IE911406A1 - New pyridazines - Google Patents

Abstract

Pyridazines of formula (I) in which the symbols have the meaning explained in the description are novel compounds with interesting pharmacological properties.

Description

Scope of application of the invention The invention relates to new pyridazines, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry as intermediate products and for the preparation of medicaments.

Description of the invention It has been found that the new compounds described in more detail below have interesting pharmacological properties by which they differ from known compounds in a surprising and particularly advantageous manner.

The invention relates to new pyridazines of the formula I wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), 1-4C-alkoxy, mono- or polyhydroxy-2-4Calkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkoxy, NH2 (amino), N3 (azido), 0-C0-R6 or NH-C0-R7, R5 represents furyl, thienyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl and 1-4C-alkoxy, R6 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C•E 911406 - 2 alkoxycarbonyl-1-4C-alkyl, carboxy-1-4C-alkyl, amino, 1-4C-alkylamino, phenylamino, amino-1-4C-alkyl, mono- or di-1-4C-alkylamino-1-4C-alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di-1-4Calkylaminomethyl, R7 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, amino, 1-4C-alkylamino or phenylamino, R8 represents hydrogen, halogen or 1-4C-alkyl, X represents 0 (oxygen) or NH, E1 represents -CHg- (methylene), -CHpCHg- (1,2-ethylene) or -CHCCH^)(1,1-ethylene), E2 represents -C^- (methylene), -CH2CH2- (1,2-ethylene) or -CHCCH^)(1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds. 1_4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, iso-butyl, sec.-butyl, tert.-butyl, propyl, isopropyl, ethyl and in particular the methyl radical. 1_3C-Alkylene represents trimethylene, ethylene or in particular methylene. 1_4C-Alkoxy radicals contain one of the abovementioned 1-4C-alkyl radicals in addition to the oxygen atom. The methoxy radical is preferred.

Monohydroxy-2-4C-alkoxy represents a 2-4C-alkoxy radical selected from the abovementioned 1-4C-alkoxy radicals, to which a hydroxyl radical is bonded. The hydroxyethoxy radical is preferred. Polyhydroxyalkoxy represents a 34C-alkoxy radical selected from the abovementioned 1-4C-alkoxy radicals, to which more than one hydroxyl radicals are bonded, it being possible for the polyhydroxyalkoxy radical to be characterized by the following formula cmH(2m+l-p)(°H)p-CH2-θin which ra denotes the number 2 or 3 and p denotes the number 2 or 3. The 1,2-dihydroxypropoxy radical (glyceryl radical) is preferred. •Ε 911406 - 3 1-4C-Alkoxy-1-4C-alkoxy represents the abovementioned 1-4C-alkoxy radicals to which a 1-4C-alkoxy radical is bonded. An example which may be mentioned is the methoxyethoxy radical. 1-4C-Alkylcarbonyloxy-1-4C-alkoxy represents the abovementioned hydroxy-14C-alkoxy radicals to which a 1-4C-alkylcarbonyl radical (acyl radical) is bonded. An example which may be mentioned is the acetoxyethoxy radical.

Halogen in the context of the present invention is bromine, chlorine or fluorine. 1-4C-Alkoxy-1-4C-alkyl represents the abovementioned 1-4C-alkyl radicals to which a 1-4C-alkoxy radical is bonded. An example which may be mentioned is the methoxyethyl radical. 1-4C-Alkoxycarbonyl radicals contain one of the abovementioned 1-4C-alkoxy radicals in addition to the carbonyl group. The methoxycarbonyl and the ethoxycarbonyl radical are preferred. 1-4C-Alkoxycarbonyl-1-4C-alkyl represents the abovementioned 1-4C-alkyl radicals to which a 1-4C-alkoxycarbonyl radical is bonded. The methoxycarbonylmethyl and the methoxycarbonylethyl radical are preferred.

Carboxy-1-4C-alkyl represents the abovementio^1-4C-alkyl radicals to which a carboxyl radical (-COOH) is bonded. The carboxymethyl and the carboxyethyl radical are preferred. 1-4C-Alkylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methylamino and the ethylamino radical.

Amino-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals to which an amino group is bonded. An example which may be mentioned is the aminomethyl radical.

Mono- or di-1-4C-alkylamino represents an amino radical which is substituted by one or two of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methylamino, ethylamino, diisopropylamino and in •Ε 911406 - 4 particular the dimethylamino radical.

Mono- or di-1-4C-alkylamino-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals to which a mono- or di-1-4C-alkylamino radical is bonded. An example which may be mentioned is the dimethylaminoethyl radical.

A preferred halogenomethyl radical is the chloromethyl radical.

A preferred di-1-4C-alkylaminomethyl radical is the diethylaminomethyl radical.

Preferred possible salts for compounds of the formula I are all the acid addition salts. Salts which may be mentioned in particular are the pharmacologically tolerated salts of the inorganic and organic acids usually used In galenics. Salts which are not pharmacologically tolerated and may initially be obtained, for example, as process products during preparation of the compounds according to the invention on an industrial scale are converted into pharmacologically tolerated salts by processes which are known to the expert. Examples of such suitable salts are watersoluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosylate, 2-hydroxy-3-naphthoate, 3hydroxy-2-naphthoate or mesylate.

Salts which are furthermore also possible are, however, quaternary ammonium salts, which can be obtained by reaction of compounds of the formula I with suitable alkylating agents. Examples of suitable alkylating agents which may be mentioned are 1-4C-alkyl halides, preferably methyl iodide, or benzyl halides, such as benzyl bromide, or allyl halides, such as allyl bromide.

Compounds of the formula I which are worth mentioning are those wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, - 5 R4 represents OH (hydroxyl), 1-4C-alkoxy, mono- or polyhydroxy-2-4Calkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkoxy, NH£ (amino), (azido), 0-C0-R6 or NH-C0-R7, R5 represents furyl, phenyl, or phenyl which is substituted by a substituent from the group comprising halogen, 1-4C-alkyl and 1-4Calkoxy, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, mono- or di-1-4C-alkylamino-1-4C alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by a substituent from the group comprising halogen, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di-1-4Calkylaminomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, fluorine or chlorine, X represents 0 (oxygen), E1 represents -CH2- (methylene) or -CH2CH2- (1,2-ethylene), E2 represents -CH2- (methylene) or -CH2CH2- (1,2-ethylene) and n represents the number 0 or 1, and the salts of these compounds.

Compounds of the formula I which are to be singled out are those wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), mono- or polyhydroxy-2-4C-alkoxy, NH2 (amino), (azido), O-CO-R6 or NH-C0-R7, R5 represents phenyl, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, phenyl, or phenyl which is hx substituted*morpholinomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, X represents 0 (oxygen), E1 represents -CH2- (methylene) or -CH2CH2- (1,2-ethylene), E2 represents -CH2- (methylene) or -CH2CH2- (1,2-ethylene) and n represents the number 0, and the salts of these compounds. - 6 Compounds of the formula I which are to be singled out in particular are those wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), polyhydroxy-3-4C-alkoxy, NH2 (amino), (azido), 0-C0-R6 or NH-C0-R7, R5 represents phenyl, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, or phenyl which is substituted by morpholinomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, X represents 0 (oxygen), E1 represents -CH2- (methylene), E2 represents -CH2- (methylene) or -CH2CH2- (1,2-ethylene) and n represents the number 0, and the salts of these compounds.

One or more chirality centres may be present in the compounds I, depending on the nature of the substituents. The invention relates to all the enantiomers and diastereomers, as well as mixtures and racemates thereof.

Examples of compounds according to the invention are summarized in the following Table 1: •Ε 911406 -7CM <χ co Q£ c o o o o O O O O O O O O —1 PM PM PM PM PM PM PM PM PM Psi PM X x x X X X X X X X X X LJ X CM lj lj o LJ LJ LJ LJ LJ LJ LJ LJ LJ LU 1 f 1 1 » ί 1 ί 1 1 I X I CM CM CM CM CM CM CM CM CM CM rr LJ CM CM PM Psi PM PM PJ PM Psi Psi PM Psi PM PM LU x 3: 3: 3: 3: 3: X 3: X X X X X o lj o lj LJ LJ LJ LJ LJ LJ LJ LJ LJ X o o o o o o o o X o o o o Z Lu 00 X x X x X x X X X X X X £X rr 0£ 1 1 1 1 1 Pl X LJ Pl PM 1 Psi X r— X M-J pi LJ pi >> >1 / \ LU X PM X -σ “O Ό ( J z to lj X lj •r~ • r— • r- 1 Pl Pl Pl Pl Pl OS PM lj S- ί- L z PM X X X X X x PM z >s >1 >1 X LJ LJ LJ LJ tj lj X Q- CL Cl Psi LJ LJ r>4 I x Λ X CM cn rr LJ O C_5 I?I Y Y tn XZ x: _C j= _c -C _C x: -C. X -C -C az Ol CL CL CL CL Q. o. CL CL CL· Q. Q_ o. CO to tO to Ό to to to to to to to to or (X cc C£ cc CC cx az az az az oz az rf o o o o o o c o σ o o o a oz o o c_> LJ LJ LJ LJ LJ LJ LJ LJ LJ LJ o o o o o o O o o O O o o pi n pi P-l Pl PI Pl Pl Pl n Pl Pl Pl cn X X X X X X X X X X X X X £X lj LJ o LJ LJ LJ LJ LJ LJ LJ LJ LJ O CM n n M ΓΗ pi pi Pl Pl Pl Pl Pl Pl Pl Q£ x X X X X X X X X X X X X lj LJ o LJ LJ LJ LJ LJ LJ LJ LJ LJ LJ tn tn tn tn tn tn tn tn tn un tn tn tn ce QC oz az oc CC oc CL CL (X oz oz oz PM PM PM Psi PM Psi PM psi Psi PM Psi PM PM oz x x X X 3: 3: X X X X X X X lj lj lj LJ LJ LJ LJ LJ LJ LJ LJ LJ LJ -8Ό Φ •Η +J β ο ϋ φ ι—I Λ (ΰ £< C o o o o o o o o o o o o o o o o o o o o o o σ CJ CJ CJ CJ CJ CJ X X X X X X Cl CJ CJ Cl CJ CJ CJ CJ CJ CJ CJ CJ CJ Cl ca ca ca CJ ra CJ ca CJ CJ ru a: x X X X X Cl X CJ CJ CJ CJ CJ X X X X X X X X X X X CM cj CJ CJ CJ CJ CJ X CJ X X X X X CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ LU 1 CJ CJ CJ CJ CJ CJ I 1 1 CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM cj CJ ra CJ ca ra CJ CJ ra CJ CJ CJ ra CJ CJ ra ca ra ra ra ca ca ra LU X X X X X X X X X X X X X X X X X X X X X X X X cj CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ cj CJ CJ CJ CJ CJ CJ CJ CJ X o o o o o o o o o o o o o o o o o o o o o o o o Lu LU c_> Lu o co x X X X X X X X X X X X X X X X X X X cc r** cc 11 1 ci X CJ CJ r— CJ n a—> >1 o X Cl o CJ Lui F— o CJ X z \ 1 X o CJ o o ca N IO CJ o \ / Cl Cl Cl Cl X ra rc OC 1 X CJ X X X X X X CJ X -σ CJ CJ CJ <_) o CJ CJ X ca CJ loi X ε X CJ X X Y ιοι CJ CJ CJ Y ,Λ, o Y in X X X X X X X X X X X X X X X X X >1 >, X X X O£ Q_ a. CL a. x X a. CL Cl. x CL x o. X Cl CL Q_ i- 1 CL CL Cl 3 3 Lu Lu X n ri o X X CJ CJ X o o CJ X o ci ci IO lO IO io IO IO io IO IO IO X CJ o X X X Qi Oi Oi Oi Oi oi Oi Qi oi Qi Qi CJ X X CJ CJ CJ 1 CC 1 CJ X CJ X X o o o o X X o o X o X o O o o o CJ CJ CJ o o o o CJ CJ CJ CJ o o CJ CJ o CJ o CJ CJ CJ CJ o σ CJ X o o o o o o o o o o o CJ o o Cl n n n n Cl Cl CJ Cl Cl Cl Cl Cl Cl Cl n Cl Cl Cl Cl CO X X X X X X X X X X X X X X X X X X X X X X X X cc CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CM ci ci n Cl n ci ci Cl Cl Cl Cl n Cl Cl Cl Cl Cl Cl ci Cl Cl cc X X X X X X X X X X X X X X X X X X X X X X X X CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ >> in in in m in in in in in in in in in in in in in in in -M -U> in in in X cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc ex X X 3 X X Qi ^“1 CJ Cl CJ Cl Cl CJ CJ CJ ot JM ru CJ ru ru ra CJ ra CO CO CJ CJ ca CC X X X X X X X X X X X X X X X X X X X X X X CJ CJ CJ o CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ CJ o o CJ CJ CJ ♦C“ -9Table 1 (continued) c o O o o o o o o o o o o o o fM IM IM IM fM IM X X X m ra fM IM IM IM IM IM X X X u> o o X X X X X X X X UJ MJ M3 C\J im fM IM o UJ uj MJ UJ UJ UJ C_3 IM IM IM UJ x X X 1 I 1 I 1 I 1 I X X X uj UJ u> CM CM CM CM CM CM CM CM UJ UJ U) CM CM CM CM CM CM IM IM IM fM IM fM fM IM IM IM fM fM fM UJ x X X X X X X X X X X X X X uj u u uj uj uj U) UJ u> UJ MJ UJ UJ UJ X o o o o o o o O o O o o o o 00 x X X X X X X X X X X X X X OC r** Q£ 1 1 1 t ί 1 1 1 d X X X IM uj IM o o u X X uj IM X X IM / \ X IM IM o ( 1 fM U> o C3 l£> X u \ / X X IM UJ UJ EX (M 1 X IM uj X I 1 1 1 1 o fM o fM UJ fM fM uj X IM UJ X fM X X 1 o X 1 uj X UJ UJ fM IM uj IM IM u> IM fM X X X X X fM X X uj uj IO uj uj X U) UJ Y u >> in _c X -C _c .c. -C u _c JC .C -C JZ JC ex Q- CL Cl CL CL Q. 3 o. CL o. CL CL CL U_ X X o X X o 1 X X ID M3 M3 lO M3 lO lO M3 IM o o IM © © (X CC ex OC CC CC cc ae X fM IM X IM IM I 1 UJ X X MJ X X Tf o o o o o o CJ o IM UJ UJ IM U) U) ex uj u> uj uj UJ UJ MJ X X X X X X ωχ x 1 t UJ l/KO—O «< j—<*> MJ (/1 MJ—O •C J—-CT) o o o o o o o o fM EX CM fM CC IM o X X o X X UJ UJ MJ UJ o o O O d d d d d d d d d d d d co X X X X X X X X X X X X X X Q£ UJ uj uj UJ UJ U) UJ UJ UJ MJ UJ UJ UJ UJ CM M d d d d d d d d d d d d d EX X X X X X X X X X X X X X X uj u u uj o UJ UJ o u> UJ UJ UJ UJ UJ >) LD tn in in in in in +J in in in in m in Qi CC cc CC cc QC oc Z3 cc cc O£ cc cc cc fM fM fM fM fM fM fM CO fM fM IM IM IM IM ae X X X X X X X X X X X X X U u uj UJ U> UJ UJ o UJ UJ UJ UJ u> UJ in The invention furthermore relates to a process for the preparation of the compounds according to the invention and their salts. The process is characterized in that a) pyrrolo-pyridazines of the formula II wherein R1, R2, R3 and n have the abovementioned meanings and Y represents a suitable leaving group (in particular chlorine or bromine), are reacted with phenyl compounds of the formula III wherein R4, R8, X, E1 and E2 have the abovementioned meanings, or in that b) to prepare compounds I in which R4 represents 0-C0-R6 and R6 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, carboxy-1-4C-alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di—1— 4C-alkylaminomethyl, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with carboxylic acids (or their derivatives) of the formula IV R6—CO—Ζ (IV) wherein R6 has the abovementioned meanings and Z represents OH (hydroxyl) or a suitable leaving group, or in that c) to prepare compounds I in which R4 denotes 0-C0-R6 and R6 denotes 14C-alkylamino or phenylamino, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with isocyanates of the formula V R6'—N=C=O (V) wherein R6’ denotes 1-4C-alkyl or phenyl, or in that d) to prepare compounds I in which R4 denotes NH-C0-R7 and R7 denotes 14C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl-1-4Calkyl, compounds of the formula I in which R4 denotes NH2 (amino) are reacted with carboxylic acid derivatives of the formula VI R7—CO—Z (VI) wherein R7 has the abovementioned meanings and Z represents a suitable leaving group, or in that e) to prepare compounds I in which R4 denotes Ng (azido), compounds of the formula I wherein R4 denotes OH (hydroxyl) are reacted with methanesulphonyl chloride, and the mesyloxy compound formed is then reacted with an alkali metal azide, or in that f) to prepare compounds I wherein n denotes the number 1, compounds of the formula I wherein n denotes the number 0 are oxidized, or in that g) to prepare compounds I in which R4 denotes mono- or polyhydroxy-2-4Calkoxy, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with alcohol derivatives of the formula VII CmH(2m+l-p)(θκ')p~CH2-Y' (VII) wherein m represents an integer from 1 to 3» P represents an integer from 1 to 3, R’ represents a protective group and Y’ represents a suitable leaving group, and the protective group(s) R’ is/are then split off, and in that, if desired, the compounds I obtained according to a), b), c), d), e), f) or g) are then converted into their salts, or in that, if desired, the compounds I are then liberated from the resulting salts of the - 12 compounds I.

The reaction of the pyrrolo-pyridazines II with the compounds III is carried out (depending on the nature of the compound II) in an anhydrous, inert solvent or without further addition of solvent, using an excess of the compound III as the solvent. Possible anhydrous, inert solvents are, in particular, aprotic, polar solvents, such as e.g. dimethylsulphoxide, tetrahydrofuran, dioxane, dimethylformamide or N-methylpyrrolidone.

Suitable leaving groups Y which may be mentioned are, in particular, halogen atoms, it being possible for the compounds II to be obtained in the manner described below.

Depending on the nature of the compounds III, their reaction with the pyrrolo-pyridazines II requires the presence of an auxiliary base or an excess of the compound III. Possible auxiliary bases are, for example, organic amines (such as triethylamine or diisopropylamine), alkali metal carbonates (such as sodium carbonate or potassium carbonate) or alkali metal hydroxides (such as sodium hydroxide or potassium hydroxide), but preferably those compounds which are capable of deprotonating the compounds III smoothly. Metal hydrides (e.g. sodium hydride) or alkali metals (e.g. sodium) may be mentioned in particular here, these being either employed for deprotonation of the compounds III before the reaction with II or added to the reaction mixture of II and III. In a preferred process variant, the deprotonation can also be carried out by means of an alkali metal alcoholate, such as, for example, potassium tert.-butylate, in the presence of a crown ether, such as, for example, 18-crown-6.

The reaction temperature is between 0° and 150°C - depending on the reactivity of the compound III or its salts with bases - temperatures between 0°C and 50°C being adequate in the case of a higher reactivity, but higher temperatures being necessary in the case of a lower reactivity, in which case the boiling point of the solvent used or the excess compound III used as the solvent is preferred.

The reaction of the compounds I where R4 = OH with the carboxylic acids (or their derivatives) IV according to process variant b) is carried out in a manner which is known per se, such as is known to the expert on the basis of his technical knowledge of esterification reactions. The esterification is carried out in inert solvents, such as, for example, dioxane or tetrahydrofuran, and, depending on the nature of the group Z, either in the presence of a dehydrating agent or an agent which bonds water chemically, such as, for example, dicyclohexylcarbodiimide (if Z = OH), or in the presence of an auxiliary base (e.g. triethylamine), if Z represents a leaving group, for example a halogen atom (in particular chlorine). If R6 represents a carboxy-1-4C-alkyl radical, the leaving group Z employed is preferably an alkoxycarbonyloxy radical (mixed anhydride), in particular the isobutoxycarbonyloxy radical, without further addition of an auxiliary base or a dehydrating agent.

The reaction of the isocyanates V according to process variant c) is carried out in a manner which is known per se in inert, anhydrous solvents, such as, for example, toluene.

The reaction according to process variant d) is carried out in a manner which is known per se, such as is known to the expert for the preparation of amides from reactive carboxylic acid derivatives and amines. If an excess of the compound I is not used, the reaction is preferably carried out in the presence of an auxiliary base (such as triethylamine) in a suitable inert solvent (e.g. tetrahydrofuran).

The introduction of the azido radical according to process variant e) is likewise carried out in a manner which is known per se, and the mesyloxy compound intermediately formed does not need to be isolated, but rather can be further processed by direct reaction with the alkali metal azide (for example sodium azide) to give the desired azide.

The N-oxidation according to process variant f) is carried out under reaction conditions such as are familiar per se to the expert. The Noxidation is preferably carried out with the aid of m-chloroperoxybenzoic acid in methylene chloride at room temperature.

The etherification according to process variant g) is carried out in a manner which is known per se, for example in accordance with the Williamson ether synthesis, a preferred suitable leaving group Y* being the toluenesulphonate group. The protective groups R’ used depend on the nature of the (poly)hydroxyalkyl radical. Thus, for example, 1,2-diols can - 14 be protected by conversion into their acetonides, and other OH groups by silylation (e.g. with trimethylchlorosilane), or in another manner familiar to the expert, and the protection removed again.

The pyrrolo-pyridazines of the formula II are accessible from corresponding hydroxypyridazines VII for example by halogenation.

The halogenation of the hydroxypyridazines (= pyridazinones) VII is carried out in the presence of suitable solvents, or preferably without a solvent. Possible suitable solvents are only anhydrous solvents, such as e.g. openchain or cyclic ethers (diethyl ether, diethylene glycol dimethyl ether, dioxane or tetrahydrofuran), or (aromatic) hydrocarbons, such as e.g. cyclohexane, benzene or toluene, which are inert towards the halogenating agent. Possible halogenating agents are all the known reagents which split off halogen, in particular those compounds which are suitable for use on an industrial scale. Examples which may be mentioned are phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide, phosphorus oxytrichloride or phosphorus oxytribromide.

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

The hydroxypyridazines VII (= pyridazinones) are prepared by reacting pyrroles of the formula VIII - 15 OHC R3 (VIII) Z'-OC R2 wherein R1, R2 and R3 have the abovementioned meaning and Z* represents a suitable leaving group, with hydrazine.

The reaction of the pyrroles VIII with hydrazine is advantageously carried out in inert polar, aqueous or preferably anhydrous solvents, e.g. in alcohols, such as methanol or ethanol, or in dimethylsulphoxide, dimethylforrnamide 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 Z* 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 Z’ is, for example, the alkoxy radical, in particular the ethoxy or methoxy radical.

The compounds VIII, in which R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, are prepared by reacting correspondingly substituted compounds VIII in which R1 represents hydrogen with halogen compounds of the formula IX Rl-Z (IX) wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5 and Z” represents halogen (chlorine, bromine or iodine), in a suitable manner.

The reaction of VIII (where R1 = hydrogen) with IX is carried out under basic conditions in the presence of a phase transfer catalyst. Catalysts which may be mentioned are, in addition to onium salts, such as e.g. tetrabutylammonium chloride, above all crown ethers, such as dibenzo-18'c »11406 - 16 crown-6, dicyclohexyl-18-crown-6 and in particular 18-crown-6.

Possible bases which are employed and are used at least in a molar ratio, preferably in excess, are above all alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) or alkali metal alcoholates (e.g. sodium ethylate or potassium tert.-butylate). If an anhydrous solvent is used, the hydroxides or alcoholates used are preferably employed in finely powdered form.

The reaction is carried out (depending on the nature of the phase transfer catalyst and the base employed) in aqueous or in particular anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or scarcely miscible with water. Water/solvent mixtures which may be mentioned are, for example, the mixtures of water with chloroform, methylene chloride or benzene. Aqueous or anhydrous solvents which may be mentioned are, for example, methylene chloride, tetrahydrofuran or xylene.

The choice of reaction temperature during the reaction of VIII with IX depends on the other reaction conditions, temperatures between 20°C and the boiling point of the solvent employed as a rule being preferred.

The compounds of the formula VIII in which R1 denotes hydrogen are known or can be prepared by processes analogous to known processes [e.g. P. J. Crook et al., Liebigs Ann. Chem. 748 (197Ό 26—373The following examples illustrate the invention in more detail without limiting it. The invention preferably relates to the new compounds mentioned by name in the examples and the salts of these compounds. M.p. denotes melting point, and the abbreviation h is used for hour(s) and the abbreviation min for minutes. Ether is understood as meaning diethyl ether.

,E 911406 - 17 EXAMPLES End products a. 1-Benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3-d]pyridazine g (72 mmol) potassium tert.-butylate and 0.8 g (3 mmol) 18-crown-6 (98%) are added in succession to a solution of 10 g (72 mmol) 2-(hydroxymethyl)benzyl alcohol in 200 ml anhydrous N-methylpyrrolidone. This mixture is stirred at room temperature for 2.5 h. A solution of 7.8 g (28.8 mmol) 1benzyl-7-chloro-2,3-dimethyl-pyrrolo[2,3-d]pyridazine in 90 ml anhydrous Nmethylpyrrolidone is then added dropwise in the course of 30 min. The mixture is stirred at room temperature for a further 2.5 h, 800 ml icewater are then added and the mixture is extracted with 3 x 400 ml ethyl acetate. The organic extracts are washed with 2 x 250 ml water and then dried over magnesium sulphate. After concentration, the residue which remains is chromatographed on silica gel (mobile phase: ethyl acetate). After concentration and crystallization from ethyl acetate, 5.6 g (52%) of the title compound are isolated. M.p. 167-169°C.

The following are prepared in an analogous manner: lb. 1-Benzyl-2,3-dimethyl-7-[3-(hydroxymethyl)-benzyloxy]-pyrrolo[ 2,3-d 3pyridazine 6.2 g 3-(hydroxymethyl)-benzyl alcohol, 250 ml N-methylpyrrolidone, 5.0 g potassium tert.-butylate, 0.4 g 18-crown-6 and 4.0 g 1-benzyl-7-chloro-2,3dimethyl-pyrrolo[2,3-d]pyridazine are reacted at room temperature for 16 h. Purification as in Example 1a. Yield: 45%, m.p. 150-152°C. lc. 1-Benzyl-2,3-dimethyl-7-[ 4-(hydroxymethyl)-benzyloxy]-pyrrolo[ 2,3-d]pyridazine 4.5 g 4-(hydroxymethyl)-benzyl alcohol, 150 ml N-methylpyrrolidone, 3.7 g potassium tert.-butylate, 0.3 g 18-crown-6 and 3.0 g 1-benzyl-7-chloro-2,3dimethyl-pyrrolo[2,3-d]pyridazine are reacted at room temperature for 16 h.

Purification as in Example 1a. Yield: 31%, m.p. 146-147°C. - 18 ld. 7-[2-(Hydroxymethyl)-benzyloxy]-1,2,3-trimethyl-pyrrolo[2,3-d]pyridazine 2.49 g 2-(hydroxymethyl)-benzyl alcohol, 150 ml N-methylpyrrolidone, 2.02 g potassium tert.-butylate, 0.2 g 18-crown-6 and 1.37 g 7-chloro-1,2,3trimethyl-pyrrolo[2,3-d]pyridazine are reacted at room temperature for 3 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate/methanol = 10:1) and then recrystallized from diisopropyl ether. Yield: 33%, m.p. 155-158°C. le. 7-(2-(Aminomethyl )-benzyloxy]-1-benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazine dihydrochloride 0.63 g 2-(arainomethyl)-benzyl alcohol hydrochloride, 10 ml Nmethylpyrrolidone, 0.8 g potassium tert.-butylate, 0.05 g 18-crown-6 and 0.5 g 1-benzyl-7-chloro-2,3-dimethyl-pyrrolo[2,3-dJpyridazine are reacted at room temperature for 5 h. The oil obtained after extraction and concentration is taken up in 5 ml methanol, the mixture is diluted with 25 ml ether and two equivalents of ethereal hydrochloric acid are then added. After crystallization overnight, the crystals are filtered off and rinsed with ether. Yield 51%, m.p. 178°C (decomp.). f. 1-Benzyl-2,3-di methyl-7-[ 2-(2-hydr oxyethyl)-benzyloxy]-pyrrolo[ 2,3-d]pyridazine and 1g. 1-Benzyl-2,3-dimethyl-7-[2-(2-hydroxyethyl)-phenylethoxy]-pyrrolo[2,3-d]pyridazine 3.71 g 2-(2-hydroxyethyl)-benzyl alcohol, 100 ml anhydrous tetrahydrofuran, 2.81 g potassium tert.-butylate, 0.18 g 18-crown-6 and 2.2 g 1-benzyl-7chloro-2,3-dimethyl-pyrrolo[2,3-d]pyridazine are reacted at room temperature for 16 h. Working up is carried out as in Example 1a. To separat the two title compounds 1f and 1g, the product is chromatographed on silica gel (mobile phase: ethyl acetate). After concentration of the fractions of Rf = 0.15 and recrystallization from cyclohexane, compound 1g of m.p. 168-173°c is obtained. Product 1f of m.p. 130-133°^ is obtained in the same manner from the fractions of Rf = 0.10. - 19 2a. 7-[ 2-(Acetoxymethyl)-benzyloxy]-1-benzyl-2,3-dimethyl-pyrroloC 2,3-d]pyridazine 345 μΐ glacial acetic acid are added to a solution of 750 mg (2 mmol) 1benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3-d]pyridazine and 1.25 g (6 mmol) dicyclohexylcarbodiimide in 60 ml anhydrous tetrahydrofuran at 35°C, and the mixture is stirred at room temperature for 18 h. 60 ml water are then added. The solution is brought to pH 9 and then concentrated to 50 ml. The precipitate is filtered off and extracted by stirring in 50 ml ethyl acetate for 30 min. After renewed filtration, the mother liquor is concentrated and the residue is chromatographed on silica gel (mobile phase: ethyl acetate). The fractions of Rf = 0.3 are concentrated and then recrystallized from diisopropyl ether. Yield 80?, m.p. 111-114°C.

The following are prepared in an analogous manner: 2b. Methyl 2-[( 1-benzyl-2,3-dimethyl-pyrroloi 2,3-d ]pyridazin-7-yl )oxymethyll-phenylmethyl malonate 375 mg 1-benzyl-2,3-dimethyl-7-[ 2-(hydroxymethyl)-benzyloxy]-pyrrolo[ 2,3djpyridazine, 630 mg dicyclohexylcarbodiimide, 360 mg malonic acid monomethyl ester and 40 ml tetrahydrofuran are reacted at room temperature for 18 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate). Yield: 80?, colourless oil. 2c. Methyl 2-C(1-benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazin-7-yl)oxymethyll-phenylmethyl succinate 505 mg 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3dlpyridazine, 845 mg dicyclohexylcarbodiimide, 565 mg succinic acid monomethyl ester and 60 ml tetrahydrofuran are reacted at room temperature for 18 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate/methanol = 10:1). Yield: 44?, colourless oil. - 20 2d. 2-[(1-Benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazin-7-yl)-oxymethyl]phenylmethyl 4-(1-morpholinomethyl)-benzoate 410 mg 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3dlpyridazine, 930 mg dicyclohexylcarbodiimide, 730 mg 4-(1morpholinomethyl)-benzoic acid and 60 ml tetrahydrofuran are reacted at room temperature for 18 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate/methanol = :1). Yield 38%, colourless oil. The entire yield is dissolved in 3.5 ml boiling ethanol, and a solution of 80 mg citric acid in 1 ml hot ethanol is added. After cooling and filtration, the citric acid salt (citrate) of the title compound is isolated. Yield: 80%, m.p. 156-158°C (decomp.). 2e. 7-[2-(Propionyloxymethyl)-benzyloxy]-1-benzyl-2t3-dimethyl-pyrrolo[2,3-d3-pyridazine 560 mg 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3dlpyridazine, 1.06 g dicyclohexylcarbodiimide, 450 mg propionic acid and 50 ml tetrahydrofuran are reacted at room temperature for 24 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate). The fractions of Rf = 0.4 are concentrated and the residue is then crystallized by stirring in cyclohexane. Yield: 81%, m.p. 118121°C. 2f. 7-[2-(Butyryloxymethyl)-benzyloxy]-1-benzyl-2,3-dimethyl-pyrrolo[2,3d]pyridazine 560 mg 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3d]pyridazine, 1.17 g dicyclohexylcarbodiimide, 600 mg butyric acid and 50 ml tetrahydrofuran are reacted at room temperature for 24 h. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate). The fractions of Rf = 0.4 are concentrated and the residue is then crystallized by stirring in ethyl acetate and cyclohexane. Yield: 57%, m.p. 109-111oCe 2g. Succinic acid mono{[2-(1-benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazin7-yl)-oxymethyl]-phenylmethyl ester} A solution of 510 mg N-methylmorpholine in 10 ml methylene chloride is added to a suspension of 1.19 g succinic acid in 40 ml anhydrous methylene chloride at -10°C, and the mixture is stirred for 1 h. A solution of 690 mg isobutyl chloroformate in 10 ml methylene chloride is then added dropwise, and the mixture is then stirred again at -10°C for 1 h. A solution of 1.5 g 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]pyrrolo[2,3-d]dyridazine in 40 ml methylene chloride is subsequently added dropwise in the course of 30 min. The mixture is stirred first at -10°C for a further 1 h and then at room temperature for 96 h. Thereafter, the reaction mixture is extracted with 3 x 100 ml water. The organic extracts are dried over magnesium sulphate and concentrated. For purification, the mixture is chromatographed on silica gel (mobile phase: ethyl acetate/methanol 10:1). The fractions of Rf = 0.1 are concentrated and the residue is crystallized from diisopropyl ether/ethyl acetate. Yield: 58%, m.p. 169°C (decomp.). a. 1-Benzyl-2,3-dimethyl-7-[ 2-(N-methylcar bamoyloxymethyl )-benzyloxy]pyrrolo[2,3-d]pyridazine pi (0.58 mmol) methyl isocyanate are added to a solution of 200 mg (0.53 mmol) 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3-d]pyridazine in 10 ml anhydrous toluene at 50°C, and the mixture is then stirred at 50°C for 2 h. After concentration, the residue is crystallized from ethyl acetate/diisopropyl ether. Yield: 85%, m.p. 136-138°C. b. 1 -Benzyl-2,3-dimethyl-7-C 2-(N-phenylcar bamoyloxymethyl )-benzyloxy ]pyrrolo[2,3-d]pyridazine 160 pi (1.5 mmol) phenyl isocyanate are added to a solution of 500 mg (1.33 mmol) 1-benzyl-2,3-dimethyl-7-[2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3-d]pyridazine in 25 ml anhydrous toluene at 50oc> and the mixture is then stirred at 50°C for 2 h. After concentration, the residue is crystallized from ethyl acetate. Yield: 61%, m.p. 175-176°C. - 22 4. N-(2-((1-Benzyl-2,3-dimethyl-pyrrolo[2,3-d3pyridazin-7-yl)-oxymethyl]phenylmethyl}-acetamide A solution of 0.1 ml (1.4 mmol) acetyl chloride in 5 ml anhydrous tetrahydrofuran is added dropwise to a solution of 0.5 g (1.3 mmol) 7-(2(aminomethyl)-benzyloxy3-1-benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazine dihydrochloride and 0.44 ml (3.2 mmol) triethylamine in 10 ml anhydrous tetrahydrofuran at 0°C. The mixture is then stirred at 0°C for a further 15 min, 50 ml water are added and the mixture is extracted with 2 x 50 ml ethyl acetate. The organic extracts are washed with 50 ml water, dried with magnesium sulphate and concentrated. The residue is crystallized from ethyl acetate. Yield: 62%, m.p. 159-161°C. . 7-[2-(Azidomethyl)-benzyloxy3-1-benzyl-2,3-dimethyl-pyrrolo( 2,3-d 3pyridazine A solution of 75 pi methanesulphonyl chloride (0.96 mmol) in 2 ml anhydrous N-methylpyrrolidone is added dropwise to a solution of 0.3 g (0.8 mmol) 1benzyl-2,3-dimethy1-7-[2-(hydroxymethyl)-benzyloxy3-pyrrolo[2,3-d3pyridazine and 0.23 ml (1.6 mmol) triethylamine in 5 ml anhydrous Nmethylpyrrolidone at 0°C. The mixture is stirred at 0°C for a further 10 min, and 63 mg (0.96 mmol) sodium azide and 20 mg 18-crown-6 are then added. After a further hour at 0°C, water (10 ml) is added and the mixture Is then extracted with 2 x 10 ml ethyl acetate. The organic extracts are washed with 10 ml water, dried over magnesium sulphate and concentrated.

The residue is chromatographed on silica gel (mobile phase: ethyl acetate). The fractions of Rf = 0.5 are concentrated and then crystallized from ethyl acetate/diisopropyl ether. Yield 33%, m.p. 120-121°C. 6a. (2R)-1 -0-{ [2-(1-benzyl-2,3-dimethyl-pyrrolo[ 2,3-d] pyridazin-7-yl)oxymethyl3-phenylmethyl}-2,3-0-isopropylidene-glycerol 280 mg sodium hydride are added to a solution of 1.5 g 1-benzyl-2,3dimethyl-7-(2-(hydroxymethyl)-benzyloxy]-pyrrolo[2,3-d3pyridazine in 100 ml anhydrous dimethylformamide, and the mixture is then stirred at room temperature for 2 h. After dropwise addition of a solution of 2.31 g R2,3-0-isopropylidene-glycerol 1-toluenesulphonate in 15 ml dimethylformamide, the mixture is stirred at room temperature for 96 h. - 23 While cooling (0°C), 150 ml water are then added and the mixture is extracted with 3 x 150 ml ethyl acetate. The organic extracts are washed with 150 ml water, dried over magnesium sulphate and concentrated. For purification, the product is chromatographed on silica gel (mobile phase: ethyl acetate). The fractions of Rf = 0.2 are concentrated.

Crystallization gives the title compound of m.p. 116-122°C [oc]p2 = +8° (c 1, chloroform). «r 6b. (2R)-1 -0-{ [2-(1-benzyl-2,3-dimethyl-pyrrolo[ 2,3-d ]pyridazin-7-yl )oxymethyl]phenylmethyl}-glycerol ml 6 N hydrochloric acid are added to a solution of 490 mg (2R)—1—0—{[2 (1-benzyl-2,3-dimethyl-pyrrolo[2,3-d]pyridazin-7-yl)oxymethyl]phenylmethyl}-2,3-0-isopropylidene-glycerol in 12 ml ethanol, and the mixture is stirred at room temperature for 1 h.

The mixture is then diluted with 50 ml water, brought to pH 9 with saturated sodium carbonate solution and extracted with 3 x 80 ml ethyl acetate. The organic extracts are washed with 100 ml water, dried over magnesium sulphate and concentrated. For purification, the product is chromatographed over silica gel (mobile phase: ethyl acetate/methanol 10:1). The fractions of Rf = 0.15 are concentrated and crystallized from cyclohexane. Yield: 65?, m.p. 127-131°C, [β<]θ2 = +13° (c = 1, chloroform) - 24 STARTING COMPOUNDS Aa. Methyl 3-formyl-1,4,5-trimethyl-pyrrole-2-carboxylate 14.6 g potassium tert.-butylate and 24.0 g methyl 3-formyl-4,5dimethylpyrrole-2-carboxylate are added to a solution of 2.8 g 18-crown-6 in 500 ml anhydrous tetrahydrofuran at room temperature. The suspension is stirred at room temperature for 15 min, and a solution of 18.5 g methyl iodide in 100 ml anhydrous tetrahydrofuran is then added dropwise in the course of 30 min. The suspension is stirred at room temperature for 20 h. The reaction mixture is poured onto 500 ml water and extracted with 3 x 300 ml methylene chloride. After drying over sodium sulphate, the extract is concentrated to give 30 g brown crystals, which are purified on silica gel (mobile phase: petroleum ether/ethyl acetate = 7:3). After concentration, 20.9 g (81%) of the title compound are obtained as colourless crystals of m.p. 88-9O°C.

The following compound is prepared in an analogous manner: Ab. Methyl 1-benzyl-3-formyl-4,5-dimethyl-pyrrole-2-carboxylate 0.98 g 18-crown-6, 4.96 g potassium tert.-butylate, 8.00 g methyl 3-formyl4,5-dimethyl-pyrrole-2-carboxylate and 7.80 g benzyl bromide are reacted in 400 ml anhydrous tetrahydrofuran and the mixture is worked up. For purification, the crude product is chromatographed on silica gel (mobile phase: toluene/ethyl acetate = 2:1). After the fractions of Rf = 0.65 have been combined and concentrated, 10.9 g (91%) of the title compound are obtained as a pale yellow oil, which crystallizes only partly.

Ba. 1,2,3-Trimethyl-6,7-dihydro-pyrrolo[2,3-d]pyridazin-7-one .2 g hydrazine hydrate (about 100%) are added dropwise to a suspension of 20.0 g methyl 3-formyl-1,4,5-trimethyl-pyrrole-2-carboxylate in 150 ml glacial acetic acid at room temperature in the course of 10 min. The mixture is then heated under reflux for 1 h and the clear solution is poured onto 400 ml ice-water. A pale precipitate thereby separates out, and is filtered off with suction and rinsed with about 100 ml water. After drying over potassium hydroxide at 40°C, 16.45 g (93%) of the title - 25 compound of m.p. 3O3-3O5°C are obtained.

The following compound is prepared in an analogous manner: Bb. 1-Benzyl-2,3-dimethyl-6,7-dihydro-pyrrolo[2,3-d]pyridazin-7-one 12.0 g methyl 1-benzyl-3-formyl-4,5-dimethyl-pyrrole-2-carboxylate and 2.2 g hydrazine hydrate (about 100%) are reacted in 150 ml glacial acetic acid and the mixture is worked up. 10.0 g (89%) of the title compound of m.p. 246-248°C are isolated in this manner.

C. 7-Chloro-1,2,3-trimethyl-pyrrolo[2,3-d]pyridazine A suspension of 16.0 g 1,2,3-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 poured onto 400 ml ice-water and the pH is brought to 5.5 with 10 N sodium hydroxide solution. The precipitate which thereby separates out is filtered off with suction, washed with 200 ml water and dried at 50°C over potassium hydroxide. For purification, the crude product (19 g) is dissolved in 500 ml 2 N hydrochloric acid and the solution is extracted with 3 x 200 ml methylene chloride. The aqueous phase is then brought to pH 5.5 with 10 N sodium hydroxide solution, whereupon a white precipitate forms, which is filtered off with suction, washed with 100 ml water and dried over potassium hydroxide. 14.6 g (83%) of the title compound of m.p. 162°C are isolated.

D. 1-Benzyl-7-chloro-2,3-dimethyl-pyrrolo[2,3-d]pyridazine A suspension of 9.5 g 1-benzyl-2,3-dimethyl-6,7-dihydro-pyrrolo[2,3-d]pyridazin-7-one in 100 ml phosphorus oxychloride is heated under reflux for 2 h. The clear solution is then poured carefully onto 300 ml ice-water, the pH is brought to 8.5 with 10 N sodium hydroxide solution and the mixture is extracted with 3 x 200 ml methylene chloride. After the combined organic extracts have been dried over sodium sulphate and concentrated, 13 g crude product are obtained as a brown oil. After addition of ethyl acetate, the oil crystallizes spontaneously, and after recrystallization from ethyl acetate 7.5 g (74%) of the title compound of m.p. 125-127°C are isolated. - 26 Commercial usefulness The compounds of the formula I and their salts have useful pharmacological properties which render them commercially usable. In particular, they exhibit a pronounced inhibition of gastric acid secretion and an excellent protective action on the stomach and intestine in warm-blooded animals.

The compounds according to the invention are moreover distinguished by a high action selectivity, the absence of substantial side effects and a wide therapeutic range.

In this connection, protection of the stomach and intestine is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as e.g. ulcus ventriculi, ulcus duodeni, gastritis, irritable stomach of hyperacid or medicamentous origin), which can be caused, for example, by microorganisms, bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics), chemicals (e.g. ethanol), gastric acid or stress situations.

Surprisingly, the compounds according to the invention prove to be significantly superior in their excellent properties to the compounds known from the prior art in various models in which the antiulcerogenic and antisecretory properties are determined. On the basis of these properties, the compounds of the formula I and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary medicine, in which they are used, in particular, for the treatment and/or prophylaxis of ulcer conditions of the stomach and/or intestine.

The invention thus furthermore relates to the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.

The invention also relates to the use of the compounds according to the invention for the preparation of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.

The invention moreover relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned - 27 diseases.

The invention furthermore relates to medicaments which contain one or more compounds of the formula I and/or their pharmacologically tolerated salts.

The medicaments are prepared by processes which are known per se, with which the expert is familiar. The pharmacologically active compounds (= active compounds) according to the invention are employed as medicaments either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or excipients, in the form of tablets, coated tablets, capsules, suppositories, plasters (e.g. as TTS), emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95%.

The expert is familiar with what auxiliaries or excipients are suitable for the desired medicament formulations on the basis of his technical knowledge. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersing agents, emulsifiers, foam suppressants, flavour correctants, preservatives, solubilizing agents, dyestuffs or, in particular, permeation promotors and complexing agents (e.g. cyclodextrins).

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

In general, it has proved advantageous in human medicine to administer the active compound or compounds, in the case of oral administration, in a daily dose of about 0.01 to about 20, preferably 0.05 to 5 and in particular 0.1 to 1.5 mg/kg body weight, if appropriate in the form of several, preferably 1 to 4, individual doses, to achieve the desired result. In the case of parenteral treatment, similar or (especially for intravenous administration of the active compounds) as a rule lower dosages can be used. Any expert can easily determine the particular optimum dosage and mode of administration required for the active compounds on the basis of his technical knowledge.

If the compounds and/or salts according to the invention are to be employed - 28 for the treatment of the abovementioned diseases, the pharmaceutical formulations can also contain one or more pharmacologically active constituents from other groups of medicaments, such as antacids, for example aluminium hydroxide and magnesium aluminate; tranquillizers, such as benzodiazepines, for example diazepam; spasmolytics, such as e.g. bietamiverine and camylofin; anticholinergics, such as e.g. oxyphencyclimine and phencarbamide; local anaesthetics, such as e.g. tetracaine and procaine; and if appropriate also enzymes, vitamins or amino acids.

Combination of the compounds according to the invention with other drugs which inhibit acid secretion, such as, for example, I^-blockers (e.g. cimetidine or ranitidine), or furthermore with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine and zolenzepine), with the aim of intensifying the main action in the additive or superadditive sense and/or eliminating and reducing side effects, should be mentioned in particular. ΙΕ9114Ο6 Pharmacology The excellent protective action on the stomach and the inhibiting action on gastric secretion of the compounds according to the invention can be demonstrated in studies on animal experiment models. The compounds according to the invention investigated in the model described below have been given numbers which correspond to the numbers of these compounds in the examples.

Testing of the secretion-inhibiting action on the perfused rat stomach The influence of the compounds according to the invention following intravenous administration on pentagastrin-stimulated acid secretion by the perfused rat stomach in vivo is shown in the following Table 2.

Table 2 Maximum inhibition of acid secretion No. N Dose (%) approx. ED50 +) (pmol/kg) (number of (pmol/kg) i.v. animals) i.v. 1a 4 1.0 53 5 3.0 70 1.0 2 10.0 98 2a 4 1.0 31 4 2.0 71 1.5 4 3.0 71 3 10.0 95 5 4 1.0 43 4 3.0 78 1.3 4 10.0 95 +) ED50 = dose (interpolated) which causes a maximum inhibition of HCl secretion by 50%. - 30 IE 911406 Method After tracheotomy, the abdomen of anaesthetized rats (CD rat, female, 200 250 g; 1.5 g/kg i.m. urethane) was opened by a median abdominal incision, a PVC catheter was fixed transorally in the oesophagus and another catheter was fixed via the pylorus such that the tube ends just projected into the lumen of the stomach. The catheter from the pylorus led to the outside via a lateral opening in the right abdominal wall.

After thorough flushing (approx. 50 - 100 ml), warm physiological NaCl solution at 37°C was caused to flow through the stomach continuously (0.5 ml/min, pH 6.8 - 6.9; Braun-Unita I). The pH (pH-meter 632, glass electrode EA 147; 0=5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH up to pH 7 (Dosimat 655 Metrohm), the HCl secreted were determined in the portions of effluate collected at 15 min intervals (25 ml measuring cylinder).

The gastric secretion was stimulated by continuous infusion of 1 pg/kg (= 1.65 ml/h) i.v. pentagastrin (v. fem. sin.) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). The substances to be tested were administered intravenously (v. jugularis sin.) in 1 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.

The body temperature of the animals was kept constant at 37.8 - 38°C by infra-red irradiation and heated cushions (automatic, infinitely adjustable control via rectal temperature probes).

The maximum decrease in acid secretion (15 min fractions) of each treated group in comparison with that of the untreated control group (= 100%) served as a measure of the secretion-inhibiting action. The ED50 designates that dose which causes maximum inhibition of the HCl secretion by 50%.

Claims (14)

1. PATENT CLAIMS

1. Pyridazines of the formula I (I) wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by.R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), 1-4C-alkoxy, mono- or polyhydroxy-2-4Calkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkoxy, NH 2 (amino), N^ (azido), O-CO-R6 or NH-CO-R7, R5 represents furyl, thienyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl and 1-4C-alkoxy, R6 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, carboxy-1-4C-alkyl, amino, 1-4C-alkylamino, phenylamino, amino-1-4C-alkyl, mono- or di-1-4C-alkylamino-1-4C-alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di-1-4Calkylaminomethyl, R7 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, amino, 1-4C-alkylamino or phenylamino, R8 represents hydrogen, halogen or 1-4C-alkyl, X represents 0 (oxygen) or NH, E1 represents -CH 2 - (methylene), -CH 2 CH 2 - (1,2-ethylene) or -CH(CH^)(1,1-ethylene), - 32 E2 represents -CI^- (methylene), -CH2CH2- (1,2-ethylene) or -CHiCH^)(1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds.

2. Compounds of the formula I according to Claim 1, wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), 1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1—4C— alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkoxy, NH2 (amino), N (azido), 0-C0-R6 or NH-C0-R7, R5 represents furyl, thienyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl and 1-4C-alkoxy, R6 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, amino, 1-4C-alkylamino, phenylamino, amino 1-4C-alkyl, mono- or di-1-4C-alkylamino-1-4C-alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen 1-4C-alkyl, 1-4C-alkoxy, nitro, halogenomethyl, morpholinomethyl, Nmethylpiperazinomethyl and di-1-4C-alkylaminomethyl, R7 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, amino, 1-4C-alkylamino or phenylamino, R8 represents hydrogen, halogen or 1-4C-alkyl, X represents 0 (oxygen) or NH, E1 represents -CH 2 - (methylene), -CH2CH2- (1,2-ethylene) or -CH(CH·^(1,1-ethylene), E2 represents -CH2- (methylene), -CH2CH2- (1,2-ethylene) or -CHiCH^)(1,1-ethylene) and n represents the number 0 or 1, and the salts of these compounds.

3. Compounds of the formula I according to Claim 1, wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), 1-4C-alkoxy, mono- or polyhydroxy-2-4C•Ε 911406 - 33 alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkoxy, NH 2 (amino), Ng (azido), O-CO-R6 or NH-CO-R7» R5 represents furyl, phenyl, or phenyl which is substituted by a substituent from the group comprising halogen, 1-4C-alkyl and 1-4Calkoxy, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, mono- or di-1-4C-alkylamino-1-4C alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by a substituent from the group comprising halogen, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di-1-4Calkylaminomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, fluorine or chlorine, X represents 0 (oxygen), E1 represents -CH 2 - (methylene) or -CH 2 CH 2 - (1,2-ethylene), E2 represents -CH 2 - (methylene) or -CH 2 CH 2 - (1,2-ethylene) and n represents the number 0 or 1, and the salts of these compounds.

4. Compounds of the formula I according to Claim 1, wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), mono- or polyhydroxy-2-4C-alkoxy, NH 2 (amino), Ng (azido), O-CO-R6 or NH-CO-R7, R5 represents phenyl, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, phenyl, or phenyl which is by substituted*morpholinomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, X represents 0 (oxygen), E1 represents -CH 2 - (methylene) or -CH 2 CH 2 - (1,2-ethylene), E2 represents -CH 2 - (methylene) or -CH 2 CH 2 - (1,2-ethylene) and n represents the number 0, and the salts of these compounds.

5. Compounds of the formula I according to Claim 1, wherein ,E 911406 R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), polyhydroxy-3-4C-alkoxy, NH 2 (amino), (azido), O-CO-R6 or NH-CO-R7, R5 represents phenyl, R

6. Represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, carboxy-1-4Calkyl, 1-4C-alkylamino, phenylamino, or phenyl which is substituted by morpholinomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, X represents 0 (oxygen), El represents -CH 2 - (methylene), E2 represents -CH 2 - (methylene) or -CH 2 CH 2 - (1,2-ethylene) and n represents the number 0, and the salts of these compounds. 6. Compounds of the formula I according to Claim 1, wherein R1 represents 1-4C-alkyl, or 1-3C-alkylene which is substituted by R5, R2 represents 1-4C-alkyl, R3 represents 1-4C-alkyl, R4 represents OH (hydroxyl), NH 2 (amino), (azido), 0-C0-R6 or NH-CO- R7, R5 represents phenyl, R6 represents 1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, 1-4C- alkylamino, phenylamino, or phenyl which is substituted by morpholinomethyl, R7 represents 1-4C-alkyl, R8 represents hydrogen, X represents 0 (oxygen), E1 represents -CH 2 - (methylene), E2 represents -CH 2 - (methylene) and n represents the number 0, and the salts of these compounds. 7. Process for the preparation of the compounds of the formula I according to Claim 1 and their salts, characterized in that - 35 a) pyrrolo-pyridazines of the formula II R3 I ' R2 (II) wherein R1, R2, R3 and n have the abovementioned meanings and Y represents a suitable leaving group (in particular chlorine or bromine), are reacted with phenyl compounds of the formula III R8 wherein R4, R8, X, E1 and E2 have the abovementioned meanings, or in that b) to prepare compounds I in which R4 represents 0-C0-R6 and R6 represents 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4Calkoxycarbonyl-1-4C-alkyl, carboxy-1-4C-alkyl, pyridyl, imidazolyl, phenyl, or phenyl which is substituted by one or two identical or different substituents from the group comprising halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro, halogenomethyl, morpholinomethyl, N-methylpiperazinomethyl and di—1— 4C-alkylaminomethyl, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with carboxylic acids (or their derivatives) of the formula IV R6—CO—Ζ (IV) wherein R6 has the abovementioned meanings and Z represents OH (hydroxyl) or a suitable leaving group, or in that c) to prepare compounds I in which R4 denotes 0-C0-R6 and R6 denotes 14C-alkylamino or phenylamino, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with isocyanates of the formula V - 36 R6' — N=C=0 (V) wherein R6’ denotes 1-4C-alkyl or phenyl, or in that d) to prepare compounds I in which R4 denotes NH-CO-R

7. And R7 denotes 14C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl-1-4Calkyl, compounds of the formula I in which R4 denotes NHj (amino) are reacted with carboxylic acid derivatives of the formula VI R7—CO—Z (VI) wherein R7 has the abovementioned meanings and Z represents a suitable leaving group, or in that e) to prepare compounds I in which R4 denotes Ng (azido), compounds of the formula I wherein R4 denotes OH (hydroxyl) are reacted with methanesulphonyl chloride, and the mesyloxy compound formed is then reacted with an alkali metal azide, or in that f) to prepare compounds I wherein n denotes the number 1, compounds of the formula I wherein n denotes the number 0 are oxidized, or in that g) to prepare compounds I in which R4 denotes mono- or polyhydroxy-2-4Calkoxy, compounds of the formula I in which R4 denotes OH (hydroxyl) are reacted with alcohol derivatives of the formula VII C m H (2m-+l-p) 2 -Y· (VII) wherein m represents an integer from 1 to 3» P represents an integer from 1 to 3, R’ represents a protective group and Y’ represents a suitable leaving group, and the protective group(s) R· is/are then split off, and in that, if desired, the compounds I obtained according to a), b), c), d), e), f) or g) are then converted into their salts, or in that, if desired, the compounds I are then liberated from the resulting salts of the compounds I.

8. Medicaments containing one or more compounds according to one or more - 37 of Claims 1 to 6 and/or their pharmacologically tolerated salts.

9. Compounds according to one or more of claims 1 to 6 and their pharmacologically tolerated 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 tolerated salts for the preparation of medicaments for the prevention and treatment of gastrointestinal diseases. ,E 911406 -3811. A compound substantially as hereinbefore described with reference to the Examples.

11. 12. A process substantially as hereinbefore described with reference to the Examples.

12. 13. A medicament substantially as hereinbefore described with reference to the Examples.

13.

14. A use substantially as hereinbefore described with reference to the Examples.