DE2554703A1 - SUBSTITUTED 2- (BETA-NAPHTHYLOXY) - AETHYLPYRAZOLONE - Google Patents

Description

z 1975

The present invention relates to new pyrazolone derivatives, Process for their production and their use as pharmaceuticals.

It has already become known that some pyrazole derivatives can be used as antipyretics, analgesics and anti-inflammatory drugs (cf. G. Ehrhart and H. Ruschig, 'Arzneimittel ¹ , Volume 1, page 148 (1972)).

Substituted 2- (ß-naphthyloxy) -äthylpyrazolones are new and not described as therapeutic agents.

It has been found that pyrazolones of the general formula I

R ¹

CH

R ²

Le A 16 876

709 823/1011

255A703

in which

and R ²

and otherwise “2

for hydrogen, trifluoromethyl or one Alkyl, aryl, aralkyl or heteroacryl radical, the aforementioned radicals optionally substituted are

in the event that R denotes hydrogen, trifluoromethyl, alkyl having more than 4 carbon atoms , heteroaryl or substituted aryl or aralkyl, denotes an unsubstituted naphthyl radical

represents a substituted naphthyl radical which has 1 to 3 identical or different substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy, alkylamino, cyano, trifluoromethoxy, nitro, hydroxy, SO alkyl (η = 0 to 2) or SO _n ~ Contains trifluoromethyl (n = 0 to 2), where optionally two substituents on the aryl radical together form a branched or unbranched, saturated or unsaturated, 5- to 7-membered, isocyclic or heterocyclic ring which can contain 1 to 2 oxygen or sulfur atoms, or stands for a biphenyl radical,

have therapeutically valuable properties.

In addition to the form represented by formula I, the compounds according to the invention can also be used in one of the following tautomeric forms or as mixtures of such tauto-

1 2
merer forms exist, where R and R are given above

Mean leftovers.

Le A 16 876

- O _M

709823/1011

R ¹ . R ¹

CH ₂ CH ₂

Ia CH ₂ CH ₂ Ib

O

I I

"2 " 2

It has also been found that pyrazolones of the formula I are obtained if

A) hydrazines of the formula II

R ² - 0 - CH ₉ - CH ₉ - NH - NH ₉ II

in which

derivatives of the formula III

R has the meaning given above, with ß-keto ^ acid

R ¹ - C - CH ₀ - C III

in which

R has the meaning given above, and

X for a leaving radical such as hydroxy, alkoxy, Aralkoxy, amino or alkylamino radical

optionally in the presence of inert and basic solvents or acidic catalysts such as alkali and alkaline earth hydroxides and carbonates or such as hydrohalic acids, Sulfuric acid or sulfonic acids, converted at temperatures between 10 and 200 ° C,

Le A 16 876 - 3 -

. 7 09823/1011

or

'S-

B) Naphthoxyethyl derivatives of the formula IV

R ² - O - CH ₂ - CH ₂ - A IV

in which

2
R has the meaning given above and

A is a leaving group such as halogen or the

Dialkyloxonium, dialkylsulfonium or trialkylammonium radical or represents the aryl or trifluoromethylsulfonic acid residue,

with pyrazolone (5) derivatives of the formula V

in which

R has the meaning given above,

optionally in the presence of inert solvents and inorganic solvents or organic bases such as alkali hydroxides, carbonates, alcoholates, hydrides or amides at temperatures converts between 10 and 200 ° C,

or

C) Acetylenecarboxylic acid derivatives of the formula VI

2 "

Z-C-C = C-R VI

Le A 16 876 - 4 -

709823/1011

2 5 b 4 / O 3 * / to .

in which

R has the meaning given above and

2
Z is hydroxy, alkoxy, aralkoxy, amino or

Alkylamino radical means with hydrazines of the formula II

R ² - 0 - CH ₂ - CH ₂ - NH - NH ₂ II

in which

2
R has the meaning given above,

optionally in the presence of inert solvents and inorganic solvents or organic bases at temperatures between 50 ° and 200 ° C.

The novel β-naphthyloxyethylpyrazolones according to the invention surprisingly show strong antithrombotic effects. Of the pyrazolone (5) derivatives known from the prior art are So far, antithrombotic effects have not become known, so that the compounds according to the invention with regard to this special pharmaceutical effects represent a new class of substances and are to be regarded as an enrichment of pharmacy.

Depending on the type of starting materials used, the synthesis of the compounds according to the invention are represented by the following formula schemes, where 3-methyl-1- (2- (6-fluoro-ßnaphthyloxy) -ethyl) -pyrazolon- (5) and 3-phenyl-1- (2- (8-f luorß-naphthyloxy) -ethyl) -pyrazolon- (5) chosen as examples and the possible, optionally isolable intermediate stages of the Reaction sequence were not reproduced.

Le A 16 876 - 5 -

709823/1011

ORIGINAL INSPECTED

CH

CH

Le A 16

709823/1011

■ + /

OC ₂ H ₅

CH ₂

O ι

Le A 16 876

. 7 0982 3/1011

Process variant A. - . f ^ According to method A, a hydrazine of formula II

R ² - O - CH ₂ - CH ₂ - NH - NH ₂ II

with a ß-keto acid derivative of the formula III

, 0

1 ^

RC-CH ₀ -C III

0 ^X

brought to reaction.

In the formula II stands

2
R is preferably an unsubstituted or substituted naphthyl radical, which is replaced by one, two or three identical or different substituents from the group consisting of alkyl or alkenyl, each with up to 8 carbon atoms, in particular with up to 4 carbon atoms, alkoxy with up to 6 carbon atoms, in particular with up to to 4 carbon atoms, cycloalkyl or cycloalkenyl with 5 to 7 carbon atoms, halogen, such as fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, methyl mercapto, methylsulfonyl, trifluoromethyl mercapto, trifluoromethylsulfonyl, nitro, cyano, dialkylamino, hydroxy, carbonamido or sulfonamido, optionally through one or two straight-chain or branched alkyl groups each having 1 to 4 carbon atoms is substituted, the aforementioned alkyl groups together with the nitrogen atom being able to form a 5- to 7-membered heterocyclic ring, which optionally contains an oxygen atom as an additional hetero atom, or the other if necessary by an SO -alkyl group, where η stands for 0 or 2,

Le A 16 876 - 8 -

709823/1011

and the alkyl radical contains 1 to 4 carbon atoms and where optionally two substituents on the naphthyl ring together form a branched or unbranched one saturated or unsaturated 5- to 7-membered, isocyclic or heterocyclic ring form the -a May contain sulfur or oxygen atom, or for a BiphenyIres t.

2
R. .

The hydrazine derivatives used as starting materials according to formula II are known from the literature or can be prepared by processes known from the literature (cf.Kost, A.N., Sagitullin, R.S. uspekhi Khimii 196 4 pp. 159 ff .; Houben-Weyl Vol. X, 2, P. 40 ff).

Examples are:

2- (3-ethyl-ß-naphthyloxy) -ethylhydrazine 2- (6-ethyl-ß-naphthyloxy) -ethylhydrazine 2- (8-ethyl-ß-naphthyloxy) -ethylhydrazine 2- (6-ethyl-1-methyl-ß-naphthyloxy) -ethylhydrazine 2- (7-Ethy1-3,4-dimethyl-ß-naphthyloxy) -ethylhydrazine 2- (1 - ((Ethylthio) methyl) -ß-naphthyloxy) -ethylhydrazine 2- (3-allyloxy-ß-naphthyloxy) -ethylhydrazine 2- (1-Bromo-ß-naphthyloxy) -ethylhydrazine 2- (3-Bromo-ß-naphthyloxy) -ethylhydrazine 2- (4-Bromo-ß-naphthyloxy) -ethylhydrazine 2- (5-bromo-ß-naphthyloxy) ethyl hydrazine

Le A 16 876 - 9 -

709823/1011

2- (6-bromo-ß-naphthyloxy) -ethylhydrazine 2- (7-bromo-ß-naphthyloxy) -ethylhydrazine 2- (8-bromo-ß-naphthyloxy) -ethylhydrazine

2- (4-Bromo-1-methyl-ß-naphthyloxy) -ethylhydrazine 2- (i-Bromo-3-nitro-ß-naphthyloxy) -ethylhydrazine 2- (i-bromo-4-nitro-ß-naphthyloxy) -ethylhydrazine 2- (3-Bromo-i-nitro-ß-naphthyloxy) -ethylhydrazine 2- (6-Bromo-1-nitro-β-naphthyloxy) -ethylhydrazine 2- (6-bromo-1-chloro-β-naphthyloxy) -ethylhydrazine 2- (6-bromo-1,3-dichloro-β-naphthyloxy) ethyl hydrazine 2- (6-Bromo-1-methoxy-ß-naphthyloxy) -ethylhydrazine 2- (i-Bromo-6-methoxy-ß-naphthyloxy) -ethylhydrazine 2- (1-bromo-6-methyl-ß-naphthyloxy) -ethylhydrazine

2- (6-Bromo-4-chloro-1-methyl-ß-naphthyloxy) -ethylhydrazine

2-O-tert-butyloxy-ß-naphthyloxy) ethyl hydrazine

2- (6-tert-butyl-1-chloro-β-naphthyloxy) -ethylhydrazine

2- (1-chloro-4-nitro-ß-naphthyloxy) -ethylhydrazine 2- (i-chloro-6-fluoro-β-naphthyloxy) -ethylhydrazine 2- (4-chloro-1-methyl-ß-naphthyloxy) -ethylhydrazine 2- (1-chloro-ß-naphthyloxy) -ethylhydrazine 2- (3 ~ chloro-ß-naphthyloxy) -ethylhydrazine 2- (4-chloro-ß-naphthyloxy) ethyl hydrazine 2- (6-chloro-ß-naphthyloxy) -ethylhydrazine 2- (8-chloro-ß-naphthyloxy) -ethylhydrazine 2- (1,3-dichloro-β-naphthyloxy) ethyl hydrazine 2- (1,4-dimethoxy-ß-naphthyloxy) ethyl hydrazine 2- (3,6-dimethoxy-ß-naphthyloxy) ethyl hydrazine 2- (6,7-dimethoxy-β-naphthyloxy) ethyl hydrazine 2- (7,8-dimethoxy-β-naphthyloxy) ethyl hydrazine 2- (3,5-dimethyl-β-naphthyloxy) -ethylhydrazine 2- (6,7-dimethyl-ß-naphthyloxy) -ethylhydrazine 2- (7,8-dimethyl-ß-naphthyloxy) -ethylhydrazine

Le A 16 876 - 10 -

70982 3/1011

255A703

2- (1,6-Dinitro-ß-naphthyloxy) -ethylhydrazine 2- (4,8-Dinitro-ß-naphthyloxy) -ethylhydrazine 2- (6-fluoro-β-naphthyloxy) -ethylhydrazine 2- (8-fluoro-ß-naphthyloxy) -ethylhydrazine 2- (3-fluoro-ß-naphthyloxy) -ethylhydrazine 2- (8-iodo-ß-naphthyloxy) ethyl hydrazine 2- (8-isopropyl-ß-naphthyloxy) ethyl hydrazine 2- (6-methylmercapto-ß-naphthyloxy) -ethylhydrazine 2- (1- (methylmercaptomethyl-ß-naphthyloxy) -ethylhydrazine 2- (1- (methoxymethyl) -ß-naphthyloxy) -ethylhydrazine 2- (1-methoxy-ß-naphthyloxy) -ethylhydrazine 2- (3-methoxy-ß-naphthyloxy) ethyl hydrazine 2- (4-methoxy-ß-naphthyloxy) -ethylhydrazine 2- (1- (methylsulfonyl) -ß-naphthyloxy) -ethylhydrazine 2- (3- (methylsulfonyl) -ß-naphthyloxy) -ethylhydrazine 2- (5- (methylsulfonyl) -ß-naphthyloxy) -ethylhydrazine 2- (7- (methylsulfonyl) -ß-naphthyloxy) -ethylhydrazine 2- (3- (methylsulfinyl) -ß-naphthyloxy) -ethylhydrazine

2- (6- (trifluoromethylsulfonyl) -ß-naphthyloxy) -ethylhydrazine

2- (6- (Dimethylaminomethyl) -ß-naphthyloxy) -ethylhydrazine 2- (1-nitro-ß-naphthyloxy) -ethylhydrazine 2- (3-nitro-ß-naphthyloxy) -ethylhydrazine 2- (4-nitro-ß-naphthyloxy) -ethylhydrazine 2- (5-nitro-ß-naphthyloxy) -ethylhydrazine 2- (7-nitro-ß-naphthyloxy) -ethylhydrazine 2- (8-nitro-ß-naphthyloxy) -ethylhydrazine 2- (6-propyl-β-naphthyloxy) -achylhydrazine 2- (3-trifluoromethyl-ß-naphthyloxy) -ethylhydrazine 2- (4-trifluoromethyl-ß-naphthyloxy) -ethylhydrazine 2- (6-trifluoromethyl-β-naphthyloxy) -ethylhydrazine 2- (3,4,7-trimethyl-β-naphthyloxy) -ethylhydrazine 2- (3,5,8-trimethyl-β-naphthyloxy) ethyl hydrazine 2- (1/3, x 5-tribromo-ß-naphthyloxy) -ethylhydrazine 2- (1, 4, 6-Tribroiti-ß-naphthyloxy) -ethylhydrazine 2- (1 / 3,4-trichloro-ß-naphthyloxy) ethyl hydrazine 2- (1,3,6-trichloro-β-naphthyloxy) ethyl hydrazine

Le A 16 876 -11 -

709823/1011

25b4703

In the formula III stands

R preferably for a hydrogen atom, a trifluoromethyl group, a straight-chain or branched alkyl group with 1 to 4 carbon atoms, which is optionally replaced by halogen, Alkoxy is substituted by 1-2 C atoms, methyl mercapto or phenoxy, or for a carbalkoxyalkyl radical or a pyridyl radical

or for an unsubstituted or substituted phenyl radical which is replaced by 1-2 identical or different substituents from the group consisting of alkyl or alkenyl with up to 4 carbon atoms, alkoxy with up to 4 carbon atoms, cycloalkyl or cycloalkenyl with 5 to 7 carbon atoms, halogen, such as fluorine, Chlorine or bromine, trifluoromethyl, trifluoromethoxy, nitro and phenyl is substituted,
or

for an unsubstituted or substituted benzyl radical which is replaced by 1 or 2 identical or different substituents from the group consisting of alkyl or alkenyl with up to 4 carbon atoms, alkoxy with up to 4 carbon atoms, cycloalkyl or cycloalkenyl with 5 to 7 carbon atoms, halogen, such as fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, Nitro or phenyl is substituted.

The ß-keto acid derivatives used as starting materials according to formula III are known from the literature or can be prepared by processes known from the literature (cf. Org. Synth. Coll. I, p. 249).

Le A 16 876 - 12 -

709823/1011

25o47Q3

Examples are:

Ethyl acetoacetate Methyl acetoacetate Acetoacetic acid n-propyl ester Acetoacetic acid isopropyl ester Acetoacetic acid n-butyl ester Trifluoroacetoacetic acid ethyl ester Propionylacetic acid methyl ester Benzoylacetic acid ethyl ester (4-chlorobenzoyl) -acetic acid ethyl ester (3-methylbenzoyl) -acetic acid methyl ester (4-Methoxybenzoyl) -acetic acid ethyl ester (3-Nitrobenzoyl) -acetic acid ethyl ester (Phenylacetyl) -acetic acid ethyl ester ((4-fluorophenyl) -acetyl) -acetic acid methyl ester ((3-Trifluoromethylphenyl) acetyl) acetic acid ethyl ester (Methylmercapto) acetyl acetic acid ethyl ester (Cyclohexyl) acetyl acetic acid ethyl ester

Suitable diluents are all inert and - if miscible with water - organic, if appropriate diluted with water Solvent in question. These preferably include hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, Alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether, ethers such as tetrahydrofuran, Dioxane, glycol dimethyl ether, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric acid triamide, Sulphoxides such as dimethyl sulphoxide, sulphones such as sulfolane and bases such as pyridine, picoline, collidine, lutidine and quinoline.

Le A 16 876 - 13 - _{Λ Λ} .

709823/1011

The basic condensing agents are inorganic and organic Bases in question.

These preferably include alkali hydroxides such as sodium hydroxide, potassium carbonate and alcoholates such as sodium alcoholate and potassium alcoholate.

Inorganic and organic acids are suitable as acidic catalysts. These preferably include hydrohalic acids, Sulfuric acid and sulfonic acids such as toluenesulfonic acid and trifluoromethylsulfoiic acid.

The reaction temperatures can vary within a wide range will. In general, between 10 and 200 ° C., preferably between 20 and 100 ° C., are used Normal pressure, but you can also work in closed vessels at higher pressure.

When carrying out the method according to the invention according to In reaction scheme A, 1 mol of the hydrazine and 1 mol of the β-keto acid ester are reacted. You can do both start from an acid addition salt of the hydrazine as well as from the hydrazine in free form.

The addition of 1 to 10% of a catalyst is advantageous.

It is also possible to proceed in such a way that an appropriate amount of a base is used to neutralize any hydrazine salt chosen added to the reaction mixture.

The reaction can also be carried out in such a way that one first obtains an open-ring compound and this then in a second Reaction step thermally or by the action of a basic or acidic condensation agent to the invention Compounds cyclized.

Le A 16 876 - 14 -

709823/101 1

However, the single-stage synthesis is particularly advantageous.

The compounds according to the invention fall in this procedure in the form of their salts and can by recrystallization from a suitable organic solvent or by dissolving with dilute sodium hydroxide solution, filtration in the presence of animal charcoal and reprecipitation with dilute acids getting cleaned.

Process variant B

According to method B, a naphthoxyethyl derivative of the formula IV R ² - O - CH ₂ - CH ₂ - A IV

with a Pyrazolone 0 (5 )-derivative the formula V V Γ r ^r1 X j implemented. I.
H

The formula IV says

A preferably for a leaving radical such as halogen or the dialkyloxonium, dialkylsulfonium or trialkylammonium radical, or the phenyl or trifluoromethyl sulfonic acid residue,

but especially for chlorine or bromine, and 2
R preferably has that specified under process variant A.

Meaning.

Le A 16 876 - 15 -

709823/1011

The compounds of the formula IV used as starting materials are known from the literature or can be prepared by methods known from the literature (cf., for example, Houben-Weyl, 'Methods of Organic Chemistry ¹ , Volume V, 3 (1962) and Volume V, 4 (196O)). Examples of the halogen compounds used in particular include:

2- (ß-naphthyloxy) ethyl chloride 2- (ß-naphthyloxy) ethyl bromide 2- (6-Bromo-ß-naphthyloxy) ethyl bromide 2- (6-n-Buty1-1-chloro-ß-naphthyloxy) ethyl chloride 2- (8-chloro-β-naphthyloxy) ethyl chloride 2- (5,8-dibromo-β-naphthyloxy) ethyl chloride 2- (6/7-dimethoxy-ß-naphthyloxy) ethyl chloride 2- (1,6-dinitro-β-naphthyloxy) ethyl chloride 2- (8-fluoro-β-naphthyloxy) ethyl chloride 2- (8-isopropyl-ß-naphthyloxy) ethyl chloride 2- (1-isopropenyl-ß-naphthyloxy) ethyl chloride 2- (6-methylmercapto-ß-naphthyloxy) ethyl chloride

2- (1 - ((Methylmercapto) methyl) -ß-naphthyloxy) ethyl chloride

2- (1- (methoxymethyl) -ß-naphthyloxy) ethyl chloride 2- (6-methoxy-ß-naphthyloxy) ethyl chloride 2- (3-methoxy-5-nitro-ß-naphthyloxy) ethyl chloride 2- (5-methylsulfonyl-ß-naphthyloxy) ethyl chloride 2- (6-methyl-ß-naphthyloxy) ethyl chloride 2- (1-methylthio-ß-naphthyloxy) ethyl chloride 2- (6-nitro-ß-naphthyloxy) ethyl chloride 2- (6-propyl-ß-naphthyloxy) ethyl chloride 2- (5-trifluoromethyl-ß-naphthyloxy) ethyl chloride

2- (5-trifluoromethyl sulfonyl-ß-naphthyloxy) ethyl chloride

Le A 16 876 - 16 -

709823/1011

25b4703

W V (β

In Formula V

R ¹

0 Ν ™ V

H
R has the meaning given under process variant A.

The pyrazolone (5) derivatives used as starting materials according to formula V are known from the literature or can be prepared by methods known from the literature (cf. e.g. B. Graham et al, J. Amer. former Soc. 7-1, 983 (1949); R. Jones et al, Tetrahedron 19_, 1497 (1963)).

3- (2-Ethoxyethyl) pyrazolone-5 3- (2-propyloxyethyl) pyrazolone-5 3- (2-n-Butyloxyethyl) -pyrazolon-5 3- (2-iso-propyloxyethyl) -pyrazolon-5 3- (4-chlorophenyl) pyrazolone-5 3- (3,4-dimethylphenyl) pyrazolone-5 3- (4-nitrophenyl) pyrazolone-5 3- (3-trifluoromethylphenyl) pyrazolone-5 3- (Cyclohexylmethyl) -pyrazolone-5 3-Benzyl-pyrazolone-5 3- (3,4-Difluorobenzyl) -pyrazolone-5 3- (4-Nitrobenzyl) pyrazolone-5 3- (methoxycarbonylmethyl) pyrazolone-5

All inert solvents can be used as diluents. These preferably include hydrocarbons such as benzene, toluene, Xylene, alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether, ethers such as tetrahydrofuran, Dioxane, glycol dimethyl ether, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide and sulfones such as suIfolan.

Le A 16 876 - 17 -

709823/101

ο, 25b4703

Inorganic and organic bases are suitable as bases. These preferably include alkali metal hydroxides and carbonates such as sodium hydroxide and carbonate, alcoholates such as sodium alcoholate, alkali hydrides and amides such as sodium hydride or Sodium amide.

The reaction temperatures can vary within a wide range will.

It is preferred to work between 20 and 120.degree. You work under normal pressure, but it can also be done in closed vessels be worked at higher pressure.

When carrying out the process according to the invention according to reaction scheme B, first of all in a suitable solvent represented a salt from one mole of the pyrazolone derivative V with the aid of an equimolar amount of a base. To the solution one mole of the halogen compound is added to this salt and the entire reaction mixture is preferably added at an elevated temperature touched.

The compounds according to the invention are preferably isolated such that the solvent is distilled off in vacuo, the residue is taken up in water and the aqueous mixture weakly sour. The compounds according to the invention obtained in this procedure can be purified by recrystallization Easily clean with a suitable solvent.

Le A 16 876 - 18 -

709823/1011

Process variant C

According to method C, an acetylenecarboxylic acid derivative is used

Formula VI

Il

Z ² - C - C = C - R ¹ VI

with hydrazines of the formula II

R ² - O - CH ₂ - CH ₂ - NH - NH ₂ II

implemented.
In Formula VI has

R preferably has the meaning described under variant A.

and
2

Z preferably represents hydroxyl, an optionally branched one Alkoxy group with 1 to 6 carbon atoms, in particular an alkoxy group with 1 to 2 carbon atoms, a benzyloxy, an amino, an alkylamino or a dialkylamino group each having 1 to 4 carbon atoms per alkyl group.

The acetylenecarboxylic acid derivatives of the formula VI used as starting materials are known from the literature or can be prepared by methods known from the literature (see, for example, Beilstein's Handbook of Organic Chemistry 2.ι ^ΙΙΣ '1447 ff (1961) and 9_, III, 3061 ff (1971)).

Examples are:

Ethyl propiolate, n-butyl propiolate, isopropyl propiolate, Benzyl propiolate, propiolic acid amide, propiolic acid dimethylamide, propiolic acid ethylamide, tetrolic acid ethyl ester, Tetrolic acid n-propyl ester, tetrolic acid isopropyl ester, Ethyl phenylpropiolate, butyl phenylpropiolate, isopropyl phenylpropiolate, phenylpropiol

Le A 16 876 - 19 -

7 0 9 8 2 3/1011

acid benzyl ester, phenylpropiolic acid amide, phenylpropiolic acid ethylamide, Phenylpropiolic acid dimethylamide.

In the formula, R has the meaning given under process variant A. With regard to the presentation and indication of examples The statements under process variant A. also apply.

Suitable diluents are all inert and - if miscible with water - optionally organic diluted with water Solvent in question. These preferably include hydrocarbons such as benzene, toluene, xylene, halogen, hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, Alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether, ethers such as tetrahydrofuran, Dioxane, glycol dimethyl ether, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, sulfones such as suIfolan and bases such as pyridine, picoline, collidine, lutidine and quinoline.

The basic condensing agents are inorganic and organic Bases in question. These preferably include alkali hydroxides such as sodium hydroxide, potassium carbonate and alcoholates such as sodium alcoholate and potassium alcoholate.

The reaction temperatures can vary within a wide range will. In general, between 50.degree. And 200.degree. C., preferably between 70.degree. And 150.degree. C., is used. One works at normal pressure, however, it is also possible to work in closed vessels at higher pressure.

Le A 16 876 - 20 -

709823/101 1

2 b b 4 7 O

When carrying out the method according to the invention according to Reaction Scheme C is optionally used in a suitable Diluent 1 mole of the acetylenecarboxylic acid derivative VI reacted with 1 mole of hydrazine II. The usually crystalline, if appropriate after evaporation of the diluent accruing compounds according to the invention can easily by recrystallization from a suitable solvent getting cleaned.

The amounts stated in process variants A to C. can of course be varied slightly.

In addition to the preparation examples mentioned, the following are according to the invention Active ingredients mentioned in detail:

Le A 16 876 - 21 -

709823/101 1

¹ g of 3-methyl-1- (2- (3-allyloxy-β-naphthyloxy) -ethyl) -pyrazolone- (5)> 3-methyl-1- (2- (6-bromo-β-naphthyloxy) -ethyl ) -pyrazolon- (5) £ 3-methyl-1- (2- (3-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) oo 3-methyl-1- (2- (4-bromo- ß-naphthy loxy) ethyl) pyrazolone (5) σν

3-methyl-1- (2- (6-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethyl-i- (2- (7-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (8-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (4-bromo-1-methyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-methyl-1- (2- (i-bromo-3-nitro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (1-bromo-4-nitro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (3-bromo-1-nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5)

3-methyl-1- (2- (6-bromo-1-chloro-β-naphthyloxy) ethyl) -pyrazolone- (5) ^-1 3-methyl-1- [2- (6-bromo-1,3 -dichlor-β-naphthyloxy) -ethyl) -pyrazolone- (5) - »3-methyl-1- (2- (6-bromo-1-methoxy-β-naphthyloxy) -ethyl) -pyrazolone- (5) 3 -Methyl-1- (2- (i-bromo-6-methoxy-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-methyl-1- (2- (i-bromo-6-methyl-ß- naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (6-bromo-4-chloro-1-methyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl- 1- (2- (1- (2-butenyl) -β-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl1-1- (2- (6-tert-butyl-β-naphthyloxy) -ethyl ) -pyrazolon- (5) 3-methyl-1- (2- (4-tert-butyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

3-methyl-1- (2- (6-butyl-5-ethyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) <π

3-methyl-1- [2- (δ-tert-butyl-i-chloro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) ^

3-methyl-1- (2- (1-chloro-β-naphthyloxy) -ethyl) -pyrazolon- (5) - * J

3-methyl-1- (2- (3-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (4-CUlOr-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

3-trifluoromethyl-1- (2- (6-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethyl-1- (2- (8-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethyl-i- (2- (1,3-dichloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

3-trifluoromethyl-1- (2- (1,7, 8-trichloro-ß-naphthyloxy) -ethy]) - pyrazolone- (5) 3-trifluoromethyl-i- (2- (1-chloro-4-nitro-ß-naphthyloxy) -ethy]> - pyrazolone- (5) 3-trifluoromethyl-1- (2- (1-chloro-6-fluoro-ß-naphthyloxy) -ethyl} -pyrazolon- (5) 3-trifluoromethyl-1- (2- (i-chloro-6-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethyl-1- (2- (4-chloro-1-methy1-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-Methy1-1- (2- (3,4-dichloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

ο 3-Methy1-1- (2- (5,8-dichloro-β-naphthyloxy) -ethyl) -pyrazolone- (5) ^ 3-Methy1-1- (2- (4,8-dichloro-β-naphthyloxy ) -äthyl) -pyrazolon- (5) ¹ ^ _Μ 3-Methy1-1- (2- (3,6-dimethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

- * .- ^ω 3-methyl-1- (2- (5,6-dimethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) ^ &

Q 3-methyl-1- (2- (6,7-dimethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

~ * 3-Methyl-1- (2- (3,4-dimethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (7,8-dimethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (6,7-dimethoxy-1-methy1-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (6,7-dimethy1-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethyl-1- (2- (7,8-dimethyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-methyl-1- (2- (4,6-dimethy1-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

3-Methy1-1- (2- (5,7-dimethy1-ß-naphthyloxy) -ethyl) -pyrazolone- (5) ^ ₀

3-methyl-1- [2- (4,8-dimethyl-β-naphthyloxy) -ethyl) -pyrazolone- (5) ⁰ ^

3-methyl-1- (2- (3,8-dinitro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 4> -

3-methyl-1- (2- (4,7-dinitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) "^?

3-methyl-1- (2- (4,8-dinitro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) _> 3-methyl-1- (2- (6-ethyl-ß-naphthyloxy) - ethyl) -pyrazolon- (5) ^ 3-methyl-1- (2- (8-ethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

5 ^ 3-methyl-1- (2- (7-ethyl-8-methyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (1 - ((ethylthio) methyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (6-fluoro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (8-fluoro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (3-fluoro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (8-isopropyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

ο 3-methyl-1- (1-isopropenyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

O ₀ 3-methyl-1- (2- (6-methylmercapto-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

^ J '3-methyl-1- (2- (1-methylmercaptomethyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) "- * j * 3-methyl-1- [2- (1-methoxymethyl-ß -naphthyloxy) -ethyl) -pyrazolon- (5) ο '3-methyl-1- (2- (3-ethoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) ~ ^ _ 3-methyl-1- (2- (4-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

3-methyl-1- (2- (5-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (7-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-trifluoromethy1-1- (2- (6-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-tri fluoromethy1-1- (1- (8-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Methy1-1- (2- (6-methoxy-1,5-dimethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (3-methoxy-5-nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5)

If 3-methyl-1- (2- (1 > 3-methyl-1- (2- (3 σ » 3-methyl-1- (2- (5 876 3-methyl-1- (2- (6
3-methyl-1- (2- (7 3-methyl-1- (2- (8 3-methyl-1- (2- (6 3-methyl-1- (2- (6 3-methyl-1- (2- (7 O 3-methyl-1- (2- (8 co
OO 3-methyl-1- (2- (1 to 3-methyl-1- (2- (3 to 3-methyl-1- (2- (4 O I. 3-methyl-1- (2- (5 - * I. 3-methyl-1- (2- (6 3-methyl-1- (2- (7 3-methyl-1- (2- (8 3-methyl-1- (2- (3 3-methyl-1- (2- (4 3-methyl-1- (2- (5 3-methyl-1- (2- (6 3-methyl-1- (2- (7 3-methyl-1- (2- (8 3-methyl-1- (2- (3 3-methyl-1- (2- (4

■ (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

• (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

• (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

• (methylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

• (methylsulfinyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ (trifluoromethylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ (trifluoromethylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ (trifluoromethylsulfonyl) -ß-naphthyloxy) -ethyl) -pyrazolon- (5) • methyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

■ methyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) -methyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) ■ methyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -methyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) ■ methyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -methyl-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolan- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -nitro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) -trifluoromethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) -trifluoromethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

T-O er. cn

3-methyl-i- (2- (5-trifluoromethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-i- (2- (6-trifluoromethyl-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-methyl-1- (2- (1,3,4-trichloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3- (4-nitrophenyl) -1- (2- (3-fluoro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3- (4-methoxyphenyl) -1- (2- (6-fluoro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-ethyl-1- (2- (8-fluoro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Benzyl-1- (2- (3-fluoro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3- (4-fluorobenzyl) -1- (2- (6-fluoro-ß-naphthyloxy) - ethyl) pyrazolone (5) 3- (3,4-dichlorobenzy1) -1- (2- (8-fluoro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-n-Butyl-1- (2- (6-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-Cyclohexyl-i- (2- (8-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3- (2-methoxyethyl) -1- (2- (4-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3- (2- (methylmercaptomethyl) -1- (2- (6-chloro-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-isopropyl-i- (2- (8-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3-n-Butyl-1- (2- (4-chloro-ß-naphthyloxy) -ethyl) -pyrazolon- (5) 3- (Pyridyl- (3)) - 1- (2- (6-methyl-ß-naphthyloxy) -ethyl-pyrazolone- (5) 3- (3,4-Dimethoxypheny1) -1- (2- (7-methy1-ß-naphthyloxy) -ethyl-pyrazolone- (5) 3- (3,4-Dimethoxybenzyl) -1- (2- (8-methyl-ß-naphthyloxy) -ethyl-pyrazolone- (5) 3-ethyl-1- (2- (6-methoxy-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-Cyclohexylmethyl-1- (2- (7-methoxy-ß-naphthyloxy) -ethyl) -pyrazolone- (5) 3-trifluoromethyl-i- (2- (8-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5)

2 5 b 4 7 O 3

The new compounds of the invention are available as medicaments usable substances,

When used orally or parenterally, they cause a strong reduction in thrombotic deposits and can therefore for the treatment and prophylaxis of thrombembolic diseases can be used.

The new active ingredients can be converted into the usual formulations in a known manner, such as tablets, capsules, Dragees, pills, granules, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutical suitable carriers or solvents. Here, the therapeutically effective compound should in each case at a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts that are sufficient in order to achieve the stated dosage range.

The formulations are prepared, for example, by Extension of the active ingredients with solvents and / or carriers, optionally with the use of emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic Solvents can be used as auxiliary solvents.

Auxiliaries are listed by way of example;

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), Alcohols (e.g. ethyl alcohol, glycerine), glycols (e.g. propylene

Le A 16 876 - 27 -

7 0 9 8 2 3/1011

Glykox, Pclyäthyleneglykol), solid carriers, such as e.g. natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic rock flour (e.g. highly dispersed Silicic acid, silicates), sugar (e.g. cane, milk and grape sugar), emulsifiers such as nonionic and anionic Emulsifiers (e.g. polyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), Dispersants (e.g. lignin, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. Magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably oral or parenteral.

In the case of oral use, tablets can of course also contain additives, such as, in addition to the carrier substances mentioned Sodium citrate, calcium carbonate and calcium phosphate, together with various additives such as starch, are preferred Contain potato starch, gelatin and the like. Lubricants such as magnesium stearate and sodium lauryl sulfate can also be used and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs for Oral applications are intended, the active ingredients can be used with various flavor enhancers in addition to the abovementioned auxiliaries or dyes are added.

In the case of parenteral use, solutions can be used

the active ingredients using suitable liquid carriers

materials are used.

Le A 16 876 - 28 -

709823/1011

25b4703

In general, it has proven to be advantageous for parenteral administration to use amounts of about Oy01 to 50 mg / kg, preferably about 0.1 to 10 mg / kg of body weight per day for effective results, and at oral administration, the dosage is about 0.1 to 500 mg / kg, preferably 0.5 to 100 mg / kg of body weight per day.

Nevertheless, it may be necessary to use the The specified amounts vary, depending on the body weight of the test animal or the type of application route, but also on the basis of the animal species and its individual nature Behavior towards the drug or the type of its formulation and the time or interval at which the administration takes place. So in some cases it can be sufficient with less than the aforementioned minimum amount get along, while in other cases the upper limit mentioned must be exceeded. In the case of the application If larger amounts are involved, it may be advisable to divide them up into several individual doses over the course of the day.

This information applies both to the application of the invention Connections in both veterinary and human medicine.

The following example is given for the formulations:

200 g 3-benzyl-1- (2- (3-fluoro-ß-naphthyloxy) ethyl) -pyrazolon- (5) are ground to a powder, mixed with 300 g of lactose and 200 g of potato starch and, after moistening, with a aqueous gelatin solution granulated through a sieve.

Le A 16 876 - 29 -

709823/101 1

After drying, 60 g of talc and 5 g of sodium auryl sulfate are added added. About 10,000 tablets with an active ingredient content of 20 mg each are pressed from this mixture.

To demonstrate the antithrombotic effect of the invention Compounds was the 3- (trifluoromethyl) -1- (2- (ß-naphthyloxy) -ethyl) -pyrazolon- (5) described in Example 2 Administered to rats.

The other compounds show comparable properties.

Rats with a weight of 170 to 180 g were exposed to the left jugular vein under ether anesthesia and used for Stimulation of thrombus formation for 2 minutes at -12 ° C subcooled. The thrombus was dissected from the vein 4 hours later and weighed. The test animals received this Test preparation in tragacanth mucus immediately before hypothermia of the vessel wall. Testing for protective antithrombotic Effectiveness thus took place in the first 4 hours after stimulation of the thrombus formation.

The results of the investigations with the inventive Connections are shown in the following table:

Le A 16 876 - 30 -

709R2 3/1011

Tabel

Control on animals without active ingredient

Animals treated with the compound according to the invention (10O mg / kg ρ.ο.)

Thrombus size in .ug (mean)

115 + 12

52 + 8

Number of attempts inhibition in%

14th

12th

54%

The results show that the compounds according to the invention significantly inhibit the formation of venous thrombi.

After a 4 hour exposure time, the size of the thrombi is ^{reduced by 5 4} %.

The compounds according to the invention are therefore suitable for prophylaxis against thromembolic diseases.

In addition to the inhibiting effect on the formation of thrombi, the compounds according to the invention are also distinguished by a very strong thrombolytic effect. Thrombotic deposits that have already formed are dissolved again under their influence. Corresponding thrombolytic effects could previously only by repeated intravenous administration of toxic doses of fibrinolytic, j _{[e w} streptokinase and

Le A 16 87fi

- 31 -

709823/1011

Urokinase can be achieved while the invention Compounds are administered orally and only once a day. They therefore represent an enrichment for pharmacy.

Le A 16 876 - 32 -

709823/1011

255A703 '3ο-

Example 1 (variant A)

0-CH ₃

O <

3- (2-Methoxy-isobutyl) -1- (2- (ß-naphthyloxy) -äthylpyrazolon- (5): To 0.1 mol (20.2 g) of (β, β-dimethyl-ß-methoxy-propionyl) -acetic acid ethyl ester were in 20 ml of abs. Ethanol were 0.1 mol (20.2 g) 2- (ß-naphthyloxy) ethyl hydrazine in a little abs. Ethanol added. After the exothermic initial reaction has ended the reaction mixture was refluxed for 4 hours. After cooling, the reaction mixture was concentrated. Included the crude reaction product crystallized out. For purification, the product was recrystallized from a little ethanol.

Yield: 23.1 g (68% of theory). Melting point: 98-1OO ° C

Example 2

3-Tri fluorine thy 1-1- (2- (ß-naphthyloxy) -ethyl-pyrazolon- (5) was according to the procedure described in Example 1 from trif luoroacetessigsäureäthylester and 2- (ß-naphthyloxy) ethyl hydrazine obtain.

Le A 16 876 - 33 -

709823/1011

Yield: melting point:

59% of theory 202-2O4 ° C

Example 3

CH ₂ -CH ₂

■ α

O CH-C- OCH

3- (methoxycarbonylmethyl) -1- (2- (ß-naphthyloxy) -ethyl-pyrazolone- (5) was according to the procedure described in Example 1 from (^ - (methoxycarbonyl) -acetoacetic acid ethyl ester and 2- (ß-naphthyloxy) ethyl hydrazine obtain.

Yield: melting point:

65% of theory 155-157 ° C

Example 4

OCH ₂ -S-CH ₃

3- (methylmercaptomethyl) -1- (2- (ß-naphthyloxy) -ethyl) -pyrazolone- (5) was analogous to the procedure described in Example 1 from ^ - (methylmercapto) -acetoacetic acid ethyl ester and 2- (ß-naphthyloxy) ethyl hydrazine obtain.

Yield: melting point:

83% of theory 143-145 ° C

Le A 16

- 34 -

709823/101 1

Example 5

3- (Cyclohexy! Methyl) -1- (2- (ß-naphthyloxy) -ethyl) -pyrazolone- (5) was according to the procedure described in Example 1 from ^ -Cyclohexylacetessigsäureäthylester and 2- (ß-naphthyloxy) ethyl hydrazine obtain.

Yield: 86% of theory. Melting point: 158-16O ° C

Example 6

CH-, O-CH ₂ -CH ₂ -N

3-Methyl-1- (2- (6-methoxy-ß-naphthyloxy) -ethyl) -pyrazolon- (5) was prepared analogously to Example 1 from methyl acetoacetate and
2- (6-methoxy-ß-naphthyloxy) ethyl hydrazine obtained.

Yield: 59% of theory. Melting point: 182-184 ° C

Example 7

Le A 16 876 - 35 -

7 0 9 8 2 3/1011

255A703

3-methyl-1- (2- (5-bromo-β-naphthyloxy) -ethyl) -pyrazolone- (5) was analogous to Example 1 from isopropyl acetoacetate and 2- (5-bromo-ß-naphthyloxy) ethylhydrazine obtain.

Yield: 84% of theory. Melting point: 175-177 ° C

Example 8

0-CH ₂ -CH ₂ -N

3-trifluoromethyl-i- (2- (5-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) was obtained analogously to Example 1 from ethyl trifluoroacetoacetate and 2- (5-bromo-ß-naphthyloxy) ethylhydrazine.

Yield: 57% of theory. Melting point: 210-212 ° C

Example 9

CH ₂ -S-CH

0-CH ₂ -CH ₂ -N 0

3- (MethylmercaptomethyD-1- (2- (5-bromo-ß-naphthyloxy) -ethyl) -pyrazolon- (5) was analogous to Example 1 from 2- (5-bromo-ß-naphthyloxy) ethyl hydrazine and methyl methyl mercaptoacetoacetate obtain.

Yield: 63% of theory. Melting point: 160-162OC

Le A 16 876 - 36 -

709823/1011

Example 10 :

0-CH ₂ -CH ₂ -N

CH ₂ -COOCH ₃

3- (MethoxycarbonylmethyD-1- (2- (5-bromo-ß-naphthyloxy) -ethyl) pyrazolone- (5) was obtained analogously to Example 1 from acetone dicarboxylic acid methyl ester and 2- (5-bromo-ß-naphthyloxy) -ethylhydrazine.

Yield:

54% of theory

CH,

Melting point: 177-179 ° C

Example 11

0-CH ₂ -CH ₂ -N

3-Cyclohexylmethyl-i- (2- (5-bromo-ß-naphthyloxy) -ethyl) -pyrazolone- (5) was analogous to Example 1 from i ^ -Cyclohexylacetessigsäureäthylester and 2- (5-bromo-ß-naphthyloxy) -ethylhydrazine obtained.

Yield:

81% of theory

Melting point: 175-177 ° C

Le A 16 876

- 37 -

709823/1011

Example 12 (variant B)

V3.

.0-CH ₂ -CH ₂ -NO

To a suspension of 0.12 mol (2.9 g) of sodium hydride in 200 ml of abs. Dimethylformamide was 0.1 mol (18.0 g) 3-cyclohexylmethyl) Pyrazolon- (5) added in portions.

After the evolution of H _{2 had} ended, 0.1 mol (28.5 g) of 2- (5-bromo-β-naphthyloxy) ethyl chloride were added dropwise to the reaction solution. The mixture was then stirred for 2 hours at 60 ° C., the solvent was distilled off in vacuo, the residue was taken up in water and acidified with dilute acetic acid.

The crude product obtained in this way was made from an ethanol / dimethylformamide mixture recrystallized.

Yield:
Melting point:

28% of theory 175-177 ° C

Example 13

0-CH ₀ -CH ₉ -N

CH.

H ₃ CO

To 0.1 mol (11.2 g) of ethyl tetrolate were 0.1 mol (23.2 g) 2- (6-methoxy-ß-naphthyloxy) -ethy! Hydrazine given. The reaction mixture was refluxed for 8 hours together with 70 ml of n-butanol heated.

Le A 16 876

- 38 -

709823/1011

The reaction solution was then concentrated, the solid residue was recrystallized twice from an ethanol / dimethylformamide mixture (10: 1).

Yield: 45% of theory. Melting point: 182-184 ° C

Example 14

Analogously to Example 1, 3-methyl-1- (2- (4-biphenylyloxy) ethyl) pyrazolone (5) is obtained from ethyl acetoacetate and 2- (4-biphenyloxy) ethyl hydrazine.
Yield: 79% of theory
Melting point: 175 ° C

Example 15

CH

0-CH ₂ -CH ₂ -N

As in Example 1, 3-methyl-1- (2- (2-biphenylyloxy) ethyl) pyrazolone (5) is obtained from ethyl acetoacetate and 2- (2-biphenyoloxyethylhydrazine).

Yield: 72% of theory. Melting point: 115-117 ° C

Le A 16 876 - 39 -

709823/101 1

Claims (4)

Claims in which R ¹ and "2 and otherwise R ² represents hydrogen, trifluoromethyl or an alkyl, aryl, aralkyl or heteroacrylic radical, the aforementioned radicals being optionally substituted in the event that R ¹ denotes hydrogen, trifluoromethyl, alkyl having more than 4 carbon atoms, heteroaryl or substituted aryl or aralkyl, denotes an unsubstituted naphthyl radical represents a substituted naphthyl radical which has 1 to 3 identical or different substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy, alkylamino, cyano, trifluoromethoxy, nitro, hydroxy, SO alkyl (η = O to 2) or SC ^ -Trifluoromethyl Le A 16 87 6 - 40 - 709823/1011 (η = O to 2), where optionally two substituents on the aryl radical together have a branched or unbranched, saturated or unsaturated, 5- to 7-membered, isocyclic or heterocyclic ring, which can contain up to 2 oxygen or sulfur atoms, or for one Biphenyl radical . 2) Process for the preparation of pyrazolones of the general formula I. O "N ? ^H 2 ? ^H 2 O R ² in which
"1 and
"2 for hydrogen, trifluoromethyl or an alkyl, aryl, aralkyl or heteroacryl radical stands, where the aforementioned radicals are optionally substituted stands for the case where R ¹ is hydrogen, trifluoromethyl, alkyl having more than 4 carbon atoms, heteroaryl or substituted aryl or aralkyl, for a unsubstitu ierten naphthyl Le A 16 876 - 41 - 7 0 9 8 2 3/1011 and otherwise
R ² represents a substituted naphthyl radical which has 1 to 3 identical or different substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy, alkylamino, cyano, trifluoromethoxy , nitro, hydroxy, SO alkyl (η = O to 2) or SO _n ~ Contains trifluoromethyl (n = O to 2), where optionally two substituents on the aryl radical together form a branched or unbranched, saturated or unsaturated, 5- to 7-membered, isocyclic or heterocyclic ring, which can contain 1 to 2 oxygen or sulfur atoms, or stands for a biphenyl radical, characterized in that one A) hydrazines of the formula II RO- CH ₂ - CH ₂ - NH II in which
R ² has the meaning given above with β-keto acid derivatives of the formula III in which. R ¹ - C - CH ₂ - C III has the meaning given above, and for a leaving residue such as hydroxy, alkoxy, Aralkoxy, amino or alkylamino radical Le A 16 876 - 42 - 709823/1011 optionally in the presence of inert solvents and basic or acidic catalysts such as alkali and alkaline earth metal hydroxides and carbonates or such as hydrohalic acids, sulfuric acid or sulfonic acids, at temperatures between 10 and 200 ° C,
or B) Naphthoxyethyl derivatives of the formula IV R ² - O - CH _n - CH ₀ - A IV in which R has the meaning given above and A is a leaving group such as halogen or the
Represents dialkyloxonium, dialkylsulfonium or trialkylammonium radical or the aryl or trifluoromethylsulfonic acid radical, with pyrazolone (5) derivatives of the formula V .1 ■ in which R has the meaning given above, optionally in the presence of inert solvents and inorganic solvents or organic bases such as alkali hydroxides, carbonates, alcoholates, hydrides or amides at temperatures converts between 10 and 200 ° C, or C) Acetylenecarboxylic acid derivatives of the formula VI OM "J Z ^ -C-CSC-R VI Le A 16 876 - 43 - 709823/1011 in which R ^{1 has} the meaning given above and Z ² denotes a hydroxy, alkoxy, aral-oxy, amino or alkylaminores.t, with hydrazines of the formula II R ² - O - CH ₂ - CH ₂ - NH - NH ₂ II in which R has the meaning given above, optionally in the presence of inert solvents and inorganic or organic bases at temperatures between 50 ° and 200 ° C. 3) Antithrombotic agent containing a pyrazolone according to formula I in claim 1. 4) Process for the preparation of antithrombotic agents, characterized in that pyrazolones according to claim 1 are mixed with inert non-toxic pharmaceutically suitable carriers. Le A 16 876 - 44 - 709823/101 1