l / -1-phthalazon with a melting point of 148 to 150 ° C obtained after recrystallization from ethyl acetate in 75 % yield, the structure of which is given below:

I!
H ₀ OCNHCH ₉ CH ₀ N

CH,

In a similar way, 4- / lJ- (ß-diethylaminoethyl) -carbamoxj ⁷ rüethyl / -1-phthalazone with a melting point of 116 to 120 ° C (recrystallized from ethyl ether), 4 - / Ν- (y-dimethylaminopropyl) - carbamoxymethvl / -2-phenyl-1-phthalasone with a melting point of 159 to 160 ° C

209842/1200

(recrystallized from ethyl acetate), 7-bromine-4- / K- (B-dimethylaminoethyl) -carbamoxyinethyl / - '1-phth.alazon with a melting point of 184 to 186 ° C (recrystallized from ethyl acetate), and 4- / R- (γ-dimethylaminopropyl) -carbamoxymethyl7-2-methyl-1-phthalazone oxalate with a melting point of 168 to 169 ° C (recrystallized from ethanol) obtain.

Examples 71 to 78

In the same way as in Example 28 by the reaction of 4-phenoxycarbonyloxymethyl-i-phthalazon and N-Methylpiperazin das 4 - /] tf, N- (Ethylenmethyliminoäthylen) -carbamoxymethyl7-1-phthalazon with a melting point of 152 to 154 ° C (recrystallized from methanol) in one 80% yield obtained, the structure of which is given below:

In the same way, 4- / N- (y-diethylaminopropyl) -carbamoxymethyl7-1-phthalazone ^with a melting point of 133 to 135 ° C (recrystallized from ethyl acetate / petroleum ether), 4- _u / S- (y- Diethylaminopropyl) carbamoxymethyl / -7-methoxy-1-phthalazone with a melting point of 162 to 163 ° C (recrystallized from ethyl acetate), 4- / Ji- (B-dimethylaminoethyl) -carbamoxymethyl / -7-methoxy-1-phthalazone

209842/1 200

with a melting point of 159 to 160 ° C (recrystallized from ethyl acetate), 6,7-dimethyl-4- / Ii- (0-dimethylaminoethyl) -carbamoxymethvl7-1-phthalazon with a melting point of 172 to 173 ° C ■ (recrystallized from Ethyl acetate), 6,7-dimethyl-4- / TT, N- (ethylenemethyliminoethylene) -carbamoxymethyl7-1-phthalazon with a melting point of 208 to 210 ° C (recrystallized from ethanol / η-hexane), 7 ^ chloro-4- / N, N- (äthylenmethyliininoäthylen) -carbamoxymethyl / -i-phthalazon with a melting point of 171 to 172 ° C (recrystallized from ethanol / n-hexane) and 5-aoetylamino-4- / N, N- (ethylene methyliminoethylene) -carbamoxymethyJL / -1-phthalazone with a melting point of 243 to 245 ° C (recrystallized from ethanol / n-hexane) obtain.

Examples 79 to 80

In a similar manner as in Example 52, 2-methyl-1-hydroxymethyl-4-phthalazone by reacting and O-Dimethylaminoäthylamin 4- / TT (beta-dimethylaminoethyl) -carbamoxymethy _{<l7-2-methyl-1-phthalazonoxalat} with a melting point of 193 to 195 ° C (recrystallized from ethanol) obtained in a yield of 54%. The 4- / U- (β-dimethylaminoethyl) -carbamoxymethyl / -2-phenyl-1-phthalazone with a melting point of 155 to 157 ° C. (recrystallized from ethyl acetate) was obtained in the same way.

Example 81 (biological effect )

After oral administration of 10 mg / kg of the compound according to the invention on rabbits, the intensity of the plate aggregation caused by adenosine diphosphate induced was determined by the Born method

209842/1200

(Born, H. Physiol. 162, p. 67 (1962), see also O'Brien, J. Clin. Path. Ijj, p. 452 (1962), Lancet,

1, p. 779 (1968). C '^ fA)

The rabbit was injected with adrenaline (^ -g / kgj 3 hours after the oral administration of the sample. 5 minutes after the injection, 4.5 ml of blood was drawn from the carotid artery and then with 0.5 ml of a 3.8% solution After the blood had been centrifuged at 1000 g for 30 minutes, 0.9 ml aliquots were taken from the supernatant liquid, 0.1 ml each of a 3 ^× 10 molar and 10 molar aliquots were added to the aliquots "molar solution of adenosine diphosphate was added

-6 molar concentrations of ADP in serum 3 ζ 10 or 10 "^. The intensity of platelet aggregation was below Using the platelet aggregator iless device (model 169, Evans Elect. Ltd. England) measured. The intensities of ADP-induced platelet aggregation are given as a percentage of the pre-injection value. How out Table IV shows that the compounds according to the invention showed lower values of ADP-induced platelet aggregation, so that they prevented an increase in coagulability and thrombogenicity.

2098A2 / 12ÜÜ

Table IV

link

Saline solution (comparison) dibenzyline (comparison)

Pyridine carbamate (comparison)

Aspirin (comparison)

4- (N-methylcarbamoxymethyl) -1-phthalazone

4- (N-ethylcarbamoxyraethyl) -1-phthalazone

4— (N-methylcarbamoxy-

methyl) -2-phenyl-1-phthalazone

4- (N-methylcarbamoxymethyl) -7-methoxy-1-phthalazone

4- (N-methylcarbamoxy-

methyl) -7 ~ chloro-1-phthalazone

4- (Ν, Ν-dimethylcarbamoxymethyl) -1-phthalazone

4- (N, N-pentamethylene carbamoxymethyl) -1-phthalazone

4- (N-methylcarbamoxymethyl)

2- (N-methylcarbamoyl) -1-phthalazone

4- (N-methylcarbamoxymethyl) 2-methylsulfonyl-1-phthalazone

7-Bromo-4- (N -raethylcarbamoxymethyl) -1-phthalazone

4- (N-methyl carbamoxymethyl) -5-acetylamino-1-phthalazone Increase in the intensity of ADP-induced platelet aggregation

3 χ 10 M 10 "" - ^ M

121.8 + 7.8%

101.7 + 8.7% 106.7 + 7.5%

109.0 + 5.9% 100.8 + 6.5%

106.0 + 3.0% 111.5 + 2.6%

90.4 + 5.4% 85th, 7 + 5.2%

91.3 + 5.1% 86.0 + 5.2%

101.1 + 6.7% 96.2 + 4.8%

93.3 + 5.3% 95.4 + 5.5%

94.6 + 5.5% 95.2 + 5.7%

100.2 + 6.3% 98.6 + 6.7%

97.0 + 6.8% 96.1 + 5.8%

96.2 + 5.6% 93.2 + 6.0%

98.5 + 6.1% 96.8 + 5.1%

95.1 + 5.2% 93.9 + 5.8%

99.6 + 5.9% 9 * 6.2 + 5.6%

2 0 3.8 4 2/1 2 0 0

Claims (11)

Claims / il 4-carbamoxymethyl-i-phthalazone derivatives accordingly the general formula wherein R. is a hydrogen atom or an alkyl group, R _{2 is} a hydrogen atom, an alkyl group which can be branched or cyclic, or an alkenyl, aryl, aralkyl, dialkylaminoalkyl, furfuryl, picolyl or pyridyl group, R, a Hydrogen atom, an alkyl, aryl, carbamoyl, N-alkylcarbamoyl, Ν, Ιϊ-dialkylcarbamoyl, alkylsulfonyl or arylsulfonyl group, R ^ a hydrogen atom or a halogen atom, an alkyl or alkoxy group, Rr a hydrogen atom or halogen atom, an alkyl, alkoxy, amino, acylamino, alkoxycarbonyl or carbamoyl group and R, - together with R ₂ can form a divalent alkylene group which can be interrupted by a heteroatom, while the groups R ^ and Rr- in all positions C-5, C-6, C-7 or C-8 of the phthalazone ring can be present. 2. As a phthalazone according to claim 1 4- (N-Methylcarbamoxymethy1) -1-phthalazone. 3. As a phthalazone according to claim 1 4 - ^ - 1 sop ropy 1-carbamoxymethyl) -1-phthalazone. 209642/1200 4. As a phthalazone according to claim 1 4- (N-methylcarbamoxymethyl) -7-methoxy-1-phthalazone, 5 As a phthalazone according to claim 1 methy1carbamoxymethy1) -1-phthaiazon. 6. As a phthalazone according to claim 1 methylcar "bamoxymethyl) -1-phthalazon. 7. As. Phthalazone according to claim 1 (methylenecarbamoxymethyl) -1-phthalazone. 8. As a phthalazone according to claim 1 (N-methylcarbamoxymethyl) - 'T-phthalazone. 9. As a phthalazone according to claim 1 4-ZN-Cß-Di methylaminoethyl) carbamoxymethyl7-1-phthalazon. 10. As a phthalazone according to claim 1 4- ^ N- (γ-diethylaminoprcpyl) -carbamoxymethyl7-1-phthalazon. 11. Process for the preparation of phthalazone derivatives according to the general formula: 7-chloro-4- (N-4- (N, N-di-4- (N, N-penta-6,7-dimethyl-4- O
CH ₂ OCNR ₁ R ₂ wherein R. is a hydrogen atom or an alkyl group, Rp a hydrogen atom, an alkyl group that is branched or can be cyclic, or an alkenyl, aryl, aralkyl, dialkylaminoalkyl, furfuryl, picolyl or pyridyl group a hydrogen atom, an alkyl, aryl, Carbamoyl-, N-alkylcarbamoyl-, Ν, Ν-dialkylcarbamoyl-, Alkylsulfonyl or arylsulfonyl group, R ^ a water 209842/1200 Substance atom or a halogen atom, an alkyl or alkoxy group, R _n - a hydrogen or halogen atom or an alkyl, alkoxy, amino, acylamino, alkoxycarbonyl or carbarnoyl group and R ^ together with R ₂ can form a divalent alkylene group , which can be interrupted by a hetero atom, while R ₁ and R _{1 can be present in} all positions C-5, C-6, C-7 or C-8 of the phthalazone ring, characterized in that
a) a compound of the general formula II wherein R ,, R ^ and R, - the meanings given for formula I. with an isocyanate of the formula: R ₂ NCO, III where Rp has the same meaning as in formula I, but does not mean a hydrogen atom, is reacted, or b) a compound of the general formula II according to an known processes into a compound of the general formula: 209842/1200 H ₂ OC-XZ IV where IL, R. and Rj- have the same meanings as in Formula I and X is an oxygen or sulfur atom, Z is a lower alkyl group or an aryl group, which can be substituted, converted and then connected the compound IV with ammonia or an amine of the formula: where R. and Rp have the same meanings as for formula I own, is implemented or c) a compound of the general formula IX with phosgene to a compound of the general formula: VI 20 9 8Λ2 / 1200 wherein R ₇ -, R ₁ and Kr have the same meanings v / ie in formula I, reacted; and then the intermediate compound of the formula VI is reacted with ammonia or an amine of the formula ¹ Z, or d) a compound of the general formula II with a derivative of carbamic acid of the formula: C-X, VII where R. and R _{0 have} the same meanings vüe in formula I and Y is a halogen atom, a kV.'oy:; / - ₅ Apflox? -, j alkylthio or arylthio group, is reacted e) a compound of the general formula P O O -C-CHpOCIiR ₁ Rp YlIl, 'COHH ₀ I. vrorin R., Rp, R ₁ and R ₁ - have the same meanings v / ie in formula I, with a hydrazine »lierivat of the formula ₀ NHR. , IZ wherein R _{7 has} the same meaning as in formula I, is implemented. 209 842/1200