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WO1992006979A1 - Nouvelles diazines - Google Patents

Nouvelles diazines Download PDF

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Publication number
WO1992006979A1
WO1992006979A1 PCT/EP1991/001928 EP9101928W WO9206979A1 WO 1992006979 A1 WO1992006979 A1 WO 1992006979A1 EP 9101928 W EP9101928 W EP 9101928W WO 9206979 A1 WO9206979 A1 WO 9206979A1
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Prior art keywords
compounds
formula
phenyl
dimethyl
alkyl
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PCT/EP1991/001928
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German (de)
English (en)
Inventor
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
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Publication of WO1992006979A1 publication Critical patent/WO1992006979A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • novel compounds inte ⁇ esting pharmacological properties described in more detail below comprise, by which it is under ⁇ divorced be ⁇ known compounds in a surprising and particularly advantageous manner.
  • the invention relates to new diazines of the formula I
  • 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.
  • 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.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate,
  • Quaternary ammonium salts which can be obtained by reacting compounds of the formula I with suitable alkylating agents are also suitable as salts.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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,
  • A represents 0 (oxygen), NH, N-CN (cyanamido), S (sulfur), SO (sulfinyl) or S (sulfonyl),
  • 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
  • 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.
  • 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.
  • 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
  • Rl, R2 and R3 have the meanings given above and X represents a suitable leaving group, reacted with hydrazine, or that
  • 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.
  • Y represents the radical -A-B-R6 and A, B and R6 have the meanings given above, or their salts with bases, or that
  • R2 and R3 have the meanings given above and R4 is hydroxyl or the substituent -A-B-R6, reductively debenzyl ert, or that ma
  • V represents a suitable leaving group and B and R6 have the meanings given above, or that
  • 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.
  • Suitable solvents are only water-free solvents, such as.
  • B. open-chain or cyclic ethers diethyl ether, diethylene glycol diethyl ether, dioxane or tetrahydrofuran
  • (aromatic) hydrocarbons such as.
  • cyclohexane, benzene or toluene in question which are inert towards the halogenating agent.
  • 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.
  • 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).
  • the leaving group X ' is the methylsulfonyl group, which can be introduced by alkylation of the 7-mercapto compound and subsequent oxidation.
  • 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.
  • metal hydrides e.g. sodium hydride
  • alkali metals e.g.
  • 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.
  • an alkali metal oolate such as, for example, kaiium tert-butoxide
  • 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
  • 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).
  • 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.
  • a suitable solvent such as, for example, dimethyl sulfoxide, dimethylformamide, ethanol or preferably methanol
  • the reaction according to process variant f) is carried out in a manner which is customary for the production of sulfides from thiols.
  • 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
  • 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.
  • 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.
  • 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).
  • 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 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.
  • an alkali metal cyanate for example potassium cyanate
  • 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.
  • halogen formate esters such as chloroformate esters
  • 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.
  • sulfuryl chloride for example
  • 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.
  • 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.
  • a suitable solvent e.g. B. in acetone
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • Rl is 1-4C-alkyl or R5-substituted 1-3C-alkyl and Z is halogen (chlorine, bromine or iodine), in a suitable manner.
  • 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).
  • alkali metal hydroxides e.g. sodium or potassium hydroxide
  • alkali metal alcoholates e.g. sodium ethylate or potassium tert-butoxide.
  • 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.
  • water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene.
  • water-containing or water-free solvents are dichloromethane, tetrahydrofuran or xylene.
  • 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.
  • 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.
  • 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
  • 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 ⁇ ] (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 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.
  • Example Ba 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.
  • 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.
  • 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
  • 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.
  • 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.
  • stomach 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.
  • gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
  • microorganisms Campylobacter pylori
  • medications eg certain anti-inflammatory drugs and anti-rheumatic drugs
  • chemicals eg ethanol
  • 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.
  • auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • 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.
  • 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.
  • similar or generally lower doses in particular when the active substances are administered intravenously
  • 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.
  • 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.
  • 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
  • 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.
  • H 2 blockers for example cimetidine, ranitidine
  • peripheral anticholinergics for example pirenzepin, telenzepin, zolenzepin
  • gastrin antagonists with the aim of increasing the main effect in an additive or superadditive sense and / or eliminating or
  • 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.
  • 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%.
  • 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 product of the degree of severity (according to the following point scale) and the number of ulcers serves as an individual lesion index.
  • the ED50 denotes the dose which reduces the mean lesion index or the HCl secretion by 50% compared to the control.
  • Table 2 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.
  • ED50 dose (interpolated) that causes a maximum inhibition of HCl secretion by 50%.
  • 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.
  • the stomach was continuously flowed through with 37 ° C physiological NaCl solution (0.5 ml / min, pH 6.8-6.9; Braun-Unita I).
  • 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.
  • the body temperature of the animals was measured by infrared radiation and heating pads
  • 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%.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des diazines ayant la formule (I), dans laquelle les substituants ont la notation donnée dans la description, constituent de nouveaux composés ayant des propriétés pharmacologiques intéressantes.
PCT/EP1991/001928 1990-10-15 1991-10-10 Nouvelles diazines WO1992006979A1 (fr)

Applications Claiming Priority (2)

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CH3317/90-7 1990-10-15
CH331790 1990-10-15

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WO1992006979A1 true WO1992006979A1 (fr) 1992-04-30

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008190A1 (fr) * 1991-10-25 1993-04-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrrolo-pyridazine a effets protecteurs du tube gastro-intestinal
AU680998B2 (en) * 1994-01-19 1997-08-14 Sankyo Company Limited Pyrrolopyridazine derivative
WO1999028322A1 (fr) * 1997-11-28 1999-06-10 Astrazeneca Ab Composes heterocycliques permettant d'inhiber la secretion d'acide gastrique, leurs procedes de preparation et leurs compositions pharmaceutiques
JP2003119140A (ja) * 2001-08-08 2003-04-23 Sankyo Co Ltd ピロロピリダジン化合物を含有する医薬
US6670360B2 (en) 1999-06-15 2003-12-30 Sankyo Company, Limited Optically active pyrrolopyridazine derivatives
WO2004029057A1 (fr) * 2002-09-25 2004-04-08 Sankyo Company, Limited Composition medicale permettant de traiter ou de prevenir une douleur viscerale
US6734181B2 (en) 2000-02-10 2004-05-11 Sankyo Company, Limited Pyrrolopyridazine compounds
WO2004084899A1 (fr) * 2003-03-24 2004-10-07 Sankyo Company, Limited Composition medicinale qui comprend un compose de pyrropyridazine
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
JP2015017141A (ja) * 2010-03-15 2015-01-29 プロクシマゲン リミテッド 新規酵素阻害化合物

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EP0290003A2 (fr) * 1987-05-08 1988-11-09 Byk Gulden Lomberg Chemische Fabrik GmbH Imidazoles

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Journal of Heterocyclic Chemistry, Band 10, Nr. 4, August 1973 (Utah, US) P. Dan Cook et al.: "Pyrrolopyridazines. 1. Synthesis and reactivity of pyrrolo[2,3-dÜpyridazine 5-oxides (1)", Seiten 551-557, siehe Seite 552, Verbindungen 5,13 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5534515A (en) * 1991-10-25 1996-07-09 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrrolopyridazines having gastrointestinal protective effects
WO1993008190A1 (fr) * 1991-10-25 1993-04-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrrolo-pyridazine a effets protecteurs du tube gastro-intestinal
US6063782A (en) * 1994-01-19 2000-05-16 Sankyo Company, Limited Pyrrolopyridazine derivatives
AU680998B2 (en) * 1994-01-19 1997-08-14 Sankyo Company Limited Pyrrolopyridazine derivative
RU2146257C1 (ru) * 1994-01-19 2000-03-10 Санкио Компани Лимитед Производные пирролопиридазина, способы их получения, противоязвенное средство
RU2241000C2 (ru) * 1997-11-28 2004-11-27 Астразенека Аб Гетероциклические соединения с замещенной фенильной группировкой, способ их получения (варианты), фармацевтические препараты на их основе и способ ингибирования секреции желудочной кислоты
US6518270B1 (en) 1997-11-28 2003-02-11 Astrazeneca Ab Heterocyclic compounds for inhibition of gastric acid secretion, processes for their preparation and pharmaceutical compositions thereof
WO1999028322A1 (fr) * 1997-11-28 1999-06-10 Astrazeneca Ab Composes heterocycliques permettant d'inhiber la secretion d'acide gastrique, leurs procedes de preparation et leurs compositions pharmaceutiques
US6670360B2 (en) 1999-06-15 2003-12-30 Sankyo Company, Limited Optically active pyrrolopyridazine derivatives
US6734181B2 (en) 2000-02-10 2004-05-11 Sankyo Company, Limited Pyrrolopyridazine compounds
US7951398B2 (en) 2000-12-07 2011-05-31 Nycomed Gmbh Pharmaceutical preparation comprising an active dispersed on a matrix
US7175854B2 (en) 2000-12-07 2007-02-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix
JP2003119140A (ja) * 2001-08-08 2003-04-23 Sankyo Co Ltd ピロロピリダジン化合物を含有する医薬
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US8431154B2 (en) 2002-02-20 2013-04-30 Takeda Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidone as excipient
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
WO2004029057A1 (fr) * 2002-09-25 2004-04-08 Sankyo Company, Limited Composition medicale permettant de traiter ou de prevenir une douleur viscerale
WO2004084899A1 (fr) * 2003-03-24 2004-10-07 Sankyo Company, Limited Composition medicinale qui comprend un compose de pyrropyridazine
JP2015017141A (ja) * 2010-03-15 2015-01-29 プロクシマゲン リミテッド 新規酵素阻害化合物

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