DD248362A5 - PROCESS FOR THE PREPARATION OF NEW PYRIDAZINONE - Google Patents

Abstract

The invention relates to novel pyridazinones and to a process for the preparation of these compounds of the general formula I in which X, R 1 and R 2 have the meaning given in the specification. Because of their pharmacological properties, the compounds of general formula I and their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids are suitable for the treatment of chronic heart failure or angina pectoris and / or for the prophylaxis of arterial thromboembolism and arterial occlusive diseases. Formula I

Description

· _-,:; Field of the Invention -'- 'Yv'"";;..;;: ·... "

The invention relates to a process for the preparation of novel pyridazinones which are used in medicaments as active ingredient. ^: -. ·. '-: .- -; ~ ^ ^: ~ " ^: \ i ^x ^ -:. \ '^ ^: ' i - :: -, -'-. - - ':''"' -. '. .. <-. -t .. -. : '- * -:.: r- ~ ^: * 2, y "

Characteristic of the known technical solutions \ ~ ^ _v '-

US Pat. No. 4,026,891 and European Patents No. 0,008,391 and O.Q34 * .743 already describe pyridazoline which has valuable pharmacological properties; have, in particular, cardiotonic, an effect on the blood pressure and / or antithrombotic effects. . - "

, Object of the invention / ','. .:. - '' ·. · - - ' ^: _r .

It is the object of the invention to provide novel compounds which have valuable pharmacological properties, in particular _s cardiotonic effects. ~ ">. ~ ' -; -. ·

Explanation of the essence of the invention . ; "· '- .'-'"''''.

The invention is based on the object 'a method for. Preparation of new pyridazinones which are "pyridazinones" which are known from the pyridazinones and are bonded by a nitrogen atom or a carbon atom

"N

(V. M19 85 * 852881

distinguish aromatic heterocyclic radical in the 2-position, and their acid addition salts, in particular their physiologically '' compatible. Acid addition salts with inorganic. or organic acids'. "" ...- :. ; '/ -'-:''-"' /

It was found that. the new pyridazinone the. general formula. '' .. "-.'- '.'., -. '/ *''-^Y' -... '··''Y' · '- -""' .. 'Y - ^ '.' ... :

^; "-." . "'- " ''.;;:, (D

"where" · · · · · · · · "" - · -. ^ -. : "~ - \ - '-: -. ; -:: ' .. '^''- : ... ·; ^'. '.. ""-' · '''-". - -. ··· .- -X is an imino group optionally substituted by an alkyl or phenylalkyl group, an oxygen or sulfur atom,. .. - ' ' -. ^; _: ·; '' _. . ''"-'.'^.; - ':'" / · '·',;'- · s. , '^, "-''

E ^ "a bonded via a nitrogen saturated 5- to 7-membered Alkyleniminoring or a bonded via a carbon 5- to 7-membered saturated imino, N-alkyl-imino, .. 1-phenylalkyl-imino, U Alkanoyl-imino- '' or H-alkoxycarbonyl-imino-alkylene ring, wherein the above-mentioned rings in the carbon skeleton substituted by one or two alkyl groups' and a methylene group in the 4-position of a 6- or 7-membered ring by an oxygen - or sulfur atom, a sulphinyl, sulphonyl, imino, alkylimino, Phenylalkylimino-, alkoxycarbonyl or j.mino- Alkanoyliminogruppe may be substituted, an optionally linked by one or zv / ei alkyl via a nitrogen atom saturated 5- to 7 -membered alkyleneimino ring in which a -CHpCHn group is replaced by a -WH-CO group, the GO group of this -IJH-CO group being linked to the already present H atom, a nitrogen atom bonded via a nitrogen atom.

5-membered heteroaromatic ring, which may additionally contain an oxygen or sulfur atom, e "xn or two nitrogen atoms, an oxygen or sulfur atom and a nitrogen atom, where the heteroaromatic ring is represented by one or two alkyl groups and in the PaIIe of the pyrazoles may also be substituted by a hydroxy group and- an alkyl group, a bound via a carbon atom 5- or 6-membered heteroaromatic ring, which is an oxygen or sulfur atom, one, two or three nitrogen atoms, an oxygen or sulfur atom and or.two may contain nitrogen atoms, the heteroaromatic rings being substituted by one or two alkyl groups, by an amino or alkanoylamino group and in the case of the pyridines also by one or two halogen atoms or by a halogen atom and an amino or morpholino group and Ro is a hydrogen atom or an alkyl group, wherein all of the aforementioned alkyl, -. alkano yl or alkoxy groups can each contain 1 to 3 Kohlenstoff.atome; mean, as prepared according to the invention.

Cyclization of a compound of the general formula optionally formed in the reaction mixture.

IT H

, (II)

in the

Rp as defined above,

one of the radicals A or B is a

² I ^Z 2

R, '- C-X - group and

¹IΪ2 ? 3

the other of the radicals A or B is an amino group or a Z

R, ¹ - C-NH - or R ₁ '-C = N- group

where X is as defined above and R-. 'represents one of the above-mentioned carbon-bonded radicals R, Z, and Z', which may be the same or different, nucleophilic leaving groups such as optionally substituted amino, alkoxy, phenylalkoxy, phenoxy, alkylmercapto, phenylalkylmercapto or phenylthio groups or

Z- and Z- together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl or phenylalkyl group, where the abovementioned alkyl moieties may each contain 1 to 3 carbon atoms, or an alkylenedioxy group having 2 or 3 carbon atoms and

Z-, which mean Z, the meanings mentioned above or an imidazolyl group, a chlorine, bromine or iodine atom.

For Z ^ and Z ₂ , for example, each of the methoxy, ethoxy, propoxy, benzyloxy, methylmercapto, ethylmercapto, propylmercapto, phenylmercapto or Benzylmercaptogruppe and

for Z ₃ those of the chlorine, bromine or iodine atom, the methoxy, ethoxy, phenoxy, methylmercapto, ethylmercapto, phenyl

mercapto, benzylmercapto or imidazolyl group into consideration.

The reaction is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, glycol, glycol monomethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, tetralin or sulfolane, optionally in the presence of a condensing agent such as phosphorus oxychloride, Thionyl chloride, sulfuryl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, glacial acetic acid, acetic anhydride, N, N ¹ -dicyclohexyl-carbodiimide, carbonyldiimidazole, potassium or potassium tert-butoxide at temperatures between 0 and 300 ⁰ C, but preferably at the boiling point of the reaction mixture, for example at temperatures between 50 and 285 ⁰ C, performed. However, the reaction can also be carried out in the melt.

If R ₁ denotes one of the abovementioned radicals bonded via a carbon atom, then the reaction is particularly advantageously carried out in an excess of the acylating agent used for the preparation of a corresponding compound of general formula II, for example with an excess of the nitrile, anhydride, ester, thioester, Orthoesters, amides, thioamides, halides or Methojodids performed.

b) reaction of a carboxylic acid of the general formula

C-CH ₂ -L CH ₂ -COOH, (III)

in the

R and R _{2 are} as defined above,

or their reactive acid derivatives such as their esters, amides or halides with hydrazine.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, ice-sig, propionic acid and / or in an excess of hydrazine or hydrazine hydrate at temperatures between 0 and 200 ⁰ C, for example at temperatures between 20 and 15O ⁰ C. but preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid such as sulfuric acid or p-toluenesulfonic acid as a condensing agent. However, the reaction can also be carried out without a solvent.

c) For the preparation of compounds of the general formula I in which R 1 represents one of the radicals mentioned above bonded via a nitrogen atom:

Reaction of a compound of the general formula

(IV)

in the

R ₂ and X are as defined above and

z. a nucleophile-exchangeable group such as a halogen atom, a sulfo group or a substituted mercapto group, e.g. a chlorine or bromine atom, a sulfo, methylthio, ethylthio, phenylthio, 2-nitrophenylthio, 4-nitrophenylthio, 2,4-dinitrophenylthio, pyridine-4-thio or pyridine-2-thio group, with an amine of the general formula

H - R ₁ ", (V)

in the

R-, "one of the above-mentioned radical R ₁ bound via a nitrogen atom represents.

The reaction is carried out in the melt or in a suitable solvent such as tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an acid-binding agent such as. Potassium carbonate or pyridine at elevated temperatures, for example at temperatures between -50 and 200 ⁰ C, but preferably at temperatures between 100 and 180 ⁰ C performed.

d) For the preparation of compounds of general formula I in which X represents an oxygen atom or an imino group optionally substituted by an alkyl or phenylalkyl group:

Hydrogenation of a compound of the general formula

(VI)

// I ^ I '

in the

R ₁ and R _{2 are} as defined above and X ^{1 is} an oxygen atom or an optionally substituted by an alkyl or phenylalkyl imino group, wherein the alkyl moiety may each contain 1 to 3 carbon atoms, means.

The catalytic hydrogenation is carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or .Palladium / carbon at temperatures between 0 and 75 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar performed.

If, according to the invention, a compound of the general formula I in which R 1 contains an imino and / or amino group can be prepared by alkanoylation into a corresponding compound of the general formula I in which R 1 is an alkanoylimino and / or alkanoylamino group contains, be transferred or

a compound of the general formula I in which R- represents a pyridine radical which is bonded via a carbon atom and is substituted by halogen atoms, this can be represented by catalytic dehalogenation and hydrogenation in a compound of the general formula I in which R 1 is a piperidino radical bonded via a carbon atom , be transferred, or

a compound of general formula I in which R- represents a pyridine radical substituted by one or two halogen atoms bonded via a carbon atom, this may be converted by halogen exchange into a corresponding compound of general formula I ₇ in the R-, one bonded via a carbon atom Pyridine radical which is substituted by an amino or morpholino group and optionally substituted by a halogen atom, be converted.

The subsequent alkanoylation is expediently carried out in a solvent such as methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, acetonitrile or dimethylformamide with a corresponding ester, anhydride,

anhydride or acid halide, optionally in the presence of an acid binding agent such as sodium carbonate or pyridine or with an appropriate alkanoic acid in the presence of an acid-activating agent or dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, N, N ¹ -dicyclohexylcarbodiimide, Ν, Ν ¹ Carbonyldiimidazole or N, N ¹ -thionyldiimidazole at temperatures between 0 and 200 ⁰ C, but preferably at temperatures between 20 and 100 ⁰ C performed.

The subsequent dehalogenation and hydrogenation is carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium / carbon at temperatures between 0 and 75 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar performed.

The subsequent halogen exchange is advantageously carried out with ammonia or morpholine in a solvent such as dioxane or dimethylformamide optionally in a pressure vessel at temperatures between 50 and 150 ⁰ C.

The compounds of the general formula I thus obtained can be separated into their optically active antipodes by means of racemate resolution on the basis of their optically active carbon atom in position 4 or 5 of the pyridazinone ring, provided that R _{2 represents} an alkyl group.

The racemate resolution is conveniently carried out by fractional crystallization of the corresponding salts with optically active acids, such as tartaric acid, dibenzoyltartaric acid, malic acid, camphoric acid or camphorsulfonic acid, or by chromatography on optically active adsorbents.

9 ^A -AO- <- "

Furthermore, the resulting compounds of general formula I can be converted into their acid addition salts, in particular for pharmaceutical use, into their physiologically tolerated salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the general formulas II to VI used as starting materials are obtained by methods known from the literature or are known from the literature.

Thus, for example, a corresponding o-diamino compound of the general formula II is obtained by reacting a corresponding 3- (3-nitro-4-acylaminobenzoyl) propionic acid with hydrazine and subsequent reduction of the nitro group (see US Pat. No. 4,026,891), a corresponding o-hydroxy-acylamino or o-mercapto-acylamino compound of the general formula II by reacting a correspondingly substituted 3-benzoyl-propionic acid with hydrazine, optionally subsequent reduction of the nitro group and subsequent acylation of the amino compound thus obtained.

A compound of general formula III used as starting material is obtained by reacting a corresponding ρ, α-dihaloacetophenone with a corresponding malonic ester. The correspondingly substituted 3-benzoyl-propionic acid derivative thus obtained is then saponified, decarboxylated, nitrated, the halogen atom is replaced by an amino, hydroxy or mercapto group, the nitro group reduced and the amino compound thus obtained after reaction _with a corresponding carboxylic acid derivative to the desired compound implemented the general formula III.

_v - ·:. 24Β 36

A compound used as starting material of the general Pormel 17 is obtained for example by. Ring closure of one. corresponding thiourea or by reaction of a corresponding o-amino-hydroxy "compound with potassium ethylxanthogenate and subsequent reaction of the 2-kercaptobenzoxazol thus obtained with a corresponding electrophosphile, ZoB., With an alkyl halide or a ITitrohalogenbenzol"

A compound of the general formula VI used as starting material is obtained by reacting a corresponding acrylic acid derivative with hydrazine.-Pur The meanings mentioned in the definition of the radicals X, R 1 and R _{2 are} , for example, ## STR3 ## that of the oxygen or sulfur atom, the imino, methylimino, ethylamino, n-propylimino, benzylimino, 1-phenylethylimino, 2-phenylethylimino or 3-phenylpropylimino group. , _;

for R ^ the 1-pyrrolidinyl, piperidino, T-Hexahydroazep-. inyl, '2-methyl-i-pyrrolidinyl, 3-methyl-i-pyrrolidinyl, 2-methyl-piperidino, 2-n-propylpip.erid.ino7, 3-methylpiperidino, 4-methyl piperidino, 2-ethyl-piperidino, 4-ethyl-piperidino, 4-isopropyl-piperidino, 2 ·, 6-dimethyl-piperidino, 3,5-dimethyl-piperidino, 1-piperazinyl, 4-methyl 1-piperazinyl 4-ethyl-T-piperazinyl, 4-n-propyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 4-Formy1-1-piperazinyl, 4-Acety1-1 _r piperazinyl, 4-Propiony1-1-piperazinyl, '4-Methoxycarbony1-1-piperazinyl', 4-Ethoxycarbony1-1-piperazinyl, 2-pyrrolidinyl, 3_Py _r i <olidinyl-, 2-piperidino, 3-piperidino , 4-piperidino, N-methyl-2-pyrrolidinyl, N-methyl-3-pyrrolidinyl, .N-methyl-4-piperidino, H-ethyl-4-piperidino, Ii-isopropyl-4-piperidino- , H-formyl-4-piperidino, U-acetyl-4-piperidinoj ·, N-propionyl-4-piperidino, morpholino, thiomor-pholino, 1-oxido-4-thiomorpholino, 1,1-dioxide ^ -thiomor-pholino, imidazoline

ai -

2-on-1-yl, 2-methyl-2-imidazolin-1-yl _T , imidazolidin-2-one-4-yl, 2-methyl-4-yl-dihydro-imidazo-1 1-yl, imidazolin-2-one-4-yl, tetrahydrodfuran-2-yl, 4-methyl-2-piperazinyl, 4-ethyl-2-piperazinyl * -, .4-n-piropyl 2-pipe: tfazinyl, 1,4-dimethyl-2-piperazinyl, 1'-diethyl-1-piperazinyl, 1-ethyl-4-methyl-2-piperazinyl, 1-pyrroleyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, '', H-ethyl-2-pyrrorylo, N-methyl-1-pyrrolyl, 1-ethyl-3-pyrrolyl, 2-thienyl, 3-Thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 1-imidazolyl, 2-methyl-1-imidazolyl, 4-methyl-1-imidazolyl -, 2-ethyl-1-imidazolyl, '4-ethyl-1-1-imidazolyl, 2-amino-5-pyridyl, "2-yl- ^1- amylamino-5-pyridyl, 2-acetylamino-5-pyridyl -, 2-Propionylamino-5-pyridyl, 2,6-dichloro-4 - pyridyl, _i 2-chloro-6-amino-4-pyridyl, 2-chloro-6-morpholino-4-pyridyl. , ^, ö-dichloro-pyridyl,, 2-chloro-6-monophosphino-3-pyridyl, 1-pyrazolyl, 4-methyl-i-pyrazolyl,: 3-hydroxy-4-methyl- 2-pyrazolinyl, 5-oxazolyl, 4-methyl-5-oxaz olyl-, 4-PyrazoIyI-, 3-imino-4-pyrazoIyI-, Λ-Γ \ .2.3-7-triazolyl, 1- / 1.2.47TrXaZoIyI-, 2-hydroxy-1-imidazoIyI-, 4-hydroxy 1-imidazolinyl, 4-methyl-1-imidazolyl, 2-imidazolyl, imidazolidin-2-one-1-yl, 2-pyrimidyl, 5-pyrimidyl, 4-pyrimidyl, 5-thiazolyl , 2-Thiazolyl, 2-oxazolyl or triazol-3-yl group into consideration. ,; · · '"

Preferred compounds of the above general formula I are 3 "but those in which..."

X is the imino group, an oxygen or sulfur atom, R _{1 is} a pyrrolidinyl, piperidino, 1-hexahydroazepinyl, mprpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxothiomorpholino, 1 bonded via a nitrogen atom, 1 Piperazinyl, 4-methyl-1-piperazihyl, 4-acetyl-1-piperazinyl, _T 4-carbethoxy-1-piperazinyl, .1-imidazolyl, 1-pyrazolyl, 1-, 2-4-7-triazole, Imidazolidin-2-on-1-yl or 3-hydroxy-2-pyrazolyl group or a piperidino, N-acetyl-piperidino, puryl, thienyl, pyrrolyl, bonded via a carbon atom,

- 13; * .- '66 648/12

Pyridyl, amino-pyridyl, acetylamino-pyridyl, pyrimidyl, pyrazinyl, qxazolyl, dihalo-pyridyl or halo-morpholino-pyridyl group, wherein all the above-mentioned radicals in the carbon skeleton may be substituted by a methyl group, and. "-" ·. _. ~

Rp represents a hydrogen atom or a methyl group in the 5-position o. -

However, particularly preferred compounds of the above general formula I are those in which; ... Σ an oxygen atom or the imino group ,. R- ^{y represents} the 1-pyrrolidinyl, 1-imidazolyl-r, 2-puryl, 2-thienyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-carbethoxy-1-pipe, razinyl , 4-morpholino, 4-thiomorpholino, 1-r0xido-4-thiomorpholino and 4-pyridyl groups and - _v Rg in 5-Stelluhg mean the methyl group

, - fc -

The novel compounds of general formula I, their optically active antipodes and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, have valuable pharmacological properties, in particular cardiovascular effects, namely a cardiotonic and / or hypotensive, and an antithrombotic effect »

For example, the connections are different

A = 5-methyl-6- / 5- (1-imidazolyl) -benzo: azol-5-yl7-4,5-dihydro-3 (2H) -pyridazinone,

B = 5-Methyl-1-6 / 2 - (- 1 -piperazinyl) -benzo2azol-6-y] _t 7-4, 5-dihydro · '3 (2H) -pyridazinone,

C = 5- (methyl 1-6- / 2- (4-carbethoxy-1-piperazinyl) benzoxazol-6-yl / -4,5-dihydro-3 (2H) -pyridazinone,

D = .5-methyl-6- / 2- (i-pyrrolidinyl) -benzimidazol-5-yl7-4,5-dihydro-3 (2H) -pyridazinone,

248

E = 5-methyl-6- [2- (4-thiomorpholino) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone;

F. = 5-Methyl-6- [2- (1-imidazolyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

examined for their biological properties as follows:

1. Determination of Born and Cross Platelet Aggregation (J. Physiol 170, 397 (1964)):

Platelet aggregation was measured in platelet-rich plasma of healthy volunteers. In this case, the course of the decrease in the optical density after the addition of commercially available collagen from the company Sigma, St. Louis / USA, which contains 1 mg of collagen fibrils per ml, was measured photometrically and registered. From the inclination angle of the density curve was closed on the aggregation speed (Vmax). The point of the curve where the greatest light transmittance existed was used to calculate the "optical density" (O.D.). For maximum aggregation release, add about 0.01 ml of the collagen solution to 1 ml of platelet-rich plasma. , ,

The following table contains the found value: Table I

connection ^EC 50 A 3.1 x 10 ^-8 mol / l

B

2. Determination of hypotensive and positive inotropic effect on the anesthetized cat:

The studies were performed in cats that were anesthetized with pentobarbital sodium (40 mg / kg i.p.). The animals breathed spontaneously. Arterial blood pressure was measured in the abdominal aorta with a Statham pressure transducer (P 23 Dc). To measure the positive inotropic effect, the pressure in the left ventricle was measured with a catheter tip manometer (one billion PC-350 A). From this, the contractility parameter dp / dt__ "by means of

iHaX

an analog differentiator won. The substance to be tested was injected into a femoral vein. The solvent used was polydiol 200. The substance was tested on 3 cats, dose 0.1 i.v ..

The following table contains the mean values:

substance dose blood pressure Increase of duration mg / kg i.v. modification dp / dt in% (Half-value in mmHg Time) A 0.1 - 43 / -45 + 49 25 minutes B 0.1 - 45 / -43 + 88 12 minutes C 0.1 - 45 / -50 + 66 12 minutes D 0.1 - 13 / -17 + 68 13 minutes e 0.1 + 2 / -12 + 65 10 mins F 0.1 - 35 / -20 +81 8 minutes

In this context, it should be noted that no toxic side effects of the substances were observed in the biological studies.

- "16 - 66 648/12

On the basis of their pharmacological properties, the compounds of the general formula I and their optically active antipodes and their physiologically tolerated acid addition salts with organic or organic acids for the treatment of chronic heart failure or angina pectoris and / or for the prophylaxis of arterial.Thromboembolien and arterial occlusive diseases. ./ '' _. '· ·'

For this purpose, the new compounds, optionally in combination, with other active ingredients ,, in the usual phar-.mazeutischen Anwendungsformen.wie teach such as tablets, dragees, powders, suspensions, suppositories or.Ampullen. The single dose is in this case in adults Λ - 4 x daily with intravenous administration 1-50 mg, preferably 2 to 40 mg, ^ and in oral application 5 - 150 mg, preferably 5 100 mg. , - ''. _ '.

Embodiment . '-'.

The following examples are intended to explain the invention in more detail: - ·. ,

example 1

5-Methyl-6- [2- (2,6-dichloro-4-pyridyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone.

4.0 g (10.2 mmol) of N- [2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -2,6-dichloro -pyridine-4-carboxylic acid amide are dissolved in 50 ml of glacial acetic acid, heated for 5 minutes at 100 ⁰ C, then cooled to room temperature, the precipitated product is filtered off, washed with diethyl ether and dried in air

Yield: 86% of theory, Melting point: 260-264 ⁰ CC ₁₇ H ₁₃ Cl ₂ N ₅ O (374.2) Calcd. : C 54.56 H 3.50 N Gef .: 54.30. 3.67

Example 2

5-Methy1-6- [2- (2-pyrazinyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyrazine-2-carboxamide analogously to Example 1.

Yield: 47.7% of theory, melting point:> 300 ^° C.

Calc .: C 62.74 H 4.61 N 27.44 F .: 63.00 4.76 27.62

18 72 Cl 18 95 18 95 18 85

-is- '248 36

Example 3

6- [2- (2-Furyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (4,5-dihydro-3 (2H) -pyridazine-5-on-6-yl) -phenyl] -furan-2-carboxylic acid amide analogous to Example 1. Yield: 36.7 % of theory, melting point:> 300 ⁰ C

Ber. : C 64.27 H 4.32 N 19.99 F .: 63.96 4.43 19.69

Example 4

6- [2- (2-Thienyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -thiophene-2-carboxamide analogously to Example 1.

Yield: 29.8% of theory,

Melting point: 170-174 ⁰ C

Calc .: C, 60.78; H, 4.08; N, 18.90, S, 10.81; F: 60.34, 4.34, 18.77, 10.62

Example 5

5-Methyl-6- [2- (3-thienyl) benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -]

pyridazinone-6-yl) -phenyl] -thiophene-3-carboxamide analogously to Example 1.

Yield: 71% of theory, Melting point: 184-186 ⁰ C.

Calc .: C, 61.91, H, 4.55, N, 18.05; S, 10.33; V: 62.22, 4.71, 18, 14, 10.66

Example 6

6- [2- (3-thienyl) benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -thiophene-3-carboxamide analogously to Example

Yield: 73% of theory,

Melting point: 176-178 ⁰ C Calc .: C 60.78 H 4.08 N 18.90 S 10.82 Found .: 60.55 4.32 18.96 10.64

Example 7

5-methyl-6- [2- (2-furyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-amino-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -furan-2-carboxamide analog

Example 1.

Yield: 24.7% of theory,

Melting point: 264-266 ° C Calc .: C 65.30 H 4.80 N 19.04 Found: 65.62 4.95 19.34

- 248

Example 8

5-Methyl-6- [2- (3-pyridyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

2 g (6.0 mmol) of N- [2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) pyridazinone-6-yl) -phenyl! -Pyridine-3-carboxamide are added in 40 glacial acetic acid and heated for 20 hours in a steel bomb with glass insert to 150 ⁰ C. Thereafter, the acetic acid is distilled off, the residue is stirred with water, then filtered off with suction and dried. Further purification is carried out by chromatography over silica gel (eluent: dichloroethane + 6% ethanol).

 Yield: 38.3% of theory, m.p .: 223-225 ° C Calc .: C 66.66 H 4.61 N 18.29 V: 66.53 4.35 18.20

Example 9

5-methyl-6- [2- (4-pyridyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-Hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinon-6-yl) -phenyl] -pyridine-4-carboxamide analog

Example 8.

Yield: 39.9% of theory,

Melting point: 238-240 ⁰ C

Calc .: C 66.66 H 4.61 N 18.29

Gef .: 67.00 4.73 18.65

- 21 - 2

Example 10

5-Methyl-6- [2- (2-acetamino-5-pyridyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -2-acetaminopyridine-5-carboxylic acid amide analogously to Example Yield : 20.7% of theory, melting point: 299-300 ⁰ C Calc .: C 62.80 H 4.72 N 19.27 Found .: 62.90 5.01 18.98

Example 11

5-Methyl-6- [2- (2-furyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

  Prepared from N- [2-Hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) pyridazinone-6-yl) -phenyl] -furan-2-carboxamide analog

Example 8.

Yield: 22.2% of theory, Melting point: 204-205 ⁰ C Calc .: C 65.08 H 4.44 N 14.23 Found .: 64.79 4.44 14.27

Example 12

5-Methyl-6- [2- (2-thienyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -]

22 *. * 0 3

pyridazinone-6-yl) -phenyl] -thiophene-2-cocottonamide analogously to Example 8.

Yield: 50.5% of theory, melting point: 214-215 ° C calc .: C 61.71 H 4,21 N 13,50 S 10,30 V: 61.46 4.25 13.31 10, 37

Example 13

5-methyl-6- [2- (3-thienyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-Hydroxy-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinon-6-yl) -phenyl] -thiophene-3-carboxamide analog

Example 8.

Yield: 22.3% of theory, Melting point: 222-224 ⁰ C Calc .: C 61.71 H 4.21 N 13.50 S 10.30 Found .: 61.37 4.12 13.50 10.60

Example 14

6- [2- (4-Methyl-oxazol-5-yl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -4-methyl-oxazole-5-carboxylic acid amide analog

Example 8.

Yield: 12.7% of theory, melting point: 238-24O ⁰ C calc .: C 60.80 H 4.08 N 18.91 Gef .: 60.98 4.18 18.90

- 23 - 248

Example 15

6- [2- (3-Thienyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (4,5-dihydro-3 (2H) -pyridazin-5-on-6-yl) -phenyl] -thiophene-3-carboxamide analogously to Example 8.

Yield: 15% of theory, Melting point: 262-263 ⁰ C.

Ber .:. C 60.60 H 3.73 N 14.14 S 10.79 Vig .: 60.56 3.54 14.00 10.93

Example 16

5-Methyl-6- [2- (2-thienyl) benzothiazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

1.7 g (4.9 mmol) of N- [2-mercapto-5- (5-methyl-4,5-dihydro-3 (2H) -5-pyridazinone-6-yl) -phenyl] -thiophene-2 carboxylic acid amide are melted until no gas evolution is observed. By column chromatography over 200 g of silica gel (eluent: dichloromethane + 5% ethanol), the product thus obtained is purified

Yield: 11% of theory, Melting point: 203-204 ⁰ C.

^C 16 ^H 13 ^N 3 ^OS 2 ⁽³²⁷ ' ⁴⁾

Calc .: C 58.69 H 4.00 N Gef .: 58.33 4.12

12 83 S 19 59 13 01 19 44

Example 17

5-methyl-6- [2- (2-furyl) -benzothiazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-mercapto-5- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl] -furan-2-carboxamide analogously to Example 16, yield: 28% of theory, Melting point: 223-224 ° C

Calcd .: C 61.72 H 4,21 N 13,50 S 10,30 Found: - 61,90 4,21 13,40 10,43

Example 18

5-Methyl-6- [2- (1-piperazinyl) benzoxazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

1.5 g (5.4 mmol) of 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone are mixed with 10 g of piperazine and stirred for 2 hours heated to 160 ⁰ C. Thereafter, the reaction mixture is stirred with about 300 ml of water, the undissolved product is filtered off with suction and washed with water. The purification is carried out by column chromatography (basic alumina, eluent: methylene chloride + 2% ethanol).

Yield: 44.4% of theory, m.p .: 215-216 ° C

^C 16 ^H 19 ^N 5 ° 2 (313.4)

Calc .: C 61.33 H 6.11 N 22.35

Gef.: 61.15 6.12 '22.00

Example 19

5-Methyl-6- [2- (1-pyrrolidinyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone and pyrrolidine analogously to Example 18.

Yield: 59.4% of theory, Melting point: 230-231 ⁰ C.

Calc .: C 64.41 H 6.08 N 18.78 Vessel: 64.70 6.16 18.86

Example 20

5-Methyl-6- [2- (1-imidazolyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone and imidazole analogously to Example

Yield: 31.4% of theory,

Melting point: 236-238 ° C

Calc .: C 61.01 H 4.44 N 23.72 V .: 60.76 4.62 24.01

Example 21

5-Methyl-6- [2- (4-methyl-1-piperazinyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -

2 48

4,5-dihydro-3 (2H) -pyridazinone and 1-methyl-piperazine analogously to Example 18.

Yield: 58.8% of theory, Melting point: 230-231 ⁰ C.

Calc .: C 62.37 H 6.47 'N 21.39 F .: 62.56 6.53 21,44

Example 22

5-methyl-6- [2- (2-methyl-1-imidazolyl) -benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone and 2-methyl-imidazole in dimethyl sulfoxide by heating for 3 hours at 150 ⁰ C analog Example 18

Yield: 18.8% of theory, Melting point: 214-216 ⁰ C.

Calc .: C 62.13 H 4.89 N 22.64 F .: 62.48 4.87 22.82

Example 23

6- [2- (2-methyl-l-imidazolyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone and 2-methyl-imidazole analogously to Example 18.

Yield: 54.2% of theory, melting point: 242-243 ° C

Calc .: C 61.01 H 4.44 N 23.72 Vessel: 61.00 4.38 23.78

- ²⁷ - 248 36

Example 24

5-Methyl-6- [2- (4-methyl-l-pyrazolyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone and 4-methyl-pyrazole analogously to Example 18.

Yield: 16.6% of theory, -Schmelzpunkt: 255-257 ⁰ C.

Calc .: C 62.13 H 4.89 N 22.64 F .: 61.90 5.00 22.58

Example 25

6- [2- (N-acetyl-4-piperidino) -benzimidazole-5-yl] -4, 5-dihydro-3 (2H) -pyridazinone hydrochloride

450 mg of 6- [2- (4-piperidino) benzimidazol-5-yl] -4,5-dihydro-3 '(2H) -pyridazinone are suspended in 50 ml of ethyl acetate and 15 ml of glacial acetic acid. To this is added 15 ml of acetic anhydride and heated for 2 hours at reflux. The solvent is removed and the residue triturated in ether / acetone. The mixture is then heated briefly with water and dissolved after removal of the water, the residue obtained in ethanol, treated with activated charcoal and filtered off. Upon addition of the filtrate with ethereal hydrochloric acid, the desired product is obtained.

Yield: 210 mg (37% of theory), melting point: from 237 ^° C. (acetone).

£. * + \ j OC Example 26

5-Methyl-6- [2- (N-acetyl-4-piperidino) -benzimidazol-5-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- [2- (4-piperidino) benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone and acetic anhydride analogously to Example 25.

Yield: 16% of theory, Melting point: 245-248 ⁰ C.

Calc .: C 64.57 H 6.56 N 19.82 V: 64.40 6.54 20.00

Example 27

6- [2- (4-piperidino) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone hydrochloride

3.6 g of 6- [2- (2,6-dichloro-4-pyridyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone are dissolved in 100 ml of methanol for 6 hours in a Hydrogenated pressure vessel at 50 ⁰ C and 5 bar hydrogen in the presence of palladium / carbon. The mixture is then filtered off, the filter is admixed with ether and the precipitated crystals are filtered off with suction. The crude product obtained is dissolved in methanol, treated with activated charcoal and filtered off. Upon addition of the filtrate with ethereal hydrochloric acid, the desired product is obtained. Yield: 2.05 g (61.4% of theory), Melting point: sintering from 100 ⁰ C.

Example 28

6- [2- (2-chloro-6-morpholino-4-pyridyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

900 mg of 6- [2- (2,6-dichloro-4-pyridyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone are suspended in 15 ml of morpholine and 1 hour at 100 ⁰ C heated. It is then cooled, filtered off with suction, boiled 1 χ with water and dried well. Thereafter, the residue obtained is dissolved in dimethylformamide, mixed with activated charcoal, filtered off and the desired product is precipitated by the addition of petroleum ether.

Yield: 300 mg (29.2% of theory), melting point: above 300 ^° C.

Example 29

5-Methyl-6- [2- (2-pyridyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

6.5 g (20 mmol) of N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyridine-2-carboxylic acid amide (prepared from pyridine-2-carboxylic acid, N, N'-carbonyldiimidazole and 2-hydroxy-4- (S-methyl-4,5-dihydro-3 (2H) -pyridazinon-6-yl) -aniline) are at 120 ⁰ C. added with stirring in 60 g of polyphosphoric acid and kept at this temperature for 1 hour. After cooling, it is diluted with ice-water, made alkaline with ammonia and extracted with methylene chloride. The extract is washed with water, dried with sodium sulfate and distilled off the solvent in vacuo. The residue is stirred with acetone, the resulting crystals are filtered off with suction and recrystallized from isopropanol / water.

- 30 - 248 3 ^ 2

Yield: 4.5 g (73.3% of theory), m.p .: 233 ° C

Calc .: C 66.66 H 4.61 N 18.29

Gef .: 66.75 4.76 18.28

Example 30

5-Methyl-6- [2- (3-thienyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

3.0 g (9.1 mmol) of N- [2- (hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl] -thiophene-3-carboxylic acid amide (prepared from thiophene-3-carboxylic acid, N, N-carbonyldiimidazole and ¹ 2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) aniline and 0.5 g of p- Toluene sulfonic acid are dissolved in 50 ml of glacial acetic acid and heated to reflux for 8 hours The glacial acetic acid is then distilled off in vacuo, the residue stirred with water and diisopropyl ether, filtered with suction and washed with water and then with acetone The crude product is recrystallized from dioxane.

Yield: 1.6 g (56.4% of theory), m.p .: 235 ^° C.

Calc .: C 61.72 H 4.21 N 13.50 S -10.30. Result: 61.45 4.45 13.52 10.14

Example 31

5-methyl-6- [2- (2-furyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -furan-2-carboxamide and polyphosphoric acid analogously to Example 29.

14 23 O 16 25 13 99 16 47

- 31 -

Yield: 40% of theory, melting point: 209 ^° C.

Calc .: C 65.08 H 4.44 N Gef .: 64.93 4.61

Example 32

5-Methyl-6- [2- (2-thienyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -thiophene-3-carboxylic acid amide and polyphosphoric acid at 13O ⁰ C analogously to Example 29 Yield: 16.1% of theory, melting point: 222 ^° C.

Calc .: C 61.72 H 4.21 N 13.50 S 10.30

Gef .: 61.68 4.42 13.50 10.25

Example 33

5-Methyl-6- [2- (3-pyridyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2Ή) -pyridazinone-6-yl) -phenyl] -pyridine-3-carboxamide and polyphosphoric acid at 15O ⁰ C analogously to Example 29. Yield: 25% of theory, melting point: 218 ^° C.

Calc .: C 66.66 H 4.61 N 18.29 F .: 66.44 4.69 18.15

Example 34

5-Methyl-6- [2- (2-pyrazinyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyrazine-2-carboxamide and polyphosphoric acid analogously to Example Yield: 21.7% of theory, melting point: 242 ° C calc .: C 62.53 H 4,26 N 22,79 Gef.: 62,80 4,17 22,60

Example 35

5-methyl-6- [2- (4-pyridyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) pyridazinone-6-yl) -phenyl] -pyridine-4-carboxylic acid amide and polyphosphoric acid analogously to Example 'Yield: 49, 1% of theory, melting point: 228 ^° C. Calc .: C 66.66 H 4.61 N 18.29 V: 66.75 4.54 18.14

Example 36

5-Methyl-6- [2- (1-acetyl-4-piperidino) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -]

248

pyridazinone-6-yl) -phenyl] -1-acety1-piperidine-4-carboxylic acid arid and polyphosphoric acid analogously to Example 29. Yield: 60.3% of theory, melting point: 199 ^° C.

Calc .: C 64.39 H 6.26 N 15.81 F .: 64.60 6.20 16.06

Example 37

5-Methyl-6- [2- (4-methyl-5-oxazolyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -4-methyl-oxazole-5-carboxylic acid amide and polyphosphoric acid at 140 ⁰ C analogous to Example Yield: 28.2% of theory, melting point: 217 ^° C.

Calc .: C 61.93 H 4.55 N 18.05 Found: 62.12 4.70 18.28

Example 38

5-Methyl-6- [2- (5-pyrimidinyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyrimidine-5-carboxylic acid amide and polyphosphoric acid at 150 ⁰ C in analogy to Example 29 . ' Yield: 16.3% of theory, melting point: 279 ^° C.

Calc .: C 62.53 H 4.26 N 22.79 Found: 62.48 4.27 22.57

4 ο

Example 39

5-Methyl-6- [2- (2-amino-5-pyridyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -o-acetamino-pyridine ^ -carboxamide and polyphosphoric acid at 150 ⁰ C analogously to Example 29. Yield: 8.2% of theory, mass spectrum: M = 321 m / e

Calc .: C 63.54 H 4.71 N 21.79 F .: 63.45 4.85 21.59

Example 40

6- [2- (2-pyridyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyridine-2-carboxamide and polyphosphoric acid analogously to Example 29.

Yield: 29.1% of theory.

Melting point: 282-283 ° C

Ber. : C 65.75 H- 4,14 N 19,17 F .: 66,03 4,16 19,33

Example 41

6- [2- (2-furyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (4,5-dihydro-3 (2H) -pyrida-

Zinon-6-yl) -phenyl] -furan-2-carbonsäurea'mid and Polyphos · phoric acid analogously to Example 29. Yield: 31.3% of theory, Melting point: 261-262 ⁰ C Calc .: C 64.05 H 3 , 94 N 14.94 F .: 63.89 4.02 14.91

Example 42

5-Methyl-6- [2- (4-thiomorpholino) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and thiomorpholine analogously to Example 18.

Yield: 56.5% of theory, m.p .: 218 ° C. Calc .: C, 58.16, H, 5.49, N, 16.96, S, 9.70, Foth .: 58.24, 5.49, 17.20, 9.54

Example 43

5-Methyl-6- [2- (1-piperidino) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and piperidine analogously to Example 18.

Yield: 85.4% of theory, melting point: 235 ° C

Calc .: C 65.37 H 6.45 N 17.94

Gef.: 65.45 6.50 18.02

.36- - ⁴ S 3

Example 44

5-Methyl-6- [2- (1-oxido-4-thiomorpholino) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 1-oxidothiomorpholine analogously to Example 18

Yield: 65.3% of theory, melting point: 257-26O ⁰ C.

Calc .: C 55.48 H 5.24 N 16.17 S 9.26 O 13.86 F .: 55.60 5.20 16.44 9.44 13.61

Example 45

5-Methyl-6- [2- (1,1-dioxo-4-thiomorpholino) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 1,1-dioxo-thiomorpholine analogously to Example 18.

Yield: 63.5% of theory,

Melting point: 280 ^° C.

Calc .: C 53.03 H 5.00 N 15.46 S 8.85 G .: 53.00 5.16 15.51 8.96

Example 46

5-Methyl-6- [2- (4-methyl-1-piperazinyl) -benzoxazol-6-yl] -4,5x-di-ihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -

4,5-dihydro-3 (2H) -pyridazinone and N-methylpiperazine analogously to Example 18.

Yield: 61% of theory, melting point: 198 ^° C.

Calc .: C 62.37 H 6.47 N 21.39 F .: 62.62 6.50 21.44

Example 47

5-Methyl-6- [2- (4-carbethoxy-1-piperazinyl) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) 4,5-dihydro-3 (2H) -pyridazinone and 4-carbethoxy-piperazine analogously to Example 18.

Yield: 72.7% of theory, melting point: 239 ° C. Calc .: C 59.21 H 6.02 N 18.17. Found: 59.53 6.00 18.37

Example 48

5-methyl-6- [2- (1-pyrrolidinyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and pyrrolidine analogously to Example

18th ·

Yield: 73.8% of theory,

Melting point: 234 ° C. Calc .: C 64.41 H 6.08 N 18.78

Gef .: 64.64 6.07 18.85

Example 49

5-Methyl-6- [2- (1-piperazinyl) benzoxazole-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and piperazine in the melt analogously to Example 18

'Yield: 70.0% of theory, melting point: 213 ⁰ C.

Calc .: C 61.33 H 6.11 N 22.35 F .: 61.56 6.01 22.51

Example 50

5-Methyl-6- [2- (4-methyl-1-imidazolyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 4-methyl-imidazole at 15O ⁰ C analogously to Example 18.

Yield: 73.5% of theory, - -

Melting point: 258 ° C

Calc .: C 62.13 H 4.89 N 22.64 F .: 62.05 4.86 22.50

Example 51

6- [2- (1-piperidino) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihy

- 39 - · ^Μ ν - Ö

dro-3 (2H) -pyridazinone and piperidine analogously to Example Yield: 62% of theory, Melting point: 198-199 ⁰ C.

Calc .: C, 64.41, H, 6.08, N, 18.78, Fn: 64.62, 6.0, 18.71

Example 52

6- [2- (4-morpholino) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and morpholine analogously to Example Yield: 73.3% of theory, Melting point: 240 ⁰ C.

Calc .: C 59.99 H 5.37 N 18.66 V .: 60.20 5.37 18.81

Example 53

6- [2- (1-Pyrrolidinyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and pyrrolidine analogous to Example Yield: 78.9% of theory, m.p .: 265-266 ° C

Re: C 63.37. H 5.67 N 19.71 Vessel: 63.50 '5.73 19.55

- 40 - -2 43

Example 54

6- [2- (4-methyl-l-imidazolyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 4-methyl-imidazol at 150 ⁰ C analogously to Example 18. Yield: 17% of theory, m.p. : 280-282 ⁰ C Calc .: C 61.01 H 4.44 N 23.72 Found:. 60.80 4.44 23.49

Example 55

6- [2- (4-Carbethoxy-1-piperazinyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 4-carbethoxy-piperazine analogously to Example 18. Yield: 50.1% of theory, m.p .: 242 -243 ° C calc .: C 58.21 H 5.70 N 18.86 F .: 58.39 5.84 18.65

Example 56

6- [2- (1-piperazinyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihy

JL H 8 - 41 -

dro-3 (2H) -pyridazinone and piperazine (melt) analogously to Example 18.

Yield: 36.7% of theory, melting point: 182-183 ⁰ C.

Calc .: C 60.19 H 5.72. N 23.40 Found: 60.20 5.60 23.43

Example 57

6- [2- (1-oxido-4-thiomorpholino) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 1-oxidothiomorpholine analogously to Example 18.

Yield: 39.1% of theory, melting point:> 310 ^° C.

Calc .: C 54.20 H 4.85 N 16.86 S 9.65 V .: 54.35 5.11 16.87 9.57

Example 58

6- [2- (1,1-dioxido-4-thiomorpholino) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and 1,1-dioxo-thiomorpholine analogously to Example 18.

Yield: 33.3% of theory, melting point: 298-299 ° C

Calc .: C 51.71 H 4.63 N 16.08 S 9.20 F .: 51.60 4.83 16.14 9.30

Example 59

6- [2- (4-methyl-l-piperazinyl) benzoxazole-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and N-methylpiperazine analogously to Example 18.

Yield: 41.5% of theory, Melting point: 247-248 ⁰ C.

Calc .: C 61.33 H 6.11 N 22.35 V: 61.20 6.31 22.35

Example 60

6- [2- (4-thiomorpholino) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and thiomorpholine analogously to Example 18. Yield: 39.2% of theory, melting point: 253-254 ° C

Calc .: C 56.95 H 5.10 N 17.71 S 10.13 F .: 56.87 5.21 17.68 10.30

Example 61

5-n-propyl-6- [2- (1-imidazolyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-n-propyl-6- (2-methylthio-benzoxazol-5-yl) 4,5-dihydro-3 (2H) -pyridazinone and imidazole analogously to Example 18.

- 43 - < 4 8 36

Yield: 30.3% of theory, Melting point: 190-192 ⁰ C.

Calc .: C 63.15 H 5.30 N 21.67 V .: 63.09 5.51 21.52

Example 62

5-n-propyl-6- [2- (1-piperazinyl) benzoxazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-n-propyl-6- (2-methylthio-benzoxazol-5-yl) 4,5-dihydro-3 (2H) -pyridazinone and piperazine analogously to Example 18.

Yield: 65.2% of theory, melting point: 162-164 ° C

Calc .: C 63.33 H 6.79 N 20.52

F .: 62.98 6.93 20.32

Example 63

5-Methyl-6- [2- (1-imidazolyl) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) 4,5-dihydro-3 (2H) -pyridazinone and imidazole at 160 ⁰ C in analogy to Example eighteenth

Yield: 17% of theory, melting point: 219 ° C

Calc .: C 61.01 H 4.44 N 23.78 O 10.84

Gef .: 61.00 4.51 23.63 10.76

- 44 - 2 is 3

Example 64

5-Methyl-6- [2- (4-morpholino) benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-methylthio-benzoxazol-6-yl) -4,5-dihydro-3 (2H) -pyridazinone and morpholine analogously to Example 18.

Yield: 81.2% of theory, melting point: 209 ^° C.

Calc .: C 61.14 H 5.77 N 17.82. Gef .: 60,93 5,59 17,91

Example 65

6- [2- (3-thienyl) benzoxazole-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -thiophene-S-carboxamide and glacial acetic acid / p-toluenesulfonic acid analogously to Example 30.

Yield: 22.2% of theory,

Melting point: 272-273 ° C

Calc .: C 60.59 H 3.73 N 14.13 S 10.78 V .: 60.60 3.68 13.99 10.66

Example 66

5-Methyl-6- [2- (2-acetamido-5-pyridyl) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) -]

- 45 - '2 48 36

pyridazinon-6-yl) phenyl] ^ - aeetamino-pyridin-S-carboxylic acid

amide and glacial acetic acid / p-toluenesulfonic acid analogously to Example 30. Yield: 12% of theory, melting point:> 300 ^° C.

Calc .: C 62.80 H 4.72 N 19.27

Gef.: 62.66. 4,96 19,25

Example 67

5-methyl-6- [2- (2,6-dichloro-3-pyridyl) -benzoxazol-6-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-4- (5-methyl-4,5-dihydro-3 (2H) pyridazinone-6-yl) -phenyl] -2,6-dichloro-pyridine-3-carboxamide and glacial acetic acid. p-toluenesulfonic acid analogously to example 30. yield: 40% of theory, melting point: 268-270 ⁰ C.

Calc .: C 54.42 H 3.22 N 14.93 Cl 18.90 F .: 54.52 3.33 14.70 18.88

Example 68

5-n-propyl-6- [2- (4-pyridyl) benzoxazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from N- [2-hydroxy-5- (5-n-propyl-4,5-dihydro-3 (2H) -pyridazinone-6-yl) -phenyl] -pyridine-4-carboxylic acid amide analogously to Example 8.

Yield: 40.1% of theory,

Melting point: 200-202 ⁰ C

Calc .: C 68.24 H 5.42 N 16.76

; Gef .: 68.26 5.38 16.91

- 46 - 2 48 3 6

Example 69

5-Methyl-6- [2- (2-chloro-6-morpholino-3-pyridyl) -benzoxäzol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- [2- (2,6-dichloro-3-pyridyl) -benzoxazol-6-yl] -4,5-dihydro-3 (2H) -pyridazinone and morpholine analogous to Example 28

 Yield: 22% of theory, melting point: 236 ° C

Ber. : C 59, 22 H 4 , 73 N 16 45 Cl 8th, 39 10 Gef .: 59, 26 4 , .82 16 63 8th, 58 example 70

5-Methyl-6- [2- (1-imidazolyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4- (2-chloro-benzimidazol-5-yl) ^ -oxo-S-methyl-butyric acid methyl ester

12 g (46 μl) of methyl 4- (benzimidazol-2-on-5-yl) -4-oxo-3-methylbate are refluxed in 200 ml of phosphorus oxychloride for 1.5 hours. Subsequently, the excess phosphorus oxychloride is distilled off in vacuo and the remaining residue is decomposed with ice cooling with water. It is neutralized with ammonia, extracted with ethyl acetate, the ethyl acetate phase is washed twice with water, dried over magnesium sulfate and concentrated to dryness. The residue is purified by chromatography (silica gel: 0.032-0.063 mm, eluant: ethyl acetate / petroleum ether = 2/1).

Yield: 7.9 g (61.2% of theory), Melting point: 135-136 ⁰ C.

b) 4- [2- (1-Imidazolyl) benzimidazol-5-yl] -4-oxo-3-ethyl

But it is acid ester!

1.5 g (5.3 mmol) of 4- (2-chloro-benzimidazol-5-yl) -4-oxo-3-methyl-butyric acid methyl ester and 1.1 g (16 mmol) of imidazole are mixed and left for 1.5 hours heated to 13O ⁰ C for a long time. This gives a clear tough melt, which is added after cooling with water. It is extracted three times with ethyl acetate, the combined ethyl acetate solutions are washed three times with water, dried over magnesium sulfate and evaporated to dryness.

Yield: 1.5 g (90% of theory), Melting point: 130-140 ⁰ C.

• Re: C 61.53 H 5.16 'N 17.94 F: 61.21 5.47 17.87

c) 5-Methyl-6- [2- (1-imidazolyl) -benzimidazol-5-yl] -4,5- dihydro-3 (2H) -pyridazinone

1.4 g (4.3 mmol) of methyl 4- [2- (1-imidazolyl) benzimidazol-5-yl] -4-oxo-3-methylbutyrate are mixed with 30 ml of acetic acid * and 3.8 ml of 80% Hydrazine hydrate heated to 105 ⁰ C for 1.25 hours. After cooling, it is mixed with about 100 ml of water and extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed twice with water, dried over magnesium sulfate and evaporated. The residue is purified by chromatography (silica gel:

0.032-0.063 mm, eluent: methylene chloride / ethanol = 1: 0 to 1: 0.14).

Yield: 0.29 g (22.9% of theory), Melting point: 282-285 ⁰ C (dec.)

- ⁴⁸ "Λ JJ ^ λ J Λ

Example 71

5-Methyl-6- [2- (4-methyl-1-piperazinyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from methyl 4- [2- (4-methyl-1-piperazinyl) benzimidazol-5-yl] -4-oxo-3-methylbutyrate and hydrazine hydrate analogously to Example 70c

Yield: 67% of theory, melting point: 317-32O ⁰ C (dec.).

Example 72

5-Methyl-6- [2- (4-morpholino) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (4-morpholino) -benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c

Yield: 51% of theory, mass spectrum: M = 313 m / e IR spectrum (methylene chloride): 1665 cm ^-1 "(carbonyl)

Example 73

5-Methyl-6- [2- (1-pyrrolidinyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (1-pyrrolidinyl) benzimidazol-5-yl] 4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c.

C 4 S 3 <S

Yield: 75.3% of theory, m.p .: 233-236 ° C

Ber. : C 64.63 H 6.44 N 23.55 V: 64.42 6.67 23.36

Example 74

5-Methyl-6- [2- (4-thiomorpholino) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridäzinon

Prepared from 4- [2- (4-thiomorpholino) -benzimidazol-5-yl] 4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c.

Yield: 73% of theory,

UV spectrum (ethanol): 224 nm (0.18), 246 nm (0.28),

323 nm (0.33),

IR spectrum (methylene chloride): 1665 cm "(carbonyl) 1625-1630 cm" ¹ (C = N)

Example 75

5-Methyl-6- [2- (2-pyrrolyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (2-pyrrolyl) -benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c.

Yield: 36% of theory, Melting point: 305-310 ⁰ C (dec.) IR spectrum (methylene chloride): 1630 cm '(carbonyl)

- so - 2i8 3 6

Example 76

5-Methyl-6- [2- (l-oxido-4-thiomorpholino) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (l-oxido-4-thiomorpholino) benzimidazol-5-yl] -4-oxo-3-IIlethyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c

Yield: 84% of theory, Melting point: 105 ⁰ C (dec.)

UV spectrum (ethanol): 221 nm (0.34), 245 nm (0.53), 319 nm (0.63), IR spectrum (methylene chloride): 1655 cm (carbonyl)

Example 77

5-Methyl-6- [2- (1-hexahydroazepinyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (1-hexahydroazepinyl) benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c

 Yield: 19% of theory, m.p .: 295-298 ° C (dec.)

Mass spectrum: M: 325 m / e

Example 78

5-Methyl-6- [2- (1-pyrazolyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (1-pyrazolyl) -benzimidazol-5-yl] -4-oxo

Methyl 3-methylbutyrate and hydrazine hydrate analogously to Example 70c.

Yield: 37% of theory, Melting point: 290-292 ⁰ C.

5.Ber .: C 61.21 H 4.80 N 28.56 Gef .: 61.17 4.89 28.49

Example 79

5-Methyl-6- [2- (4-acetyl-1-piperazinyl) -benzimidazol-5-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (4-acetyl-1-piperazinyl) benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Example 70c

Yield: 44% of theory, melting point: 295-302 ⁰ C.

Calc .: C 61.00 H 6.26 N 23.71 V .: 61.30 6.43 23.56

Example 80

5-Methyl-6- [2- (imidazolidin-2-one-1-yl) -benzimidazol-5-yl] 4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (imidazolidin-2-one-l-yl) benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c

 Yield: 7% of theory, melting point: 285 ° C. (dec.)

Mass spectrum: M = 312 m / e

Example 81

5-Methyl-6- [2- (1-piperidino) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (1-piperidino) benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate 'analogous to Example 70c

 Yield: 49% of theory, m.p .: 185 ° C (dec.) 'Mass: m = 311 m / e

Ί0 Example 82

5-Methyl-6- [2- (3-hydroxy-4-methyl-2-pyrazolyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 4- [2- (3-hydroxy-4-methyl-2-pyrazolyl) -benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Example 70c. · Yield: 67% of theory, Melting point: 260-265 ⁰ C (dec.) Mass Spec tower: M = 324 m / e

Example 83

5-Methyl-6- [2- (4-morpholino) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4- [2- (4-Morpholino) -benzimidazol-5-yl] -4-oxo-3-methyl- butyric acid morpholide

Prepared from 4- (2-sulfo-benzimidazol-5-yl) -4-oxo-3-methyl

24a 362

butyric acid analogously to Example 70a

 Yield: 30% of theory, mass M: M = 386 m / e

Calc .: C 62.16 H 6.78 N 14.50 F .: 61.90 6.86 14.36

b) 5-Methyl-6- [2- (4-morpholino) -benzimidazole-Sryl] -4,5-dihydro -3 (2H) -pyridazinone

Prepared from 4- [2- (4-morpholino) -benzimidazol-5-yl] -4-oxo-3-methyl-butyric acid morpholide and hydrazine hydrate analogous to Example 70c.

Yield: 61% of theory, mass spectrum: M = 313 m / e

Example 84

5-Methy1-6- [2- (1- [I.2.4] triazolyl) -benzimidazole-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

a) 4- [l- [1.2.4] triazolyl-benzimidazol-5-yl] -4-oxo-3-methyl-1-ylic acid a thy! ester

260 mg (1 mmol) of 4- (2-chloro-benzimidazol-5-yl) -4-oxo-3-methyl-butyric acid methyl ester with 980 mg (14 mmol) of 1,2,4-triazole in an oil bath at 160 ⁰ C. heated. After 45 minutes, cooled and triturated with 50 ml of hot methanol. Then distilled from 10 to 20 ml of methanol, the resulting precipitate is filtered while hot and dried in air.

Yield: 0.22 g (74% of theory), Melting point: 300-306 ⁰ C (dec.).

2 4g35

b) 5-Methyl-6- [2- (1- [1,2,4] triazolyl) -benzimidazol-5-yl] -4,5- dihydro-3 (2H) -pyridazinone

280 mg (1 mmol) of 4- [1- [1.2.4] triazolyl-benzimidazol-5-yl] -A- oxo-3-methyl-butyric acid methyl ester with 5 ml of ethanol and 1 ml of 98% hydrazine hydrate for one hour on 100 ⁰ C heated. The solvent is then distilled off in vacuo, the residue is combined with water and extracted 3 times with ethyl acetate. The combined ethyl acetate phases are washed twice with water, dried over sodium sulfate and concentrated in vacuo. The residue obtained is purified by chromatography (.Kieselgel, eluent: ethyl acetate).

Yield: 107 mg (40% of theory), Melting point: 228-230 ⁰ C.

Example 85

5-Methyl-6- [2- (3-methyl-1-pyrazolyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

Prepared from 5-methyl-6- (2-chloro-benzimidazol-5-yl) -4,5-dihydro-3 (2H) -pyridazinone 'and 3-methyl-pyrazole analogously to Example 84b.

Yield: 87% of theory,

Melting point: 320-322 ⁰ C (dec.)

Calc .: C 62.32 H 5.23 N 27.26

F .: 62.32 5.21 27.43

Example 86

5-Methyl-6- [2- (1-pyrrolidinyl) -benzimidazol-5-yl] -4,5-dihydro-3 (2H) -pyridazinone

295 mg (1 mmol) of 5-methyl-6- [2- (1-pyrrolidinyl) benzimidazol-5-yl] -3 (2H) -pyridazinone are dissolved in 20 ml of glacial acetic acid and at room temperature and 5 bar of hydrogen in the presence of Hydrogenated platinum dioxide. After completion of the hydrogen uptake, the catalyst is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is purified by chromatography (silica gel, eluent: methylene chloride / ethanol = 1: 0 to 1: 0.2).

 Yield: 30% of theory, melting point: 233-236 ° C

Claims (6)

, -248 312 Inventive claim 1. Process for the preparation of new pyridazinones of the general formula R 2 · X is an imino group optionally substituted by an alkyl or phenylalkyl group, an oxygen or sulfur atom, - R _{1 is} a bonded via a nitrogen saturated 5- to 7-membered Alkyleniminoririg or bound via a carbon atom 5- to 7-membered saturated imino, N-alkyl-imino, N-phenylalkyl-imino, N-alkanoylimino or N-alkoxycarbonyl-imino-alkylene ring, wherein the. above-mentioned rings in the carbon skeleton substituted by one or two alkyl groups and a methylene group in the 4-position of a 6- or 7-membered ring by an oxygen or sulfur atom, a sulfinyl, sulfonyl, imino, alkylimino, phenylalkylimino, Alkoxycarbonylimino or alkanoylimino group may be replaced by a saturated 5- to 7-membered alkyleneiminoring optionally bonded by one or two alkyl groups via a nitrogen atom in which a -CHpCHp group is replaced by an -NH-CO- group, 24 wherein the CO group of this -NH-CO group is linked to the already existing N atom, a bonded via a nitrogen atom 5-membered hetexoarornatischen ring which additionally an oxygen or sulfur atom, one or two nitrogen atoms, an oxygen or In which the heteroaromatic ring may be substituted by one or two alkyl groups and, in the case of the pyrazoles, also by a hydroxy group and an alkyl group, a 5- or 6-membered heteroaromatic ring bonded via a carbon atom and having an oxygen atom or sulfur atom, one, two or three nitrogen atoms, an oxygen or sulfur atom and one or two nitrogen atoms may contain, wherein the heteroaromatic rings-by one or two alkyl groups, by an amino or alkanoylamino group and in the case of pyridines also by a or two halogen atoms or by a halogen atom and an amino or morpholino group substitui can be tuiert, and. - Rp represents a hydrogen atom or an alkyl group, wherein all the above-mentioned alkyl, alkanoyl or alkoxy groups may each contain 1 to 3 carbon atoms, their optically active antipodes, when R _{2 is} not a hydrogen atom, and their acid addition salts, characterized in that a) for the preparation of compounds of the general formula I in which R _{1 represents} one of the radicals mentioned above bound via a carbon atom, a compound optionally formed in the reaction mixture the general formula
R in the R _? as defined in claims 1 to 5, one of the radicals A or B is a. R. ' - C - X "group and the other of the radicals A or B is an amino group or a Z ₁ Z ₉ . Z, R £ - C - NH or R ₁ "-C = N- group where X is as defined in claims 1 to 5 and R ₁ "represents one of the radicals bonded via a carbon atom mentioned for R ₁ in claims 1 to 5, Z. and Z ", may be the same or different, nucleophilic leaving groups or Z 1 and Z ₂ together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl or phenylalkyl group, wherein the abovementioned alkyl moieties each have 1 to 3 carbon atoms fig 362 or an alkylenedioxy group having 2 or 3 carbon atoms and. ·. - ' Z _{x has} the meanings mentioned above for Z ₁ or is an imidazolyl group, a chlorine, bromine or oxygen atom, is cyclized, or b) a carboxylic acid of the general formula C -    CH "- COOH , (III) in the R ₁ and R _{2 are} as defined in claims 1 to 5, or whose reactive acid derivatives are reacted with hydrazine, or c) for the preparation of compounds of the general formula I, in which R _{1 is} one of the radicals attached via a nitrogen atom mentioned in claims 1 to 5. represents a compound of the general formula , (IV) in the - . R ₂ and X are as defined in claims 1 to 5 and _ 60- Z _{4 represents} a nucleophilically exchangeable group, with an Arnin of the general formula H-R ₁ ",, (V) in the - R ₁ "represents one of the mentioned for R in claims 1 to 5 is bonded via a nitrogen atom radical, is reacted or d) for the preparation of compounds of the general formula I in which X represents an oxygen atom or an optionally substituted by an alkyl- or phenylalkyl-substituted imino group, a compound of the general formula ^{Λ R} in the R ₁ and Rp are as defined in claims 1 to 5 are and . , * X 'is an oxygen atom or an imino group optionally substituted by an alkyl or phenylalkyl group, wherein the alkyl moiety may contain in each case 1 to 5 carbon atoms, is hydrogenated, and FROM 36 2 if desired, subsequently a compound of the general formula I in which R ₁ contains an imino and / or amino group is converted by alkanoylation into a corresponding compound of the general formula I in which R _{1 is} an alkanepylimino and / or alkanoylamino group contains, is transferred or ' a compound of the general formula I in which R _{1 is} a pyridine radical which is bonded via a carbon atom and substituted by halogen atoms, by catalytic dehalogenation and hydrogenation to give a compound of the general formula I in which R. represents a piperidinyl radical bonded via a carbon atom ^ is transferred, or · a compound of the general formula I in which R _{1 represents} a pyridine radical which is bonded via one carbon atom and substituted by one or two halogen atoms, - by halogen exchange into a corresponding compound of the general formula I in which R _{1 represents} a pyridine radical bonded via a carbon atom which is substituted by an amino or morpholino group and optionally substituted by a halogen atom, or ' a compound of the general formula I thus obtained which contains an optically active carbon atom in position 4 or 5 of the pyridazinone ring, if R. represents an alkyl group, is resolved into its optically active antipodes by means of racemate resolution or 248 36 ' 6Ä- a compound of the general formula I thus obtained is converted into its acid addition salts , in particular into its physiologically tolerable salts with inorganic or organic acids. 2. The method according to item 1, characterized in that the pyridazinones for X is the imino group, an oxygen or sulfur atom, R _{1 is} a pyrrolidinyl- _t- piperidino, 1-hexahydroazepinyl, morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxideothioraorpholino, 1-piperazinyl, 4-methyl-1-piperazinyl bonded via a nitrogen atom. , 4-acetyl-1-piperazinyl, 4-carbethoxy-1-piperazinyl , 1-imidazolyl, 1-pyrazolyl , 1 - / ~ 1.2.4_J 7 -triazolyl, imidazolidin-2-one-1-yl or 3-hydroxy-2-pyrazolyl group. or a piperidino group attached through a carbon atom, N-'Acetyl-piperidino, furyl, thienyl, pyrrolyl, pyridyl, amino-pyridyl, Acetylaminopyridyl-, pyrimidyl, pyrazinyl, oxazolyl, dihalo-pyridyl or Halogenmorpholino-pyridyl group, wherein all the above-mentioned radicals iw carbon skeleton may be substituted by a methyl group, and R _{2 represents} a hydrogen atom or a methyl group in the 5-position, their optically active antipodes, when R _{2 is} not a hydrogen atom, and their acid addition salts. , 3. The method according to item 1, characterized in that the pyridazinones for X is an oxygen atom or the imino group, R ₁ is 1-pyrrolidinyl, 1-imidazolyl, 2-furyl, 3-thienyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-carbethoxy-1-piperazinyl, 4- Morpholino, 4-thiomorpholino, l-oxido-4-thiomorpholine »and 4-pyridyl group and : ~ ~ R ₉ in the 5-position mean the methyl group whose optically active antipodes, when R _{2 is} not a hydrogen atom, provides., And their acid addition salts. U method according to item 1, characterized in that the pyridazinone is 5-methyl-5-one-pi "" 2- (1-imidazolyl) -benzoxazol-5-yl-7 "-4", 5-dihydro-3- (2H) -pyridazinone # whose optically active antipodes and its acid addition salts are prepared. " 5, process according to item 1, characterized in that the pyridazinone is 5-methyl-6 - / 2- (1-piperazinyl) -benzoxazinone-6-yl-7,5-dihydro-3 (2H) -pyridazinone, its optically active antipodes and its acid addition salt are prepared. 6i Method according to item 1, characterized in that the reaction is carried out in a solvent. 7t process according to "points la and 6, characterized in that the reaction in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, glacial acetic acid, Acetic anhydride, N, N'-dicyclohexyl-carbodiimide, carbonyldiimidazole, Kaliumme.thylat or potassium tert-butylate is performed. _8, procedure according to points la ». 6 and 7, characterized in that the reaction is carried out at temperatures between O and 300 ⁰ C, but preferably at the boiling temperature of the reaction mixture, 9 »Process according to points Ib and 8, characterized in that the reaction is carried out in the presence of an acid as a condensing agent» 10. The method according to the points Ib, 6 and 9, characterized in that the reaction at temperatures between 0 and 200 ⁰ C, but preferably at the boiling temperature of the reaction mixture is carried out * 11. The method according to the items Ic and 6, characterized in that the reaction is carried out in the presence of an acid-binding agent. 12 * Process according to the points Ic, 6 and 11, characterized in that the reaction at temperatures between 50 and 200 C, but preferably at temperatures between 100 and 180 ⁰ C, is performed. 13. The method according to the items Id and 6, characterized in that the reaction in the presence of a hydrogenation catalyst at temperatures between ο and 75 ⁰ C. is carried out. 14, method according to the points Id, 7 and 13, characterized in that the reaction is carried out at a hydrogen pressure of 1 to 5 bar and at room temperature.