JPS6013766A - Tetrahydropyridazinone derivative, manufacture and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to general formula (I) 2 / OH2 deceased (In the formula, R is the formula Indicates the residue.

R1 is a hydrogen atom, an alkyl group, an aralkyl group, in which the aryl moiety is optionally substituted, or an acyl group of the formula -〇〇-R'; R2 is a hydrogen atom, an alkyl group, optionally substituted; represents a phenyl group which may be substituted with a basic group or optionally substituted with a basic group, Ra, R4 and all are independent of each other), a rogen atom, cl-c, an alkyl group,
-OH, 010g alkoxy group, 0□-CI+alkanoyloxy group, benzoyloxy group, C1-C, alkylmercapto group NH2゜C, -a, monoalkylamino group, total a, -C5 dialkylamino group, 0 □
-04 7 alkanoylamide groups.

R3 and door further represent a nitro group, a cyan group, C and -C3, respectively.
represents an alkylmercapto-alkylsulfoxy- and hyalkylsulfonyl group, an alkyl~(C+'s)-oxycarbonyl group, a group of formula -NRI OR+ 1, in which R3 and R4 represent an alkyl group, alkoxy group, alkylamino group, dialkylamino group, alkylmercapto group, alkylsulfoxy group and alkylsulfonyl group further include a hydroxy group, a
, -o, , preferably 01 or 02 alkoxy group, carboxyl group as a whole 02-0. an alkoxycarbonyl group of the formula (wherein R1l+ and RIG are each independently a hydrogen atom,
a, -C, alkyl group - which is itself C, -C.

Alkoxy group, halogen atom, especially chlorine atom and bromine atom, -NH2, alkyl group may be substituted with C7-0, mono- and dialkylamino group, or in this case, R11+ and R16 indicate that these are bonded together with the N-atom to form a 5-split, 6-membered heterocycle optionally containing other heteroatoms, such as pyrrolidine, piperidine, piperazine, alkylpiperazine, morpholine, thiomorpholine do. ) an aminocarbonyl group, an amino group, 0. -05, preferably C, -C, monoalkylamino group, overall 02-
by the dialkylamino group of R6 or by the heteroatom 1-
R4 and RI' may be substituted by a heterocycle of 5- or 6-G[ having 3 atoms, R4 and RI' additionally represent a hydrogen atom, and R6 and R7 independently represent a hydrogen atom, a halogen atom, Especially chlorine atom and bromine atom, amino group, C, -O, monoalkylamino group, overall O, -a,
represents a dialkylamino group, hydroxy group, O, -a, alkoxy group or O, -0, alkyl group.

R8 represents a hydrogen atom, a, -C, alkyl group, O, -0, alkanoyl group, or a residue of the formula; RIG represents a residue of the formula C, -C, alkanoyl group - optionally C, -OH, -Nu, -, substituted by a chlorogen atom, especially a chlorine atom or a bromine atom C , -C, a benzoyl group of the formula 11 optionally substituted by an alkoxy group or an extended nalphenoxy group, where n=2, 3 or 4, m=Q, 1 or 2, in which case preferably n + m = 3 or 4, X is an oxygen atom,
A sulfur atom, a group with the formula = N-R', provided that the cyclic nucleus C1 is also C, -C, preferably C0 or C2
Alkyl group, chlorine atom.

A heteroaryl residue which may be substituted by a bromine atom or a double-bonded oxygen atom (=0)K, R11 is a hydrogen atom, c, -c, an alkyl group 0. -0.
It represents an alkanoyl group, or RIG and l'(11
together with the N-atom to which they are attached form a pyrrolidine-, piperidine-, piperazine-, morpholine- or thiomorpholine ring or a formula (where p=3.5 or 5; q=2
or 3) (wherein r = 1 or 2) (wherein U is 0, 1 or 2, t = o, 1 or 2) - this may optionally further include C, -C5, preferably a, optionally substituted by a C2 alkyl/I/ group-
form, R1! to R14 are hydrogen atoms, O, -0, alkyl groups, C, -0, alkoxy groups, nitro groups, cyan groups, halogen atoms, especially chloro- or bromine-atoms, amino groups,
C, -C, monoalkylamino group, total C, -a, dialkylamino group, C, -C.

Indicates an alkanoylamino group or a benzoylamino group.

) and its acid addition compounds.

General formula (in the formula, R stands for phenyl nucleus substituent R3, R
4 and R5 have the meanings given above. ) and their physiologically compatible salts exhibit valuable pharmacological effects. This is significantly superior to previously known compounds with the same tendency of action.

Compounds of the general formula (I), in which R represents an unsubstituted phenyl nucleus, with the proviso that R3 also represents a hydrogen atom, and their physiologically compatible salts, likewise exhibit valuable pharmacological actions. show.

The substituents R3 to R5 of the residue represented by R can be present at any position on the phenyl nucleus. When R' and R5 are hydrogen atoms, -R3 has the above meaning, and 2-9 of the phenyl nucleus
Present in the 3- or 4-position. In the case of double substitution, only HM is a hydrogen atom, R3 and R' have the above meanings independently of each other, 2.3-, 3.2-, 2.4-, 4.2-
, 2.5-, 5.2-, 2.6-.

It can be present in the 3.4-, 4.5- or 3,5-position. Preferably, the doubly substituted phenyl nucleus denoted by R has only optionally substituted amino groups and only acyloxy groups. That is, only R3 has the above meaning,
-NH, having a mono- or dialkylamino group or an alkanoyl- or benzoyloxy group.

Optionally present third substituent (R5 = hydrogen atom)
is preferably a chloro atom, an alkyl residue, especially a methyl group, or an alkoxy group, especially a methoxy group.

5- or 6-membered ring hetero term having 1 to 5 heteroatoms - R'' or R4 means alkyl-, alkoxy-, alkylamino-, dialkylamino-, alkylmercapto-, alkylsulfoxy -Can also exist as a substituent of the haalkylsulfonyl group-
is an aromatic and heteroaromatic five-membered ring having 1, 2 or 5 N-atoms, such as virol, virol-N-oxide, pyrazole, imidazole.

- Triazole, pyrrolidine, pyrrolidine-N-oxide, pyrazoline, imidacilline, θ-triazoline,
5-membered rings having an oxygen atom, such as furan and tetrahydrofuran; 5-membered rings having a sulfur atom, such as thiophene, tetrahydrothiophene, thiophene-6-oxide, tetrahydrothiophene-8-oxide, tetrahydrothiophene-dioxide; 5-membered rings with heteroatoms, such as oxazole, oxazoline, thiazole, thiazoline, oxadiazole, oxadiazoline or aromatic and heteroaromatic 6-membered rings with 1, 2 or 3 N-atoms, e.g. is pyridine, pyridine-N-oxide, piperidine, pyridazine, di-, tetra- and hexahydropyridazine, pyrazine, di,
Tetra- and hexahydropifurans, pyrimidines, di, tetra- and hexahydropyrimidines, s-triazines, di.

Tetra- and hexahydro-8-triazines, 6-membered rings with 1 or 2 oxygen atoms, such as bira/, di- and tetrahydro-birans, 1. O- and 1,4-dioxane, 1,3- and 1,4-dioxene, 1,4-dioxadiene or (iitE Yellow W 6 with 1 or 2 children)
members, such as thiavirane and tetrahydrothiapyran and di-oxide and S-dioxide, 1,4
-Zitian.

1,4-dithiane and 1,4-dithiadiene as well as dioxide and θ-dioxide or six-membered rings with various heteroatoms, such as 1,3 in the form of their tautomers.
- and 1,4-oxazine, dihydro-1,6- and -
1,4-oxazine, morpholine, 1.3- and 1.4
-thiazine, dihydro-1,5- and -1,4-thiazine, theomorpholyl/, 1,4-oxathiane, 1,4-
They are oxathiane and 1,4-oxathiadiene.

Said hete c1m can itself additionally have C, -C, preferably C1 or C, 1 or 2, preferably 1, alkyl group. When present in hydrogenated or partially hydrogenated form, it can also contain double-bonded oxygen (keto functionality). =Alkyl- as R3 or radical in a nitrogen heterocycle having an NE- group in the ring.

alkoxy-, alkylamino-dialkylamino-,
The bond with an alkylmercapto, alkylsulfoxy or alkylsulfonyl group can also be effected via the N-atom of this -NH- group. Insofar as nitrogen heterocycles with a keto function form tautomeric forms, they can also exist in this form.

Preferred heterocyclic residues include, for example, virol, vilorin,
Pyrrolidine, pyrrolidone, imigol-(1)-yl, imidazo-yv-4-yl, 2-methyl-imidazo-A/-4-yl, oxazole, oxazoline, oxazolidine, oxazolidone, especially 2-oxazolidon-5-yl , oxazol-2-yl, 5-methyl-
Oxadiazol-/I/-2-yl, pyrid-2-, -3
- or -4-yl; 2-hydroxy-4-methyl-pyrid-6-yl or 2-pyridon-4-methyl-6-yl
, 2-pyrone-4-1-5- or -6-yl, 2-pyrone-4-methyl-6-yl.

RIG means a heteroaryl residue of the above formula, such as a carboxylic acid of the formula, such as pyrrolidine-2-carboxylic acid, pyrrolidine-2-carboxylic acid substituted in the 1-position by R8, pyrrolid-2-one-5-carboxylic acid; acid, whose 1-position is R' [thus substituted derivatives, furan-2-
or -3-carboxylic acid or thiophene-2- or -3-
Derived from carboxylic acid.

Examples of the residue Ha(57) include pyrrolid-2-one-1-yl, piperid-2-one-1-yl, and cab-lactam residues of the following formula.

The residues of the formula O 1 1 are, for example, the following: succinimide residue 1 geltarimide residue 1 benztartarimide residue I symmetric dimethylsuccinimide residue and pimelic acid imide residue.

For example, the residue becomes It is.

When R11 is a hydrogen atom, RIG preferably has the following meanings: 1-formylrubiolJdine-2-carbonyl-, pyrrolidine-2-carbonyl-11-acetyl-pyrrolidine-2-carbonyl, 5-oxo pyrrolidine-2-carbonyl-12furylcarbonyl-12
j, 4-pyridyl-carbonyl-12-thenylcarbonyl-benzoyl-, 0+''+P-methylbenzoyl-109m, p-methoxybenzoyl-13,4-dimethoxybenzoyl-, 0+m+p, 'lorbenzoyl-,
o+]TI+p-cyanobenzoyl-, 0+m+p-nitrobenzoyl-, 4-chlorophenoxyacetyl-,
Chloroacetyl-, dichloroacetyl- and aminoacetyl groups.

When R11 is not a hydrogen atom, the following combination R'. /R1
Niacetyl group/acetyl group, acetyl group/C1-C with 1 preferred.

Alkyl group, chloroacetyl group / 0+-Cs alkyl group, c, -c, alkyl group / C1''!1 alkyl group,
Especially acetyl group/methy/I/ group, acetyl group/ethyl group, chloroacetyl group/methyl group, chloroacetyl group/ether group, methyl group/methyl group, methyl group/methyl group.

When RIG and R11 are taken together to form a divalent residue bonded to the N-atom, they are butylene-1-carbony/L/g, penticine-1-carbonyl group, butylene-1,4- Dicarbonyl group, butenylene-1,4
-dicarbonyl group, phenylene-1,2-dicarbonyl group, phenylene-1-sulfonyl-2-carbonyl group,
A phenylene-1-sulfenyl-2-carbonyl group, a phenylene-1-sulfenyl-2-carbonyl group, and a pyridyl-2,6-dicarbonyl group are preferred.

The positions and combinations of the substituents HH to RI4 of the phenoxy residue R1, which are substituents of the alkanoyl group represented by RIG, and the positions and combinations of the substituents Hall to R14 of the benzoyl residue of formula R3- The same table rules and preferred conditions as given for R11K apply.

The phenyl group represented by R is preferably one in which R4 and R11 represent a hydrogen atom, and R3 has the following meanings: o, m, p-2) o group, Olm, p-cyano group, 0
1ml p-alkoxycarbonyl group, 2-. 3-also 1-
j4-pyridylmethyl group, 5-methyl-(1,!+,4
-oxydiazole)-2-yl-methoxy group, 2-2
3- or 4-pyridylmethoxy group, (4-methyl-2-
pyrron-6-yl)-methoxy group, (4-methyl-2-
Pyridon-6-y/I/)-methoxy group, (2-methyl-imidazol-4(5)-yl)-methoxy group, 2-
(1-imidazolyl)-ethoxy group, (oxazolidin-2-one)-5-ylmethoxy group, 2-(methoxy)-ethoxy group and 2-(dimethylamino)-ethoxy group, R7R4/R' is Preference is also given to residues R which are combinations: alkyl group/H/H; fluoro-, chloro- or bromine atom/Tl/Fi; alkoxy group/H/I (; alkyl group/alkyl group/H; alkyl group/alkoxy group /H
:Alkoxy group/Alkoxy group/T1;Alkoxy group/
Alkoxy group/alkoxy group; monoalkylamino group/
E/H; dialkylamino group/H/H niacetylamino group/H/I (and residues R and R4 in which Ha is the above-mentioned substituted alkyl- and especially alkoxy group are hydrogen atoms or alkyl groups of the above-mentioned chain length) or an alkoxy group, especially a methyl or methoxy group, R5 is a hydrogen atom.

Preferred such residues for R are methylphenyl, especially 4-methylphenyl, methoxyphenyl, especially 4-methoxyphenyl, chlorphenyl, especially 4
-chlorophenyl group, dimethoxyphenyl group, especially 3,
4-dimethoxy7-1-A4, trimethoxyphenyl group, especially 3°4.5-)dimethoxyphenyl group, dimethylaminophenyl group, especially 4-dimethylaminophenyl group, 4-acetylaminophenyl group.

Furthermore, as the residue A, the following are preferable.

2-chenyl group, 3-pyridyl group, 2-furyl group, 2-
pialyl group, 3-indolyl group, 4-(5-amino-1
, 3-dimethyl-pyrazol-yl) group.

The alkyl radical R1 denotes may be straight-chain or branched and generally has 1 to 5 carbon atoms.

Preferred alkyl radicals for R1 are straight-chain and have 1 to 5 carbon atoms, especially 1 or 2 carbon atoms. The aralkyl group denoted by R1 is preferably a phenalkyl group, which has 1 to 3, especially 1 or 2, carbon atoms in the alkyl bridge. The phenyl nucleus of the phenalkyl group represented by R1 is unsubstituted. However, it can have one or two substituents. In this case, the following may be mentioned as substituents: halogen atoms, in particular fluoro-, chloro- or bromine atoms, 01-C, preferably C1 or C, alkyl groups, c, -c, preferably a- or ct Alkoxy group, amino group, C, -C, preferably C1 or C, monoalkylamino group, total 02 to C6, preferably C
7-C4 dialkylamino group.

The substituent of the phenyl nucleus of the phenylalkyl group in which R1 is;t-t- can be present at any position. Individual substituents can be in the 2-23- or 4-positions of the phenyl nucleus.

In the case of double substitution, the substituents are 2,3-; 3,2-; 2
,4-; 4,2-; 2,5-; 5,2-; 2
, 6-: 3.4-; can be in the 4, 3- or 3.5-position. The phenalkyl group substituted twice on the phenyl nucleus is preferably an optionally di-substituted amino group IWA
I don't have L.

Optionally) the second substituent present is preferably chloroA
/atom, an alkyl group, especially a methyl group or an alkoxy group,
Especially the methoxy group.

If R' denotes an alkanoyl group of the formula -〇〇-R@, the alkyl radical R9 can likewise be straight-chain or branched. Generally there are 1 to 5 alkyl groups, especially 1
or has 2 carbon atoms.

When R1 represents an acyl group of the formula -00-Re and R9 represents a pyridyl group, the pyridyl group can be bonded to the 2-23- or 4-position.

The phenoxy group bonded to the alkyl group represented by R9 as a substituent may be unsubstituted or a halogen atom, preferably a chloro atom, an a, -C, alkyl group, preferably a methyl group or a C, -a, alkoxy group , preferably by a methoxy group. Particularly preferred compounds according to the invention are those in which R' represents a hydrogen atom, C8 or O, an alkyl group, especially a methyl group, a C,-a3 alkanoyl group, especially an acetyl group, a benzoyl group or a nicotinoyl group.

The alkyl group denoted by R2 may be straight-chain or branched and generally has 1 to 5 carbon atoms. A basic radical, by which the alkyl group by R2 may optionally be di-substituted, is of the formula (where RI 7 and HIS are independently a hydrogen atom,
C, -O6 alkyl group, 08-0. A cycloalkyl group or R17 and Hll taken together indicate an O, -C, borimethylene chain, which may optionally be interrupted by an oxygen or sulfur atom or by a residue =N-R9. , in this case R111 is a hydrogen atom, C, -C, alkyl group,
Preferably the methyl group or the alkyl bridge represents a C, -R3 phenalkyl group, preferably a benzyl group. ).

The phenyl group denoted by R2 may be unsubstituted or may carry up to 3, preferably up to 2, in particular 1 of the following substituents: -rogen atom; a, -c, alkyl group ; -OH; O, -0, alkoxy group: C
I'5 alkanoyloxy group; benzoyloxy group;
0l-CI+alkylmercapto group; "l: CI
"5 monoalkylamino group; total C!-O, dialkylamine group y CI '4 alkanoylamino group,
In this case, O, -C, the alkyl group itself is -NH2, O, -
C! , a monoalkylamino group, a total of 02-C dialkylamino groups and an O,-0, alkanoylamino group.

Furthermore, the same preferential rules mentioned above regarding the substituents of the phenyl group represented by R apply to the number and position of these substituents.

It is particularly advantageous for the tetrahydropyridazinone derivatives according to the invention to combine several of the abovementioned preferred features.

Of these groups of compounds according to the invention, preference is also given to those in which R1 is a hydrogen atom and also those in which R2 is a hydrogen atom, in particular the tetrahydrobyridazinones according to the invention in which R' and R2 are hydrogen atoms. Apart from its good pharmaceutical efficacy, it is used as an intermediate for further reaction with alkylating or acylating agents to form the compounds according to the invention (R1 and/or IR2 do not represent a hydrogen atom). .

In principle all inorganic and organic acids are suitable for salt formation, the strength of which is sufficient to protonate the compounds according to the invention. The selection is therefore carried out in a known manner. Examples for suitable acids are HO2, T(Br, H2SO
, phosphoric acid, formic acid, acetic acid, butionic acid, lactic acid, oxalic acid, fumaric acid, tartaric acid, benzoic acid, salicylic acid, and methanesulfonic acid.

Suitable salts of the compounds according to the invention involve their pharmacologically acceptable acids.

The tetrahydropyridazinone derivatives and their salts according to the present invention have valuable pharmacological activities.6 The tetrahydropyridazinone derivatives according to the present invention are prepared by combining acyl-γ-butyrolactone of general formula (It) with hydrazine according to the following reaction formula. or by reaction with a hydrazine visiting conductor of the general formula (lit), (It) (nI) (Ia), in which R and R2 have the abovementioned meanings, when a compound according to the invention has to be prepared. (as long as R1 is not a hydrogen atom.) Then, the human miximethyl group at the 5th position is replaced with the formula CM)R''-x
(IV) (wherein R1 has the above-mentioned meaning or is a residue capable of leaving as an anion).

The production of the compound according to the present invention having the general formula CI&) is carried out in 2
Crab can be done in two independent processes.

That is, first, the butyrolactone derivative (n) and hydrazine (NH, -NH,) are reacted to form the tetrahydropyridazinone derivative (Ib) according to the present invention.

? OH This can, if desired, be an alkylating agent in the 2-position in a known manner. This method is advantageous if the corresponding substituted hydrazine of general formula (TII) is available.

The first reaction step in the production of tetrahydrodione derivatives according to the present invention, acyl-γ of the general formula (H)
The reaction between -butyrolactone and hydrazine represented by the general formula (m) includes reacting γ-ketocarboxylic acid or a γ-ketocarboxylic acid derivative with hydrazine under ring-closing conditions to form the corresponding tetrahydropyridazinone derivative. This reaction as well as the reaction conditions have been known per se for some time. "Liebigs Annale" by Fischer
'N aer Ohemie' Volume 236, Page 147,
Levualic acid (γ-ketovaleric acid) in 188fS
and phenylhydrazine to form 2-F22/I/
-5-methyl-tetrahydropyridazinone-(3). Further description of this reaction can be found in Liebigs Annalen der Oh
emie% Vol. 724, pp. 217-220 (1969
) is found in

Preferably, the reaction is carried out in a liquid phase. In this case, the presence of an inert solvent or diluent is generally necessary. Water is often suitable as a solvent. However, in particular organic solvents such as alkanols; alkanediols; diglycols or triglycols and their ethers and half-ethers; dialkyl ethers; cyclic ethers, such as tetrahydrofuran or dioxane; strongly polar aprotic solvents, such as DMF, DMSO or pyridine; hydrogen,
For example, use is made from the group of penzole, doluol, quidyrole; aliphatic or aromatic halogenated hydrocarbons, such as methylene chloride, chloroform, trichlorethylene, monochloropenzole, dichlorpenzole.

The reaction can in principle be carried out at room temperature to the boiling point of the respective solvent used. In the case of a low boiling point solvent, it is treated in a closed system at a temperature higher than the boiling point of the presser solvent to promote cyclization. Generally the reaction is not carried out above 200°C. 5
Preferably, the treatment is carried out at a reaction temperature of 0 to 100°C. The reaction can also be accelerated by an acid catalyst. If the reaction is carried out at low temperatures, the intermediate hydrazone of general formula (a) can optionally be isolated as a hydrate.

(n) (Ila) This can then be converted into the lithic tetrahydropyridazinone of the general formula CI&) by heating as described above, optionally with polyacid catalysis.

The compound according to the invention of the general formula (Ia) obtained in the first step has a hydroxymethyl group in the 5-position of the tetrahydrobyridazinone system. This group can be etherified or esterified if desired in a second reaction step. The etherification or esterification of aliphatic residues and attached sulfoTl-groups has already been described numerous times. The conditions for this reaction are therefore very well known. Prospects for reaction conditions and reagents that are advantageous in this regard are e.g.
eyl volume 6/3, pages 22 onwards and aouben w
eyx Vol. 8, pp. 516 onwards; Synthesis (1982) No. 8
Page 33; J, Mea, Ohem, Volume 25, No. 620
It is clear from page (19'82).

Within the scope of the invention, the optional etherification of the hydroxymethyl group in position 5 can be carried out by heating the compound of the general formula (Ia) with the alkylating agent of the general formula (F/). In the alkylating agent with the general formula RIX,
indicates a residue that can leave as an anion. Many such residues are likewise known from the literature.

Examples for this are halogen atoms, alkylsulfato groups or, for example, arylsulfonyloxy groups. Depending on the type of residue X, the progress of the reaction is preferably accelerated by the addition of a suitable catalyst or base. Suitable bases are, for example, tertiary amines, preferably inorganic bases, such as alkali hydroxides, or salts of alkali metals with weak inorganic or organic acids, especially carbonates of alkali metals, for example. It is advantageous to carry out the alkylation reaction in a solvent, preferably an organic solvent or an excess of alkylating agent. Solvents used in the alkylation are, for example, ethers, especially cyclic ethers, such as tetrahydrofuran or dioxane, aromatic hydrocarbons, such as penzole, doluol or quidylol.

Any desired esterification of the hydroxymethyl group in the 5-position can likewise be carried out in a manner known per se. Particular preference is given to using carboxylic acid imidazolides as esterification agents of the formula RIK.

Other suitable esterifying agents are those in which X is, for example, an alkanoyloxy group. In this case, carboxylic acid anhydrides are used. The esterification reaction can in principle be carried out without the respective solvent. However, especially when using reactive esterification agents, it is preferred to work in a solvent or diluent to moderate the reaction. All organic solvents that do not react with the alkylating agent are suitable. Mainly aromatic hydrocarbons,
For example, using penzol, doluol, and quijirol as a solvent,
Used as a diluent or dispersant. In this case, especially if the tetrahydropyridazinone according to the invention is to be prepared in the form of a free base rather than a salt, the acylation can likewise be carried out in the presence of a basic acid acceptor, for example a tertiary organic amine base. is advantageous. Acylation of the above type can also be carried out in the presence of pyridine or pyridine derivatives as a solvent.

In this case the solvent itself acts as an acid acceptor.

Acylation of the compounds according to the invention of the general formula (Ia) can also be carried out at temperatures ranging from normal room temperature to up to 150° C.; higher temperatures generally no longer offer any advantages. It is particularly advantageous to carry out the acylation in the range below the boiling point of the solvent or dispersant used, in particular at temperatures from room temperature to 60.degree.

According to the above reaction scheme, the residue R2 is introduced into the compound according to the invention as follows. That is, a monosubstituted hydrazine at R1 is used for the reaction with the ketocarboxylic acid derivative. However, as already mentioned, residue R2 can be expressed by the general formula (I
b) can also be introduced later into the compounds according to the invention. The introduction of a residue R2 in the 2-position of the compound according to the invention of the general formula (lb) can be carried out by alkylation or arylation using an alkylating or arylating agent of the general formula (V) R2X (V) do. The N-alkylation of hete c1-cyclic compounds is likewise state of the art and is described in numerous publications, for example 1 hete cf
It is described in detail in "Cyclic Compounds", Vol. 28, pp. 37 et seq. (1973).

In the alkylating agent R1K, X represents a residue which can be separated as an anion, preferably a halogen atom, an alkylsulfato group or a haarylsulfonyloxy group. The progress of the reaction is advantageously accelerated by the addition of a suitable catalyst or a base which captures the released residue X as an anion. Suitable bases are, for example, tertiary amines, preferably inorganic bases, such as alkali hydroxides or salts of alkali metals and weak inorganic or organic acids, especially carbonates of alkali metals, for example. Any alkylation reaction is preferably carried out in a solvent, for example in water or in an organic solvent. The solvents used for the alkylation are, for example, ethers, especially cyclic ethers,
For example, tetrahydrofuran or dioxane, aromatic hydrocarbons such as penzole, doluol or quidylol.

Acyl-γ-butyrolactone of the general formula (If) (wherein R is the formula R8, R4 and R6 are each independently an iodo atom, 03
- c, alkyl group, -OH, O, -C, alkoxy group, a, -O5 alkanoyloxy group, benzoyloxy group, C1-C, alkylmercapto group, -NH2°C,
-C, monoalkylamino group, total C2-C, dialkylamino group, C, -C, alkanoylamino group, R4 and R6 additionally represent a hydrogen atom, residue Ra,
One of R4 or R5 is 〇- or m-methoxy group, 〇-
or m-methyl group or -ethyl group, 0- or m-brome, 0-fluoro and 0-chloro, the other two represent hydrogen atoms, and two of the residues R3, R4 or R5 are 2. ! +
-, 2.4-, 2.5-.

2.6-. 3.5-dimethoxy group, -dichloroρ, -difluoro or 3,4-difluoro, one of the residues represents a hydrogen atom, or all three residues R8, R' and R5 are 2.3. 4-12, 5.5-12.5.6-12,
4.5-1 or 2,4.6-) dimethoxy group, and R3 and R4 are further a nido c1 group, a cyan group, and each C1-
off alkylmercapto-alkylsulfoxy- and alkylsulfonyl groups, alkyl-(C+'a)-oxycarbonyl groups, formula -NRI.

In this case, the alkyl group, alkoxy group, alkylamino group, dialkylamino group, alkylmercapto group, alkylsulfoxy group, and alkyl group represented by R3 and the bracket are further hydroxyl groups, O, -0,
Preferably u O, or c, alkoxy group, carboxyl group as a whole is C2-0? an alkoxycarbonyl group of the formula (wherein R11' and RI6 are independently hydrogen atoms).

C, -C, alkyl group - which is itself C, -C.

Alkoxy groups, halogen atoms, especially chlorine and bromine atoms, -NH, and alkyl groups with 0. -04 may be substituted with mono- and dialkylamino groups, or in this case, R11+ and R16 together with the 11 atoms to which they are bonded together form a 5- or 6-membered ring residue,
Optionally forming a heterocycle with other 5-teroatoms, such as pyrrolidine, piperidine, piperazine, alkylpiperazine, morpholine, thiomorpholine, an amino group, C, -a,, preferably i L < h C+ -Ct monoalkylamino The group may be substituted by a total of C, -C6 dialkylamino groups or a 5- or 6-membered heterocycle having 1 to 3 heteroatoms. ) indicates an aminocarbonyl group.

R' and R11 additionally represent a hydrogen atom, R6 and R7 are independently a hydrogen atom, a hydrogen atom, especially a chlorine atom and a bromine atom, an amino group, 01'! 1
Monoalkylamino group, total C, -C, dialkylamino group, hydroxy group, 0, -0. Indicates an alkoxy group or a C, -C, alkyl group.

R6a and R? are, independently of each other, chlorogen atoms, in particular chloro and bromine atoms, amino groups, C1-C, monoalkylamino groups, dialkylamino groups of C, -C, in total, hydroxy groups, a, -a.

represents an alkoxy group or an O,-0,alkyl group, and when the pyridyl group is bonded at the 2- or 4-position and the chenyl group is bonded at the 3-position, it additionally represents a hydrogen atom, R1 is a hydrogen atom, C, -C represents an alkyl group, C1-C represents an alkanoyl group, or a residue of the formula.

R'tiCs - C + alkyl group - which is substituted by an optionally substituted phenoxy residue 14 - represents a residue of the formula or pyridyl group, RIO is a C, -C, alkanoyl group - which is optionally substituted -NH, a benzoyl group of the formula -1 which may be substituted by a halogen atom, in particular a chlorine atom or a bromine atom, a Ci's alkoxy group or a phenoxy group of RIG, a benzoyl group of the formula (where n=2.3 or 4.m=o, 1 or 2, in this case preferably n-4-m=3 or 4, X represents an oxygen atom, a sulfur atom, a group of the formula=N-R", provided that
The ring nucleus is further 01-0. , preferably O, or a Ct alkyl group, or a chlorine atom.

Pro-octatom or double-bonded oxygen atom (m=0')K
Therefore, it may be replaced. ) heteroaryl residue, R11 is a hydrogen atom, 'c, -c+11 alkyl group, O,
-C, represents a furcyl group, or RIG and R1
1 is trapped together with the N-atom to which they are bonded to form a bilysine-, piperidine-, piperazine-, morpholine- or thiomorpholine ring or a formula (wherein: 9=5.5 or s; q
==2 or 3) (in the formula, r = 1 or 2) (0H3)u (in the formula, U is 0, 1 or 2, t = 0.1 or 2)
It is. ), which may optionally be further substituted by a VCO, -C, preferably C, -C, alkyl group -
form.

R11 to RIG are hydrogen atoms a, -C, alkyl group, 0, -0. Alkoxy groups, nitro groups, cyan groups, halogen atoms, especially chloro- or bromine atoms, amino groups,
a, -O, monoalkylamino group, total C, -O, dialkylamine group, C1-05 alkanoylamino group or benzoylamino group. ) had not been previously described. They are therefore also subject of the invention as intermediates for the preparation of the tetrahydropyridazinone according to the invention of the general formula (Il).

Acyl-γ-butyrolactones of the general formula (If) used as starting compounds for the preparation of the tetrahydropyridazinone derivatives according to the invention a. (II) The meaning of R is the same in general formulas (II) and (W. Oxymethylation of 01(- acid compounds by reaction with formaldehyde is likewise already known in the prior art). (Regarding this J, Org, Ohem, 24° No. 586-
89 pages (1959), Synthesis (1980) No. 825-82
(See page 8).

The reaction can be carried out in the presence or absence of a solvent and using aqueous formaldehyde, paraformaldehyde or formaldehyde dissolved in an organic solvent. The reaction is generally carried out in the presence of a weakly basic catalyst, such as ammonium acetate or piperidine acetate. When working in aqueous media, preference is given to using alkali- or alkaline-earth metal hydroxides or basic-acting salts as basic catalysts. Hydroxymethylation generally proceeds at a significant rate already at room temperature. The reaction can therefore be carried out at room temperature between 20 and 100<0>C. After human α-oxymethylation, the reaction mixture was acidified and 2-3
Stir for a time at a temperature of 20-120°C, preferably at room temperature. At this time, ring closure of the hydroxymethyl-γ-ketobutyric acid formed into a butyrolactone conductor of general formula (II) occurs.

In principle, after acidification, hydroxymethyl to r-ketobutyric acid is subjected to IIR in its free, non-ring-closed form and reacted with hydrazine or a hydrazine derivative R2-NH-NH2 to give the tetrahydrobyridazinone derivatives according to the invention. It can also be done (K, Fischex.

Liebigs' Annalen dex Ohem
ie 9).

The γ-ketobutyric acid visiting conductor represented by the general formula (■) used in the production of the acyl-γ-butyrolactone represented by the general formula (It) can be obtained by various known methods. Irrespective of the nature of the residue R, the addition of aldehydes of the formula R--OHO to acrylic acid or acrylic (8Vj) conductors, especially acrylic esters, leads in high yields to the desired γ-ketobutyric acid or -butyric acid derivatives.

The addition reaction with H, Ang;ev by 5tcttex
Yanate Ohemie” (1976) Heft
21, IX, pages 695 et seq., are carried out over the same catalysts as are suitable for known benzoin condensations. In this connection, cyanide ions and quaternary thiazolium salts are particularly used. Polar solvents are suitable as solvents for carrying out the addition reaction with. Particular preference is given here to lower alkanols, such as methanol or haethanol and dimethylformamide. At room temperature, most addition reactions reach significant rates that can be further increased by heating.

It is preferable to process at room temperature to 60°C, preferably 30 to 50T. Examples of aldehydes which can be reacted with acrylic acid or a7 acrylic acid derivatives, in particular acrylic esters, in the described process are benzaldehyde, 2-, 3- or id 4-chlorobenzaldehyde, 2,4- or 3,
4-dichlorobenzaldehyde, 4-bromobenzaldehyde, 2-25- or 4-methyl- or -ethylbenzaldehyde, 4-isobutyl-benzaldehyde, 2-. 3- or 4-hydroxybenzaldehyde, 2
, 4-dihyde α-xybennaldehyde 2-. 3- or 4-methoxy- or -ethoxybenzaldehyde, 2.
4-53.4- or 3.5-dimethoxybenzaldehyde, 3,4.5-) dimethoxybenzaldehyde, p
-acetoxybenzaldehyde, p-penzyloxypenzaldehyde, 2-25- or 4-methylmercaptobenzaldehyde, 2-23- or 4-amino-monomethylamino- or -dimetelaminobenzaldehyde)
-, 2-, 3- or 4-nitrobenzaldehyde, 3-
Methyl-53-ethyl or 3-butylpyridine-2-
aldehyde, 4-15- or 6-methylpyridine-2-
Aldehyde, 4-chloropyridine-2-aldehyde, 5
-nitro-pyridine-2-aldehyde, 4-chloro-6
-Methylpyridine-2-aldehyde, 4,6-cyclopyridine-2-aldehyde, 4,6-cymethylpyridine-2-aldehyde, 6-methyl-4-nitroviridine-
2-aldehyde, 5-bromo- or 5-chloro-pyridine-3-aldehyde, 2- or 6-methylpyridine-3
-aldehyde, 5,6-chloropyridine-3-aldehyde, 2-methylpyridine-4-aldehyde, 6-ethylpyridine-4-aldehyde, 2-methyl-5-ethylpyridine-4-aldehyde, 2,6-cyclo Lupyridine-4-aldehyde, 2,6-dimethylpyridine-4-aldehyde, 6-nidropyridine-4-aldehyde, 5-chloro- or 5-bromo-thiophene-2-aldehyde,
3- or 4-bromothiophene-2-aldehyde, 4゜5-dichloro- or 4,5-dibromothiophene-2-
Aldehyde, 4- or 5-nitrothiophene-2-aldehyde F", !-7'Romu 4-nitrothiophene-2-
Aldehyde, 5-methyl-5-x thiA/-1-butyl- or -isobutyl-thiophene-2-aldehyde, 3
-Methyl-5-nitrothiophene-2-aldehyde, 2
-chloro-12-bromo- or 2-nitrothiophene-
3-aldehyde, 2.5-dichlorothiophene-3-aldehyde, 2,5-dimethyl- or 2,5-diethylthiophene-3-aldehyde, 2-butyl-5-methylthiophene-3-aldehyde, 5- t.Butyl-2-methylthiophene-3-aldehyde.

When R is a substituted phenyl group or a heteroaryl residue, the γ-ketobutyric acid visiting conductor with the general formula It can also be obtained by acylation with acids or succinic acid-ester chlorides.Friedel-Crabzou reactions using succinic anhydride have also been in the prior art for a long time and are described in numerous publications, for example J. Am. Ohem, Boa, 7 Q, No. 3197
Page (194B); LiebigEI AnnaN
en a-ahemie, 462 + p. 148 (192B); detailed in U.S. Pat.

In the case of Friedel-Craf acylation, the reactants are combined with each other in an inert solvent, preferably an inert aromatic hydrocarbon or carbon disulfide in the presence of a Friedel-Craf catalyst at room temperature to the boiling point of the solvent. Make it react. When carbon disulfide is used as a solvent, sufficient cooling must be taken into consideration. The solvent thereby does not evaporate. When using nido-aupenzole, a solvent that is very well suited for carrying out the Friedel-Craf reaction, it is well known that 50
'Do not process above C. This is because otherwise there will be a violent reaction. When γ-ketobutyric acid with the general formula (vO) has to be produced (in the formula R
Hatatoeha is a chlorphenyl group, an alkylphenyl group or a hasyalkyl phenyl group. ), succinic anhydride can be reacted in a simple manner in a large excess of the Friedel-Craft catalyst and the corresponding substituted penzole derivative, thereby simultaneously acting as a solvent. Generally, Lewis acids, such as LIIO13,5bO1, are known as Friedel-Crach catalysts.

Br3. ZnO1tt, or protic acid, even ij
'HF.

Use H2BO3, E, PO, or P2O. Preference is given to treatment with aluminum chloride as Friedel-Craft catalyst.

The acid addition salts of tetrahydropyridazinone according to the invention are prepared in a known manner by simple mixing of the compounds according to the invention with the desired acid.

For the preparation of acid addition salts of the compound of general formula (I), this compound is dissolved in an organic solvent and a solution of the desired acid is added. For example, the hydrochloride 0 of a pyridazinone according to the invention of the general formula (I) can be obtained as follows: the compound is dissolved in alcohol and an equivalent of a solution of hydrogen chloride in ethanol is added to the alcoholic solution.

Tetrahydropyridazinone derivatives according to the invention of the general formula (1), in which R is a phenyl group substituted as defined above or an unsubstituted or substituted heterocyclic residue, and also of the general formula (1) ) and tetrahydropyridazinone (in the formula, R is an unsubstituted phenyl group) and its physiologically compatible salts have significant antithrombotic, platelet aggregation inhibiting, antianginal, and cardiotonic effects. and blood pressure lowering effect. This is surprisingly significantly superior to previously known compounds with the same tendency of action. Therefore, it is excellently suited for treating diseases of the heart and circulatory system. It shows excellent effectiveness in various tests. For example, Born, Nat.
Platelet aggregation by ure 194 + p. 927, (1961); 1 Rachidonic Acid Mortality in Domestic Rabbits, Science 193, p. 1085 (1974); Inhibition of arterial and venous hemophilia in domestic rabbits, oral administration to awake dogs. Effective blood flow pattern when administered.

Tests in the above and in a series of other tests have shown that the compounds which can be prepared according to the invention are of low toxicity and have a particularly beneficial mode of action which did not exist in this form in known preparations. It became clear that

Therefore, tetrahydropyridazinone derivatives according to the invention of the general formula (1), in which R is a phenyl group substituted according to the above definition or an optionally blotted heterocyclic residue, as well as the general formula (1) ), where R is an unsubstituted phenyl group. ) can be administered alone or in admixture with each other, preferably in the form of pharmaceutical preparations, and all derivatives thereof falling within the above definition are the subject matter of the present invention.

The pharmaceutical preparations according to the invention contain as active ingredient an effective dosage of at least one tetrahydropyridazinone derivative according to the invention or an acid addition salt thereof.

The dosage of the tetrahydropyridazinone derivative according to the invention is generally 0.1 to 1000 η per day, preferably 1
~100 m9, which is adapted in a known manner to the requirements of the individual case.

The dosage varies within the above dosage range depending on the type of administration, so
Various absorption conditions are taken into account in known manner.

Therefore, for intravenous administration, the dosage is selected at a lower rate than the above-mentioned dosage range, and for oral administration, the dosage is selected at a higher rate. Daily doses generally provide doses for several days, e.g. two days, with individual doses generally
The weight per kg is 0.01 to 10 cm.

Pharmaceutical preparations generally contain 0 per unit of the tetrahydropyridazinone derivative according to the invention or a pharmacologically acceptable salt thereof, in addition to the usual pharmaceutically acceptable carriers or excipients. .05-100mg, preferably 1
Contains ~50m9.

Suitable carriers are, for example, water, vegetable oil, starch, gelatin, lactose, magnesium stearate, wax, petrolatum, and the like. As additives, for example wetting agents, propellants, preservatives, etc. can be used.

The pharmaceutical preparations can be, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures.

The pharmaceutical preparation may contain, in addition to the compound of general formula (1), one or more other pharmaceutically active substances, such as blood flow promoters such as dihydroergocristen, nicergoline, fuenine, nicotinic acid and its esters. , biriller carbonyl, benziclane, cinnarizine, naftidrofuryl, lauvazine and pinkamine; inotropic positive compounds - such as digoxin, acetyldigoxin 1.
Methyldigoxin and lanato glycosides; coronary artery dilators such as carbochromene, divirididamole, nifedipine and hiberhexiline; antianginal compounds such as insorbit dinitrate, isosorbit mononitrate, glycerol nidrade, molsidomine and velapamil: β-receptors Blocking agents such as globulanol, oxybrenolol, atenolol, metoprolol and penbutolol and oogenesis metabolizers such as BiIJ IJNol may be included.

The invention is illustrated by the following example. Reaction conditions, reducing agent,
The alkylating agents and acylating agents are within the prior art and claims, and the tetrahydropyridazinone derivatives used are within the scope of claims 1 4-(3,4-dimethoxyphenyl)-carbonyl-
γ-butyrolactone 15.0 g (0.06 mol) and hydrazine hydra) 5.5 g (0.0
7 mo/I/) in ethanol 200 at reflux for 10 hours. After cooling, the precipitated product is taken off with suction, washed and dried.

Yield: 11.6. j7. Melting point: 203-205°C Elemental analysis: (C43H16N204) Calculated value (to): 059. I H6, I N10.60
24.2 Measured value sand i: 059. OH6, IN10.
5 024.5 4-(3,
4-Dimethoxyphenyl)-carbonyl-γ-butyrolact/ is prepared as follows: 25.8 jq (0.1 mol) of 4-(3,4-dimethoxyphenyl)-4-oxybutyric acid in a 2% caustic soda solution. 220 moth, then add 8.5 g of 69% formaldehyde solution and stir at 50° C. for 3 hours. After acidification with hydrochloric acid and stirring overnight at room temperature, the semi-solid product was filtered off with suction, added to acetic acid ester and diluted with bicarbonate).
and evaporate to dryness.

Yield: 5.6 i Melting point: 114-116°C Elemental analysis; Calculated value (to): 062.4 H5,6032.0 Measured value (%J: 065.2 H5,7030,9 required 4-
(3,4-dimethoxyphenyl)-4-oxo-butyric acid is obtained as follows: aluminum chloride (water-free) 240
88 I of succinic anhydride (O,A 8 mol) and veratrol (0.95 mol) are added under stirring and cooling. 2 at room temperature
After a reaction time of 4 hours, it is poured onto a mixture of ice, water and concentrated hydrochloric acid, the nitropenzole is removed by steam distillation, it is cooled and the precipitate that has separated out is suctioned off.

For purification, it is dissolved under heat in soda solution, filtered over a flame, acidified, vacuumed, washed with neutral water, and dried.

Yield: 137. ! i' Melting point 156-158°C Elemental analysis: (C12H1405) Calculated value: 060.5 H5,9055,6 Measured value: Cu
2O,515,8033,4 examples 2 3-one 4-C4-methylphenyl)-carbonyl-γ-butyrolactone 10.2 F! ((1,05 mol) and hydrazine human sheet 3.0 (0,06 mol) in ethanol/
Heat under open reflux for 1 hour in I/150m.

The resulting solution is evaporated under reduced pressure and the residue is taken up in methylene chloride. The methylene chloride solution is filtered if necessary and then stirred vigorously with an equal volume of water. The desired product precipitates out during this time. Vacuum, wash with water, and dry.

Yield: 7,6 g (70% of theory) Melting point 177~
178℃ Elemental analysis: (C42H14N202) Calculated value (Solution: C66, OH6,5N12.8 014
．． 7 Measured value (Solution: 065.6 H6,5N13.0
015.1 The 4-(4-methylphenyl)-carbonyl-γ-butyrolactone used in the above example is prepared as follows: 4-(4-methylphenyl)-4-oxo-butyric acid q 1
1 g (o, smo/L/) is dissolved in 1 ioo7 of 0.5N caustic soda solution, then 447 d (0.55 mol) of 39% formaldehyde solution are added dropwise and stirred for 8 hours at room temperature. After acidification with 55 ml of concentrated hydrochloric acid, further stirring for 12 hours and extraction with ether, the ether layer was separated, washed with sodium bicarbonate solution and evaporated. The residue is recrystallized from ethyl acetate.

Yield: 1 <5.1.9 Melting point = 88-89℃ Elemental analysis "Cl2H1205) Calculated value (To), 070.6 H5,9023,5 Measured value (Flight: C70,4H6,0025, 6 cases 6 3- 4-(4-chlorophenyl)-carbonyl-r-butyrolacto y 9.0 jq (0.04 mol) and hydrazine Hitlerde (o, 06 mol) in ethanol 1
Heat under reflux in 50 ml for 1 hour. The resulting solution is evaporated to dryness and the residue is recrystallized from methanol.

Accommodation: 3.1. fi' (theoretical value 62%) melting point = 1
70-172℃ Elemental analysis = (C11H11CtN202) Calculated value Open:
0554 H4,6N11.7 013.4 0t14
．． 9 Measured value open: 055. OH4,9N11.3 012
．． 9 C No. 14.5 The 4-(4-chlorophenyl)-carbonyl-γ-butyrolactone used in the above example is prepared as follows: 4-(4-chlorophenyl)-4-oxo-butyric acid 106
．． 39 (0.5 mol), 0.5N caustic soda solution 1
100d and 39% formaldehyde solution 447 (0,
55 mol) are reacted and worked up as described above.

Yield: 47.6 g Melting point: 282-83°C Elemental analysis: (C4,H, at C3) Calculated value:
C! 58.8 H4,00t15.8 021.4 measurement value ((4):059.I H4,00215,; 02
1.8 Example 4 4-(4-acetylaminophenyl)-carbonyl-γ
-butyrolactone 9.917 (0.04 mol) and hydrazine hittride 2.5 jq) 0.05 mol)
The mixture is heated under reflux in 150 ml of ethanol for 2 hours and worked up as in Example 3.

Yield: 3.67i (64% of theory) Melting point: 22
9: ~230℃ Elemental analysis = (C43H15N305) Calculated value (%j: c!59.8 H5,8N16.1 0
18.4 measured value (Tao: 059.6 H5,8N15.
6 018.9 The 4-(4-acetylaminophenyl)-carbonyl-r-butyrolactone used in the above example is prepared as follows: 4-(4-acetylaminophenyl)-4-oxo-butyric acid 94.1 g (0.4 mol), 880 ml of 0.5N caustic soter solution and 35 ml of 39% formaldehyde solution
(0.44 mol) is used and worked up as described above.

Yield: 27g Melting point = 152-154°C Elemental analysis = (C43H13N04) Calculated value (to): C63,2H5,5025,9N5.
7 measurement value (4:0611 115.5 026.5 N
5.5 Example 5 Chill/-ester=1.3 g (o,o 1 mol) of cotinic acid and 1.7 g (o,o 1 mol) of carbonyldiimidazole are heated under reflux for 15 minutes in 30 ml of tetrahydrofuran. After cooling, 2.6 g (0.01 mol) of 6-(3,4-dimethoxyphenyl)-5-hydroxymethyl-2,3,4,5-tetrahydro-pyridazin-6-one are added with stirring. After a reaction time of 12 hours evaporated and the residue taken up in methylene chloride and washed with sodium bicarbonate solution,
Dry, evaporate and recrystallize the residue from methanol.

Yield: 2.5, lit (68% of theory) Melting point =
89-91℃ Elemental analysis: (C19■, -505) Calculated value (%j: 061.8 H5,2N11.4 02
1.7 Measured value (□□□: 060.(SH5,9N1
0.9 022.4 For example, the following compounds can be prepared in a similar manner.

6-(4-dimethylaminophenyl)-5-hydroxymethyl-2,3,4,5-tetrahydropyridazin-3-one, acetic acid-((6-(5,4-dimethoxyphenyl)=3-
Oxo-2,3,4,5-tetrahydro-pyridazine-
5-yl)-methyl)-ester, pyridine-3-carboxylic acid ~C(6-C4-chlorophenyl)-3-oxo-2,5,4,5-tetrahydro-pyridazin-5-yl)-methy/ I/)-ester, 2-(2-dimethylaminoethyl)-5-hydroxymethyl-6-(4-methyl-phenyl)-2j, 4.5-
Tetrahydro-pyridazin-3-one, 6-(4-acetoxyphenyl)-5-hydroxymethyl-2,3,4,5-tetrahydro-pyridazine-3-
on, 6-(4--jromphenyl)-5-hydroxy7'
fk-2,3,4,5-tetrahydropyridazine-3
-one, 6-(3-aminophenyl)-5-hydroxymethyl-
2,3,4,5-tetrahydro-pyridazin-3-one, 5-hydroxymethyl-6-C5-hydroxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3
-one, 6-(3,4-dimethoxyphenyl)-5-hydroxymethy/l/-2-phenyl-2,3,4,5-tetrahyto4-pyridazine, 6-(3-methoxyphenyl)-5- Hydroxymethyl-2,! +, 4.5-tetrahuman 4-pyridadi-pyridazine, 5-hydroxymethyl-6-(2-methylphenyl)
-2,3,4,5-tetrahuman 4-pyritacin-3-one, 5-hydroxymethyl-6-(3-pyridyl)-2,3
,4,5-tetrahydro-pyridazin-3-one, ? 5-(2-chlorophenyl)-5- and droxymethyl-2,3,4,5-tetrahydro-pyridazin-3-one, 5-hydroxymethyl-+5-(3,4,5-)dimethoxyphenyl)-2 ,3,4,5-tetrahuman tetra-
Pyridazine-6-one.

Example 6 4.7 g (0,025 mol) of 4-chlorophenoxyacetic acid and 4.51 of carbonyldiimidazole! (0,02
7 mol) Heated under reflux for 15 minutes in 100 g of total tetrahydrone. After cooling, 6.7 g (0,025 mo/L/) of 6-'(3゜4-dimethoxyphenyl)-5-hydroxymethyl-2,3,4,5-tetrahydropyridazin-3-one is added with stirring. .

After a reaction time of 5 hours, evaporate at room temperature and work up as in Example 5.

Yield: 8.11i (75% of theory) Melting point: 150
~151℃ Elemental analysis'C2+H2I"l"206(432,8
6) Calculated value %): 058j H4, 90t8.2 H
6,5022,2 measurement value (to): 058'j H4,8
018,5H6,5022,1 example 7 4-(4-acetylaminophenyl)-carbonyl-γ
-Butyrolactone 7.49 (0.03 mo/L/) and methylhydrazine 27 d (0.038 mol) are heated in 30 d of ethanol for 1 hour at room temperature and then for 6 hours under reflux. After cooling, the precipitated product is vacuumed and washed.

Yield: 4.6.9 (56% of theory) Melting point: 219
~221℃ Elemental analysis: C44E, 7N, 03 (275851) Calculated value (Sample: 061.I H6,2N15.3 017.4
Measured value (to): 061. o H5,9N15.4 01
7.7 Example 8 4-(4-acetylaminophenyl)-carbonyl-γ
4-7 g (0.01 q mol) of butyrolactone and 2 m (0.02 mol) of phenylhydrazine are heated in 30 ml of ethanol for 1 hour at room temperature and then for 16 hours under reflux. The precipitated product is aspirated and recrystallized from 90% ethanol.

Yield: 1.0. j7 (16% of theoretical value) Melting point: 221~
222℃ Elemental analysis' C19HyNs C5 (557, 38) calculated value): C! 67.6 H5,7N12,5 014
．． 2 measurement value (to): C67, 5H5, 9N12.601
4.1 Example 9 4-(2-furyl)-carbonyl-r-butyrolactone 4.79 (0,026 mole/I/) and hydrazine 1.5 (0.06 mole) The solution was dissolved in 40 ml of ethanol at room temperature and then stirred for 1 hour at 50° C. After evaporation, the reaction product was fractionated through silicic acid using methylene chloride/methanol 9:1 as a developing agent. Separate by chromatography.

Yield: 1.4 g (28% of theory) Melting point: 161-166°C Elemental analysis: O, H, oN203 (194,19) Calculated value: 055.7 H5,2N14.4 024.7 Measured value: 055. 6 H4,91J14.4 025.
Example 10 7.29 (0.04 mo/l/) 4-(2-pyrrolyl)-carbonyl-γ-butyrolactone and 2.5 g (o, o 5 mole) of hydrazine hydride were dissolved in ethanol for 4 hours at room temperature. Stir with The crystallized product was vacuumed and washed with ethanol.

Yield: 7. Og (86% of theoretical value) Melting point: 140~
142℃ Elemental analysis 20, H,3N,05 (211,22) Calculated value: 051.2 H6,2N19.9 022.7 Measured value: CSI, o H6,2N20.0 023.03-one (a) Compound 5.29 (0,025m
1) 50 ml of ethanol - 1 ml of ethanolic hydrochloric acid
Heat to reflux for 90 minutes with a drop containing -. After evaporation of the charge, the residue is triturated with petroleum ether. At this time, the residue crystallizes.

The obtained crude crystals are vacuumed and recrystallized from ethanol.

Yield: 2.2 g (46% of theory) Melting point: 202
~206℃ Elemental analysis: C2 bow, N30□ (193,21), calculated value: 056. OH5,7N21.7 016.6 Measured value:
056.4 H5,91J21.9 016.5 Case 1
1 No3-one 4-(!l-nitrophenyl)-carbonyl-γ-butyrolactone 3.5 jJ (0,015 mol) and hydrazine hittride 0.87 $ (0,016 mol) in 30
Heat at room temperature for 60 hours at reflux. After evaporation, the residue is fractionally crystallized from ethyl acetate/petroleum ether.

Yield: i, 1 g (60% of theory) Melting point: 246-
248℃ Elemental analysis: O+1H11NsO4 (249-2!l
) Calculated value: 053. OH4,4N16.9 025.
7 Measured value: C53,D H4,15N16.8 02
6. .

Example 12 Nor3-one 4-(5-indolyl)-carbonyl-γ-butyrolactone s,+,ji+ (o, o14 mol) and hydrazine hydra-) 0.85 rt(9,(0,018% k
) was stirred with 5 ml of ethylene glycol monomethyl ether and 1 ml of acetic acid at 80'C for 118 hours. After adding 10 ml of petroleum ether to the reaction mixture, the product crystallizes out in good purity.

Yield: i, 2! I (65% of theoretical value) Melting point: 235-237℃ Elemental analysis 2C! 13H,lJ,0□ (243,27
) Calculated value, 064.2 H5,4Hj7.3 013.
2 measurement value: 063.8 H5,5N17.1 015
．． 5 examples 15 i4-(4-(2-(1-imidazolyl)-ethoxy)-
phenyl)-carbonyl-γ-butylactone 5.2
g (0,017 mol) and hydrazine Hitlerd 1 company (
0.02 mol) in 1B of total ethanol for 1 hour at room temperature and then stirred at 60° C. for 16 hours. After cooling, 15 ml of ether is added to the charge, and the precipitated product is taken off with suction F, washed with ether and dried.

Yield: 2.79 (51% of theory) Melting point: 199~
200'C Elemental analysis: cl, a, 8n4o5(s 14.3s
) Calculated value: 061.1 1i5.8 Hj 7.8
015.3 Measured value: 061.5 H5,6N j 1
3.1 015.1 Example 14 Nor-3-one 4-(4-methoxyphenyl-carbonyl)-r-butytetralactone 9.49 (o,o 43 mol) and hydrazine hydra-) 4 g (0.08 mol) ) is heated under reflux in 80 m9 of ethanol for 6 hours.

After evaporation, the residue is recrystallized from water.

Yield: 2.5. li + (25% of theoretical value) melting point = 154
~156℃ Elemental analysis' C+2H+4N205 (2s 4.26
) Calculated value: 061.5 H6, ON12.0 020
．． 5 Measured value: C62, ORI N11.6020.5
Example 15 ±4 11.8 fi (0,06 mol) of 4-(2-chenyl-carbonyl)-γ-butyrolactone and 3.1 g (0,062 mol) of hydrazine hydrazine were incubated in 100 ml of ethanol for 2 hours at room temperature. Stir with

Suction the precipitated hydrazone and add 60ml of triol.
and 6 ml of acetic acid were added, and the mixture was heated under reflux for 2 hours. After cooling,
The precipitated product is vacuumed, washed and dried.

Yield: 3.6.9 (29% of theoretical value) Melting point: 160-162°C Elemental analysis: C, J(,0N202B (210,19
) Calculated value: 051.4 H4.8NLS, 5015.
2 S15.2 measurement value: 050.9 H4,8N13
．． 4015.4815.2 Example 16 4-(4-(5-methy#-1,3,4-oxydiazol-2-yl)-methoxy-phenyl-carbonyl)-
γ-Butyrolactone q, ag (a, as mol) and 1.6 fl (0,052 mol) of hydrazine hydrogen chloride are stirred in 50 ml of ethanol for 12 hours at room temperature. After addition of 5 ml of acetic acid, heat under reflux for 2 hours, evaporate, dissolve in acetic acid ethyl ester and extract with aqueous potassium carbonate solution. The organic layer is evaporated and the residue is crystallized from methylene chloride.

Yield: 6g (64% of theory) Melting point: 164-136°C Elemental analysis +5H16N404 (516,32) Calculated value: 057.D H5,I N17.7 020.2
Measured value: 056.7 B5.3 N17,2 021
．． Example 3 17 4-(4-(1-pyrrolidinyl-2-one)-phenyl-carbonyl)-γ-butyrolactone 8.4.9 (0
,031 mol) and hydrazine hittride 1.79 (
0,034 mol) of ethanol s.

ml for 2 hours at 50° C., cooled and vacuumed. The obtained hydrazone was mixed with 70ml of ethanol and 5ml of acetic acid.
ml under reflux for 2 hours, cooled, vacuum plated, and dried.

Yield: 4.29 (48% of theory) Melting point = 219-220°C Elemental analysis: a, 5B1. x5o3(287,32) Calculated value: 062.7 H6, ON14. (5016,7
Measured value + 062A H6,4N14.5 017.5
Example 18 6-(4-(2-methoxyethoxy)-7224-(4
-(2-methoxyethoxy)-phenyl-carbonyl)
-γ-butyrolactone 13.7, li' (0,052
Mo/I/) to hydrazine Hitlerd 2.89 (0,0
56 mol) in 80yn9 of ethanol as described above.

Yield: 12.5.9 (87% of theory) Melting point = 187~
188℃ Elemental analysis: C44H48N2o4 (278,31) calculated value + 060.4 J (6,5N10.1 023.0
Measured value: Cj60.9 B7. ON10.2 021
．． 8 examples 19 4-(4-(3-pyridyl-methoxy)-phenyl-carbonyl)-r-7'Tyrolactone 7.5F (0,0
25 mol) to hydrazine Hitlerde 1.4, li' (
0,028 mol) in 50 yt of ethanol as described above.

Yield:! l: 6.4 g (82% of theory) Melting point: 2
22-223℃ Elemental analysis: O4, Hl, N, O, (511,34) calculated value = 065.6 B5.5 N13.5 015.4
Measured value: 065.8 B5.4 N13.8 015
．． 1 example 20 No-3-one 4-((4-methyl-2-pyridon-6-y/I/)-
methoxy-phenyl)-carbonyl-r-butyrolactone 611 (0,018 mol) and hydrazinehydra)
1 g (0.02 mol) are reacted in 50° C. of ethanol as described above.

Yield: 5.411 (88% of theory) Melting point: 65~
68℃ Elemental analysis: 0,8H,,N,O,(341,s 7
) Calculated value: 065.5 B5.6 N12.3018.
7 Measured value: 052.8 B5.3 N12.5 019
．． Example 2 21 10.69 (0,045 mol) of 4-(4-methoxymercaptophenyl)-carbonyl-γ-butyrolactone was dissolved in 70 d of ethanol with 2.5 f of hydrazine hydrogen chloride.
Stir with i (0.05 mol) for 90 minutes at room temperature.

After adding 8 ml of acetic acid, heat under reflux for 1 hour, remove with suction F,
dry.

Yield: 7.1 i (63% of theory) Melting point = 158
~160℃ Elemental analysis: c12m, 4m2o2s (2s u, s
2) Calculated value: 057.6 B5.611.201
2.8 S12.8 measurement value, 057.8 B5.6
N11.1 012.9812.7 Example 22 Nor 3-one 4-(4-(2-methoxyethylamino-carbonyl-
4.0 g (0,012 mol/I/) of methoxy)-phenyl)-carbonyl-γ-butyrolactone and 0.717 (0,014 mol) of hydrazine 7-) are reacted in 20 ml of ethanol as described above.

Yield: 2.111 (55% of theory) Melting point: 169
~171℃ Elemental analysis: C16H2,N,03 (535,36) Calculated value: C57,3H6,3N12.5 023.9 Measured value: (357,OH6,ON12.4 024.5
Example 23 4-(4-(aminocarbonylmethoxy)-phenyl)
-Carbonyl-γ-butyrolactone 11.3.9 (0
,043 mol) and hydrazine hydra) 2.4.9
(0,048 mol) are reacted as described above in 70 ml of ethanol.

Yield: 6.5/i (55% of theory) Melting point = 23
8-240℃ Elemental analysis: C43H15N304 (277,28) Calculated value: (!56.5 H5,5N15.2 023.1
Measured value: Cu2S, 5 H5,9N15.6024.
0 example 24 4-(3,4-dimethoxyphenyl)-carbonyl-r
-butyrolactate 77.59 (0.03 mol) and methylhydrazine 2 ml (0°03 moA/) total ethanol 5
Stir in 0 ml for 1 hour at room temperature and then for 17 hours at 90°C. After cooling, the precipitated product is taken off with suction F and dried.

Yield: f: 4-3 g (52% of theory) Melting point = 158-160°C Elemental analysis = 014H48N204 (278,31) Calculated value: 060.4 H6,5N10.1 023.0 Measured value: C! 60.2 H6,6N10.2 025.0
Example 25 75.09 (0,014 mol) of -3-one 4-(4-cyanophenyl)-carbonyl-r-butyrolactate and 1 ml (0,021 mol) of hydrazine hydride were dissolved in 50 ml of ethanol.
Stir in m1 and DMF 50 for 10 hours at room temperature.

After addition of 1 ml of acetic acid, stir at 80° C. for 18 hours and work up as described above. The product is crystallized by addition of 2 ml each of diethyl ether, petroleum ether and acetic acid ethyl ester.

Collection fl: 1.2. li+(68% of theory) melting point=18
3-186°C Elemental analysis: 0,2H1,N302 (229,24) Calculated value: 062.9 H4,8N18j 014.0 Measured value: 061.9 H4,9N17.7 014.2 Example 26 6-((4 -hydroxycarbonylmethoxy)4-(4
-hydroxycarbonylmethoxy)-phenyl)-carbonyl-γ-dabutyrolactone 65 i (0,025
mole) and 2.8 g (0,056
mol) in 50 ml of ethanol for 3 hours at room temperature. After addition of 8 ml of acetic acid, heat under reflux for 1 hour, cool, evacuate and dry.

Yield: 6.817 (99% of theory) Melting point = 187
°C Elemental analysis: C13H14N20. (278,27) Calculated value: 056. I H5,11J10.1 028.7
Measured value: 056. OH5,2N10.2 028.9
Example 27 4-(5,4,5-)dimethoxyphenyl)-carbonyl-γ-butyrolactone 11.2.9 (o,o 4 mol) and 2 drops of hydrazine hydrogen hydride (0.04 mol) were dissolved in 60 mfL of ethanol. Stir for 1 hour at room temperature and apply suction.

Yield: 10.5.9 (84% of theory) Melting point = 154~
157°C Compound 7 produced in column (a). Oji (0,022
mol) in 20 m DMF' and 1 ml acetic acid for 5 hours at 80°C. After evaporation, it is taken up in methylene chloride, washed with potassium carbonate solution, evaporated and recrystallized from ethanol.

Yield: 4. Oi (61% of theoretical value) Melting point: 173~
175°C Elemental analysis: C44H18N2o5 (294,31) calculated value, C57,I H6,2H9,5027,2 analysis value: 057. D H5,8H9,7027,9 examples 28 4-(3-indolyl)-carbonyl-γ-b Above example 1
This compound, which was used as the starting compound for 2, is prepared as follows.

4-(6-indolyl)-4-oxo-butyric acid 21.7
g (o, 1 mol), 39% formaldehyde solution 8 m
1 and 150 ml of 3.5% caustic soda solution for 24 hours.
Stir in an autoclave at 0°C. After addition of 10 ml of concentrated hydrochloric acid, stirred again for 12 hours at room temperature, extracted with methylene chloride, washed with sodium bicarbonate solution and evaporated.
Recrystallize from Drol.

Yield: 10.4 g (45% of theory) Melting point: 188-191°C Elemental analysis: 0,3H4,N O, (229,24) Calculated value: 068. I H4,8H6,1020,9 Measured value: C67,7H4,9N<S, 3020.8 Other 4-aryl-carbonyl-γ-butyrolactones can be produced in a similar manner. Examples include 4-(s-nitrophenyl)-carbonyl-γ-butyrolactone 4-(1-acetyl-2-pyrrolidinyl)-carbonyl-γ-butyrolactone 4-(1-formyl-2-pyrrolidinyl)-carbonyl-γ-butyrolactone 4-(2-pyrrolidinyl)-carbonyl-γ-butylo2
Chthone 4-(2-pyrrolyl)-carbonyl-r-butyrolactone 4-(2-furyl)-carbonyl-γ-butyrolactone 4-(4-cyanophenyl)-carbonyl-γ-butyrolactone 4-(4-methoxycarbonylphenyl) -Carbonyl-γ-butyro2chtone 4-(4-nitrophenyl)-carbonyl-γ-butyrolactone 4-(4-aminocarbonylaminophenyl)-carbonyl-r-butyrolactone 4-(4-(2-(1-imidazolyl) )-ethoxy)-
phenyl)-carbonyl-r-phthyrolactone 4-(4-(2-oxo-1,3-oxazolidine-5
-A/)-methoxyphenyl)-carbonyl-γ-butyrolactone 4-(4-(1,4-dioxobutyleneimino)-phenyl)-carbonyl-γ-butyrolactone The following example is a tetrahydropyridazinone according to the invention. 1 shows the formulation of derivative preparations.

Example A Active substance per tablet (finely ground) 50 ■ Lactose (powdered) 150 Corn starch (white) 230 mg Polyvinylpyrrolidone 15 ■ Magnesium stearate 5 rrq450 m'i Example B Injection solution active substance 4 m'' Sodium chloride 0. 7 ■ Water for injection Total volume 1 ml Example C Pharmaceutical active substance for rectal use 20 ■ Suppository base Total volume 29 Example D Emulsion active substance 60 m 7 Glycerin (pure), 2~2.DI Polyethylene stearard Neutral oil flavoring as appropriate Demineralized water Total volume 100ml Example E Active substance solution Active substance 8ml ml Erylene glycol 1.5 ■ Glycofurol Total volume 4ml Diluent: Water for injection 6 Moth agent Hikaru Esaki Good agent Mitsushi Ezaki〕〕〕 Here here here〕 Here // (C07D 401104 213:00 237:00 ) (C07D 401/12 213:00 237:00 ) 237:00 ) 237:00 ) (C07D 403/10 207:00 237:00') ■Int, C1,3 identification symbol Agency Internal serial number (C07
D 403/12 233:00 237:00 ) (C07D 405104 237 :00 307:00') (C07D 405106 207:00 7242-4C 307:00 ) (C07D 405106 209:00 7132-4C 307: 00 ) (C07D 405/10 207:00 307:00 ) (C07D 405/12 213:00 7138-4C 233:00 7133-4 C 2371006970-4C 333:00 ) gj) Int, C1,” Identification code Internal office reference number 3
33:00) (C07D 413/10 30'7:o.

263:00) Priority claim March 30, 1984 ■West Germany (DE
)■P3411850.0 0 Inventor Rudy Bayerle, Federal Republic of Germany, Frankfurt ω An der Pferfuenmaur 44 0 Inventor Melita Just, Federal Republic of Germany Siennetzk-Hütstenberg 6 0 Inventor Piero Martorana, Federal Republic of Germany Republic of Part-Homburg, Kaiserfriedrich Friedrich-Fremenade 108 0 Inventor Helmut Born Federal Republic of Germany Siennetzk Franzbergring 11 0 Inventor Rolf Eberhard ° Nitz Federal Republic of Germany Frank Alt-Ind. Heinrich Bingemeruwake 64 Procedural Amendment July 1980 zO [1 Commissioner of the Patent Office Mr. Manabu Shiga ■ Case Description 1982 Patent Application No. 124602 2 Title of Invention Tetrahydropyridazinone Derivatives, Process for Producing the Same, and the like Purpose 3, Relationship with the case of the person making the amendment Applicant 4, Agent>Details) Page 5, Column for detailed explanation of the invention in the specification to be amended & Contents of the amendment 1) Page 131, line 4 of the specification Add the following sentence next to .

[The tetrahydropyridazinone derivatives according to the invention exhibit a therapeutically particularly valuable combination of antithrombotic, inotropic and antianginal action with a slight reduction in blood pressure at almost small doses.

The following Tables 1 to 5 show the action data of the compounds according to the invention obtained in various in vivo and in vitro tests.

The values of arterial thrombosis prevention shown in Table 1 were determined using the Menta and Neuter method (Naunyn-schmteaeb method) in rats.
er7s Arch, PharmacoL, 301
.

115 (1977)), and the values of the venous thrombosis model were measured in domestic rabbits according to Halbauer's method (1) "Incidence test of a standardized venous thrombosis model in domestic rabbits",
17. Symposium of Angiology, Kitzbühel, (1
982)).

The influence values of arachidonic acid action shown in Table 2 were determined using the method of Reholt and Fargaftchik (B
r, J, Pharmac.

65.35 (1978)).

The platelet aggregation inhibition values shown in Tables 3-5 were determined in vitro using Horn's method (J, Phystol.

162, p. 67 (1962)) using arachidonic acid, thrombin or adenosine diphosphate as flocculants.

Table 1 Experimental shadow of thrombosis (in vitro) Table 4 0.2-0.4 N, T, , H, 1 unit/7 induces inhibition of platelet aggregation within test Tt (by horn)/
H Table 5 10 μM ADP induces inhibition of platelet aggregation in vitro (by horn)

Claims (1)

[Claims] (1) General formula (1) (wherein R represents a residue of the formula R@R8, R1 is a hydrogen atom, an alkyl group, an aralkyl group - this means that the aryl moiety is optionally or an acyl group of the formula -〇〇-R9, where R2 is a hydrogen atom, an alkyl group - which may optionally be substituted with a basic group -1 or an optionally substituted (R3, R4 and R11 are mutually unrelated), rogene atom, a, -C, alkyl group, -0H,01-c, alkoxy group C, -C, alkanoyloxy group, benzoyloxy group, C, -C, alkylmercapto group, -N R2
,0,-0,monoalkylamino group, total O,-0,
dialkylamine group, C1-04 alkanoylamino group, R3 and R numbers are further nitro group, cyan group, CI ”
5 alkylmercapto-alkylsulfoxy- and alkyls)honyl groups, alkyl-CCt-Cs)-oxycarbonyl groups. The formula -NRI' represents a group with R, in which R3 and R
The alkyl group, alkoxy group, alkylamino group, dialkylamino group, alkylmercapto group, alkylsulfoxy group, and hyalkylsulfony group represented by 4 have a hydroxyl group, C, -C, preferably C1 or C, alkoxy group, carboxyl group as a whole 02
-07 alkoxycarbonyl group, formula (in the formula, H1l+ and R16 are hydrogen atoms independently of each other)
a, -C, alkyl group - which itself is Q, -0,7
A/joxy groups, /\Ogeyi atoms, especially chlorine and bromine atoms, -NH3, alkyl groups may be substituted by a, -C4 mono- and dialkylamino groups -
or R111 and R16 together with the 2N-atom to which they are attached represent a 5- or 6-membered ring, optionally containing other heteroatoms, such as pyrrolidine, piperidine, piperazine, alkyl piperazine. Forms morpholine and thiomorpholine. ), an amino group, an amino group, C1-C5, preferably C,
-C2 monoalkylamino groups, which may be substituted entirely by C2-C, dialkylamino groups or by 5- or 6-membered heterocycles having 1 to 6 heteroatoms, R- and R5 are Furthermore, R6 and R1 additionally represent a hydrogen atom, a halogen atom, especially a chloro atom and a bromine atom, an amino group, a C, -C, monoalkylamino group, a total of C2-C, dialkylamino group, hydroxy group + C, -C, alkoxy group or ha C+
-c. represents an alkyl group, R8 represents a hydrogen atom, C, -a, an alkyl group, C, -O, an alkanoyl group, or a residue of the formula %; 14 indicates a residue of the formula -1 or a pyridyl group substituted by a substituted phenoxy residue 14, "' halo10!l alkanoyl group, which optionally represents -QJ-NH,L, a norogen atom, especially a chlorine atom or a benzoyl group of the formula (11) optionally substituted by a bromine atom, C, -O, an alkoxy group or a phenoxy group, where n = 2.3 or 4, m = 0.1 or 2.
In this case, preferably n -4-m = 3 or 4, X represents an oxygen atom, a sulfur atom, M of the formula -N-R'', provided that the heterocyclic nucleus is further C1-0, preferably C
1 or 02 may be substituted with an alkyl group, a chloro atom, a bromine atom, or a double-bonded oxygen atom (-〇). ) heteroaryl residue, R11 is a hydrogen atom, c, -c, alkyl group -c, -c5
represents an alkanoyl group, or R1 (l and R11 together with the N-atom to which they are bonded are pyrrolidine-
, piperidine-, piperazine-, morpholine- or thiomorpholy (where p=3.5 or 5; ct=2 or 3) (
(wherein U is 0, 1 or 2 and t=Q, 1 or 2) - this may optionally further include a, -C, preferably O, - which may be substituted with - by a C2 alkyl group. Rlz to RI4 are a hydrogen atom, c, -c, an alkyl group, a C, an alkoxy group, a nitro group, a cyan group, a halogen atom, a chloro or bromine atom in %, an amino group -0,
-C, monoalkylamino group, total C, -C, dialkylamino group, C, -a. Indicates an alkanoylamino group or a benzoylamino group. ) and its acid addition compounds. (2) General formula (1) (wherein R represents a residue of the formula, R' is a hydrogen atom, an alkyl group, an aralkyl group - this is where the aryl moiety is optionally substituted) - or a residue of the formula -〇〇-R' represents an acyl group, where R2 is a hydrogen atom, an alkyl group which may optionally be substituted with a basic group, a phenyl group, or a phenyl group optionally substituted with a basic group. It represents a phenyl group substituted with an alkyl group, and Ra, R4 and R5 are independently a norogen atom, 0, -0. Alkyl group, -OH, C, -C, alkoxy group, O, -0, alkanoyloxy group, benzoyloxy group -C, -a, alkylmercapto group, -NH2
, a, -c, monoalkylamino group, a, -C,
dialkylamine group, 0. -6゜alkanoylamino group, R3 and R4 are nitro group, cyan group, respectively O,
-0, alkylmercapto-, alkylsulfoxy-
and hyalkylsulfonyl group, alkyl (01-05)
-oxycarbonyl group, a group of the formula -NRIORll, in which the alkyl group, alkoxy group, alkylamino group, dialkylamino group, alkylmercapto group, alkylsulfoxy group and alkylsulfonyl group represented by R8 and R4 are alkyl The moiety further includes a hydroxy group, a C7-C6, preferably Ol or C2 alkoxy group, a carboxyl group, an alkoxycarbonyl group having a total of 02 to C7, a formula (where RII+ and R16 are independently a hydrogen atom, C, - C5 alkyl group - this is itself C
, -O, alkoxy group, halogen atom, -NH,, alkyl group may be substituted with C, -C, mono- and dialkylamino groups, or R11 and R16
Together with the N-atom to which they are bonded, 5- or 6
a petro term of the -membered ring, optionally with other heteroatoms, such as pyrrolidine. Forms piperidine, piperazine, alkylpiperazine, morpholine, thiomorpholine. ) amino carbonyl group, amino group, C1-C5, preferably C5 or C2 monoalkylamino group, total C2
-C6 dialkylamino groups, optionally substituted by O, -C, dialkylamine groups or by 5- or 6-membered heterocycles having 1 to 3 heteroatoms, R' and R11 further additionally represents a bulky atom of water, R6,
R? and Ha represents a hydrogen atom, R'ij: O+~
C, alkyl group - which optionally contains 0.0 halogen atoms. −
0. - or pyridyl group optionally substituted by an alkyl group or a phenoxy group substituted by a C,-04 alkoxy group; A halogen atom, in particular a chloro or habrome atom, 0I05 which may be substituted by an alkoxy group, or a benzoyl group, 1 R1+ represents a hydrogen atom, or Rlo and R11 together with the N-atom to which they are bonded form a pyrrolidine -, piperidine-. piperazine-, morpholine- or thiomorpholine ring or formula (wherein p=3.4 or 5; q=2 or 3) (wherein r
=j or 2) form a ring. ) and its acid addition compounds. (3) General formula (1) (wherein R represents a residue of the formula, R1 represents a hydrogen atom or an acyl group of the formula -〇〇-R'', Hl represents a hydrogen atom, an alkyl group, a phenyl group, or represents a phenyl group substituted with an alkyl group which is basically substituted, H8, H4 and R5 are halogen atoms, c, -a, alkyl group, -OH, C, -
C, alkoxy group, C, -C, alkanoyloxy group
0. -C, alkylmercapto group, -NH, total C
2-a represents a dialkylamino group, C, -C, alkanoylamino group, and R3 and R4 further represent a nitro group, a cyan group, an alkylmercapto group, or a group of the formula -NRIOR11. In this case, R3 and R4 mean an alkyl group and an alkoxy group in which the alkyl group further includes C, -C, preferably 01 or C2 alkoxy group, formula (wherein R111 and R11l are independently a hydrogen atom, O , -0, an alkyl group - which itself is 0, -C, optionally substituted by an alkoxy group, a chloro atom and a bromine atom) or by an aminocarbonyl group with 1 to 3 heteroatoms.
R' and R5 additionally represent a hydrogen atom, and Re, R7 and R8 represent a hydrogen atom, which may be substituted by a 5- or 6-membered heterocycle having . Ro is an O, -0, alkyl group, optionally polysubstituted by a halogen atom, a, -C, an alkyl group or a phenoxy residue substituted by a C8-04 alkoxy group - or a pyridyl group , RIO represents a, -C, an alkanoyl group or a benzoyl group, R11 represents a hydrogen atom, or RIG and R11 are combined with the N-atom to which they are bonded to form the formula (in the formula, p=3.4 or 5; r=1 or 2). ) Tetrahydropyridazinone and its acid addition compound. (4) R' is a hydrogen atom, C1 or 0□alkyl group, C
1-O, an alkanoyl group, a benzoyl group, or a nicotinoyl group, claims 1 to 6
A compound described in any one of the preceding paragraphs. (5) The compound according to any one of claims 1 to 6, wherein R' and R2 each represent a hydrogen atom. (6) The compound represented by the above general formula (1) is 6-(R4-dimethoxyphenyl)-5-hydroxymethyl-2,3,
Compounds according to claim 1, consisting of 4,5-tetrahydro-pyridazin-3one and acid addition compounds thereof. (7) General formula (1) 0 formula 1 (wherein R represents a residue of the formula -1 or an acyl group of formula -〇〇-R9, R' Id hydrogen atom, alkyl group - which may optionally be substituted with a basic group -, or optionally substituted phenyl group , R3, R4 and R5 are each independently a halogen atom, -C, alkyl group, -0H, 08-0, alkoxy group,
C, -〇, alkanoyloxy group, benzoyloxy group, 0. -0. Alkylmercapto group, -Nu, , O
, -0, monoalkylamino group, total C2-C! dialkylamino group, CI=04 alkanoylamino group. R3 and R' further represent a nitro group, a cyan group, and a Cl-C
11 alkylmercapto-alkylsulfoxy- and alkylsulfonyl groups, alkyl-CCI-C1+)-
an oxycarbonyl group, a group of the formula -NR@RII, in which case R3 and R4 represent an alkyl group,
Alkoxy group, alkylamino group, dialkylamino group,
The alkylmercaguto group, alkylsulfoxy group and alkylsulfonyl group further include a hydroxy group, O, -0, preferably 0. Or C! An alkoxy group, an alkoxycarbonyl group of C2-C in the carboxyl group as a whole, an alkoxycarbonyl group of the formula (where RI6 and R16 are independently hydrogen atoms, C
, -C, alkyl/l/ group - this is itself a C, -C, alkoxy group, a halogen atom, especially a chlorine atom and a bromine atom, -NH,, a mono- and dialkylamino group in which the alkyl group is O, -04 or in which R″′ and R16 together with the N-atom to which they are attached represent a 5- or 6-membered ring, optionally substituted by amino carbonyl group, amino group, C1-C5, preferably O, -0, monoalkylamino group, in total O!-
0, by dialkylamino groups or by heteroatoms 1 to 1
! R4 and R5 additionally represent a hydrogen atom, and R6 and R7 independently represent a hydrogen atom, an I.rogen atom, , especially chlorine and bromine atoms, amino groups, C, -a, monoalkylamino groups, total a, C6 dialkylamino groups, hydroxy groups, a, -c, a, It/koxy groups or 01-C. represents an alkyl group, R6 represents a hydrogen atom, c, c, an alkyl group, a, -c, an alkanoyl group or a residue of the formula %, R' fd O+-Os alkyl group - this may be Represents a residue of the formula 11 or a pyridyl group substituted by a phenoxy residue R1', RIO is an O, -0, alkanoyl group - this is a case of OH, -N, a halogen atom , in particular a chloro or bromine atom, a, -O, an alkoxy group or a benzoyl group of the formula - which may be substituted by an alkoxy group or a nalphenoxy group, a benzoyl group of the formula (where n=2.3 or 4, m=0.1 or 2. In this case, preferably n-1-11] = 3 or 4, X is an oxygen atom,
A sulfur atom, a group of the formula = li R4, in which case the heterocyclic nucleus is further VcC, -C6, preferably al or C
, an alkyl group, a chlorine atom, a bromine atom, or a double-bonded oxygen atom (=o)K. ), R11 is a hydrogen atom, c, -〇, an alkyl group, 0. -0°alkanoyl group, or RIO and R1+ together with the N-atom to which they are bonded represent pyrrolidine-,
piperidine-piperazine-morpholine- or thiomorpholine ring formula (wherein p=3.5 or 5; q=2 or 3) (wherein r=j
or 2) (where U is 0, 1 or 2, t = 0.1 or 2)
It is. ) which may optionally be further substituted by O, -C, preferably by an alkyl group, R12 to R14 are hydrogen atoms c, -c, an alkyl group. C, -0, alkoxy group, nitro group, cyan group. Halogen atoms, especially chromium- or bromine atoms, amino groups, C, -C, monoalkylamino groups, overall C, -C,
dialkylamino group. C, -C, represents an alkanoylamino group or a benzoylamino group. ) and its acid addition compounds, an acyl-γ-butyrolactone of the general formula (II) and hydrazine or a compound of the general formula (II)
H2 (n) (m) 1 (25) (Ia) (in the formula, R and R2 have the above-mentioned meanings) by a known method according to the following reaction formula.
), only when producing a compound in which R' does not represent a hydrogen atom, the hydroxymethyl group at the 5th position is replaced by the general formula (IV) R''-X (IV) (where R1 has the above meaning). and X is a residue that can be separated as an anion. In this case, an acyl-γ-butyrolactone of the above general formula (n) and hydrazine or hydrazine hittride (
Reactant: A method for producing the dispersion described in claim 7 by reacting with NT(, -NH2) by a known method, '9) The above general formula (I) (in which R1 and )R2
does not represent a hydrogen atom. ) To produce a tetrahydropyridazinone of the general formula (1) (in which R' and R2 represent a hydrogen atom), the tetrahydropyridazinone of the above general formula (1) (in which R' and R2 represent a hydrogen atom) is successively added to the (a) S-position in any order. For etherification or esterification of the hydroxymethyl group of the general formula (Iv) R1-X (M) (wherein R' has the above-mentioned meaning or is a residue that can be separated as an anion) becomes reaction with an etherification or esterification agent and then optionally (b) for the alkylation or arylation of the 2-position of the tetrahydropyridazinone of the general formula (v) R''-X (V
) (in which R2 and X have the meanings given above). (The effective substance of 1 is the general formula (I) (wherein R represents a residue of the formula, R1 is a hydrogen atom, an alkyl group, an aralkyl group, in which the aryl moiety is polysubstituted in some cases), or a residue of the formula C
u2-RD represents an acyl group, R2 is a hydrogen atom, an alkyl group optionally substituted with a basic group-5, or an optionally polysubstituted phenyl group, RB, R4 and R5 are mutually independent halogen atoms, 0, -0. Alkyl group -OH, C, -0, alkoxy group, C, -all alkanoyloxy group, benzoyloxy group, C, -a, alkylmercapto group, -NH!
, O, -C, l monoalkylamino group, overall O, -C
, a dialkylamino group, a C1-C, alkanoylamino group, and R3 and R' are a nitro group and a cyan group, respectively.
B represents an alkylmercapto-alkylsulfoxy- and alkylsulfonyl group, an alkyl-CC+-Ca)-oxycarbonyl group, a group of the formula -NRIoRll, in which case Ha and - mean an alkyl group, an alkoxy group. The alkylamino group, dialkylamino group, alkylmercapto group, alkylsulfoxy group and alkylsulfonyl group further include a hydroxy group, a, -C
5, preferably O8 or C, alkoxy group, carboxyl group as a whole 02-0. an alkoxycarbonyl group (in the formula, R18 and R16 are independently a hydrogen atom, a
, -C, alkyl group - is itself 0, -0. Alkoxy groups, halogen atoms, especially chlorine and bromine atoms, -NH2, alkyl groups with 0. -0. which may be substituted with mono- and dialkylamino groups,
Or at this time R11! and R16 are the N-
5- or 6-membered rings together with atoms, optionally containing other heteroatoms, such as pyrrolidine, piperidine, piperazine, alkylpiperazine,
Morpholine, thiomorpholine ) aminocarbonyl group, amino group, C1-C5, preferably a, -C, monoalkylamino group, overall f 0t
-06 dialkylamino group or heteroatom 1
may be substituted by a 5- or 6-membered heterocycle having ~3 atoms, R4 and R1+ additionally represent a hydrogen atom, and R6 and R7 independently represent a hydrogen atom, a atoms, especially chlorine and bromine atoms, amino groups, C, -C, monoalkylamino groups, dialkylamino groups in total a, -C, hydroxy groups, C, -C, alkoxy groups or C
,-C. No. 8 represents a hydrogen atom, c, -c, alkyl group -c, -o, alkanoyl group, or a residue of the formula %. R9 company C1-(!, alkyl group - which is optionally substituted by a t-substituted phenoxy residue I4), indicates a residue of the formula or pyridyl group, RIG is C, -a, alkanoyl group - this Depends on the case
J -OH, -NH3, a halogen atom, especially a chlorine atom or a bromine atom, a benzoyl group substituted by a phenoxy group of C, -C, alkoxy I4 and represented by the R1 formula (wherein n=2.5 or 4. rn=Q, 1 or 2. In this case, preferably n -)-m = 5 or 4, X is an oxygen atom, a sulfur atom, the formula ==N-R' represents a group, provided that in this case a heterocyclic nucleus is further 0. -05, preferably C1 or C, may be substituted by an alkyl group, a chloro atom, a bromine atom or a double-bonded oxygen atom (=0). )
a heteroaryl residue, R11 is a hydrogen atom, O, -0, an alkyl group, al-a. represents an alkanoyl group, or RIG and R11 are trapped together with the N-atom to which they are bonded to pyrrolidine-,
piperidine-, piperazine-, morpholine- or thiomorpholine ring or formula (wherein p=3.5 or 5; q=2 or 3) (wherein r
= 1 or 2) (wherein U is 0, 1 or 2, and t = 0.1 or 2) - which may optionally further include a, -a. Preferably, it forms - which may be substituted by a C, -C2 alkyl group, and HD to R14 are hydrogen atoms, 'I'! alkyl group,
a, -C, alkoxy group, nitro group, cyan group, halogen W atom, especially chloro- or hafrom-atom, amino group D
, -0, monoalkylamino group, total 0. -0. is a dialkylamine group, a, -C, an alkanoylamino group or a benzoylamino group, or R is an additionally unsubstituted phenyl group (R3=R4=R''-hydrogen atom). A drug containing pyridazinone and its acid addition compound for the treatment, overcoming and prevention of diseases of the heart and circulatory system. (11) General formula (II) 1 (wherein R is formula 3 R3, R4 and R11 are mutually independently fluoro-, chloro-, iodo, 0-bromo or ham-7-rom-atom, C2-C, alkyl group, 〇- or m-methyl group, -0
H, 02-0, A/Lzzoxy group, C, -C, alkanoyloxy group, benzoyloxy group, O, -0, alkylmercapto group, ~NHv + C+ 0! I monoalkylamino group, total C, -C, dialkylamino group, C, -C, alkanoylamino group, R' and R6 additionally represent a hydrogen atom, residues R3, R
One of 4 or R÷ is a methoxy group, the other two are hydrogen atoms: two of the residues R3, R4 or R11 are 2.3-1
2.4-2.5-12.6-13,5-dimethoxy group, one of the residues represents a hydrogen atom, or residues R1, R
All three of 4 and R6 are methoxy groups υ, and R3 and R4 are further nitro groups, cyan groups, and 0°-C
5 represents an alkylmercapto-alkylsulfoxy- and alkylsulfonyl group, an alkyl-(C+-C++)-oxycarbonyl group, a group of the formula -NRIORll,
In this case, R3 and R' represent an alkyl group, an alkoxy group, an alkylamino group, a dialkylamino group, an alkylmercapto group, an a/I/kylsulfoxy group, and an alkylsulfonyl group. -D. Preferably a C1 or 02 alkoxy group, an alkoxycarbonyl group with the entire carboxyl group being C2-a, an alkoxycarbonyl group of the formula (wherein R111 and RI6 are independently a hydrogen atom,
O, -C, alkyl group - which itself is a, -C, alkoxy group, halogen atom, especially chloro and bromine atom, -NH2, alkyl group substituted by O, -0, mono- and dialkylamino group In this case, R11+ and R16 represent the N to which they are bonded.
- heterocycles with 5- or 6-membered rings, optionally containing other heteroatoms, such as pyrrolidine, piperidine, piperazine, alkylpiperazine,
Morpholine and thiomorpholine are formed. ) an aminocarbonyl group, an amino group, 0. -C! , good 1
1. < is O, -0, monoalkylamino group, total C2
-C, by the dialkylamino group or by the heteroatom 1
R4 and R5 additionally represent a hydrogen atom, and R6 and R7 independently represent a hydrogen atom, a halogen atom, Especially chlorine and bromine atoms. Amino group, 01-0. Monoalkylamino group, total C
2-C6 dialkylamino group, hydroxy group, C,-
C, alkoxy group or c0. -0° alkyl group, R8 is a hydrogen atom, O, -C, alkyl group, a, -o, alkanoyl group, or a residue of the formula; R9 is O, -05 alkyl group - this may be 14 or a pyridyl group substituted by a phenoxy-substituted residue 14;
-OH, -NH2, optionally substituted by a halogen atom, in particular a chloro or bromine atom, O, -0, an alkoxy group or a phenoxy group of the formula -, a benzoyl group of the formula, where n=2.S or 4, m = 0.1 or 2, in this case preferably n -1-m = 3 or 4, or an oxygen atom, a sulfur atom, a group of formula = N-Ra, provided that in this case the heterocyclic nucleus is Furthermore, a heteroaryl residue consisting of C3- (preferably C1 or C, which may be substituted with an alkyl group, a chloro atom, a bromine atom, or a double-bonded oxygen atom (=0)), R11 is a hydrogen atom, c, -o, alkyl group, Cl-01
1 Alkanoyl group Schiff, or RIG and R11
together with the N-atom to which they are attached form a pyrrolidine-, piperidine-, piperazine-, morpholine- or thiomorpholine ring or a formula (in which p=3.5 or 5; q=2 or 3) (in the formula r =
1 or 2) (In the formula, U is 0, 1 or 2, and t==Q, 1 or 2.) -C, preferably CI'! ~, which may be substituted with an alkyl group, is formed, and R to RI4 are hydrogen atoms, C1-C, and an alkyl group. C1-C, alkoxy group, nitro group, cyan group. Halogen atoms, especially chloro- or bromine-atoms, amino groups, Cl-Off monoalkylamino groups, overall C2-
C, dialkylamino group. 0, -0. Indicates an alkanoylamino group or a benzoylamino group. ) Acid I-γ-butyrolactone represented by: θ2) General formula (W) 1 R-0-OH2C! H2-000FI (■) (R in the formula
has the meaning given above. ) is reacted with formaldehyde at 20-100°C in the presence of a basic catalyst, and then the reaction mixture is acidified and maintained at 20-120°C until the end of the ring-closing reaction. A method for producing the compound according to claim 11, which comprises: