WO1992006979A1

WO1992006979A1 - New diazines

Info

Publication number: WO1992006979A1
Application number: PCT/EP1991/001928
Authority: WO
Inventors: Gerhard Grundler; Jörg Senn-Bilfinger; Hartmann Schaefer; Georg Rainer; Kurt Klemm; Wolfgang-Alexander Simon; Christian Schudt; Richard Riedel; Stefan Postius
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date: 1990-10-15
Filing date: 1991-10-10
Publication date: 1992-04-30
Also published as: AU8712191A

Abstract

Diazines having formula (I), in which the substituents have the meaning given in the description, are new compounds with interesting pharmacological properties.

Description

New diazines

Field of application of the invention

The invention relates to novel diazines, processes for their preparation, their application to _¬ and pharmaceutical compositions containing them. The compounds of the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments used _¬ lung.

Description of the invention

It has been found that the novel compounds inte _¬ esting pharmacological properties described in more detail below comprise, by which it is unter¬ divorced be¬ known compounds in a surprising and particularly advantageous manner.

The invention relates to new diazines of the formula I

wherein

Rl represents hydrogen, 1-4C-alkyl or 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (for yl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents hydroxy, mercapto, halogen or the substituent -A-B-R6,

R5 furyl, thienyl, tetrahydrofuryl, pyridyl, phenyl, by one or two represents identical or different substituents from the group halogen, 1-4C-A1-alkyl, 1-4C-alkoxy, methylsulfonyl, nitro, azido, amino and mono- or di- 4C-alkylamino-substituted phenyl or phenyl substituted by methylenedioxy,

R6 is hydrogen, pyridyl, indanyl, thienyl, furyl, phenyl or by one or two identical or different substituents from the group halogen 1-4C-alkyl, 1-4C-alkoxy, nitro, -NH-CO-NH ₂ (ureido), amino, 1-4C-alkoxycarbonylamino and mono- or D-1-4C-alkylamino substituted phenyl there,

A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur), SO (sulfinyl) or S (sulfonyl),

B represents a bond line, -CH _Z - (methylene), -CH _Z CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds, where R2 and R3 are not methyl when R1 is hydrogen and R4 is hydroxy.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.

1-3C-alkylene stands for trimethylene, ethylene and especially methylene.

Hydroxy-1-4C-alkyl represents the abovementioned 1-4C-alkyl radicals to which a hydroxyl radical is attached. The hydroxymethyl radical is preferred.

Halogen in the sense of the present invention is bromine, chlorine and fluorine.

In addition to the oxygen atom, 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above. The methoxy radical is preferred.

Mono- or di-1-4C-alkylamino stands for amino groups which are substituted by one or two of the 1-4C-alkyl radicals mentioned above. Examples include the methylamino, ethylamino, diisopropylamino and in particular the diethyl group.

Preferred salts for compounds of the formula I are all acid addition salts into consideration. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, Succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.

Quaternary ammonium salts which can be obtained by reacting compounds of the formula I with suitable alkylating agents are also suitable as salts. Examples of suitable alkylating agents are 1-4C-alkyl halides, preferably methyl iodide, or benzyl halides, such as benzyl bromide, or allyl halides, such as allyl bromide.

To be emphasized are those compounds of the formula I in which

Rl represents hydrogen, 1-4C-alkyl or 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (for yl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents hydroxy, mercapto, halogen or the substituent -A-B-R6,

R5 represents furyl, tetrahydrofuryl, pyridyl, phenyl or phenyl substituted by one or two substituents from the group halogen, methylsulfonyl, methylenedioxy, 1-4C-alkoxy, nitro, azido and amino,

R6 is hydrogen, pyridyl, indanyl, thienyl, phenyl or by one or two substituents from the group halogen, 1-4C-alkyl, l-4C-alkoxy, -NH-CQ-NH ₂ (ureido), amino, and l-4C Alkoxycarbonylamino represents substituted phenyl,

A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur) or SO (sulfinyl),

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds, where R2 and R3 are not methyl have when Rl is hydrogen and R4 is hydroxy.

Particularly noteworthy compounds according to the invention are those of the formula

I, in which

Rl represents 1-4C-A1kyl or methylene substituted by R5,

R2 represents methyl or hydroxyethyl,

R3 represents methyl,

R4 represents the substituent -A-B-R6,

R5 represents furyl, tetrahydrofuryl, pyridyl, phenyl or phenyl substituted by chlorine, fluorine, methylsulfonyl, nitro, amino or methylenedioxy,

R6 represents hydrogen, pyridyl, indanyl, thienyl, phenyl or phenyl substituted by chlorine, fluorine, methyl or methoxy,

A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur) or SO (sulfinyl),

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds.

Preferred Rl radicals are the furfuryl (2-furylmethyl), the isobutyl and the benzyl radical and the benzyl radicals substituted by fluorine, methylsulfonyl, nitro, amino or methylene-dioxy.

Preferred radicals R2 are the methyl est and the hydroxymethyl radical.

A preferred radical R3 is the methyl radical.

Preferred radicals R4 are the benzyloxy radicals optionally substituted in the phenyl ring by fluorine, chlorine, methyl or methoxy.

Particularly preferred compounds according to the invention are those of the formula I in which

Rl represents 1-4C-alkyl or methylene substituted by R5,

R2 represents methyl,

R3 represents methyl,

R4 represents the substituent -A-B-R6,

R5 represents furyl, phenyl or phenyl substituted by fluorine,

R6 represents phenyl or phenyl substituted by chlorine or fluorine,

A represents 0 (oxygen), B represents -CH ₂ - (methylene) and n represents the number 0, and the salts of these compounds.

One embodiment (embodiment a) of the invention are diazines of the formula wherein

Rl represents hydrogen, 1-4C-alkyl or 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents hydroxy, mercapto, 1-2C-A1 ylsulfonyl or halogen,

R5 furyl, thienyl, tetrahydrofuryl, pyridyl, phenyl, by one or two identical or different substituents from the group halogen, 1-4C-A1 kyl, 1-4C-alkoxy, methylsulfonyl, nitro, azido, amino and mono- or di- 1-4C-Alkylamino substituted phenyl or phenyl substituted by methylenedioxy and n represents the number 0, and the salts of these compounds, where R2 and R3 are not methyl when Rl is hydrogen and R4 is hydroxy.

Another embodiment (embodiment b) of the invention are diazines

Formula I, wherein

Rl represents hydrogen or 1-4C-alkyl,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents the substituent -A-B-R6,

R6 pyridyl, indanyl, thienyl, furyl, phenyl or by one or two identical or different substituents from the group halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, -NH-CO-NH ₂ (ureido), Amino, 1-4C-alkoxycarbonylamino and mono- or di-1-4C-alkylamino substituted phenyl d,

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH _j ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds. Another embodiment (embodiment c) of the invention are diazines

Formula I, wherein

Rl represents 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-al yl,

R4 represents the substituent -A-B-R6,

R5 furyl, thienyl, tetrahydrofuryl, pyridyl, phenyl, by one or two identical or different substituents from the group halogen, 1-4C-A1-alkyl, 1-4C-alkoxy, methylsulfonyl, nitro, azido, amino and mono- or di represents i-4C-alkylamino-substituted phenyl or phenyl substituted by methylenedioxy,

R6 is hydrogen, pyridyl, indanyl, thienyl, furyl, phenyl or by one or two identical or different substituents from the group halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, -NH-CO-NH ₂ (ureido), amino represents 1-4C-alkoxycarbonylamino and mono- or di-1-4C-alkylamino substituted phenyl,

A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur), SO (sulfinyl) or S0 ₂ (sulfonyl),

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, where R6 is not hydrogen when B is a bond line and the salts of these compounds.

Particularly noteworthy, preferred or particularly preferred compounds of the configurations a, b and c are those in which the substituents and symbols have the meanings given above for the particularly noteworthy, preferred and particularly preferred compounds or substituents.

The following compounds may be mentioned as examples:

1-benzyl-7-benzyloxy-2,3-dimethyl-pyrrolo [2.3-d] pyridazine 1-benzyl-2,3-dimethyl-7-phenethoxy-pyrrolo [2.3-d] pyridazine 1-benzyl-2,3- dimethyl-7- [3-pyridyl (methoxy)] pyrrolo [2.3-d] pyridazine 1-benzyl-7- (2-furyl ethoxy) -2,3-dimethyl-pyrrolo [2.3-d] pyridazine 1-benzyl- 2,3-dimethyl-7- (2-thienyl ethoxy) pyrrolo [2.3-d] pyridazine 1-benzyl-7-benzyla ino-2,3-dimethyl-pyrrolo [2.3-d] pyridazine 7-benzyl oxy-1, 2,3-trimethyl-pyrrole o [2.3-d] pyri dazi n 7- (1-indanyl oxy) -1, 2, 3-trimethyl-pyrrole o [2.3-d] pyri dazi n 7- (l-Indanyl ami no) -1, 2,3-trimethyl-pyrrole o [2.3-d] pyri dazi n 7-benzyl oxy-l-isobutyl -2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n

7-benzyl oxy-2,3-dimethyl-l- (tetrahydro-2-furanylmethyl) pyrrole o [2.3-d] pyri dazi n

7-benzyl oxy-1- (2-uranyl methyl) -2, 3-dimethyl-pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (3-methoxybenzyl oxy) pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (4-methoxybenzyl oxy) pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (2-methoxybenzyl oxy) pyrrole o [2.3-d] pyri dazi n

7- (2-Methoxybenzyl oxy) -1, 2, 3-tri ethyl-pyrrole o [2.3-d] pyri dazi n

7- (2-Methoxybenzyl ami no) -1, 2, 3-trimethyl-pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (2-methoxybenzyl ami no) pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (2-f 1 uorbenzyl oxy) pyrrole o [2.3-d] pyri dazi n

1-Benzyl -2,3-dimethyl -7- (3-f 1 uorbenzyl oxy) pyrrole o [2.3-d] pyri dazi n

1-benzyl -2,3-dimethyl -7- (4-f 1 uorbenzyl oxy) pyrrole o [2.3-d] pyridazine

1-benzyl -7- (2-chloro-benzyl oxy) -2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n

7- (2-Chlorobenzyl oxy) -1, 2,3-trimethyl-pyrrole o [2.3-d] pyri dazi n

7- (2-Chlorobenzylamino) -1, 2,3-trimethyl-pyrrole o [2.3-d] pyri dazi n

7- (2-Methyl benzyl oxy) -1, 2, 3-trimethyl-pyrrole o [2.3-d] pyri dazi n

7- (1-S-Phenylethylamino) -1, 2,3-trimethylpyrrole o [2.3-d] pyriazione

7- (1-R-Pheny 1 ethyl amino) -1, 2, 3-tri methyl-pyrrole o [2.3-d] pyri dazi n

N- (1-benzyl-2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n-7-yl) cyanami d

N-Benzyl -N- (l-benzyl -2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n-7-yl) cyanami d l-benzyl -7-benzyloxy-2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n-5-oxi d

7-benzyl thi o-l, 2, 3-tri methyl-pyrrole o [2.3-d] pyri dazi n

1-Benzyl -7-benzylthi o-2, 3-dimethyl-pyrrole o [2.3-d] pyri dazi n

7-benzyl sul fi nyl -1, 2,3-trimethyl-pyrrole o [2.3-d] pyri dazi n l-benzyl -7-benzyl sul fi nyl -2,3-dimethyl-pyrrole o [2.3-d] pyri in between

7-benzyl oxy-2,3-dimethyl-l- (3-pyridylmethyl) pyrrole o [2.3-d] pyri dazi n

7-benzyl oxy-2,3-dimethyl-l-furf uryl-pyrrole o [2.3-d] pyri dazi n

1-Benzyl -7-benzyl oxy-2-hydroxymethyl -3-methyl-pyrrole o [2.3-d] pyri dazi n

7-benzyl oxy-2-hydroxymethyl -1-i sobutyl -3-methyl-pyrrole o [2.3-d] pyri dazi n -Benzyl -7- (4-f 1 uorbenzyl oxy) -2-hydroxymethyl -3-methyl - pyrrole o [2.3-d] pyri dazi n -Benzyl oxy-2-hydroxymethyl -1, 3-dimethyl-pyrrole o [2.3-d] pyri dazi n -phenethoxy-l, 2,3-trimethyl-pyrrole o [2.3- d] pyri dazi n -Benzyl -2,3-dimethyl -7- (4-fluorobenzyl oxy) pyrrole o [2.3-d] pyri dazi n-5-oxi d -Benzyl -2,3-dimethyl -7- (3-f 1 uorbenzyl oxy) pyrrole o [2.3-d] pyri dazi n-5-oxi d-benzyl -2,3-dimethyl -7- (2-f 1 uorbenzyl oxy) pyrrole o [2.3-d ] pyri dazi n-5-oxi d 7-benzyl oxy-2,3-dimethyl -1-f urf uryl pyrrole o [2.3-d] pyri dazi n-5-oxi d

2,3-Dimethyl -7- (4-fl uorbenzyl oxy) -1-for uryl-pyrrole o [2.3-d] pyri dazi n-5-oxi d

2,3-Dimethyl -1- (4-fl uorbenzyl) -7- (4-fl uorbenzyl oxy) -pyrrole o [2.3-d] pyri dazi n-

5-oxide

2,3-Dimethyl -1- (4-fl uorbenzyl) -7- (4-fl uorbenzyl oxy) pyrrole o [2.3-d] pyri dazi n

2,3-Dimethyl -7- (4-fl uorbenzyl oxy) -1- (4-methoxybenzyl) pyrrole o [2.3-d] pyri dazi n

2,3-Dimethyl -7- (4-fl uorbenzyl oxy) -1- (3-methoxybenzyl) pyrrole o [2.3-d] pyri dazi n

2,3-Dimethyl -7- (4-fl uorbenzyl oxy) -l- (2-methoxybenzyl) pyrrole o [2.3-d] pyri dazi n

2,3-Dimethyl -1- (3, 4-dimethoxybenzyl) -7- (4-fl uorbenzyl oxy) pyrrole o [2.3-d] pyri - dazi n and the salts of these compounds.

Another object of the invention is a method for producing the compounds according to the invention and their salts. The process is characterized in that

a) for the preparation of compounds I in which R4 is hydroxy, pyrrole of the formula II,

wherein Rl, R2 and R3 have the meanings given above and X represents a suitable leaving group, reacted with hydrazine, or that

b) for the preparation of compounds I in which R4 is halogen and Rl has a meaning other than hydrogen, hydroxypyridazines of the formula III,

in which Rl is 1-4C-alkyl or 1-3C-alkylene substituted by R5 and R2 and R3 have the meanings given above, with suitable halogenating agents, or in that

c) for the preparation of compounds I in which R4 represents the radical -A-B-R6, pyridazines of the formula IV,

wherein R1, R2 and R3 have the meanings given above and X 'represents a suitable leaving group (in particular chlorine and bromine), with compounds of the formula V.

H-Y (V)

wherein Y represents the radical -A-B-R6 and A, B and R6 have the meanings given above, or their salts with bases, or that

d) for the preparation of compounds I in which Rl represents a hydrogen atom and R4 has a meaning other than halogen, benzyl compounds -10-

Formula VI,

wherein R2 and R3 have the meanings given above and R4 is hydroxyl or the substituent -A-B-R6, reductively debenzyl ert, or that ma

e) for the preparation of compounds I in which R4 is -SH (mercapto), pyridazines of the formula IV in which Rl, R2 and R3 have the meanings given above and X 'is a halogen atom (in particular chlorine and bromine) a sulfurizing agent such as thiourea, or

f) for the preparation of compounds I in which R4 is the radical -AB-R6 where A is S (sulfur) and B and R6 have the meanings given above, compounds of the formula I in which R4 is -SH (mercapto) , m compounds of the formula VII

Z'-B-Rö (VII)

implemented in which V represents a suitable leaving group and B and R6 have the meanings given above, or that

g) for the preparation of compounds I in which R4 is the radical -AB-R6 where A is SO (sulfinyl) or S0 ₂ (sulfonyl) and B and R6 have the meanings indicated above, compounds of the formula I in which R4 - SB-R6 b indicates, oxidizes, or that one

h) for the preparation of compounds I in which n is 1, the compound gene of the formula I in which n is 0 is oxidized, or in that i) for the preparation of compounds I in which R4 is the cyanamido radical, compounds of the formula IV in which Rl, R2 and R3 have the meanings indicated above and X 'is a halogen atom (in particular chlorine and bromine) are reacted with cyanamides , or that one

j) for the preparation of compounds I in which R4 denotes the radical -N (CN) -B-R6, where B and R6 have the meanings indicated above, compounds of the formula I in which R4 represents the cyanamido radical with compounds of Formula VII is implemented, in which Z 'represents a suitable leaving group and B and R6 have the meanings given above, or in that

k) for the preparation of compounds I in which R2 is a hydroxymethyl est, compounds of the formula I in which R2 is formyl are reduced, or that

1) for the preparation of compounds I in which R4 is the radical -AB-R6, where R6 is phenyl substituted by -NH-CO-NH ₂ (ureido), compounds of the formula I in which R4 is the radical -AB-R6 , where R6 denotes phenyl substituted by amino, is reacted with alkali metal cyanate, or that

m) for the preparation of compounds I in which R4 is the radical -AB-R6, where R6 is phenyl substituted by 1-4C-Al oxycarbonylamino, compounds of the formula I in which R4 is the radical -AB-R6, where R6 is phenyl substituted by amino, reacted with 1-4C-alkyl halide, or that

n) for the preparation of compounds I in which R2 is CHO (formyl), in

Compounds of formula I, wherein R2 is methyl, the methyl group

Halogenation converted into the dihalomethyl group and this then hydrolyzed, or that one

o) for the preparation of compounds I in which R 2 is COOH (carboxyl), in compounds of the formula I in which R 2 is methyl, the methyl group is converted into the trihalomethyl group by halogenation and then hydrolyzed,

and that, if desired, then those according to a), b), c), d), e), f), g), h), i), j) k), 1), m), n) or o) obtained compounds I converted into their salts, or that, if desired, subsequently obtained from the salts obtained Compounds I releases the compounds I.

The reaction of the pyrroles II with hydrazine is advantageously carried out in inert polar, water-containing or preferably water-free solvents, for. B. in

Alcohols, such as methanol or ethanol, or in dimethyl sulfoxide, dimethylformamide or preferably in glacial acetic acid. The reaction temperature is between 0 and 150 C, preferably at the boiling point of the solvent used.

The leaving group X is preferably a group which is already present in the starting compounds required for the preparation of the pyrroles II and does not have to be introduced subsequently. A preferred leaving group X is, for example, the alkoxy radical, in particular the ethoxy or methoxy radical. The compounds of the formula I (with R4 = hydroxy) prepared by process a) can also be represented in the tautomeric form and correspondingly referred to as pyridazinones.

The halogenation of the hydroxypyridazines (= pyridazinones) III takes place in the presence of suitable or preferably without solvents. Suitable solvents are only water-free solvents, such as. B. open-chain or cyclic ethers (diethyl ether, diethylene glycol diethyl ether, dioxane or tetrahydrofuran), or (aromatic) hydrocarbons, such as. As cyclohexane, benzene or toluene in question, which are inert towards the halogenating agent.

All known halogen-releasing reagents are suitable as halogenating agents, in particular those compounds which are suitable for use on an industrial scale. Examples include phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide, phosphorus oxytrichloride or phosphorus oxytribromide.

The halogenation (depending on the type of halogenating agent and the solvent optionally used) is carried out at temperatures between 0 and 150 ° C., in particular at the boiling point of the solvent or halogenating agent used.

The reaction of the pyridazines IV with the compounds V takes place (depending on the type of the compound V) in an anhydrous, inert solvent or without further addition of solvent, using an excess of compound V as a solvent. In particular, aprotic, water-free, inert solvents are polar solvents such as e.g. B. dimethyl sulfoxide, tetrahydrofuran, dioxane or dimethylformamide in question. Halogen atoms may be mentioned in particular as suitable leaving groups X ', it being possible to obtain the compounds IV in the manner described under b). Alternatively, the leaving group X 'is the methylsulfonyl group, which can be introduced by alkylation of the 7-mercapto compound and subsequent oxidation.

Depending on the nature of the compounds V, their reaction with the pyridazines IV requires the presence of an auxiliary base or (if Y represents the radical -NH-B-R6) an excess of compound V. Examples of auxiliary bases are organic amines (such as triethylamine or Diisopropylamine), alkali carbonates (such as sodium carbonate or potassium carbonate) or alkali hydroxides (such as sodium hydroxide or potassium hydroxide), but preferably those compounds which are capable of deprotonating the compounds V smoothly. In particular, metal hydrides (e.g. sodium hydride) or alkali metals (e.g. sodium) may be mentioned here, which are either used before the reaction with IV to deprotonate the compounds V or are added to the reaction mixture of IV and V. In a preferred process variant, the deprotonation can also be carried out by an alkali metal oolate, such as, for example, kaiium tert-butoxide, in the presence of a crown ether, such as, for example, [18] crown-6.

The reaction temperature is - depending on the reactivity of the compound V or its oo salts with bases - between 0 and 150 C, with a higher reactivity tempera oo. _L tures between 0 and 50 C are sufficient, but higher with lower reactivity

Temperatures are required, the boiling point of the solvent used or of the excess of compound V used as solvent being preferred.

The debenzylation according to process variant d) takes place in a manner familiar to the person skilled in the art, e.g. B. with hydrogen in the presence of palladium as a catalyst (in methanol at room temperature) or with sodium in liquid ammonia (at -80 C).

The reaction with thiourea according to process variant e) is carried out in a manner familiar to the person skilled in the art by heating the reactants in a suitable solvent such as, for example, dimethyl sulfoxide, dimethylformamide, ethanol or preferably methanol, to temperatures between 40 and 150 ° C., preferably to the boiling point of the used solvent, and optionally subsequent hydrolytic workup, for example with aqueous Caustic soda.

The reaction according to process variant f) is carried out in a manner which is customary for the production of sulfides from thiols. For this purpose, the mercapto compounds are mixed with a suitable base (for example an alkali metal hydroxide, an alkali metal alcoholate or an alkali metal hydride) in a solvent which is inert to the reactants (for example tetrahydrofuran, dioxane, dimethyl sulfoxide, water or preferably dimethylformamide ) deprotonated and then with the compounds oo VII at temperatures between 0 and 100 C, preferably at room temperature

Brought reaction. The leaving group V of the compounds VII is, for example, a halogen atom, preferably a bromine or iodine atom.

The oxidation of the sulfides according to process variant g) takes place in a manner known per se and under the conditions familiar to the person skilled in the art for the oxidation of sulfides to sulfoxides or sulfones {see here for example J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2), 45-89 (1982) or E. Block in S. Patai, The Che istry of Functional Groups, Supplement E. Part 1, S 539-608, John Wiley and Sons (Interscience Publication), 1980}. Suitable oxidants are all reagents commonly used for the oxidation of sulfides to sulfoxides or sulfones, in particular peroxy acids, such as e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid or preferably m-chloroperoxybenzoic acid or, in the oxidation to the sulfone, preferably potassium permanganate.

The reaction temperature (depending on the reactivity of the oxidizing agent and degree of dilution) is between -70 C and the boiling point of the solvent used, but preferably between -30 and +30 C. The reaction is conveniently carried out in inert solvents, e.g. B. in esters or ethers, such as ethyl acetate, isopropyl acetate or dioxane, or in aromatic or chlorinated hydrocarbons, such as benzene, toluene, chloroform or preferably dichloromethane or acetic acid.

In the N-oxidation according to process variant h), similar, but generally somewhat more vigorous reaction conditions are used as in the sulfoxidation according to process variant g). Therefore, since a simultaneous sulfoxidation is difficult to avoid when carrying out the N-oxidation, preference is given to synthesizing those N-oxides in which A is not S (sulfur). The N-oxidation is preferably carried out with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The cyanamido radical according to process variant i) is introduced in a customary manner in suitable, in particular anhydrous solvents such as, for example, dioxane, tetrahydrofuran or toluene at temperatures between 70 and 150 ° C., in particular at the boiling point of the solvent used. Alkali cyanamides or quaternary are preferably cyanamides Ammonium cyanide used, the latter also being able to be formed in situ by using equimolar amounts of, for example, sodium cyanamide and tetraalkylamonium chloride (for example tetr butylammonium chloride).

The process according to variant j) is carried out in a manner similar to that already described for process variant f), but generally higher temperatures, for example the boiled temperature of the solvent used, are used when carrying out the process according to variant j) come.

The reduction of the formyl group to the hydroxymethyl group according to variant k) was carried out in a manner familiar to the person skilled in the art, for example by reaction with lithium aluminum hydride in a suitable inert solvent.

The amino group is converted into the ureido group according to variant 1) in a manner known per se by reaction with an alkali metal cyanate, for example potassium cyanate, in a weakly acidic medium, for example in semi-concentrated acetic acid.

The amino group is converted into the 1-4C-alkoxycarbonylamino group according to variant m) in a manner known per se for the production of urethane, preferably by reaction of the amino compound with halogen formate esters, such as chloroformate esters, in inert solvents.

The halogenation / hydrolysis according to variants n) and o) proceeds essentially according to the same procedure, with sulfuryl chloride, for example, being used as the halogenating agent. Depending on the excess in which the halogenating agent is used and the reaction temperature used, either the dihalomethyl or the trihalomethyl compound is preferably formed, whereby - if a mixture is present - it is separated in a customary manner during working up, in particular the solubility in water the resulting acid or its salts. The substances according to the invention obtained according to process variants a) to o) are isolated and cleaned in a manner known per se, e.g. B. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.

Acid addition salts are obtained by dissolving the free compounds in a suitable solvent, e.g. B. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added.

The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can by alkalization, e.g. B. with aqueous ammonia solution, are converted into the free compounds, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.

Quaternary ammonium salts are obtained in an analogous manner by dissolving the free compound in a suitable solvent, e.g. B. in acetone, or in a chlorinated hydrocarbon, such as methylene chloride or chloroform, to which the desired alkylating agent is then added. These salts are also obtained by filtering, falling over, precipitating with a non-solvent for the addition salt or by evaporating the solvent.

The compounds II - insofar as they are new compounds - are also the subject of the invention. Compounds II in which Rl is 1-4C-alkyl or 1-3C-alkylene substituted by R5 are prepared by correspondingly substituted compounds II in which Rl is hydrogen with halogen compounds of the formula VIII,

Rl-Z (VIII)

in which Rl is 1-4C-alkyl or R5-substituted 1-3C-alkyl and Z is halogen (chlorine, bromine or iodine), in a suitable manner. The reaction of II (with R1 = hydrogen) with VIII takes place under basic conditions in the presence of a phase transfer catalyst. As catalysts in addition to onium salts, such as. B. tetrabutylammonium chloride, especially Kronen¬ ether, such as dibenzo [18] crown-6, dicyclohexyl [18] crown-6 and in particular [18] crown-6 mentioned.

Bases used, which are used at least in a molar ratio, preferably in excess, are, in particular, alkali metal hydroxides (e.g. sodium or potassium hydroxide) or alkali metal alcoholates (e.g. sodium ethylate or potassium tert-butoxide). When working in an anhydrous solvent, the hydroxides or alcoholates used are preferably used in finely powdered form.

The reaction takes place (depending on the type of phase transfer catalyst and the base used) in water-containing or, in particular, water-free organic solvents, or in a mixture of water and an organic solvent which is immiscible or hardly miscible with water. Examples of water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene. Examples of water-containing or water-free solvents are dichloromethane, tetrahydrofuran or xylene.

The choice of the reaction temperature in the reaction of II with VIII depends on the other reaction conditions, temperatures between o 20 ° C. and the boiling point of the solvent used being generally preferred.

Compounds of the formula II in which Rl is hydrogen are known or can be prepared analogously to known processes [e.g. B. P. J. Crook et al., Liebigs Ann. Chem. 748 (1971) 26-37].

The following examples illustrate the invention without restricting it. The compounds of the general formula I mentioned by name in the examples and the salts of these compounds are a preferred subject of the invention. Mp means melting point, the abbreviation h is used for hour (s) and the abbreviation min is used for minutes. "Ether" means diethyl ether. Examples

FINAL PRODUCTS

la. 7-benzyloxy-l, 2, 3-tri methyl-pyrrole o [2.3-d] pyridazine

0.61 g of sodium are dissolved in 20 ml of benzyl alcohol, 5.0 g of 7-chloro-l, 2,3-trimethyl-pyrrolo [2,3-d] pyridazine are added and the mixture is then heated to 100 ° C. for 30 minutes. The reaction mixture is poured into 100 ml of water, extracted with 3 × 50 ml of dichloromethane, dried with sodium sulfate and concentrated. The brown 01 obtained is used to separate benzyl alcohol at 100 C (0.2 torr) in

Ball tube distilled and the residue taken up in 30 ml of hot ethyl acetate. After cooling, a light precipitate precipitates, which is suctioned off and recrystallized from methanol / water. 2.5 g (37%) of the title compound of mp 102-104 C are isolated.

The following connections are made in an analogous manner:

Ib. 1-benzyl-7-benzyl oxy-2, 3-dimethyl-pyrrole o [2.3-d] pyri dazi n

0.44 g of sodium, 30 ml of benzyl alcohol and 5.0 g of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine are reacted at 100 ° C. for 1.5 hours. The yellow oil remaining after the bulb tube distillation is crystallized from ethyl acetate. o 4.5 g (71%) of the title compound with a melting point of 136 ° C. are isolated.

lc. 7-benzyloxy-l-isobutyl -2,3-dimethyl-pyrrole o [2.3-d] pyr dazine

670 mg of 7-chloro-l-isobutyl-2,3-dimethyl-pyrrolo [2,3-d] pyridazine, 80 mg of sodium o and 7.5 ml of benzyl alcohol are reacted at 115 ° C. for 4 hours and worked up. The oil remaining as residue after tube distillation is chromatographed on silica gel (eluent: toluene / dioxane = 1: 1). After concentration of the fractions with R = 0.4, a colorless oil is obtained which crystallizes rapidly after addition of diisopropyl ether. 200 mg (23%) of the title compound of mp 95-97 C are isolated. ld. 7-Benzyloxy-2,3-dimethy1-IR, S-tetrahydrof urf uryl -pyrrole o [2.3-d] pyridazine

600 mg of 7-chloro-2,3-dimethyl-1-R, S-tetrahydrofurfuryl-pyrrole or [2.3-d] pyridazine, 65 mg of sodium and 6 ml of benzyl alcohol are reacted at 110 ° C. for 3 hours and worked up. Cleaning and isolation are carried out as described in Example 1c. o 200 mg (26%) of the title compound of mp 119-123 C are obtained.

le. 1-Benzyl -2, 3-dimethyl -7- (2-phenylethoxy) pyrrole o [2.3-d] pyri dazi n

1.0 g of l-benzyl-7-chloro-2, 3-dimethyl-pyrrolo [2.3-d] pyridazine, 80 mg of sodium and 5 ml of 2-phenylethanol are reacted at 90 ° C. for 1.5 hours and worked up. The residue remaining after the tube tube distillation is recrystallized from ethyl acetate. 0.90 g (70%) of the title compound of mp 155-157 C are isolated.

lf. 7-benzyloxy-2,3-dimethyl-1- (3-pyridylmethy1) pyrrolo [2.3-d] pyridazine

41 mg of sodium, 4 ml of benzyl alcohol and 410 mg of 7-chloro-2,3-dimethyl-l- (3-methyl-pyridyl) pyrrolo [2.3-d] pyridazine are reacted at 110 C for 1.5 h. That after the

Oil remaining in a tube of tube distillation is chromatographed on silica gel (eluent: toluene / dioxane = 1: 1). After concentration of the fractions with R = 0.23 f and stirring with di isopropyl ether, 250 mg (48%) of the title compound are isolated as o colorless crystal lisate with a melting point of 151-152 ° C.

lg. 7-benzyloxy-2, 3-dimethyl-1-uryl-pyrrolo [2.3-d] pyridazine

170 mg of sodium, 16 ml of benzyl alcohol and 1.6 g of 7-chloro-2,3-dimethyl-1-furfuryl-o pyrrolo [2.3-d] pyridazine are reacted at 100 ° C. for 3 h. The oil remaining after the Kugelrohr distillation is chromatographed on silica gel (eluent: toluene / dioxane = 1: 1). After concentration of the fractions with R = 0.35 and recrystallization from di isopropyl ether, 1.60 g (80%) of the title compound are isolated as a colorless crystal lisate of mp 121-123 ° C.

2. 1-Benzyl -2,3-dimethyl -7-ethoxy-pyrrole o [2.3-d] pyridazine

0.5 g of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine is dissolved in 30 ml of anhydrous ethanol and a solution of 0.14 g of sodium in 50 ml of ethanol is added. It is refluxed for 3 days and then on Given 100 ml of water, extracted with 3 x 100 ml of dichloromethane, dried over sodium sulfate and concentrated. The remaining yellow residue is recrystallized from ethyl acetate. 200 mg (39%) of the title compound of mp 134-135 C are isolated.

3. 1-Benzyl-2,3-dimethyl-7- (3-pyridylmethyloxy) pyrrolo [2.3-d] pyridazine

400 mg of 3-hydroxymethylpyridine are dissolved in 1 ml of anhydrous dimethylformamide, and 130 mg of sodium hydride (80% suspension) are added. After 30 minutes, a solution of 0.5 g of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine in 2 ml of anhydrous diethylformamide is added dropwise and the mixture is stirred at room temperature for 16 h . It is then added to 10 ml of water, extracted with 3 × 10 ml of ethyl acetate, dried with sodium sulfate and the residue which remains after concentration is chromatographed on silica gel (eluent: toluene / dioxane = 1: 1). The fractions with R = 0.3 are concentrated. The remaining oil is crystallized from diisopropyl ether. 0.22 g (34%) of the title compound of o mp 95-100 C are isolated.

4. 1,2,3-trimethyl-7- (1-R, S-indanyloxy) pyrrolo [2.3-d] pyridazine

A solution of 1.75 g of 1-indanol in 10 ml of anhydrous dimethylformamide is added to a suspension of 0.43 g of sodium hydride (80% suspension) in 10 ml of anhydrous diethylformamide and stirred for 30 minutes at room temperature. A solution of 7-chloro-l, 2,3-trimethyl-pyrrolo [2,3-d] pyridazine in 10 ml of anhydrous diethylformamide is then added dropwise, and the mixture is then heated to 50 ° C. for 1.5 hours. The reaction mixture is added to 50 ml of water and with

3 x 50 ml of dichloromethane extracted. The organic extracts are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: toluene / dioxane = 9: 1). The brown, crystalline residue thus obtained is after clarification with bleaching earth, z. B. Tonsil ^® , recrystallized from ethyl acetate. 180 mg (24%) of the title compound of mp 132-134 C are isolated.

5. 2,3-dimethyl -7-ethoxy-pyrrolo [2.3-d] pyridazine

0.15 g of 1-benzyl-2,3-dimethyl-7-ethoxy-pyrrolo [2.3-d] pyridazine is dissolved in 20 ml of liquid ammonia and 160 mg of sodium are added at -78 ° C. After 8 h, the mixture is warmed to room temperature and the residue in 100 ml dichloromethane / water ser (1: 1) added. The organic phase is dried over sodium sulfate and concentrated. 50 mg (49 H) of the title compound of mp 293-95 C are isolated.

6a. 1-benzyl-2,3-dimethyl-7- (4-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine

To a solution of 8.67 g (68 mmol) of 4-fluorobenzyl alcohol (98%) in 100 ml of anhydrous tetrahydrofuran, 13.14 g (113.6 mmol) of potassium tert-butoxide (97%) and 500 are added in succession mg (1.8 mmol) [18] Krone-6 (98%). This suspension is stirred for 15 minutes at room temperature. A solution of 6.16 g (22.7 mmol) of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine in 50 ml of anhydrous tetrahydrofuran is then stirred with vigorous stirring at room temperature dripped. The mixture is stirred for a further 3 h at room temperature, then mixed with 250 ml of water and extracted with 3 x 200 ml of ethyl acetate. After the organic extracts have been dried over sodium sulfate, the mixture is concentrated and the remaining residue is chromatographed on silica gel (eluent: toluene / ethyl acetate = 10: 1). After concentration and stirring in hot diisopropyl ether, 6.85 g (83%) of the title compound are isolated. Mp 144-147 C.

The following connections are made in an analogous manner:

6b. 1-benzyl-2,3-dimethyl-7- (3-methoxybenzyloxy) pyrrolo [2.3-d] pyridazine

Purification: Chromatography on silica gel (eluent: toluene / dioxane = 2: 1) and subsequent stirring from cyclohexane. Yield: 81%, mp 92-94 C.

6c. 1-Beπzyl-2,3-dimethyl-7- (3-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine o Purification as in Example 6b. Yield: 70%, mp 104-106 C.

6d. 1-Benzy! -2,3-dimethyl-7- (2-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine o Purification as in Example 6b. Yield: 80%, m.p. 129-133 C.

6e. 1-benzyl-7- (2-chlorobenzyloxy) -2,3-dimethyl-pyrrolo [2.3-d] pyridazine

The title compound is - as described in Example 6a - prepared using dimethylformamide as a solvent. Purification: chromatography on silica gel (eluent: toluene / ethyl acetate = 2: 1) and subsequent crystallization from cyclohexane. Yield: 54%, mp 120-122 C.

6f. 7- (2-methyl benzyl oxy) -1,2,3-tri methyl-pyrrolo [2.3-d] pyridazine o Purification as in example 6b. Yield: 68%, mp 146-147 C.

6g. 7- (2-Chlorobenzyl oxy) -1, 2,3-trimethyl-pyrrole o [2.3-d] yri dazi n

Purification as in example 6b and additional crystallization from ethyl acetate. Yield: 57%, mp 158-161 C.

6h. 7-benzyl oxy-2, 3-dimethyl -1- (4-fl uorbenzyl) pyrrole o [2.3-d] pyri dazi n

Purification: Chromatography on silica gel (eluent: ethyl acetate) and crystal oilation from diisopropyl ether. Yield: 67%, mp. 134-137 C.

6i. 2, 3-Di methyl -1- (4-fl uorbenzyl) -7- (4-fl uorbenzyl oxy) pyrrolo [2.3-d] pyri da tin

Purification: Chromatography on silica gel (eluent: ethyl acetate) and crystallization from diisopropyl ether. Yield: 70%, mp 148-150 C.

6y 1- (4-Ami nobenzyl) -2,3-dimethyl -7- (4-fluorobenzyl oxy) pyrrole o [2.3-d] pyridazine

To a solution of 0.95 ml (8.6 mmol) of 4-F1 uorbenzyl alcohol in 20 ml of anhydrous tetrahydrofuran, 1.5 g (14 mmol) of potassium tert-butyl and 60 mg (0 , 22 mmol) [18] Krone-6. The suspension is 15 min. stirred at room temperature. Then a solution of 0.9 g (2.8 mmol) of 1- (4-azidobenzyl) -7-chloro-2,3-dimethyl-pyrrolo [2,3-d] pyridazine in 30 ml of water-free tetrahydrofuran is added with vigorous stirring R temperature dropped. It is stirred for a further 2 h at room temperature, then ιr. t 100 ml of water are added and extracted with 3 x 50 ml of ethyl acetate. After the organic extracts have been dried over sodium sulfate, the mixture is concentrated and the remaining brown oil is chromatographed on silica gel (mobile phase: medium: toluene / dioxane = 2: 1). After concentration and crystallization from ethyl acetate, 100 mg (9%) of the title compound are isolated. M.p. 186-188 C. 6k. 2,3-dimethyl-7- (4-fluorobenzyloxy) -1- (4-methylsulfonylbenzyl) pyrrolo-

[2.3-d] pyridazine purification: chromatography on silica gel (eluent: ethyl acetate) and crystallization from diisopropyl ether. Yield: 42, mp 176-179 C.

61. 2,3-Dimethyl-7- (4-fluorobenzyloxy) -1- (3,4-methylenedioxybenzyl) pyrrolo-

[2.3-d] pyridazine purification: crystallization from diisopropyl ether / cyclohexane / ethyl acetate. Yield: 52%, mp 153-155 C.

6m. 2,3-Dimethyl-7- (4-fluorobenzyloxy) -l- (3-nitrobenzyl) pyrrolo [2.3-d] pyridazine

Purification: chromatography on silica gel (eluent: toluene / dioxane = 2: 1) and o crystallization from ethyl acetate. Yield: 36%, mp 179 C (dec.).

6n. 1-benzyl-2,3-dimethyl-7- (3-aminobenzyloxy) pyrrolo [2,3-d] pyridazine

Purification: crystallization from ethyl acetate. Yield 46%, mp 162-163 C.

6o. 7- [2- (2-aminophenyl) ethoxy] -1-benzyl-2,3-dimethyl-pyrrolo [2,3-d] pyridazine Purification: Crystallization from ethanol / cyclohexane. Yield 56%, mp. 188-191 ° C.

6p. 1-Beπzyl-2,3-dimethy_l _-— 7- (2-th.ieny-l-me-thylo.xy) -pyrrolo [2,3-d] pyridazine ₀

Cleaning: Stir from diisopropyl ether. Yield: 56%, mp 111-115 C.

6q. 1-Benzyl-2,3-dimethyl-2- (3-thienylmethyloxy) pyrrolo [2,3-d] pyridazine Purification: Stir from diisopropyl ether. Yield: 55%, mp 103-106 C.

7. 1-Benzyl-2,3-dimethyl-7- (4-methoxybenzyloxy) pyrrolo [2.3-d] pyridazine

A suspension of 180 mg (6.0 mmol) of sodium hydride (80% suspension in paraffin) in 10 ml of anhydrous dimethylformamide is mixed with 790 μ] (6.0 mmol) of 4-methoxy-benzyl alcohol and for 1 hour at room temperature touched. A solution of 544 mg (2.0 mmol) of 1-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2,3-d] pyridazine in 5 ml of diethylformamide is then added dropwise and the mixture is then added stirred for a further 4 h at room temperature. After adding 50 ml of water wi d extracted with 3 x 50 ml of dichloromethane, dried over sodium sulfate and constricted. The remaining yellow oil is chromatographed on silica gel (eluent: toluene / - dioxane = 2: 1) and the residue obtained after concentration is crystallized from diisopropyl ether. 430 mg (58%) of the title compound are isolated as colorless crystals of mp. 108-112 C.

8. 1-Benzyl -7-benzylamino-2, 3-dimethylpyrrole o [2.3-d] pyri dazi n

A solution of 1.0 g (3.7 mmol) of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] - o pyridazine in 10 ml of benzylamine is heated to 180 ° C. for 1.5 hours heated. After cooling and

The addition of 30 ml of water is extracted with 3 x 30 ml of dichloromethane and then dried over sodium sulfate. After concentration, 750 mg (60%) of the title compound are obtained from the remaining oil by adding cyclohexane as a colorless crystalline product, mp 152-158 C.

9a. 7- (1-S-Phenylethylamino) -1, 2,3-tri methylpyrrole o [2.3-d] pyri dazi n

A suspension of 500 mg (2.5 mmol) of 7-chloro-1,2,3-trimethyl-pyrrolo [2.3-d] py- ri dazin in 4 ml of S - (-) - α-methyl benzylamine is heated to 150 C for 5 h. To

Cooling and addition of 10 ml of water is extracted with 3 x 20 ml of dichloromethane. The organic extracts are dried over sodium sulfate and the excess A is separated off in a high vacuum o (80 ° C.) after being distilled through a bulb tube distillation. The residue is on silica gel (eluent: toluene / dioxane

= 1: 1) chromatographed. After concentration of the fractions with R = 0.3, the remaining oil is crystallized by adding toluene. 110 mg (15%) of the title compound of mp 165-169 C are isolated.

9b. 7- (1-R-phenylethylamino) -1, 2,3-tri methylpyrrole o [2.3-d] pyri dazi n

This compound is prepared and purified as described in Example 9a.

The product is crystallized from diisopropyl ether. 160 mg (22%) of the title compound of mp 158-162 C are isolated.

10. N- (1-benzyl-2, 3-dimethyl-pyrrolo [2.3-d] pyri dazi n-7-yl) cyanamide

A solution of 1.0 g (3.7 mmol) of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine, 0.5 g (7.4 mmol) of sodium cyanamide and 2.06 g (7.4 mmol) of tetrabutyl ammonium chloride in 20 ml of anhydrous toluene is boiled under reflux for 5 h. After cooling and adding 50 ml of water, the mixture is extracted with 3 x 30 ml of ethyl acetate, dried over sodium sulfate and concentrated. The residue is on silica gel

(Eluent: toluene / dioxane = 1: 1) chromatographed. After concentration, 690 mg (68%) of the title compound are isolated as a crystalline solid with a melting point of 293 ° C. (decomposition).

11. N-Benzyl-N- (l-benzy1-2,3-dimethyl-pyrrolo [2.3-d] pyridazin-7-yl) cyanamide

A suspension of 1.25 g (4.5 mmol) of N- (1-benzyl-2,3-dimethyl-pyrrolo [2.3-d] - pyridazin-7-yl) cyanamide in 100 ml of anhydrous dioxane is mixed with 520 mg ( 18.0 mmol) of sodium hydride (80% suspension in paraffin) are added and the mixture is heated to 75 ° C. for 30 minutes with vigorous stirring. Then a solution of 1.6 ml (13.5 mmol)

Benzyl bromide in 10 ml of dioxane was added dropwise and the mixture was then refluxed for 4 hours. After cooling, the mixture is concentrated, the residue is taken up in 100 ml of dichloromethane / water (1: 1) and extracted with 3 × 50 ml of dichloromethane. After the organic extracts have been dried over sodium sulfate, the mixture is concentrated and the residue is chromatographed on silica gel (mobile phase: ethyl acetate / methanol = 10: 1). The fractions with R = 0.35 are concentrated and the residue is recrystallized from methanol. 400 mg (24%) of the title compound are isolated as a colorless crystal oisate with a melting point of 322-325 ° C.

12. 1-Benzyl-7-benzyloxy-2,3-dimethyl-pyrrolo [2.3-d] pyridazin-5-oxide

A solution of 213 mg (1 mmol) is added to a solution of 343 mg (1 mmol) of l-benzyl-7-benzyloxy-2,3-dimethyl-pyrrolo [2.3-d] pyridazine in 15 ml of anhydrous dichloromethane at room temperature. Chloroperoxybenzoic acid (80%) in 5 ml of dichloromethane was added dropwise. After the addition has ended, the mixture is stirred for a further 2 h at room temperature and then extracted with 3 × 30 ml of sodium bicarbonate solution. The organic phase is washed with 30 ml of water, dried over magnesium sulfate and concentrated. After the residue has been stirred out of petroleum ether (40-60 ° C.), 270 mg (75%) of the title compound are isolated as a crystalline solid of mp. 184-187 ° C.

13. 7-benzylthio-l, 2,3-trimethyl-pyrrolo [2.3-d] pyridazine

1.4 g (7.2 mmol) of 7-mercapto-l, 2,3-trimethyl are added to a suspension of 220 mg (7.2 mmol) of sodium hydride (80% suspension in paraffin) in 60 ml of anhydrous dimethylformamide at room temperature -pyrrolo [2.3-d] pyridazine added in portions. The mixture is stirred for a further 15 minutes and then a solution of 0.86 ml (7.2 mmol) of benzyl bromide in 10 ml of dimethylformamide were added dropwise. The clear solution is left to stand at room temperature for a further 16 h and 60 ml of water are then added. After extraction with 3 x 50 ml of ethyl acetate, drying of the organic extracts over sodium sulfate and concentration, chromatography on silica gel (eluent: toluene / ethyl acetate = 2: 1) is carried out. 1.5 g (75%) of the title compound are isolated as a crystalline solid of mp. 119-123 C.

14. 7-Benzylsulfinyl-1,2,3-tri ethyl pyrrolo [2.3-d] pyridazine

A solution of 620 mg (2.9 mmol.) At room temperature is added to a solution of 750 mg (2.6 mmol) of 7-benzylthio-l, 2,3-trimethyl-pyrrolo- [2,3-d] pyridazine in 20 ml of anhydrous dichloromethane ) m-Chloroperoxybenzoic acid added dropwise in 20 ml dichloromethane. The solution is left to stand for a further 16 h at room temperature and then mixed with 50 ml of water and adjusted to pH 1-2 with 2N hydrochloric acid. It is extracted with 3 x 30 ml of ethyl acetate; the aqueous phase is neutralized with sodium bicarbonate solution and extracted again with 3 x 30 ml of ethyl acetate. After drying over sodium sulfate, 250 mg of the title compound are obtained as a crystalline solid. After drying over sodium sulfate, concentrating and chromatography on silica gel (eluent: ethyl acetate / methanol = 10: 1), the combined organic extracts of the acidic extraction become further

300 mg substance isolated. After recrystallization from diisopropyl ether, a total of 450 mg (57%) of the title compound of mp 154-156 C are isolated.

15. 2,3-Dimethyl-7- (4-fluorobenzyloxy) -1-furfuryl-pyrrolo [2.3-d] pyridaz n

10.7 g (95.5 mmol) of potassium tert-butylate and 0.5 g are added in succession to a solution of 6.2 ml (57.3 mmol) of 4-fluorobenzyl alcohol in 300 ml of anhydrous tetrahydrofuran (1.9 mmol) [18] crown-6. The suspension is stirred at room temperature for 0.5 h. A solution of 5 g (19.1 mmol) of 7-chloro-2,3-dimethyl-1-furfuryl-pyrrolo [2.3-d] pyridazine in 300 ml of anhydrous tetrahydrofuran is then added dropwise with vigorous stirring at room temperature. The mixture is stirred for a further 1 h at room temperature, then mixed with 600 ml of water and extracted with 3 x 400 ml of ethyl acetate. After the organic extracts have been dried with sodium sulfate, the mixture is concentrated and the remaining brown oil is chromatographed on silica gel (eluent: toluene / dioxane = 2: 1). After concentration and crystallization from ethyl acetate, 5.1 g (76%) of the title compound are isolated as white crystals of mp 128-129 C. 16. 1-Benzyl-7- (4-fluorobenzyloxy) -2-for yl-3-methyl-pyrrolo [2.3] pyridazine

A solution of a solution of 13.92 g (38.5 mmol) of 1-benzyl-2,3-dimethyl-7- (4-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine in 150 ml of anhydrous dichloromethane is added Solution of 8.25 ml (100 mmol) of sulfuryl chloride in 35 ml of anhydrous dichloromethane oo at 0 C. The mixture is stirred at 0 C for 1 h. Saturated sodium bicarbonate solution is then added at 0-4 C with vigorous stirring until pH 8 is reached. The organic phase is separated off, washed with 2 × 50 ml of sodium bicarbonate solution and with 1 × 50 ml of water, dried over magnesium sulfate and concentrated. The residue is taken up in 200 ml of aqueous dioxane (80%), mixed with 16.8 g of sodium acetate and 550 mg of [18] crown-6 and then boiled under reflux for 2 h. Then it is mixed with 200 ml of water and concentrated to half its volume. The remaining solution is extracted with 4 x 150 ml of ethyl acetate. The organic extracts are washed with 300 ml of water, dried over magnesium sulfate and then concentrated. The residue is chromatographed on silica gel (mobile phase: ethyl acetate). After concentration of the fractions with R = 0.3 and crystallization from ethyl acetate / cyclohexane, 980 mg (7%) of the title compound are isolated. Mp 139-145 ° C.

17. 1-Benzyl-7- (4-fluorobenzyloxy) -2-hydroxymethyl-3-methyl-pyrrolo [2.3-d] pyridazine

To a solution of 980 mg (2.6 mmol) of 1-benzyl-7- (4-fluorobenzyloxy) -2-formyl-3-methyl-pyrrolo [2.3-d] pyridazine in 125 ml of ethanol are added 70 mg (1.84 mmol) sodium borohydride. The mixture is stirred at room temperature for 2 h and then 150 ml of water are added. Then up to half of the volume is concentrated. The precipitate is filtered off in a high vacuum at 40 ° C

Potassium hydroxide dried and then taken up in 100 ml of hot ethyl acetate. The solution is clarified by adding 2 g of silica gel and then concentrated again. The residue is crystallized from ethyl acetate / cyclohexane. 840 mg o (85%) of the title compound are isolated. M.p. 156-161 C.

18. 1-Benzyl-2,3-dimethyl-7- [2- (2-methoxycarbonylaminophenyl) ethoxy] pyrrolo - - [2,3-d] pyridazine

To a mixture of 375 mg (ImMol) 7- [2- (2-aminophenyl) ethoxy] -1-benzyl-2,3- dimethylpyryrolo [2,3-d] pyridazine and 0.2 ml (2nd , 3 mmol) pyridine in 15 ml o N-methylpyrrolidone, a solution of 0.18 ml of methyl chloroformate in 5 ml of N-methylpyrrolidone is added dropwise at 0.degree. The mixture is stirred for a further 2 h at room temperature, mixed with 100 ml of water and extracted with 4 x 50 ml of ethyl acetate. After drying over magnesium sulfate and concentration, the residue is rested in hot diisopropyl ether. Yield: 79%, mp. 186-188 C.

19. 1-Benzyl-2,3-dimethyl-7- [2- (2-ureidophenyl) ethoxy] pyrrolo- [2,3-d] pyridazine

To a solution of 320 mg (0.86 mmol) of 7- [2- (2-aminophenyl) ethoxy] -1-benzyl-2,3-dimethyl-pyrrolo [2,3-d] pyridazine in 10 ml 50% acetic acid, a solution of 150 mg (1.8 mmol) of potassium cyanate is added dropwise at room temperature. The mixture is stirred for a further 2 h at room temperature and then mixed with 15 ml of water. The precipitate is filtered off, washed with water and dried over K0H. For cleaning, it is extracted from hot diisopropyl ether. Yield: 62%, mp. 219-220 C.

20. 1-Benzyl-2,3-dimethyl-7- (4-fluorobenzyloxy) pyrrolo [2,3-d] pyridazine-2-carboxylic acid

0.93 g (8.3 mmol) of potassium tert-butoxide and 0.05 g (0.17 mmol) are successively added to a solution of 0.54 ml (5 mmol) of 4-fluorobenzyl alcohol in 30 ml of anhydrous tetrahydrofuran [ 18] given crown-6. The suspension is stirred at room temperature for 1 h. Then a solution of 0.5 g (1.66 mmol) of l-benzyl-7-chloro-2,3-dimethyl-pyrrolo- [2,3-d] pyridazine-2-carboxylic acid in 30 ml of anhydrous tetrahydrofuran at room temperature dripped. The mixture is boiled under reflux for a further 8 h and then the solvent is distilled off. The residue is taken up in 100 ml of water, adjusted to pH 4 with glacial acetic acid and then extracted with 3 x 50 ml of chloroform. After the organic extracts have been dried with sodium sulfate, the mixture is concentrated and the remaining residue is recrystallized from methanol. Yield: 14%, mp 180 C. INITIAL CONNECTIONS

Aa. 3-Formyl-l, 4,5-trimethyl-pyrrole-2-carboxylic acid methyl ester

14.6 g of potassium tert-butoxide and 24.0 g of 3-formyl-4,5-dimethyl-pyrrole- are dissolved at room temperature to dissolve 2.8 g of [18] crown-6 in 500 ml of anhydrous tetrahydrofuran. Given 2-carboxylic acid methyl ester. The suspension is stirred for 15 minutes at room temperature and then a solution of 18.5 g of methyl odide in 100 ml of anhydrous tetrahydrofuran is added dropwise over the course of 30 minutes. The suspension is stirred for 20 hours at room temperature. The reaction mixture is poured onto 500 ml of water and extracted with 3 × 300 ml of dichloromethane. After drying over sodium sulfate, the mixture is concentrated, and 30 g of brown crystals are obtained, which is purified on silica gel (eluent: petroleum ether / ethyl acetate = 7: 3). After concentrating, 20.9 g (81%) of the title compound are obtained as a colorless crystallizate of mp 88-90 C.

The following connections are made in an analogous manner:

Ab. L-benzyl-3-formyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester

0.98 g of [18] crown 6, 4.96 g of potassium tert-butoxide, 8.00 g of 3-formyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester and 7.80 g of benzyl bromide are added in 400 ml of water-free tetrahydrofuran reacted and worked up. For purification, the crude product is chromatographed on silica gel (eluent: toluene / ethyl acetate = 2: 1). After combining the fractions with R = 0.65 and concentrating, 10.9 g (91%) of the title compound are obtained as a pale yellow oil which only partially crystallizes.

Ac. 3-Formyl-l-isobuty1-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester

0.45 g of [18] crown-6, 2.4 g of potassium tert-butoxide, 2.0 g of 3-formyl-4,5-dimethylpyrrole-2-carboxylic acid methyl ester and 3.0 g of isobutyl bromide are in 50 ml of anhydrous tetrahydrofuran reacted. After the addition of the isobutyl bromide, the mixture is heated under reflux for 4 days. For purification, it is chromatographed on silica gel (eluent: toluene / dioxane = 10: 1). The fractions with R = 0.52 are combined and after concentration, 1.2 g (46%) of the title compound are obtained as a colorless oil. Ad. 4,5-Dimethyl-3-formyl-1-furfuryl-pyrrole-2-carboxylic acid methyl ester

5.0 g of 4,5-dimethyl-3-formyl-pyrrole-2-carboxylic acid methyl ester, 6.2 g of potassium tert-butoxide, 0.7 g of [18] crown-6 and 12.8 g of furfuryl bromide in total 100 ml of anhydrous tetrahydrofuran reacted and worked up. For purification, the crude product is chromatographed on silica gel (eluent: toluene / D oxane = 10: 1). After combining the fractions with R = 0.48, concentrating and crystallizing from petroleum ether (40-60 C) / disopropyl ether, 1.8 g (25%) of the title compound are obtained as colorless crystals of mp. 75-77 C. .

Ae. 4,5-Dimethyl-1- (4-fluorobenzyl) -3-formyl-pyrrole-2-carboxylic acid methyl ester

Purification: Crystallization from cyclohexane and then from diisopropyl ether. Yield: 68%, mp 103-106 C.

Af. 1- (4-Azidobenzyl) -4,5-dimethyl-3-formyl-pyrrole-2-carboxylic acid methyl ester

Purification: chromatography on silica gel (eluent: toluene / dioxane = 9: 1). Yield: 81, mp 73-75 C.

Ag. 4,5-dimethyl-1- (4-methylsulfonylbenzyl) -3-formyl-pyrrole-2-carboxylic acid, methyl ester

Purification: crystallization from ethyl acetate / petroleum ether. Yield: 50%, mp 150-155 ° C.

Ah. 4,5-dimethyl-3-formyl-1- (3, -methylenedioxybenzyl) pyrrole-2-carboxylic acid, methyl ester

Purification: chromatography on silica gel (eluent: toluene / dioxane = 10: 1). Yield: 54%.

Ai. 4,5-Dimethyl-3-formyl-1- (3-nitrobenzyl) pyrrole-2-carboxylic acid methyl ester o Purification: crystallization from methanol. Yield: 29%, mp 135-136 C. Ba. 3-Formyl-4,5-dimethyl-IR, S-tetrahydrofurfuryl-pyrrole-2-carboxylic acid methyl ester

1.4 g of powdered potassium hydroxide, 0.7 g of tetrabutylammonium bromide and 7.26 g of tetrahydrofurfuryl bromide are added in succession to a solution of 2.0 g of 3-formyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester in 150 ml of anhydrous xylene given. The suspension is then refluxed for 3.5 hours. For working up, the still hot mixture is filtered and the filtrate is concentrated. The remaining yellow oil is purified on silica gel (eluent: toluene / ethyl acetate = 2: 1). The fractions with R = 0.5 are combined and, after concentration, 0.35 g (12%) of the title compound is obtained as a colorless oil.

Fig. 4,5-Dimethyl-3-formy1-l- (3-pyridy1methyl) -pyrrole-2-carboxylic acid methyl ester

5.45 g of 4,5-dimethyl-3-formyl-pyrrole-2-carboxylic acid methyl ester, 12.95 g of 3-picolyl chloride, 7.92 g of potassium hydroxide and 2.42 g of tetrabutylammonium bromide are described in Example Ba in 250 ml implemented anhydrous xylene and worked up. For purification, the crude product is chromatographed on silica gel (eluent: toluene / dioxane = 2: 1). After concentration of the fractions with R = 0.4 and stirring with petroleum ether (40-60 C), 1.89 g (23%) of the title compound are obtained as colorless crystals of mp. 75-77 C.

Approximately 2,3-dimethyl-6,7-dihydro-pyrrolo [2,3-d] pyridazin-7-oπ

To a suspension of 8.0 g of 3-formyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester in 160 ml of glacial acetic acid, 2.2 g of hydrazine hydrate (approx. 100%) at room temperature for 10 minutes. dripped. The mixture is then heated under reflux for 1 h and the clear solution is added to 400 ml of ice water. A light precipitate precipitates, which is suctioned off and washed with about 100 ml of water. After o drying over potassium hydroxide at 40 C, 6.9 g (96%) of the title compound o of mp 312-314 C are obtained.

The following connections are made in an analogous manner:

Cb. L, 2,3-trimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

20.0 g of 3-formyl-l, 4,5-trimethyl-pyrrole-2-carboxylic acid methyl ester and 5.2 g of hydrazine hydrate (approx. 100%) are reacted in 150 ml of glacial acetic acid and worked up. o tet. 16.45 g (93%) of the title compound of melting point 303-305 C are isolated in this way.

Cc. 1-benzyl-2,3-dimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

12.0 g of 1-benzyl-3-formyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester and 2.2 g of hydrazine hydrate (approx. 100%) are reacted in 150 ml of glacial acetic acid and worked up. 10.0 g (89%) of the title compound of mp 246-248 C are isolated.

CD. 1-isobutyl-2,3-dimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

1.0 g of 3-formyl-1-isobutyl-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester and 0.22 ml of hydrazine hydrate (approx. 100%) are reacted in 10 ml of glacial acetic acid and worked up. 0.9 g (98%) of the title compound of mp. 247-249 C are isolated in this way.

Ce. 2,3-dimethyl-1-R, S-tetrahydrofurfuryl-6,7-dihydro-pyrrolo [2.3-d] pyr dazin-7-one

1.0 g of 3-formyl-4,5-dimethyl-1-R, S-tetrahydrofurfuryl-pyrrole-2-carboxylic acid methyl ester and 0.2 g of hydrazine hydrate (approx. 100%) are reacted in 15 ml of glacial acetic acid and worked up. 0.65 g (70%) of the title compound of mp 240-242 C are thus obtained.

Cf. 2,3-dimethyl-1- (3-pyridylmethyl) -6,7-dihydro-pyrrolo [2.3-d] pyridaziπ-7-one

1.5 g of 4,5-dimethyl-3-formyl-1- (3-pyridylmethyl) pyrrole-2-carboxylic acid methyl ester and 276 mg of hydrazine hydrate are reacted in 25 ml of glacial acetic acid and worked up.

The crude product is extracted from ethyl acetate for cleaning. 1.04 g (74%) of the title compound of mp 269-271 C are isolated.

Cg. 2,3-dimethyl-1-furfuryl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

3.5 g of 4,5-dimethyl-3-formyl-1-furfuryl-pyrrole-2-carboxylic acid methyl ester and

0.65 ml hydrazine hydrate are reacted in 60 ml glacial acetic acid and worked up. O

2.6 g (80%) of the title compound of mp 271-276 C are isolated. Ch. 2,3-dimethyl-1- (4-fluorobenzyl) -6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

Cleaning: Stir the precipitate in hot diisopropyl ether. Yield: 96%, mp. 232-234 C.

Ci. l- (4-Azidobenzy1) -2,3-dimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one o Purification: crystallization from ethyl acetate. Yield: 72%, mp 178-179 C.

Cj. 2,3-dimethyl-1- (4-methylsulfonyl) -6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

Cleaning: Stir the precipitate out of hot diisopropyl ether. Yield: 95%, mp 289-293 C.

Ck. 2,3-dimethyl-1- (3,4-methylenedioxybenzyl) -6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

Cleaning: Stir the precipitate out of cold water. Yield: 82%, mp 225 C (dec.).

Cl. 2,3-Dimethyl-1- (3-nitrobeπzyl) -6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one

Cleaning: Stir the precipitate out of cold water. Yield: 92%, mp. 259-260 C.

D. 7-chloro-1,2,3-trimethyl-pyrrolo [2.3-d] pyridazine

A suspension of 16.0 g l, 2,3-trimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one in 160 ml phosphorus oxychloride is heated under reflux for 2 h. The clear solution is then carefully added to 400 ml of ice water and adjusted to pH 5.5 with ION sodium hydroxide solution. The precipitate which has precipitated is filtered off with suction, washed with 200 ml of water and dried at 50 ° C. over potassium hydroxide.

For purification, the crude product (19 g) is dissolved in 500 ml of 2N hydrochloric acid and with

3 x 200 ml of dichloromethane extracted. The aqueous phase is then with

ION sodium hydroxide solution to pH 5.5, whereby a white precipitate forms, which is filtered off, washed with 100 ml of water and dried over potassium hydroxide. 14.6 g (83%) of the title compound of mp 162 C are isolated. Ea. l-benzyl-7-chloro-2, 3-dimethyl-pyrrolo [2.3-d] pyridazine

A suspension of 9.5 g of 1-benzyl-2, 3-dimethyl-6, 7-di hydro-pyrrole or [2.3-d] pyridazin-7-one in 100 ml of phosphorus oxychloride is heated under reflux for 2 hours. The clear solution is then carefully added to 300 ml of ice water, adjusted to pH 8.5 with ION sodium hydroxide solution and extracted with 3 × 200 ml of dichloromethane. After drying the combined organic extracts over sodium sulfate and concentrating, 13 g of crude product are obtained as a brown oil. After the addition of acetic ester, the oil crystallizes spontaneously and, after recrystallization from ethyl acetate, 7.5 g (74%) of the title compound of mp 125-127 C i sol i ert.

The following compounds are produced in an analogous manner:

Eb. 7-chloro-l-i sobutyl -2,3-dimethyl-pyrrole o [2.3-d] pyri dazi n

A suspension of 800 mg l-isobutyl-2,3-dimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one in 10 ml phosphorus oxychloride was reacted and worked up. After concentration, a pale yellow oil is initially obtained, which partially crystallizes after the addition of ethyl acetate. 730 mg (84%) of the title compound are isolated.

Ec. 7-chloro-2,3-dimethyl-1-R, S-tetrahydrofurf uryl -pyrrole o [2.3-d] pyri dazi n

A suspension of 800 mg of 2,3-dimethyl-1-R, S-tetrahydrofurfuryl -6, 7-di hydro-pyrrolo [2.3-d] pyridazin-7-one in 10 ml of phosphorus oxychloride is reacted and worked up. After concentration, a pale yellow oil is obtained, which crystallizes spontaneously. 600 mg (70%) of the title compound with a melting point of 99-103 C are isolated.

Ed. 7-chloro-2,3-dimethyl-1- (3-methylpyridyl) pyrrolo [2.3-d] pyridazine

A suspension of 780 mg of 2,3-dimethyl-1- (3-pyridylmethyl) -6,7-dihydro-pyrrolo [2,3-d] pyridazin-7-one in 25 ml of phosphorus oxychloride is reacted and worked up. For purification, the crude product is chromatographed on silica gel (eluent: dichloromethane / methanol = 9: 1). After concentration of the fractions with R =

0.57 and crystallization from ethyl acetate / cyclohexane, 90 mg (11%) of the title compound are obtained as colorless crystals of mp 160-163 C. Ee. 7-chloro-2,3-dimethyl-1-furfuryl-pyrrolo [2.3-d] pyridazine

A suspension of 2.4 g of 2,3-dimethyl-l-furfuryl-6,7-dihydro-pyrrolo [2.3-d] pyridazin-7-one in 30 ml of phosphorus oxychloride is reacted and worked up. For the purification, the crude product is recrystallized from dioxane / diisopropyl ether. 1.7 g (66%) of the title compound are isolated as colorless crystals of mp. 135-138 C.

Ef. 2,3-dimethyl-7-chloro-l- (4-fluorobenzyl) pyrrolo [2.3-d] pyridazine

Purification: crystallization from ethyl acetate / cyclohexane. Yield: 57%, mp 132-133 ° C.

Eg. 1- (4-Azidobenzyl) -7-chloro-2,3-dimethyl-pyrrolo [2.3-d] pyridazine o Purification: crystallization from ethyl acetate. Yield: 67%, mp 139-140 C.

Eh 7-chloro-2,3-dimethyl-1- (4-methylsulfonylbenzyl) pyrrolo [2.3-d] pyr dazin

Cleaning: Stir from diisopropyl ether / ethyl acetate. Yield 90%, mp. 190 ° C (dec.).

Egg. 7-chloro-2,3-dimethyl-1- (3,4-methylenedioxybenzyl) pyrrolo [2.3-d] pyridazine

Purification: crystallization from ethyl acetate / cyclohexane. Yield: 57%, mp. 201 ° C (dec.).

Ej. 7-chloro-2,3-dimethyl-l- (3-nitrobenzyl) pyrrolo [2.3-d] pyridazine o Purification: crystallization from ethyl acetate. 193-196 C.

F. 7-mercapto-l, 2,3-trimethyl-pyrrolo [2.3-d] pyridazine

A suspension of 2.0 g (10 mmol) of 7-chloro-l, 2,3-trimethyl-6,7-dihydro-pyrrolo [2.3-d] pyridazine and 0.86 g (11 mmol) of thiourea in 60 ml of anhydrous methanol are heated to 65 ° C. for 24 h. After the reaction mixture has cooled, the precipitate is filtered off, washed with methanol and dried. 1.4 go (71%) of the title compound are isolated from the mp. 318-322 C as a colorless solid. G. 1-benzyl -2-formyl -3-methyl -6, 7-di hydro-pyrrole o [2.3-d] pyri dazi n-7-one

A suspension of 1.01 g (4 mmol) of 1-benzyl-2,3-dimethyl-6, 7-di hydro-pyr-o rolo [2.3-d] pyridazin-7-one in 50 ml of dichloromethane is added at 0 C under strong

Stir a solution of 1.38 g (10 mmol) of sulfuryl chloride in 10 ml of dichloromethane. The mixture is stirred for a further 2 h at 0 C and then mixed with sodium bicarbonate solution. The organic phase is separated off and extracted with 3 x 50 ml sodium bicarbonate solution. After drying over sodium sulfate and concentration, the residue is dissolved in 50 ml of 80% aqueous dioxane, 1.5 g of sodium acetate and 100 mg of [18] crown-6 are added and the mixture is heated at 100 ° C. for 2 h. After cooling, 100 ml of water are added and it is extracted with 3 x 100 ml of ethyl acetate. After drying over magnesium sulfate and concentration, the residue is purified by chromatography on silica gel (eluent: toluene / dioxane = 2: 1). After crystallization from toluene / di isopropyl ether, 630 mg (59%) of the title compound are obtained. 210-214 C.

H. 1 -Benzyl -7-chloro-2-formyl -3-methyl-pyrrole o [2.3-d] pyri dazi n

A suspension of 7.4 g (27 mmol) of 1-benzyl -2-formyl -3-methyl -6, 7-di hydro-pyrrolo [2.3-d] pyridazin-7-one in 125 ml of phosphorus oxychloride is added vigorous stirring heated at 100 C for 2 h. After cooling, excess phosphorus oxychloride is distilled off, mixed with 100 ml of water, adjusted to pH 9 and with 3 x 100 ml

Extracted ethyl acetate. After drying over sodium sulfate and concentrating the

Residue by chromatography on silica gel (eluent: toluene / ethyl acetate

2: 1) cleaned. 4.2 g (55%) of the title compound are isolated. Mp

112-116 ° C.

I. 1-Benzyl -2,3-dimethyl -7-mercapto-pyrrole o [2.3-d] pyridazine

A suspension of 10.0 g (36.8 mmol) of l-benzyl-7-chloro-2, 3-dimethyl-pyrrolo-

[2.3-d] pyridazine and 3.4 g (44.7 mmol) of thiourea in 250 ml of ethanol are heated under reflux for 4 ho. After cooling to 10 C, the precipitate is filtered off and dried at 70 C over potassium hydroxide. 7.8 g (79%) of the title compound o are isolated. Mp 289 C (dec.). J. 1-Benzyl-2,3-dimethyl-7-methylthio-pyrrolo [2.3-d] pyridazine

A suspension of 4.0 g (14.9 mmol) of 1-benzyl-2,3-dimethyl-7-mercapto-pyrrolo- [2.3-d] pyridazine in 100 ml of 2N potassium hydroxide is mixed with 1.9 ml (29.8 mmol) of methyl iodide were added and the mixture was stirred at room temperature for 30 min. Then it is extracted with 2 x 100 ml dichloromethane. The combined organic extracts are washed with 100 ml of water, dried over sodium sulfate and concentrated. The residue becomes solid after trituration with ethyl acetate / diisopropyl ether. For cleaning, it is recrystallized from aqueous methanol. 2.9 g (69%) of the titanium compound are isolated. Mp 159-160 C.

K. 1-Benzyl-2,3-dimethyl-7-methylsulfonyl-pyrrolo [2.3-d] pyridazine

A solution of 0.57 is added to a solution of 0.5 g (1.8 mmol) of 1-benzyl-2,3-dimethyl-7-methylthio-pyrrolo [2.3-d] pyridazine in 20 ml of glacial acetic acid at room temperature g (3.6 mmol) of potassium permanganate dropped in 20 ml of water. After 1 h, 30 ml of a saturated sodium sulfite solution are added and the mixture is extracted with 2 x 50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over sodium sulfate and concentrated. The residue is purified by crystallization from diisopropyl ether / petroleum ether. 380 mg (68%) of the title compound are isolated. Mp 172 C.

L. 1-benzyl-3-methyl-6,7-dihydro-pyrrolo [2,3-d] pyridazin-7-oπ-2-carboxylic acid

A suspension of 1.01 g (4 mmol) of 1-benzyl-2,3-dimethyl-6,7-dihydro-pyrolo or [2,3-d] pyridazin-7-one in 50 ml of dichloromethane is added 0 C under strong

Stir a solution of 4.4 g (32 mmol) of sulfuryl chloride in 15 ml of dichloromethane. The mixture is stirred for a further 2 h at room temperature and then mixed with sodium bicarbonate solution. The organic phase is separated off and extracted with 3 × 50 ml of sodium hydrogen carbonate solution. After drying over sodium sulfate and concentration, the residue is dissolved in 50 ml of 80% aqueous dioxane, mixed with 1.5 g of sodium acetate and 100 mg of [18] crown-6 and heated at 100 C for 2 h. After cooling, the mixture is concentrated, mixed with 100 ml of water and extracted with 3 × 50 ml of sodium hydrogen carbonate solution. The aqueous extracts are adjusted to pH 4 with glacial acetic acid and extracted with 3 x 50 ml of ethyl acetate. After drying over magnesium sulfate and concentration, the residue is purified by stirring from hot methanol. Yield: 22%, mp 292-293 ° C. M. 1-benzyl-7-chloro-3-methyl-pyrrolo [2,3-d] pyridazine-2-carboxylic acid

A suspension of 3.3 g (11.6 mmol) of 1-benzyl-2,3-dimethyl-6,7-dihydro-pyrrolo [2,3-d] pyridazin-7-one-2-carboxylic acid in 20 ml of phosphorus oxychloride is heated at 100 ° C. for 1 h with vigorous stirring. After cooling, excess Phos ^¬ oxychloride is distilled off, 100 ml of water, adjusted to pH 12 and extracted with 3 x 100 ml Essigester. The aqueous phase is then adjusted to pH 3. The precipitate is filtered off and dried over K0H. Yield: 94%, mp 200-201 C.

Industrial applicability

The compounds of the formula I and their salts have valuable pharmacological properties which make them commercially usable. In particular, they have a pronounced gastric acid secretion inhibition and an excellent gastric and intestinal protective effect in warm-blooded animals. In addition, the compounds according to the invention are distinguished by a high selectivity of action, the absence of significant side effects and a large therapeutic breadth.

In this context, "gastric and intestinal protection" means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms ( Campylobacter pylori), bacterial toxins, medications (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), stomach acid or stressful situations can be caused.

In their excellent properties, the compounds according to the invention on various models, in which the antiulcerogenic and the anti-secretory properties are determined, surprisingly prove to be clearly superior to the compounds known from the prior art. On the basis of these properties, the compounds of the formula I and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, with them being used in particular for the treatment and / or prophylaxis of gastric and / or intestinal ulcer diseases.

The invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the above-mentioned diseases.

The invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.

The invention further comprises the use of the compounds according to the invention for the treatment and / or prophylaxis of the abovementioned diseases. The invention further relates to medicaments which contain one or more compounds of the formula I and / or their pharmacologically tolerable salts.

The medicaments are produced by processes known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions are used, the active ingredient content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar with the auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active ingredient carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.

The active ingredients can be administered orally, parenterally or percutaneously.

In general, it has proven advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or generally lower doses (in particular when the active substances are administered intravenously) can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.

If the compounds and / or salts according to the invention are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium alumate; Tranquilizers, such as benzodiazepines, for example diazepam; Spa molytics such as Bietamiverin, Camylofin; Anticholinergics such as oxyphencyclimine, phencarbamide; Local anesthetics, such as tetracaine, procaine; optionally also contain fermentation, vitamins or amino acids.

In this context, the combination of the compounds according to the invention with Phar aka which inhibit acid secretion, such as H ₂ blockers (for example cimetidine, ranitidine), or furthermore with so-called peripheral anticholinergics (for example pirenzepin, telenzepin, zolenzepin) should be emphasized in particular ) and with gastrin antagonists with the aim of increasing the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further combining with antibacterially active substances (such as cephalosporins, tetracyclines, nalidixic acid, Penicil¬ linen or bismuth salts) to combat Ca pylobacter pylori.

Pharmacology

The excellent gastric protective effect and the gastric secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on animal experiments. The compounds according to the invention investigated in the models listed below have been provided with numbers which correspond to the numbers of these compounds in the examples.

1. Testing the antiulcerogenic and secretion-inhibiting effect on the modified Shay rat

Table 1 below shows the influence of the compounds according to the invention after intravenous (IV) administration on the lesion formation and the acid excretion in the modified Shay rat.

Table 1

+) ED50 = dose (interpolated) that reduces the lesion index or the HCl secretion of the rat stomach in the treated group compared to the control group by 50%. Methodology

The ulcer provocation is carried out on 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pylorus ligation (under isoflurane anesthesia) and oral application of 100 mg / lOml / kg acetylsalicylic acid. The substances to be tested are administered intraduodenally (1 ml / kg) immediately after the pylorus ligation. The wound is closed using Michel clips. 4 hours later, the animals are killed in isoflurane anesthesia by atlas dislocation and gastric resection. The stomach is opened along the large curvature and stretched out on a cork plate after the amount of gastric juice secreted (volume) and later its HCl content (titration with sodium hydroxide solution) is determined. The number and size (= diameter) of existing ulcers are determined with a stereomicroscope at a 10-fold magnification. The product of the degree of severity (according to the following point scale) and the number of ulcers serves as an individual lesion index.

The measure of the antiulcerogenic effect is the reduction in the mean lesion index of each treated group compared to that of the control group (= 100%). The ED50 denotes the dose which reduces the mean lesion index or the HCl secretion by 50% compared to the control.

2. Testing the secretion-inhibiting effect on the perfused rat stomach

Table 2 below shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo. Table 2

+) ED50 = dose (interpolated) that causes a maximum inhibition of HCl secretion by 50%.

methodology

After tracheotomy, anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and another via Pyorus fixed in such a way that the tube ends just protruded into the gastric lumen. The catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall. After thorough rinsing (approx. 50-100 ml), the stomach was continuously flowed through with 37 ° C physiological NaCl solution (0.5 ml / min, pH 6.8-6.9; Braun-Unita I). The pH value (pH meter 632, glass electrode EA 147; 0 = 5 mm, Metrohm) and by titration with a freshly prepared 0.01 N NaOH was measured in the effluate collected in 15 min intervals (25 ml measuring cylinder) up to pH 7 (Dosimat 655 Metrohm) determines the secreted HCl.

Gastric secretion was stimulated by continuous infusion of 1 g / kg (= 1.65 ml / h) IV. Pentagastrin (V. fern, sin.) Approx. 30 minutes after the end of the operation (i.e. after determining 2 pre-fractions). The substances to be tested were administered intravenously (V. jugularis sin.) In 1 ml / kg liquid volume 60 minutes after the start of the continuous pentagastrin infusion.

The body temperature of the animals was measured by infrared radiation and heating pads

(automatic, stepless regulation via rectal temperature sensor) kept at a constant o 37.8 - 38 C.

The maximum decrease in acid excretion (15 min. Fractions) of each treated group compared to that of the untreated control group (= 100%) served as a measure of the secretion-inhibiting effect. The ED50 denotes the dose that causes a maximum inhibition of HCl secretion by 50%.

Claims

1. Compounds of formula I.

wherein

Rl represents hydrogen, 1-4C-alkyl or 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-al yl,

R3 represents 1-4C-alkyl,

R4 represents hydroxy, mercapto, halogen or the substituent -A-B-R6,

R5 furyl, thienyl, tetrahydrofuryl, pyridyl, phenyl, by one or two identical or different substituents from the group halogen, 1-4C-A1-alkyl, 1-4C-alkoxy, methylsulfonyl, nitro, azido, amino and mono- or di Represents 1-4C-alkylamino-substituted phenyl or phenyl substituted by methylenedioxy,

R6 is hydrogen, pyridyl, indanyl, thienyl, furyl, phenyl or by one or two identical or different substituents from the group halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, -NH-CO-NH ₂ (ureido) Represents amino, 1-4C-alkoxycarbonylamino and mono- or di-1-4C-alkylamino substituted phenyl,

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds, where R2 and R3 are not methyl when R1 is hydrogen and R4 is hydroxy. 2. Compounds of formula I according to claim 1, wherein

Rl represents 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents the substituent -A-B-R6,

B is a hyphen, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,

Represents 2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, where R6 does not denote hydrogen when B represents a dash and the salts of these compounds.

3. Compounds of formula I according to claim 1, wherein

Rl represents hydrogen, 1-4C-alkyl or 1-3C-alkylene substituted by R5,

R2 represents 1-4C-alkyl, COOH (carboxyl), CHO (formyl) or hydroxy-1-4C-alkyl,

R3 represents 1-4C-alkyl,

R4 represents hydroxy, mercapto, halogen or the substituent -A-B-R6,

R6 is hydrogen, pyridyl, indanyl, thienyl, phenyl or by one or two substituents from the group halogen, 1-4C-alkyl, l-4C-alkoxy, -NH-C0-NH ₂ (ureido), amino, and l-4C Alkoxycarbonylamino represents substituted phenyl, A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur) or SO (sulfinyl),

B represents a bond line, -CH ₂ - (methylene), -CH ₂ CH ₂ - (1,2-ethylene) or -CH (CH ₃ ) - (1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds, where R2 and R3 are not methyl when R1 is hydrogen and R4 is hydroxy.

4. Compounds of formula I according to claim 1, wherein

Rl represents 1-4C-alkyl or methylene substituted by R5,

R2 represents methyl or hydroxymethyl,

R3 represents methyl,

R4 represents the substituent -A-B-R6,

A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur) or SO (sulfinyl),

5. Compounds of formula I according to claim 1, wherein

Rl represents 1-4C-alkyl or methylene substituted by R5,

R2 represents methyl,

R3 represents methyl,

R4 represents the substituent -A-B-R6,

R5 represents furyl, phenyl or phenyl substituted by fluorine,

R6 represents phenyl or phenyl substituted by chlorine or fluorine,

A represents 0 (oxygen),

B represents -CH ₂ - (methylene) and n represents the number 0, and the salts of these compounds.

6. Compound selected from the group consisting of 1-benz 1-7-benzyloxy-2,3-dimethyl-pyrrolo [2.3-d] pyridazine 7-benzyloxy-2,3-dimethyl-1-furfuryl-pyrrolo [2.3-d] pyridazine 1-benzyl-2,3-dimethyl-7- (4-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine 1-benzyl- 2,3-dimethyl-7- (3-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine 1-benzyl-2,3-dimethyl-7- (2-fluorobenzyloxy) pyrrolo [2.3-d] pyridazine 2,3- Dimethyl-7- (4-fluorobenzyloxy) -1-furfuryl-pyrrolo [2.3-d] pyridazine and its salts.

7. A process for the preparation of the compounds of formula I according to claim 1, characterized in that

a) for the preparation of compounds I in which R4 is hydroxy, pyrroles of the formula II,

x-oσ 'ϊtf

in which Rl is 1-4C-alkyl or 1-3C-alkylene substituted by R5 and R2 and R3 have the meanings given above, with suitable halogenating agents, or in that c) for the preparation of compounds I in which R4 represents the radical -AB-R6, pyridazines of the formula IV,

H-Y (V)

d) for the preparation of compounds I in which Rl represents a hydrogen atom and R4 has a meaning other than halogen, benzyl compounds of the formula VI,

wherein R2 and R3 have the meanings given above and R4 is hydroxyl or the substituent -AB-R6, reductively debenzylated, or that one e) for the preparation of compounds I in which R4 is -SH (mercapto), pyridazines of the formula IV in which Rl, R2 and R3 have the meanings indicated above and X ^{1 is} a halogen atom (in particular chlorine and bromine) , with a desulfurization agent such as thiourea, or that

f) for the preparation of compounds I in which R4 is the radical -AB-R6, where A is S (sulfur) and B and R6 have the meanings given above, compounds of the formula I in which R4 is -SH (mercapto ) means with compounds of formula VII

Z'-B-R6 (VII)

g) for the preparation of compounds I in which R4 is the radical -AB-R6, where A is SO (sulfinyl) or SO ₂ (sulfonyl) and B and R6 have the meanings given above, compounds of the formula I in which R4 -SB-R6 means, oxidizes, or that one

h) for the preparation of compounds I in which n is 1, compounds of the formula I in which n is 0 are oxidized, or in that

i) for the preparation of compounds I in which R4 is the cyanamido radical, compounds of the formula IV in which Rl, R2 and R3 have the meanings indicated above and X 'is a halogen atom (in particular chlorine and bromine) are reacted with cyanamides , or that one

k) for the preparation of compounds I in which R2 denotes a hydroxymethyl radical, compounds of the formula I in which R2 denotes formyl are reduced, or that 1) for the preparation of compounds I in which R4 is the radical -AB-R6, where R6 is phenyl substituted by -NH-CO-NH ₂ (ureido), compounds of the formula I in which R4 is the radical -AB-R6 , where R6 denotes phenyl substituted by amino, is reacted with alkali metal cyanate, or that

m) for the preparation of compounds I in which R4 is the radical -AB-R6, where R6 is phenyl substituted by 1-4C-alkoxycarbonylamino, compounds of the formula I in which R4 is the radical -AB-R6, where R6 phenyl substituted by amino, reacted with 1-4C-alkyl ester of haiogenoformate, or that

n) for the preparation of compounds I in which R2 is CHO (formyl), in

Compounds of formula I, wherein R2 is methyl, the methyl group

and that, if desired, then those according to a), b), c), d), e), f), g), h), i), j), k), 1), m), n) or o ) compounds I obtained are converted into their salts, or that, if desired, the compounds I are subsequently released from the salts of the compounds I obtained.

8. Medicament containing one or more compounds according to one or more of claims 1 to 6 and / or their pharmacologically acceptable salts.

9. Compounds according to one or more of claims 1 to 6 and their pharmacologically acceptable salts for use in the prevention and treatment of gastrointestinal diseases.

10. Use of compounds according to one or more of claims 1 to 6 and their pharmacologically acceptable salts for the production of pharmaceuticals for the prevention and treatment of gastrointestinal diseases.