CA1293254C - Substituted pyrrol-1-ylphenyldihydropyridazinones, their preparation and their use - Google Patents
Substituted pyrrol-1-ylphenyldihydropyridazinones, their preparation and their useInfo
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- CA1293254C CA1293254C CA000524680A CA524680A CA1293254C CA 1293254 C CA1293254 C CA 1293254C CA 000524680 A CA000524680 A CA 000524680A CA 524680 A CA524680 A CA 524680A CA 1293254 C CA1293254 C CA 1293254C
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
ABSTRACT OF THE DISCLOSURE:
Disclosed are new substituted pyrrol-1-ylphenyl-dihydropyridazinones of the formula where R1 is hydrogen, methyl or hydroxymethyl, R2 is hydrogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in which m is an integer from 1 to 4, R3, R4 and R5, independently of one another are each hydrogen or C1-C6-alkyl, R is hydrogen or, together with R1, forms a radical -(CH2)n-, in which n is 1, 2 or 3, or the radical -CH=CH-, A
and B are each hydrogen or -together form a bond, D is hydrogen, C1-C6-alkyl or phenyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl. These compounds are useful as antihypertensives and for the treatment of thrombotic disorders, cardiac insufficiency and disorders accompanied by pathological increase in the secretion of gastric acid, such as gastric and duodenal ulcers.
Disclosed are new substituted pyrrol-1-ylphenyl-dihydropyridazinones of the formula where R1 is hydrogen, methyl or hydroxymethyl, R2 is hydrogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in which m is an integer from 1 to 4, R3, R4 and R5, independently of one another are each hydrogen or C1-C6-alkyl, R is hydrogen or, together with R1, forms a radical -(CH2)n-, in which n is 1, 2 or 3, or the radical -CH=CH-, A
and B are each hydrogen or -together form a bond, D is hydrogen, C1-C6-alkyl or phenyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl. These compounds are useful as antihypertensives and for the treatment of thrombotic disorders, cardiac insufficiency and disorders accompanied by pathological increase in the secretion of gastric acid, such as gastric and duodenal ulcers.
Description
~3~
O.Z. 0050/38184 Substituted pyrrol-1-ylphenyldihydropyridazinones, their preparation and their use The invention relates to novel substituted pyrrol-1-ylphenyldihyclropyridazinones, processes for their prepa-ration and their use for the treatment of disorders.
6-Aryldihydropyridazinones having pharmacological effects are known (cf. for example J. Med. Chem. 17 (1974), Z73, J. Het. Chem. 11 (1974), 755 and J. Med. Chem. 26 (1983), 800). A number of 6-phenyldihydropyridazinones which increase myocardial contractivity and have an anti-hypertensive action are described in Europe~n Laid-Open Application 75,436 and J. Med. Chem. 28 (1985), 1405-1413.
We have found that substituted pyrrol-1-ylphenyl-dihyclropyridazinones of the formula I
7S R6 Rt A ~ R2 o - I R4 H
E/
where R1 is hydrogen, methyl or hydroxymethyl, R2 is hyd-rogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in ~hich m is an integer from 1 to 4~ R3, R4 and R5 independently of one another are each hydrogen or C1-C6-alkyl, R6 is hydrogen or, together with R1, forms a radical -(CH2)~-, in which n is 1, 2 or 3, or the rad;cal -CH=CH-~ A and ~ are each hydrogen or together form a bond, D is hydrogen, C1-C6-alkyl or phenyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl~ have useful pharmacological properties.
The specific radica!s, independently of one LZ93ZS~
O.Z. 0050/38184 Substituted pyrrol-1-ylphenyldihydropyridazinones, their preparation and their use The invention relates to novel substituted pyrrol-1-ylphenyldihyclropyridazinones, processes for their prepa-ration and their use for the treatment of disorders.
6-Aryldihydropyridazinones having pharmacological effects are known (cf. for example J. Med. Chem. 17 (1974), Z73, J. Het. Chem. 11 (1974), 755 and J. Med. Chem. 26 (1983), 800). A number of 6-phenyldihydropyridazinones which increase myocardial contractivity and have an anti-hypertensive action are described in Europe~n Laid-Open Application 75,436 and J. Med. Chem. 28 (1985), 1405-1413.
We have found that substituted pyrrol-1-ylphenyl-dihyclropyridazinones of the formula I
7S R6 Rt A ~ R2 o - I R4 H
E/
where R1 is hydrogen, methyl or hydroxymethyl, R2 is hyd-rogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in ~hich m is an integer from 1 to 4~ R3, R4 and R5 independently of one another are each hydrogen or C1-C6-alkyl, R6 is hydrogen or, together with R1, forms a radical -(CH2)~-, in which n is 1, 2 or 3, or the rad;cal -CH=CH-~ A and ~ are each hydrogen or together form a bond, D is hydrogen, C1-C6-alkyl or phenyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl~ have useful pharmacological properties.
The specific radica!s, independently of one LZ93ZS~
- 2 - O.Z. 0050/38184 another have the following preferred meanings.
If A and 8 are each hydrogen, R1 is preferably hydrogen or methyl, in particular methyl, and R2 is preferably hydrc~gen, and R1 and RZ together form a group of the S formula -(CH2)m-, in ~hich m is 1 or 2, in particular 1.
If A and 8 together form a bond, R1 is prefer-ably hydrogen and R2 is preferably hydrogen or methyl.
R3 is preferably hydrogen or C1-C3-alkyl, in particular C1-C3-alkyl, R4 is preferably hydrogen or C1-C3-alkyl, in part`icular hydrogen, R5 is preferably hydrogen or C1-C3-alkyl, in particular C1-C3-alkyl, and R6 is preferably hydrogen. If R6 together with R1 forms a radical -tCH2)n- or -CH=CH-, n is preferably 1 or 2. In particular, R6 and R1 together form the radical -(CH2)z- or -CH=CH-. A and B are each ore-ferably hydrogen.
D and E together preferably form a bond. Where D
is hydrogen, C1-C6-alkyl or phenyl, it is preferably C1-C3-alkyl or phenyl, in particular C1-C3-alkyl.
Z0 The novel compounds of the formula I, where D
and E together form a bond, are prepared by a process in which a p-aminophenyldihydropyr;daz;nane of the formula II R6 R ~ A 3 R2 H ~= I I
N ~ N
where R1, R2, R6, A and 3 have the mean;ngs described for formula I, is reacted with a tetrahydrofuran of the ~formula III RS R7 ,~
l~ 5 \
:1 1 0 R3 ~ III
i R~ R7 where R3, R4 and RS have the meanings stated in formula ~ ~33Z5~
If A and 8 are each hydrogen, R1 is preferably hydrogen or methyl, in particular methyl, and R2 is preferably hydrc~gen, and R1 and RZ together form a group of the S formula -(CH2)m-, in ~hich m is 1 or 2, in particular 1.
If A and 8 together form a bond, R1 is prefer-ably hydrogen and R2 is preferably hydrogen or methyl.
R3 is preferably hydrogen or C1-C3-alkyl, in particular C1-C3-alkyl, R4 is preferably hydrogen or C1-C3-alkyl, in part`icular hydrogen, R5 is preferably hydrogen or C1-C3-alkyl, in particular C1-C3-alkyl, and R6 is preferably hydrogen. If R6 together with R1 forms a radical -tCH2)n- or -CH=CH-, n is preferably 1 or 2. In particular, R6 and R1 together form the radical -(CH2)z- or -CH=CH-. A and B are each ore-ferably hydrogen.
D and E together preferably form a bond. Where D
is hydrogen, C1-C6-alkyl or phenyl, it is preferably C1-C3-alkyl or phenyl, in particular C1-C3-alkyl.
Z0 The novel compounds of the formula I, where D
and E together form a bond, are prepared by a process in which a p-aminophenyldihydropyr;daz;nane of the formula II R6 R ~ A 3 R2 H ~= I I
N ~ N
where R1, R2, R6, A and 3 have the mean;ngs described for formula I, is reacted with a tetrahydrofuran of the ~formula III RS R7 ,~
l~ 5 \
:1 1 0 R3 ~ III
i R~ R7 where R3, R4 and RS have the meanings stated in formula ~ ~33Z5~
- 3 - O.Z. 0050/38184 I, RS is bonded to ring atom 4 or 5 of the tetrahydro-furan ring, and R7 ;s C1-C4-alkoxy, C1-C4-alkanoyloxy, chlorine or bromine, and, if required, the compound thus obtained ;s hydrogenated at the C=0 group or reacted with an organometallic compound F-Met, where F is C1-C6-alkyl or phenyl and Met is an alkali metal atom or a radical MgX, where X is chlorine, bromine or iodine.
R7 is preferably C1-C4-alkoxyu Where R3 and R4 are not two identical radicals (Ra and Rb), the isomeric products I a and I b may be formed R5 R~ Rt A a R2 ~ ~ ~ I a ;C ~ b ~ - N
Il o R5 R5 Rl A ~ R2 I b b ~ ~ o a \~ N
li R
where R1, R2, R5, R6, A and ~ have the meanings sta15 ted for formula I.
The novel compounds of the formula I where D and E together form a bond are prepared under ac;dic condi-tions, either in a lower alkanecarboxylic acid, such as acetic acid, or in an organic solvent with the addition of an acid, such an inorganic or organic carboxylic acid or a sulfonic acid. The preparation may also be carried out in the presence of an acidic ion exchanger. The acid is used in an amoun~ of from 0.01 to 300, preferably from 0.1 to 20, mol X. The reaction can be carried out under atmospheric or superatmospheric pressure at from room temperature to the reflux temperature of the solvent used.
Temperatures of from 20 to 160C, preferably from 6û
Z~3;~:5~
R7 is preferably C1-C4-alkoxyu Where R3 and R4 are not two identical radicals (Ra and Rb), the isomeric products I a and I b may be formed R5 R~ Rt A a R2 ~ ~ ~ I a ;C ~ b ~ - N
Il o R5 R5 Rl A ~ R2 I b b ~ ~ o a \~ N
li R
where R1, R2, R5, R6, A and ~ have the meanings sta15 ted for formula I.
The novel compounds of the formula I where D and E together form a bond are prepared under ac;dic condi-tions, either in a lower alkanecarboxylic acid, such as acetic acid, or in an organic solvent with the addition of an acid, such an inorganic or organic carboxylic acid or a sulfonic acid. The preparation may also be carried out in the presence of an acidic ion exchanger. The acid is used in an amoun~ of from 0.01 to 300, preferably from 0.1 to 20, mol X. The reaction can be carried out under atmospheric or superatmospheric pressure at from room temperature to the reflux temperature of the solvent used.
Temperatures of from 20 to 160C, preferably from 6û
Z~3;~:5~
- 4 - O.Z. OO50t38184 to to 120C, are usually employed. Suitable organic solvents are aromatic hydrocarbons, such as benzene, tolu-ene, ethylbenzene, dichlorobenzene, o-, m- and p-xylene and methylnaphthalene, aliphatic or cycloaliphatic hydro-carbons, such as naphtha, heptane or cyclohexane, ethers,such as diethyl ether or tetrahydrofuran, amides, such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-pyrrolidone, and mixtures of these solvents.
The preparation is preferably carried out in a lower alkanecarboxylic acid, in particular in acetic acid, at from 60 to 120C, in particular from 70 to 100C.
Compounds of the formula I where D and E are each hydrogen are obtained by reducing the compounds of the formula I where D and E together form a bond. This re-duction can be carried out, for example, using hydrogenand a metal catalyst, such as a platinum~ palladium, nickel or cobalt catalyst, by using an organometallic hydride, such as sod;um borohydr;de, or lithim aluminum hydride, ;n a solvent which is ;nert under the reaction conditions.
The reaction of the keto compounds ~I, where D
; and E together form a ~ond) with an organometallic com-pound can be carr;ed out by a convent;onal method for Grignard reactions~ Particularly suitable alkal; metals for the rad;cal F are l;th;um and sod;um.
The ;nvent;on embraces all enantiomeric, diastere-omeric and tautomeric forms of compounds of the formula I.
The start;ng mater;als of the formulae ~I and III
are known. rhose wh;ch are unknown can be synthesized by methods similar to those known from the Literature (for the preparation of comp~unds of the formula III, cf.
Z. Chemie 13 (1973), 290-291 and Collect. Czech. Chem.
Commun. 45 (1980~, 888-891).
The compounds accord;ng to the invention has use-ful pharmacologicaL effects. In particular, they seLect-ively inhibit the phosphodiesterase III, which is cAMP-specific and has a high affinity (Low Km) for cAMP (cf.
~Z~32S~
.
The preparation is preferably carried out in a lower alkanecarboxylic acid, in particular in acetic acid, at from 60 to 120C, in particular from 70 to 100C.
Compounds of the formula I where D and E are each hydrogen are obtained by reducing the compounds of the formula I where D and E together form a bond. This re-duction can be carried out, for example, using hydrogenand a metal catalyst, such as a platinum~ palladium, nickel or cobalt catalyst, by using an organometallic hydride, such as sod;um borohydr;de, or lithim aluminum hydride, ;n a solvent which is ;nert under the reaction conditions.
The reaction of the keto compounds ~I, where D
; and E together form a ~ond) with an organometallic com-pound can be carr;ed out by a convent;onal method for Grignard reactions~ Particularly suitable alkal; metals for the rad;cal F are l;th;um and sod;um.
The ;nvent;on embraces all enantiomeric, diastere-omeric and tautomeric forms of compounds of the formula I.
The start;ng mater;als of the formulae ~I and III
are known. rhose wh;ch are unknown can be synthesized by methods similar to those known from the Literature (for the preparation of comp~unds of the formula III, cf.
Z. Chemie 13 (1973), 290-291 and Collect. Czech. Chem.
Commun. 45 (1980~, 888-891).
The compounds accord;ng to the invention has use-ful pharmacologicaL effects. In particular, they seLect-ively inhibit the phosphodiesterase III, which is cAMP-specific and has a high affinity (Low Km) for cAMP (cf.
~Z~32S~
.
- 5 - O.Z. 0050t38184 review on phosphodiesterase inhibitors: J. Med. Chem. Z8 (1985), $37-545)-The compounds according to the invention inhibitplatelet aggregation and have positive inotropic, vaso-dilatory and coronary dilatory actions. They also reduceblood pressure, inhibit the secre~ion of gastric acid and have cytoprotective effects on the gastric mucous mem-brane. They are therefore useful as antihypertensives and for the treatment of thrombotic disorders, cardiac insufficiency and disorders accompanied by pathological increase in the secretion of gastric acid, such as gastric and duodenal ulcers~
The novel compounds can be administerea orally or parenterally (subcutaneously, intravenously, intramuscu-larly or intraperitoneally) in a conventional manner.
' The dose depends on the age, condition and weightof the patient and on the route of administration. As a rule, the daily dose of active compound per patient is about 0.1-1a, preferably û.S-5, mg in the case of paren-teral administration and 1-1ûO, preferably 5-50, mg in the case of oral admin;stration.
The novel compounds may be employed in the con-vent;onal solid or liquid pharmaceutical forms, such as tablets, film tablets, capsules, granules, coated tablets, solutions or suppositories. These are prepared in a con-ventional manner, and to do so the active compounds can be mixed with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents and/or antioxidants (cf. H. Sucker et al: Pharma-zeutische Technologie, Thieme Verlag,'Stuttgart 1978).
The formulations thus obtained normally contain from 0.1 to 99~ by weight of ~he active compoundO
The Examples ~hich follow illustrate the inven-tion.
zg325~
The novel compounds can be administerea orally or parenterally (subcutaneously, intravenously, intramuscu-larly or intraperitoneally) in a conventional manner.
' The dose depends on the age, condition and weightof the patient and on the route of administration. As a rule, the daily dose of active compound per patient is about 0.1-1a, preferably û.S-5, mg in the case of paren-teral administration and 1-1ûO, preferably 5-50, mg in the case of oral admin;stration.
The novel compounds may be employed in the con-vent;onal solid or liquid pharmaceutical forms, such as tablets, film tablets, capsules, granules, coated tablets, solutions or suppositories. These are prepared in a con-ventional manner, and to do so the active compounds can be mixed with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents and/or antioxidants (cf. H. Sucker et al: Pharma-zeutische Technologie, Thieme Verlag,'Stuttgart 1978).
The formulations thus obtained normally contain from 0.1 to 99~ by weight of ~he active compoundO
The Examples ~hich follow illustrate the inven-tion.
zg325~
- 6 - O.Z. 0050/38184 6-~4-(4-Acetyl-2-methylpyrrol-1-yl)-phenyl]-4,5-dihydro-pyridazin-3-one Compound I, where R1, R2r R4, R6, A and B are each H, R3 is CH3, R5 is 5-CH3 and D and E together form a bond~
A solution of 2.8 9 ~15 millimoles) of 6-(4-amino-phenyl)-4,5-dihydropyridazinone and 3.1 9 (16.5 milli-moles) of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran-3-carbaldehyde in 30 ml of acetic acid ~as stirred forZ hours at 80C. Thereafter, the reaction solution was poured into saturated potassium carbonate solution and extracted se~eral times with methylene chloride. The organic phase was dried over Na2S04, the solvent was stripped off in a rotary evaporator and the crude product was then recryitallized from dimethylformamide/water.
3.4 9 of 6-~4-(4-acetyl-2-methylpyrrol-1-yl)-phenyl]-4,5-dihydropyridazinone of melting point 188-189C were abtained.
EXAMPLES 1B to 1H
The compounds of Examples 1B to 1H were prepared sim;larly to Example lA (compounds of the formula I, where R3 is CH3, R4 is H, R5 ;s 5-CH3 and D and E together form a bond):
25 Example R6 R1 R2 A B m.p. C
1F H H H common 231-232 bond EXAMPLES 1K to 1S
The compounds of Examples 1K to 1S were prepared similarly to Example 1A (compounds of the formula I, where 3;~5~
A solution of 2.8 9 ~15 millimoles) of 6-(4-amino-phenyl)-4,5-dihydropyridazinone and 3.1 9 (16.5 milli-moles) of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran-3-carbaldehyde in 30 ml of acetic acid ~as stirred forZ hours at 80C. Thereafter, the reaction solution was poured into saturated potassium carbonate solution and extracted se~eral times with methylene chloride. The organic phase was dried over Na2S04, the solvent was stripped off in a rotary evaporator and the crude product was then recryitallized from dimethylformamide/water.
3.4 9 of 6-~4-(4-acetyl-2-methylpyrrol-1-yl)-phenyl]-4,5-dihydropyridazinone of melting point 188-189C were abtained.
EXAMPLES 1B to 1H
The compounds of Examples 1B to 1H were prepared sim;larly to Example lA (compounds of the formula I, where R3 is CH3, R4 is H, R5 ;s 5-CH3 and D and E together form a bond):
25 Example R6 R1 R2 A B m.p. C
1F H H H common 231-232 bond EXAMPLES 1K to 1S
The compounds of Examples 1K to 1S were prepared similarly to Example 1A (compounds of the formula I, where 3;~5~
- 7 - O.Z. 0050/38184 R3 is CH3, R4 is H, RS is 5-CH3 and D and E together form a bond):
Example R6 R1 R2 A 9 1K H CH3 H common bond 1L H H CH3 common bond lN H -(CH2)4- H H-1P -CH2- H common bond 1Q -CHzCH2- H common bond 228 (decom-position) 1R -CH=CH- H H H
1S -CH=CH- H common bond 15 6-t4-(3-n-Butanoylpyrrol-1-yl)-phenyl]-S-methyl-4,5-di-; hydropyridazin-3-one (2 A1) and 6-t4-(3-formyl-2-n-pro-pylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyr;dazin-3-one (2 A2) A mixture of 5.0 g (24.6 m;llimoles) of 6-tp-aminophenyl)-S-methyl-4,5-dihydropyridazinone and 6.5 9 (3Z millimoles) of 3-n-butanoyl-2,5-dimethoxytetrahydro-furan in 100 ml of acetic acid was stirred for Z hours at 80C. After the addition of a further 2.0 9 t10 milli-moles) of 3-n-butanoyl-2,5-dimethoxytetrahydrofuran, st;rring was continued for a further 2 hours at 80C.
The solution vas evaporated down in a rotary evaporator~
! after which the residue ~as neutralized with KzC03 solu-tion and extracted ~ith CHzCl2. The organic phase was dried over Na2S04, the solvent was stripped off and the crude product was then chromatographed over 800 9 of silica gel using a 4:1 me~hylene chloride/methanol mix-ture. Recrystallization of the appropriate product-con-taining fractions from ethyl acetate gave 0.8 9 of 6-C4-3-formyl-2--n-propylpyrrol-1-yl)-phenyl~-5-methyl-4,5-di-hydropyridazine-3-one of melting point 148-149C (2 A~) and 1.~5 9 of 6-t4-(3-n-butanoylpyrrol-1-yl)-phenyl-5-~ z~ 4 - 8 - O.Z. OOS0/38184 methyl-4,5-dihydropyridazin-3-one of melting point 162-163C (2 A1).
6-t4-t2-Ethyl-3-formylpyrrol-1-yl)-phenyl]-S-S methyl-4,5-dihydropyridazin-3-one of melting point 192-193C (2 ~2) and 6-~4-t3-prop;onylpyrrol-1-yl)-phenyl]-S-methyl-4,5-dihydropyridazinone of melting point ...
: t2 B1) were obtained similarly to Example 2A by re-acting p-aminophenyl-5-methyl-4,5-dihydropyridazin-3-one with 3-propionyl-Z,5-dimethoxytetrahydrofuran and sub-jecting the product to column chromatography over alumina, : using a 4:1 methylene chloride/ethyl acetate mixture as the mobile phase.
The compounds of Examples 2C1-2F2 can be ob-tained similarly to Examples 2A and 28, by reacting amino-: phenyldihydropyridazinones of the formula II with 3-alkanoyl-2,5-dimethoxytetrahydrofurans of the formula III
tcompounds I, where D and E together form a bond, and RS
and R6 are each H):
Example Rl R2 R3 R4 A 8 .
2D1 H H i-C3H7 H H H
25 2D2 H H H i-C3H7 H H
; 2F1 CH3 Hn-C6-H13 H H H
2F2 CH3 HH n-C6H13 H -H
~30 EXAMPLE 3 6-C4-t?-Methyl-4-formylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyridazinone can be obtained similarly to Example 1A, by reacting 2,5-dimethoxy-4-formyl-2-methyltetr~hydrofuran with 6-tp-aminophenyl]-S-methyl-4,5-dihydropyridaz;n-3-one.
L293Z~
~ 9 - O.Z. 0050/38184 The compounds of Examples 4 A - 4 D can be ob-tained similarly to Example 1 A, by reacting 2,5-diethyl-Z,5-dimethoxy-3-formyltetrahydrofuran with aminophenyldi-S hydropyridazinones of the formula II (compounds of theformula I, where D and E together form a bond, R3 is C2Hs, R4 is H, R5 is 5-C2Hs and R6 is H):
Example R1 R2 A a .
4 C -CHz- H H
4 D H H common bond 6-~4-(4-(hydroxyeth-1-yl)-2-methylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyridazin-3-one A solution ot 3.1 9 t10 millimoles) of the com-pound from Example 1 C in 100 ml of ethanol was stirred overnight with 1.5 9 (Z0 millimoles) of NaaH4 at room tem-perature. The solution was evaporated down in a rotary evaporator, after which water was added and the mixture was extracted ~ith ethyl acetate. After drying had been carried out over Naz~04 and the solvent stripped off in a rotary evaporator, the crude product was recrystal-lized from dimethylformamide. 0.8 9 of 6-~4-~4-hydroxy-2S eth-1-yl)-2-methylpyrrol-1-yl)phenyl~-5-methyl-4,5-di-hydropyridazin-3-one was obtained as a diastereomeric mixture of melting point 75-78C~
The compounds of Examples 5 3 - 5 H can be ob-tained similarly to Example 5 A (starting materials for5 B: 1 a; s c: 1 D; 5 D: 1 F; 5 E: 1 G; 5 F: 2 A2; 5 G:
Z A1; 5 H: 3~. (Compounds of the formula I, where D
and E are each H).
-` ~Z932S4 - 10 - 9~Z. 0050/38184 Example R3 R4 RS R6 R1 R2 A 8 S ~ CH3 H S-CH3 H H H H H
S C CH3 ~ 5-CH3 H -CH2- H H
S D CH3 H 5-CH3 H H H common bond 5 F H n-C3H7 H H CH3 H H H
5 G n-C3H7 H H H CH3 H H H
Z2 millimoles of phenylmagnesium bromide, as a solution In diethyl ether, were added to a solution of 2.8 9 (10 millimoles) of 6-C4-(3-formylpyrrol-1-yl)-phe-nyl]-5-methyl-4,5-dihydropyridazinone (see German Laid-Open Application DOS 3,425,632) in 100 ml of absolute tetrahydrofuran at -10C, and the mixture was slowly warmed up to room temperature. The mixture was stirred ` overnight and then poured into water, and the solution was brought to pH S with acetic acid and extracted with ethyl acetate. The crude product was subjected to column 20 chromatography over silica gel, using 98:2-9:1 CH2Cl2/
CH30H, to glve 6-C4-t3-t1-phenyl-1-hydroxy~ethyl)-pyr-rol-1-yl)-phenyl]-S-methyl-4,S-dihydropyridazinone.
6-C4-t3-t1-Hydroxyhept-1-yl)-pyrrol-1-yl)-phenyl]-5-methyl-4,5-d;hydrupyridazinone can be obtained similarly ! to Example 6 A, by reacting n-hexylmagnesium bromide with 6-C4-t3-for~ylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydro-pyri~dazinone. ~
6-C4-(4-t2-Hydroxyprop-2-yl)-2-methylpyrrol-1-yl)-phenyl]
S-methyl-4,5-dihydropyridazinone can be obtained simi-larly to Example 6 A, by reacting methylmagnesium iodide with the compound fro~ Example 1 C.
~ 35 6-C4-(3-Acetyl-4-methylpyrrol-1-yl)-phenyl]-5-: ' -~ ~2~32~4 ~ O.Z. 0050/38184 methyl-4,5-dihydropyr;dazinone can be obtained sim;larly to Example 1 A, by reacting 6-l~4-aminophenyl)-5-methyl-4,5-dihydropyridazinone with 3-formyl-2,5-dimethoxy-2,4-dimethyltetrahydrofuran.
Example R6 R1 R2 A 9 1K H CH3 H common bond 1L H H CH3 common bond lN H -(CH2)4- H H-1P -CH2- H common bond 1Q -CHzCH2- H common bond 228 (decom-position) 1R -CH=CH- H H H
1S -CH=CH- H common bond 15 6-t4-(3-n-Butanoylpyrrol-1-yl)-phenyl]-S-methyl-4,5-di-; hydropyridazin-3-one (2 A1) and 6-t4-(3-formyl-2-n-pro-pylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyr;dazin-3-one (2 A2) A mixture of 5.0 g (24.6 m;llimoles) of 6-tp-aminophenyl)-S-methyl-4,5-dihydropyridazinone and 6.5 9 (3Z millimoles) of 3-n-butanoyl-2,5-dimethoxytetrahydro-furan in 100 ml of acetic acid was stirred for Z hours at 80C. After the addition of a further 2.0 9 t10 milli-moles) of 3-n-butanoyl-2,5-dimethoxytetrahydrofuran, st;rring was continued for a further 2 hours at 80C.
The solution vas evaporated down in a rotary evaporator~
! after which the residue ~as neutralized with KzC03 solu-tion and extracted ~ith CHzCl2. The organic phase was dried over Na2S04, the solvent was stripped off and the crude product was then chromatographed over 800 9 of silica gel using a 4:1 me~hylene chloride/methanol mix-ture. Recrystallization of the appropriate product-con-taining fractions from ethyl acetate gave 0.8 9 of 6-C4-3-formyl-2--n-propylpyrrol-1-yl)-phenyl~-5-methyl-4,5-di-hydropyridazine-3-one of melting point 148-149C (2 A~) and 1.~5 9 of 6-t4-(3-n-butanoylpyrrol-1-yl)-phenyl-5-~ z~ 4 - 8 - O.Z. OOS0/38184 methyl-4,5-dihydropyridazin-3-one of melting point 162-163C (2 A1).
6-t4-t2-Ethyl-3-formylpyrrol-1-yl)-phenyl]-S-S methyl-4,5-dihydropyridazin-3-one of melting point 192-193C (2 ~2) and 6-~4-t3-prop;onylpyrrol-1-yl)-phenyl]-S-methyl-4,5-dihydropyridazinone of melting point ...
: t2 B1) were obtained similarly to Example 2A by re-acting p-aminophenyl-5-methyl-4,5-dihydropyridazin-3-one with 3-propionyl-Z,5-dimethoxytetrahydrofuran and sub-jecting the product to column chromatography over alumina, : using a 4:1 methylene chloride/ethyl acetate mixture as the mobile phase.
The compounds of Examples 2C1-2F2 can be ob-tained similarly to Examples 2A and 28, by reacting amino-: phenyldihydropyridazinones of the formula II with 3-alkanoyl-2,5-dimethoxytetrahydrofurans of the formula III
tcompounds I, where D and E together form a bond, and RS
and R6 are each H):
Example Rl R2 R3 R4 A 8 .
2D1 H H i-C3H7 H H H
25 2D2 H H H i-C3H7 H H
; 2F1 CH3 Hn-C6-H13 H H H
2F2 CH3 HH n-C6H13 H -H
~30 EXAMPLE 3 6-C4-t?-Methyl-4-formylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyridazinone can be obtained similarly to Example 1A, by reacting 2,5-dimethoxy-4-formyl-2-methyltetr~hydrofuran with 6-tp-aminophenyl]-S-methyl-4,5-dihydropyridaz;n-3-one.
L293Z~
~ 9 - O.Z. 0050/38184 The compounds of Examples 4 A - 4 D can be ob-tained similarly to Example 1 A, by reacting 2,5-diethyl-Z,5-dimethoxy-3-formyltetrahydrofuran with aminophenyldi-S hydropyridazinones of the formula II (compounds of theformula I, where D and E together form a bond, R3 is C2Hs, R4 is H, R5 is 5-C2Hs and R6 is H):
Example R1 R2 A a .
4 C -CHz- H H
4 D H H common bond 6-~4-(4-(hydroxyeth-1-yl)-2-methylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydropyridazin-3-one A solution ot 3.1 9 t10 millimoles) of the com-pound from Example 1 C in 100 ml of ethanol was stirred overnight with 1.5 9 (Z0 millimoles) of NaaH4 at room tem-perature. The solution was evaporated down in a rotary evaporator, after which water was added and the mixture was extracted ~ith ethyl acetate. After drying had been carried out over Naz~04 and the solvent stripped off in a rotary evaporator, the crude product was recrystal-lized from dimethylformamide. 0.8 9 of 6-~4-~4-hydroxy-2S eth-1-yl)-2-methylpyrrol-1-yl)phenyl~-5-methyl-4,5-di-hydropyridazin-3-one was obtained as a diastereomeric mixture of melting point 75-78C~
The compounds of Examples 5 3 - 5 H can be ob-tained similarly to Example 5 A (starting materials for5 B: 1 a; s c: 1 D; 5 D: 1 F; 5 E: 1 G; 5 F: 2 A2; 5 G:
Z A1; 5 H: 3~. (Compounds of the formula I, where D
and E are each H).
-` ~Z932S4 - 10 - 9~Z. 0050/38184 Example R3 R4 RS R6 R1 R2 A 8 S ~ CH3 H S-CH3 H H H H H
S C CH3 ~ 5-CH3 H -CH2- H H
S D CH3 H 5-CH3 H H H common bond 5 F H n-C3H7 H H CH3 H H H
5 G n-C3H7 H H H CH3 H H H
Z2 millimoles of phenylmagnesium bromide, as a solution In diethyl ether, were added to a solution of 2.8 9 (10 millimoles) of 6-C4-(3-formylpyrrol-1-yl)-phe-nyl]-5-methyl-4,5-dihydropyridazinone (see German Laid-Open Application DOS 3,425,632) in 100 ml of absolute tetrahydrofuran at -10C, and the mixture was slowly warmed up to room temperature. The mixture was stirred ` overnight and then poured into water, and the solution was brought to pH S with acetic acid and extracted with ethyl acetate. The crude product was subjected to column 20 chromatography over silica gel, using 98:2-9:1 CH2Cl2/
CH30H, to glve 6-C4-t3-t1-phenyl-1-hydroxy~ethyl)-pyr-rol-1-yl)-phenyl]-S-methyl-4,S-dihydropyridazinone.
6-C4-t3-t1-Hydroxyhept-1-yl)-pyrrol-1-yl)-phenyl]-5-methyl-4,5-d;hydrupyridazinone can be obtained similarly ! to Example 6 A, by reacting n-hexylmagnesium bromide with 6-C4-t3-for~ylpyrrol-1-yl)-phenyl]-5-methyl-4,5-dihydro-pyri~dazinone. ~
6-C4-(4-t2-Hydroxyprop-2-yl)-2-methylpyrrol-1-yl)-phenyl]
S-methyl-4,5-dihydropyridazinone can be obtained simi-larly to Example 6 A, by reacting methylmagnesium iodide with the compound fro~ Example 1 C.
~ 35 6-C4-(3-Acetyl-4-methylpyrrol-1-yl)-phenyl]-5-: ' -~ ~2~32~4 ~ O.Z. 0050/38184 methyl-4,5-dihydropyr;dazinone can be obtained sim;larly to Example 1 A, by reacting 6-l~4-aminophenyl)-5-methyl-4,5-dihydropyridazinone with 3-formyl-2,5-dimethoxy-2,4-dimethyltetrahydrofuran.
Claims (3)
1. A process for the preparation of a substituted pyrrol-1-ylphenyldihydropyridazinone of the formula I
where R1 is hydrogen, methyl or hydroxymethyl, R2 is hyd-rogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in which m is an integer from 1 to 4, R3, R4 and R5 independently of one another are each hydro-gen or C1-C6-alkyl, R6 is hydrogen or, together with R1, forms a radical -(CH2)n-, in which n is 1, 2 or 3, or the radical -CH=CH-, A and B are each hydrogen or together form a bond, D is hydrogen, C1-C6-alkyl or phe-nyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl, wherein a p-aminophenyldihydropyridazinone of the formula II
II
where R1, R2, R6, A and B have the meanings described for formula I, is reacted with a tetrahydrofuran of the formula III
- 13 - O.Z. 0050/38184 III
where R3, R4 and R5 have the meanings stated in formula I, R5 is bonded to ring atom 4 or 5 of the tetrahydrofuran ring and R7 is C1-C4-alkoxy, C1-C4-alkanoyloxy, chlorine or bromine, and, if required, the compound thus obtained is hydrogenated at the C=O group or reacted with an organo-metallic compound F-Met, where F is C1-C6-alkyl or phe-nyl and Met is an alkali metal atom or a radical MgX, in which X is chlorine, bromine or iodine.
where R1 is hydrogen, methyl or hydroxymethyl, R2 is hyd-rogen or methyl, or R1 and R2 together form a radical -(CH2)m-, in which m is an integer from 1 to 4, R3, R4 and R5 independently of one another are each hydro-gen or C1-C6-alkyl, R6 is hydrogen or, together with R1, forms a radical -(CH2)n-, in which n is 1, 2 or 3, or the radical -CH=CH-, A and B are each hydrogen or together form a bond, D is hydrogen, C1-C6-alkyl or phe-nyl, and E is hydrogen, or D and E together form a bond, with the proviso that, if R3 is hydrogen, one or both of the radicals R4 and R5 are C1-C6-alkyl or D is C1-C6-alkyl or phenyl, wherein a p-aminophenyldihydropyridazinone of the formula II
II
where R1, R2, R6, A and B have the meanings described for formula I, is reacted with a tetrahydrofuran of the formula III
- 13 - O.Z. 0050/38184 III
where R3, R4 and R5 have the meanings stated in formula I, R5 is bonded to ring atom 4 or 5 of the tetrahydrofuran ring and R7 is C1-C4-alkoxy, C1-C4-alkanoyloxy, chlorine or bromine, and, if required, the compound thus obtained is hydrogenated at the C=O group or reacted with an organo-metallic compound F-Met, where F is C1-C6-alkyl or phe-nyl and Met is an alkali metal atom or a radical MgX, in which X is chlorine, bromine or iodine.
2. A substituted pyrrol-1-ylphenyldihydropyridazinone of the formula I as defined in claim 1.
3. A pharmaceutical composition comprising an effective amount of at least one derivative of the formula I as defined in claim 1 in admixture with a physilogically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863600275 DE3600275A1 (en) | 1986-01-08 | 1986-01-08 | SUBSTITUTED PYRROL-1-YLPHENYLDIHYDROPYRIDAZINONE, THEIR PRODUCTION AND USE |
| DEP3600275.5 | 1986-01-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1293254C true CA1293254C (en) | 1991-12-17 |
Family
ID=6291490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524680A Expired - Lifetime CA1293254C (en) | 1986-01-08 | 1986-12-05 | Substituted pyrrol-1-ylphenyldihydropyridazinones, their preparation and their use |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0231744B1 (en) |
| JP (1) | JPS62164680A (en) |
| AT (1) | ATE53210T1 (en) |
| CA (1) | CA1293254C (en) |
| DE (2) | DE3600275A1 (en) |
| ES (1) | ES2015273B3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3442815B2 (en) * | 1992-05-13 | 2003-09-02 | 第一製薬株式会社 | Diazabicycloalkene derivative |
| WO2020157199A1 (en) | 2019-02-01 | 2020-08-06 | Bayer Aktiengesellschaft | Annulated dihydropyridazinone compounds as anti-cancer compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2304977A1 (en) * | 1973-02-01 | 1974-08-08 | Basf Ag | 3-Aminoaryl-5-alkyl-4,5-dihydro-6(1H)-pyridazones - prepd. by reacting 2-alkyl-3-aminoaroyl-propionic acids with hydrazines |
| HU190412B (en) * | 1981-09-17 | 1986-09-29 | Warner-Lambert Co,Us | Process for producing substituted 4,5-dihiydro-6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones and 6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones |
| DE3425632A1 (en) * | 1984-07-12 | 1986-01-16 | Basf Ag, 6700 Ludwigshafen | (PYRROL-1-YL) -PHENYL-DIHYDROPYRIDAZINONE, THEIR PRODUCTION AND USE |
-
1986
- 1986-01-08 DE DE19863600275 patent/DE3600275A1/en not_active Withdrawn
- 1986-12-05 CA CA000524680A patent/CA1293254C/en not_active Expired - Lifetime
- 1986-12-24 JP JP61306698A patent/JPS62164680A/en active Pending
-
1987
- 1987-01-03 AT AT87100041T patent/ATE53210T1/en not_active IP Right Cessation
- 1987-01-03 EP EP87100041A patent/EP0231744B1/en not_active Expired - Lifetime
- 1987-01-03 ES ES87100041T patent/ES2015273B3/en not_active Expired - Lifetime
- 1987-01-03 DE DE8787100041T patent/DE3762970D1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2015273B3 (en) | 1990-08-16 |
| EP0231744A1 (en) | 1987-08-12 |
| JPS62164680A (en) | 1987-07-21 |
| EP0231744B1 (en) | 1990-05-30 |
| DE3762970D1 (en) | 1990-07-05 |
| DE3600275A1 (en) | 1987-07-09 |
| ATE53210T1 (en) | 1990-06-15 |
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