DE2238566A1 - NEW PHTHALAZONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

RATENTANWXLic

DR. E. WIEGAND DIPL-ING. W. NIEMANN

DR. M. KÖHLER DIPL-ING. C GERNHARDT 2238566

MÖNCHEN HAMBURG TELEPHONE: 55547i 8000 MÖNCHEN 15, TELEGRAMS = KARPATENT NUSSBAUMSTRASSE

August 4, 1972 V. 41243/72 - Ko / Ne - '

Mi chiro Inoue Kokuryo-cho, Chofu-shi, Tokyo, Japan

and

Masayuki Ishikawa Akazutsumi, Setagaya-ku, Tokyo, Japan

and

Takashi Tsuchiya Mnamikoiwa, Edogawa-ku, Tokyo, Japan

and

Takio Shimamoto Kitamachi, Shinjuku-ku, Tokyo, Japan

New phthalazone derivatives and processes for their manufacture

position

The invention relates to new ¹ phthalazone derivatives or pharmaceutically acceptable acid salts thereof for pharmaceutical use and a process for their production.

In one aspect of the invention this gives 1-phthalazone derivatives according to the general formula:

309807/1346

2233566

COH

wherein R is a hydrogen atom, an alkyl group, preferably an alkyl group with 1 to 3 carbon atoms, E. a hydrogen atom, an alkyl group, preferably an alkyl group with 1 to 3 carbon atoms, an alkylsulfonyl group, preferably an alkylsulfonyl group with 1 "to 3 carbon atoms in the alkyl group, an arylsulfonyl group, preferably a benzenesulfonyl group or toluenesulfonyl group, or an aryl group according to the general formula:

309807/13 4 6

where R ^ is a hydrogen atom, a halogen atom, for example Cl, Br, J or F, preferably Cl and Br, an alkyl group, preferably an alkyl group with 1 "to 3 carbon atoms, or an alkoxy group, preferably an alkoxy group with 1 to 3 carbon atoms, Rc a hydrogen atom, a halogen atom, such as CI, Br, J and F, preferably Cl and Br, an alkyl group, preferably an alkyl group with 1 to 3 carbon atoms, an alkoxy group, preferably an alkoxy group having 1 to 3 carbon atoms, or one Alkoxycarbonyl group, preferably an alkoxycarbonyl group with an alkoxy group having 1 to 3 carbon atoms,

E £ is 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 to 3 carbon atoms or an alkoxy group, preferably an alkoxy group with 1 to 3 carbon atoms, R Hydrogen atom, a halogen atom such as Cl, Br, J and F, preferably Cl and Br, an alkyl group, preferably an alkyl group with 1 to 3 carbon atoms, an alkoxy group, preferably an alkoxy group with 1 to 3 carbon atoms, an alkoxycarbonyl group, preferably an alkoxycarbonyl group with an alkoxy group with 1 to 5 carbon atoms, an amino group or an acylamino group, preferably an acylamino group with an acyl group with 1 to 3 carbon atoms, with the proviso that R, R ^, Ro and R ^ are not hydrogen atoms at the same time.

The above compounds can be according to one of the following processes can be produced:

a) A compound of the general formula:

309807/1346.

^R P Y
I. Γι Ar ^R 3 V
O

II

where E _x ., R ^ and R, have the same meanings as in formula (I) and Y is an alkoxycarbonyl group, preferably an alkoxycarbonyl group having an alkoxy group having 1 to 3 carbon atoms, or a haloarbonyl group having a halogen atom, such as Cl or Br , is reacted with an alkali borohydride in the presence or absence of a metal halide;

b) a compound of the general formula:

, III

wherein R, R ^ and R have the same meanings as in formula (I) is used with a hydrazine derivative of the formula:

NH ₂ NHR,

IV

implemented, where R. has the same meaning as in formula (I) excluding an aryl group;

c) a compound of the general formula:

3 0 9807/134 6 ·

where E., Ε2 and R-, the same meanings as in formula (I) and Z have an alkoxycarbonyl group, preferably an alkoxycarbonyl group having an alkoxy group with 1 up to 3 carbon atoms, an aldehyde or acyl group, preferably an acyl group with 1 to 3 carbon atoms, means, with a Grignard compound of the formula:

EMgX VI

implemented, wherein E has the same meanings as in formula '(I), except for a hydrogen atom, and X has a halogen atom, like Cl, Br or J, means.

The compounds according to the invention can be prepared by any of the above methods. These connections are new. In the case of a cholesterol feeding caused experimental atherosclerosis, they showed a pronounced effect in preventing the Atherosclerosis by reducing the cholesterol deposition inhibited the arterial walls. They also prevented the increase in coagulability and thrombogenicity, induced by shock treatment of the animals with cholesterol or adrenaline. I. E. they prevent one Abbreviation of the coagulation times of blood as well as the

309807 / 13Λ6

increase in platelet aggregation induced by adenosine diphosphate at the animal. The compounds of the invention are thus of value in the treatment of atherioskierotic ones and thrombo ti see diseases such as cerebral thrombosis, Coronary thrombosis, peripheral thrombo se, Verebr al atheri osklerose, Coronary atherosclerosis, atherosclerosis obliterans, Thromboangitis obliterans, thrombophlebitis, Angiopathy of diabetes mellitus and nephropathy of Diabetes mellitus.

The starting compounds corresponding to the formulas (II) and (III) used according to the invention can according to per se known processes or the new processes given below.

Ό The compounds of formula (II) can according to known methods, for example J. of Am. Chem. Soc., 68, page 1316 (1946) from naphthalene derivatives will. Examples of the compounds include 4-thoxy carbonyl-2-phenyl-1-ph thai azone, 4-methoxycarbony 1-2-m ethyl-1-phthalazon, 4-lthoxycarbonyl-2-methanesulfonyl-1-phthalazon, 4-methoxycarbonyl-2-benzenesulfonyl-1-phthalazon, 4-ethoxycarbonyl-2-toluenesulfonyl-1-phthalazon, 4-ethoxycarbonyl-2-tolyl-i-phthalazon, 4-methoxycarbonyl-2- (p-methoxyphenyl) -1-phthalazone, 4-Ä "thoxy carbonyl-2- (p-chlorophenyl) -i-phthalazon, 4- ethoxycarbonyl-2- (p-bromophenyl) -1-phthaiazon, 4-ethoxycarbonyl-2- (p-ethoxycarbonylphenyl) -1-phthalazone and 4-chlorocarbonyl-2-phenyl-1-phthalazone . Furthermore, 4-alkoxycarbonyl or 4-chlorocarbonyl-1-phthalazone derivatives, the one or two substituents, such as chlorine atom, bromine atoms, alkyl, alkoxy, Amino, acetylamino, alkoxycarbonyl groups in one of the Have positions C-5, C-6, C-7 and C-8 in the phthalazone ring, can also be used. Examples include 7-chloro-4-ethoxycarbonyl-1-phthalazon, 7-bromo-4-

309807/1346

methoxycarbonyl-i-pntlxalazon, 4-Ätnoxyearbonyl- ^ - methoxy-1-phthalazon, 4-ithoxycarbonyl ^ -Methoxy ^ -phenyl-i-phtha ^ lazon, 5-acetylamino - ^ - ethoxycarbonyl-i-phthalazon, 8-acetylamino- 4-ätlioxycarbonyl-7-iiietlioxy-1-p] itlialazon, 8-Amino ^ -chlor-A-ethoxycarbonyl-i-phthalazon, 6,7-dimethyl-r 4-ethoxycarbonyl-i -phthaiazon _t 4-methoxycarbonyl-2, 6,7-trimethyl-1-phthalazone, 2-benzenesulfonyl - ^ - ethoxycarbonyl-7-methoxy-1-phthalazone and 7-bromine-4-ethoxycarbonyl-2- (p-toluenesulfonyl) -i-phthalazone,

2) The compounds of the formula (III) can be prepared according to the following reaction schemes:

R.

COCH ₇

"COQH

COCH ₂ Br

COOH

(III)

ii) ^Ά 2

COOH

XCOOCH

COCl

COOCH,

COCHN

COOCH-, ^3rd

(III)

309807/13/1

In Ber. 40, page 72 (19O?) And Annual Report of Department of Pharmacy, Kanazawa University (Japan), Volume 12, pages 1 to 6 (1961) it is stated that there methylene phthalide or OJ -hydroxyacetyl-o-benzoic acid by hydrolysis of OJ -Bromoacetyl-o-benzoic acid is said to have been obtained. However, it was found to be 4-0xo-3 »4 - dihydroisocoumarin. The compounds of formula (III) which have an alkyl substituent in the 3-position can be prepared by alkylating 4-0xo-3 _l 4-dihydroisocoumarin. Examples of compounds of formula (III) include 4-oxo-3 »4-dihydrocoumarin, 3-methyl-4-oxo-3j4-dihydroisocoumarin, 3 _{liters of} 3-dimethyl-4-oxo-3,4-dihydroisocoumarin and their Derivatives which have one or more substituents, such as chlorine atoms or bromine atoms, alkyl, alkoxy, amino, acetylamino or alkoxycarbonyl groups in one of the positions C-5 »C-5» C-6, C-7 and C-8 im Contains phthalazone ring.

In the embodiment of the method a) the compound (I) with an equimolar amount or an excess, is preferably reacted the compound (I), an alkali metal borohydride such as sodium borohydride, potassium borohydride or lithium between 1.5 and 10 mol $ e Mol. The reaction is preferably carried out in the presence of a metal halide such as calcium chloride, magnesium bromide, lithium chloride, lithium bromide or lithium iodide. Sodium trimethoxyborohydride can also be used. If the compound (II) consists of a 4-alkoxycarbonyl-1-phthalazone derivative, ie Y in the formula (II) represents an alkoxycarbonyl group, lower, aliphatic alcohols such as methanol, ethanol or propanol can preferably be used as the solvent and the reaction is preferably carried out at a temperature between 0 and 150 ° C, in particular between 0 ° C and

309807/1346

100 ° C. When the compound (II) is obtained from a 4-chlorocarbonyl-1-phthalazone derivative exists, d. H. Y in formula (II) is a chlorocarbonyl group, can preferably be a solvent, such as dioxane, tetrahydrofuran or benzene can be used, and the reaction is preferably carried out in a Temperature between 0 and 100 ° C, in particular between and 50 ° C carried out.

In the embodiment of process b), a compound of the formula (III) is used in an equimolar amount or an excess, preferably 1 to 10 moles per mole the compound (III), a hydrazine derivative corresponding to the formula (IV) implemented. Examples of hydrazine derivatives include hydrazine, methylhydrazine, methanesulfonylhydrazine, Benzenesulfonyl hydrazine and p-toluenesulfonyl hydrazine. Even though the reaction can also be carried out in the absence of a solvent, it is preferably carried out in Presence of a solvent such as water, lower aliphatic alcohols e.g. methanol, ethanol or propanol, and at temperatures between 0 and 150 ° C, in particular carried out between 50 and 100 ° C.

In the embodiment of process c), the reaction can take place among those customary for Grignard reactions Conditions are carried out. The reaction is carried out in an anhydrous solvent, such as ethyl ether, Benzene or tetrahydrofuran carried out. Reaction temperatures between 0 and 100 ° C, in particular 0 and 50 ° C are preferred. The Grignard compound of the formula (V) is used in an amount of 1 bid $ mol de mol the compound of formula (VI) is used.

No matter which method of manufacture is used, the product can be separated and used according to the usual Procedures as given below are cleaned.

309807/1346

The products according to the invention can contain stable salts with pharmaceutically acceptable inorganic acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid or Hydriodic acid or organic acids such as oxalic acid, Maleic acid, citric acid, tartaric acid, nicotinic acid, salicylic acid and acetylsalicylic acid. These salts are soluble in water and can therefore be administered in the form of injections.

The following examples serve to further illustrate the invention without limiting it. All of the UV spectra given in the examples were determined in 95 % ethanol.

example 1

Under Buhren, 2 g of 7-methoxy ~ 4 ~ ethoxycarbonyl-1-phthalazone were added 3 g of sodium borohydride were added in portions in 100 ml of methanol. The reaction mixture was refluxed on a water bath for 1.5 hours. The excess of borohydride was destroyed by the addition of acetone and then distilled off as a solvent. The residue was dissolved in water and the solution adjusted to pH 6 to 7 with acetic acid and dried under reduced pressure. The residue was continuously using chloroform extracted from a Soxlet device. The chloroform was distilled off from the extract and the residue obtained was removed Recrystallized methanol, with 4 ~ hydroxymethyl-7-methoxy-1-phthalazone in an amount of 1.5 6 with a melting point of 229 to 230 ° C.

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C. H - N 58 , 25 4.89 15.58 58 , 42 4.82. 15.60

Elemental Analysis: Calculated (%) ( Found (%):

UV spectrum: ^ max 222 mp (£ = 20 700), 280 mn

( C = 9800), 286 um ( £ = 9800), 502 mu (£. = 4800), 314 mu (£ = 5000) 527 mu (£ = 3600)

Example 2

To a solution of 3 S 4-ethoxycarbonyl-2-phenyl-1-phthalazone in 150 ml of methanol were partially 1.2 g of sodium borohydride and 100 mg of calcium chloride with stirring added. The Ee action mixture was 1.5 hours on one Water bath held at reflux. After cooling, acetone was added to destroy the excess borohydride and then the solvent is distilled off. The residue was dissolved in water and the solution to pH 6 bis set. The solution was then extracted with chloroform. The chloroform extract was dried over MgSO ^ and distilled off. The residue was recrystallized from acetone and gave 2.5 g of 4-hydroxymethyl-2-phenyl-1-phthalazone with a melting point of 160 to 162 ° C.

Elemental analysis:

C H N

Calculated (%) (C ₁₅ H ₁₂ O ₂ N ₂₎ .71 * 41 4.80 11.11

Found (%): 71.43 4.70 11.50

UV spectrum: /) max 220 mji (£ = 55 200), 256 mu (e = 6700), 295 mju (£ = 7800)

309807 / 13AP.

Example 5

To a suspension of 2 g of 4,7-biethoxycarbonyl-1-phthalazone in 120 ml of methanol, which was heated to 70 to 80 ° G, were proportionally 1 g of sodium borohydride and 100 mg of magnesium bromide were added with stirring. After the addition of borohydride was completed, the reaction mixture became refluxed for 1.5 hours. The excess of borohydride was reduced by adding acetone destroyed and the solvent was distilled off. The residue was dissolved in water. The pH of the solution was increased to Set 6 to 7, and the solution was dried under reduced pressure. The backlog became continuous extracted with chloroform using a Soxlet device. The chloroform was distilled off from the extract and the residue recrystallized from methanol, giving 1.4 g of 7-ethoxy carbonyl-4-hydroxymethyl ~ 1 ~ phthalazone having a melting point of 224 to 225 ° C. The product has the following structure:

CH ₂ OH

C. H 11 N 58 , 06 4.87 11 , 29 58 , 25 4.58 , 46

Elemental analysis:

Calculated (%) (C ₁

Found (%): ,

UV spectrum: ^ max 215 m / i (E - 29 100), 2JO πψι

(£ - 22,700), 252m / i ( £ - 10,600),

262 m / i ( £ = 11,000), 5Ο5 ψ (£ - 10,300),

317 mji (e - 8500)

309807 / mF

Examples 4 to 14-

In a manner similar to Examples 1 to 3, the following products of formula (I) were made from the compounds of the formula (II ') obtained in a yield of 60 to 90%, as can be seen from Table I below.

COOC ₂ H ₅

NaBH,

CH ₂ OH

(II ¹ )

(D

7/1346

Table I.
By- product

play By. Rp R, melting UV spectrum Λ max

Nr. ^ Point (molecular absorbance)

(Circum-

stalli-

station

solvent _t medium

CH _x HH 147-148 ° C 22TmM-. 246 m

^ (Ethyl- (190P0) (6900

acetate) 255m / i <. 287mu

(740Ό). , (8400)

(650Ό) (3600)

CH _x H 7-CH _x O 181-182 ° C 223mu 283m

181-182 ° C 223mu 283mu

(Ethyl- (23600) (10700)

acetate) 289m * i 31 ^ u

(^) (5500)

)
^ (3500)

H H 7-Cl 213-214 ° C 25nyi 247% Ui

(Methanol) (41200) (83ΟΟ)

257mu 280mu (7200) · (79ÖO)

286nüi 31 Grandma

(83ÖO) (460Ό) 321mj * (3OOO)

CH, H 7-Cl 185-186 ° C 2i5mu 2i9mu

^ (Ethyl- (38900) (39WO

acetate) 25ima 257mu

(17100) (510Ό) 29 (7700)

H H 7-Br 222-223 ° C 27.17μ 220mu

(Methanol) (34000) (35900)

255πιμ 287mu

(6500) (83OÖ)

3i0mu 32Omu

(41QD) (2400)

C ^ -Hc H 7-CH, 0 206-207 ⁰ C 228mu 281 .au

^b ^ ⁵ (ethanol) (33ΟΟΟ) (102Ό0)

320mu (43ΟΟ)

H H 5-CH ^ CONH 206-207 ° C 222mu 255m> i

(Methanol) (28000) (9000)

27O 29 6

27O1HU 29 6m u

(9OOO) (11800)

• VI II 7-CH _x O 8-CH _x CONH 232-2 ⁷ AC _ ^ _ ,. _r _

^ ^? (Methanol) (14000) (4200)

328mu (2900)

309807/1346

! Table I (continued)

By- product

play Ey, Ep E _x melting UV spectrum /) max

No. ^ ρpunkt. (Molecular absorbance)

(Circum-

stalli-

station

solvent - medium)

CH _x H 7-Br 192-193 C 222ma c-τα, ψ,

* (Methanol) (38600) (138OO)

(2800)

CH _x SO ₅ HH 176-177 ° G 223 mu 260 mu

■ ° (ethanol / ("2500) (7800)

Hexane) 290mu 3O7mu

(93ΟΌ) (97ΟΌ)

P-CH _x -C ^ H SO ₀ HH 170-162 ° C 222mu 262mu

^{5 b # d} ;. ■ (ethanol / (20800) (7600)

Hexane) 295m »3i0mu

(9100) (9500)

Example ^

While stirring, 1 g of sodium borohydride was partially added at 60 to 70 ° C. to a solution of 1 g of 4-ethoxycarbonyl-2- (p-ethoxycarbonylphenyl) -1-phthalazone in 50 ml of ethanol. The reaction mixture was refluxed for 1 hour on the water bath and then the ethanol was distilled off. The residue was recrystallized from methanol and gave 4-hydroxymethyl-2- (p-ethoxycarbonylphenyl) -1-phthalazone in an amount of 800 mg with a melting point of 147 to 153 ° ^C.

309807-346

Elemental analysis:

Calculated (%) (Found (%):

CHN 66.66 4.97 8.64 66.15 4.65 8.87

Examples 16 to 24

In the same way as in Examples 1, 2, 3 and 15, the following products of the formula (I ¹ ) were obtained from the compounds of the formula (II ') in a yield of 60 to 90 % , as can be seen from the following Table II results.

R ₂ ? ^OOC 2 ^H 5

NaBH,

CH ₂ OH

. (HO

(I ¹ )

309807/1346

Table II

at R ₂ H R, ^E 4 Rc product game C. H Melting point (recrystall No. H H H -p-br lized from methanol) 16 • Η H H P-CH ₃ O 180-182 ° C 17th H H 3'-Cl 5'-ci 150 - 152 ° c 18th H , 0 H P-CH ₃ O 204-206 ° C 19th H 7-ci ' H P-CH ₃ O 191-192 ° C 20th H 7-ci H P-Br 192 - 194 ° c 21 Ή 7-Br 3'-Cl 5'-Cl 198-200 ° C 22nd 7-Br H P-Br 211-213 ° C 23 , 0 H P-Br 197-199 ° C 24 Example 25 220-224 ° C •

Mixture of 3 6 7-bromo-4-carboxy-2-methyl-1-phthalazone .and 30 ml of thionyl chloride was massive at 70 to 80 ° C for 50 minutes on a refluxing water bath heated. The excess of thionyl chloride was then distilled off and the residue was dissolved in 30 ml of dioxane. to the dioxane solution was partially 2 g NaBH ^ at 0 added to 10 ° C with stirring. The reaction mixture was further stirred for 1 hour and then the solvent was distilled off. The residue was in water dissolved and the solution extracted with chloroform. The chloroform was distilled off from the extract and the residue recrystallized from methanol / ethyl acetate, whereby 1.2 g of 7-bromo-4-hydroxymethyl-2-methyl-1-phthalazone with a melting point of 192 to 193 ° C were obtained.

309807/1346

Example 26

A solution of 1 g of 3-methyl-4-oxo-3,4-dihydroisocoumarin and 3 S hydrazine hydrate in 30 ml of ethanol refluxed for 3 hours on a water bath. The solution was cooled to room temperature and then the precipitated crystals are filtered off and recrystallized from methanol, 0.8 g of 4- (a-hydroxyethyl) · 1-phthalazone with a melting point of 158 to 159 ° C were obtained.

Elemental analysis:

C. H N 63.15 5.30 1 ^, 73 62.96 5.32 14.61

Calculated
Found (%):

UV spectrum: h max 225 nyi (16 100), 245 m / i (7700)

253 m / i (8200) 281 nyi (6400), 300 m / i (4400), 312 mji (2800)

Example 27

A solution of 3 g of 6,7-dimethyl-4-oxo-3,4-dihydroisocoumarin and 3 g of hydrazine hydrate in 30 ml of ethanol refluxed for 2 hours on a water bath. After cooling, the precipitated crystals were filtered off and recrystallized from methanol, with 2.6 g of ö ^ -dimethyl- ^ hydroxymethyl-i-phthalazone with a Melting point of 253-255 ° C were obtained.

Elemental analysis: Calculated (%) (C Found (%):

C. H N 64.69 5.92 13.72 64.42 5.86 13.90

3098Q7 / 134B

Example 28

In the same manner as implemented in Examples 26 and 27 was the 6 _t 7-dimethyl-4-oxo-dihydroisocumarin _m methylhydrazine it while 2.6 _i ^ 7- iiiiethyl-4-hydroxymethyl-1-phthalazone having a melting point of 152 "up to 153 ° ^c (recrystallized from ethyl acetate / petroleum ether).

Example 29

A solution of 3 g of 4-0xa-3j4 ^ dihydroisoeumarin and 3 g of p-toluenesulfonylhydrazine in 50 ml of ethanol was Heated for 5 hours on a water bath at the river Biiek. That Ethanol was distilled off and the residue was recrystallized from ethanol / η-hexane, the 4-hydroxymethyl-2- (ptoluenesulfonyl) -i-phthalazone with a melting point of

1:60 to 162 ° C was obtained example • I. 58 30th C. H N Elemental analysis: 57 , 18 4.27 8.48 Calculated (%) (C ₁₆ H ₁₄ O ₄ H ₂ S: , 87 4.43 8.65 Found (%):

In a manner similar to Example 26, 7-chloro-8-amino-4-oxo-3,4-dihydroisocoumarin was reacted with hydrazine to give 7-Chlo: 1-8-amino-4-hydroxymethyl-1-phthalazone with a melting point of 232 to 234 ° C (recrystallized from methanol) in a yield of 67%. . ■ ■

309807 / 13AB

UV spectrum: λ max 220 mu (24 800), 255 τημ (9000),

270 ill (9000), 296 mu (11 800)

Example 31

A solution of a Grignard compound was found

1 g of magnesium turnings and 5.86 g of methyl iodide in 100 ml absolute ethyl ether prepared by the usual method. The above Grignard reagent became dropwise a solution of 2.5 g of 4-ethoxycarbonyl-iphthalazon added in 50 ml of tetrahydrofuran at 10 to 15 ° C with stirring. The reaction was mixed

Heated at reflux for 2 hours and then a 10% H ^ SO ^ solution was slowly added. The precipitated Crystals were filtered off and recrystallized from ethanol to give 2.0 g of 4- (α-hydroxyisopropyl) -1-phthalazone with a melting point of 212 to 21-3 ° C. The compound has the following structure:

-C-OH

Elemental analysis:

CHN

Calculated (%) C ^c ^ i ^H ₁ 2 ° 2 ^N 2 ^: 64.69 5.92 13.72

Found (%): 64.55 6.01 13.93

309807/1346

Examples 52 to 58

In the same manner as in Example 31, the the following products of the formula (I) obtained from the compounds of the formula (II ') in a yield of 85 to 95%, as can be seen from Table III.

COOO,

CH ₅ MgI

(II)

fr)

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Table III

at
game
No. ^B 1 R. B. H ^E 5 product
Melting point
crystallization
solvent) 32 ^C 6 ^H 5 CH,
3 CH,
3 H H 1 * 3 - 1 * 5 ° C
(Ethanol / ether) 33 H CH,
3 CH,
3 H 7-ci 198-200 ° C
(Ethanol) 34 H CH, CH, H 7-CH, 0 218-220 ° C
(Ethanol) 35 H CH,
3 CH,
3 H 7-Br 191-193 ° C
(Ethanol) 36 CH,
3 CH ₃ CH,
3 H H 171-172 ° C
(Benzene) 37 CH,
3 CH,
3 CH,
3 H 7-CI 163-164 ° C
(Benzene) 38 p-bromine
phenyl CH,
3 CH,
3 7-CH, 0 158-159 ° C
(Methanol) Example 39

The compounds according to the invention showed a protective effect for increasing the coagulability and thrombogenicity by shock treatment of Animals with cholesterol or adrenaline as shown below.

After oral administration of 10 mg / kg of the compound according to the invention to a rabbit, the intensity of the platelet aggregation induced by adenosine diphosphate was determined by the method of Born (Born, J. Physiol, 162, page 67, (1962), see also O- Brien, J. Clin, Path. 1 £, page 452 (1962), Lancet, I _x page 779 (1968)).

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A rabbit was injected with adrenaline (1 mg / kg) 3 hours after the oral administration of the sample, 6 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 »oily solution of I sodium citrate . After the blood had been centrifuged at 1000 g for JO minutes, 0.9 ml aliquots were removed from the supernatant liquid. To the aliquots, 0.1 ml each of 3 x 10 ~ ^ -molar and 10 "-molar solutions of adenosine diphosphate were added. Thus, the molar concentrations of ADP in the serum were 3 x 10 ~ and 1Cf ** ^{7, respectively} The intensity of platelet aggregation was determined using a platelet aggregation meter (Model 169, Evans Elect. Ltd., England). The intensities of the ADP-induced platelet aggregation value are given as a percentage of the pre-injection value. As can be seen from the following Table IV, the compounds according to the invention show lower values of ADP-induced platelet aggregation, so that an increase in coagulability and thrombogenicity was prevented.

309807/1346

Table IV Compound Increase in Intensity of ^ 50

ADP induced platelet (meykp)

5 χ 10

" ⁶ M

Saline solution (Ver 121.8 + 7.8% 115.1 + 4 equal)

Dibenzyline 101.7 + 8.7% 106.7 + 7.5%

(Comparison)

Pyridonol carbamate 109.0 + 5.9% 100.8 + 6.5% (comparison)

Aspirin (comparison) 106.0 + 5.0% 111.5 + 2.6%

4-hydroxymethyl-2- 79.5 + 4.3% 77.0 + 3.3% 4000

phenyl-1-phthalazone

4- (α-hydroxyethyl) - 82.0 + 5.2% 79.5 + 5.1% 5500

1-phthal azone

4- (α-hydroxyiso- 78.5 + 2.8% 76.9 + 4.2% 5500

propyl) -1-phthala-

4-hydroxymethyl-2-84.1 + 4.2%. 82.5 + 5.6% 5000 (p-toluenesulfonyl) - ~
1-phthalazone

4-hydroxymethyl-7- 85.5 + 5.5% 81.0 + 5.6% 5500 methoxy-1-phthalazone "~

4-hydroxymethyl-2-78.4 + 5.1% 75.4 + 5.9% 5000

methanesulfonyl-1-

phthalazone

Example 40

Influence of compounds to prevent experimental atherosclerosis

The compounds according to the invention showed a pronounced effect of preventing atherosclerosis, whereby the cholesterol deposition on the artheria wall was inhibited in the experimental atherosclerosis.

309807/1346

95 healthy, male rabbits were each fed with 150 g pellets per day containing 1 % cholesterol for 15 weeks. Then 5 of the rabbits mentioned above were killed. The remaining 90 rabbits were divided into 6 groups. While all groups were fed with standardized feed, 5 groups were each administered 10 mg / kg of the compounds according to the invention, while the remaining group was treated with a placebo consisting of potato starch. After 6, 10 and 20 weeks, respectively 5 rabbits of the 6 groups were killed and the total content of cholesterol in the arterial wall was estimated by gas chromatography. The results are given in Table V below.

1. The total cholesterol content at the end of the first 15 weeks was 48.09 + 11.6 µg / mg dry weight.

2. The total cholesterol content of the 6 groups is given in the table below. The salary is in ^ ig units to 1 mg of the dried arterial wall specified. The values in the table represent the average of 5 rabbits.

309807/13 46

Table V

Groups with a period

Treatment with (weeks)

Cholesterol content (ug)

placebo 6th 30.4 _± 3.2 10 32.9 ± 2.8 20th 26.0 + 6.4 4 — hydroxymethyl-2-
phenyl-1-phthalazone 6th
10 29.4 4 2.2
12.6 + 2.5 20th 5.3 ± 3.2 4 - (<x-hydroxyethyl) -1-
phthalazone 6th
10 30.1 4 4.2
12.4 + 2.1 20th 7.3 ± 2.6 4- (ct-hydroxyisopropyl) -
1-phthalazone 6th
10 28.9 ± 4.1
14.7 4 3.5 20th 7.6 4 2.2 4-hydroxymethyl-2- (p-
toluenesulfonyl) -1-
phthalazone 6th
10
20th 29.7 ± 4.6
13.9 ± 3.8
7.4 4 3.6 4-hydroxymethyl-7-
methoxy-1-phthal azone 6th
10 28.7 4 5.1
13.6 4 3.1 20th 8.2 4 2.4

309807/1346

Claims (12)

Claims Phthalazone derivatives or acid salts thereof according to the general formula I: where E is a hydrogen atom or an alkyl group, IL a what s first off atom, an alkyl, alkylsulfonyl or arylsulfonyl group or an aryl group of the general Formula - where E ^ is a hydrogen or halogen atom, an alkyl or alkoxy group, B ₁ - is a hydrogen or halogen atom, an alkyl, alkoxy or alkoxycarbonyl group, Eo ^β ^ ^{η is a} hydrogen or halogen atom, an alkyl or alkoxy group , IU is a hydrogen or halogen atom, an alkyl, alkoxy, alkoxycarbonyl, amino or acylamino group with the proviso that E, E ^., E2 and E, 309807/1346 are not hydrogen atoms at the same time, mean. 2. phthalazone according to claim 1, characterized in that that the phthalazone from ^ - hydroxymethyl ^ -phenyl-1-phthalazon or an acid salt thereof. 3, phthalazone according to claim 1, characterized in that that the phthalazone from ^ -hydroxymethyl -? - methoxy-2-phenyl-1-phthalazone or an acid salt thereof. 4-, phthalazone according to claim 1, characterized in that that the phthalazone from 4- (oc-hydroxyethyl) -1-phthalazon or an acid salt thereof. 5 phthalazone according to claim 1, characterized in that that the phthalazone consists of 4- (oc-hydroxyisopropyl) -1-phthalazone or an acid salt thereof. 6. phthalazone according to claim 1, characterized in that that the phthalazone from 4- (a-hydroxyisopropyl) -2-phenyl-i-phthalazon or an acid salt thereof. 7-phthalazone according to claim 1, characterized in that that the phthalazone consists of 4- (ct-hydroxyisopropyl) -7-methoxy-1-phthalazone or an acid salt thereof. 8. phthalazone according to claim 1, characterized in that the phthalazone from 4 - (<x-hydroxyisopropyl) -7-methoxy-2-phenyl-1-phthalazone or an acid salt thereof. 9. phthalazone according to claim 1, characterized in that the phthalazone from 7-Ä'thoxycarbonyl-4-hydroxymethyl-1-phthalazon or an acid salt thereof. 10. phthalazone according to claim 1, characterized in that the phthalazone from 4 ~ hydroxymethyl-2- (päthoxycarbonylphenyl) -i-phthalazon or an acid salt thereof. 309807/13 Aß 11. phthalazone according to claim 1, characterized in that that the phthalazone consists of 4-hydroxymethyl-7-methoxy-1-phthalazone or an acid salt thereof. 12. Process for the preparation of phthalazone derivatives or acid salts thereof represented by the following general formula I correspond, where E is a water to ff atom or an alkyl group, E ,. a hydrogen atom, an alkyl, alkyl sulfony 1- or arylsulfonyl or an aryl group accordingly the general formula: . I. where E ^ is a hydrogen or halogen atom, an alkyl or alkoxy group, E ^ a hydrogen or halogen atom, represent an alkyl, alkoxy or alkoxycarbonyl group, B £ a hydrogen or halogen atom, an alkyl bath Alkoxy group, E ,. a hydrogen or halogen atom, an alkyl, alkoxy, alkoxycarbonyl, amino or 309807/1346 Acylamino group with the proviso that E, B., Eg and Ε ;, are not simultaneously hydrogen atoms, mean, characterized in that (a) a compound of the general formula II: II in which E., E ₂ and B, have the same meanings as in formula (I) and X is an alkoxycarbonyl group or a halocarbonyl lip, is reacted with an alkali borohydride in the presence or absence of a metal halide or (b) a compound of the general formula: I "ν III wherein E, E ₂ and E, have the same meanings as in formula (I), with a hydrazine derivative of the formula: IV in which B. has the same meaning as in formula (I), with the exception of an aryl group, or (c) a compound of the general formula: 309807/1346 where E., Ep "^ ¹¹ ^ - ^ x ^ ie have the same meanings as" in formula (I) "and Z denotes an alkoxycarbonyl, aldehyde or acyl group", with a Grignard compound of the formula: EMgX VI wherein E has the same meaning as "in formula (I), with Except for a hydrogen atom, and X has a Ealogenatom "means, is reacted and optionally the reaction product with an acid" in the above Implementations (a), 00 unci (c) is implemented. 309807/1346