WO1999031071A1 - Nouveaux phtalazinones - Google Patents

Nouveaux phtalazinones Download PDF

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Publication number
WO1999031071A1
WO1999031071A1 PCT/EP1998/008015 EP9808015W WO9931071A1 WO 1999031071 A1 WO1999031071 A1 WO 1999031071A1 EP 9808015 W EP9808015 W EP 9808015W WO 9931071 A1 WO9931071 A1 WO 9931071A1
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Prior art keywords
alkyl
alkoxy
hydrogen
carboxyl
mono
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PCT/EP1998/008015
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English (en)
Inventor
Geert Jan Sterk
Armin Hatzelmann
Hildegard Boss
Dietrich Häfner
Rolf Beume
Hans-Peter Kley
Margaretha Van Der Mey
Ivonne Johanna Van Der Laan
Hendrik Timmerman
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Byk Gulden Lomberg Chemische Fabrik Gmbh
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Priority to AU17603/99A priority Critical patent/AU1760399A/en
Publication of WO1999031071A1 publication Critical patent/WO1999031071A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • the invention relates to novel compounds which are used in the pharmaceutical industry for the production of medicaments.
  • the invention thus relates to compounds of formula I,
  • R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is chlorine, bromine, hydroxyl, cyano, carboxyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcar- bonyloxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, imidazolyl, pyrazolyl, pyrrolyl, indolyl, isoindolyl, benzimidazolyl, benzotriazolyl, indazolyl, purinyl, a phenyl radical substitued by R22 and/or R23, a phenoxy radical substituted by R24 and/or R25, or a coumarinyloxy radical substituted by R26, in which R22 is hydrogen, halogen, 1-4
  • R5 is R6 or -C p H p -Ar, in which R6 is hydrogen, 1-8C-alkyl, 3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 7-10C-polycycioalkyl, pyridyl, or an unsubstituted or by R61 and/or R62 substituted phenyl radical, in which R61 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, nitro or halogen, and R62 is 1-4C-alkyl, nitro or halogen, Ar is an unsubstituted phenyl, naphthyl or pyridyl radical, or a phenyl radical substituted by R7 and/or R8, in which R7 is hydroxyl, halogen, nitro, 1-4
  • One embodiment of the invention are compounds of formula I, in which
  • R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is chlorine, bromine, hydroxyl, cyano, carboxyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-aIkylcar- bonyloxy, amino, mono- or di-1-4C-a!kylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, imidazolyl, pyrazolyl, pyrrolyl, indolyl, isoindolyl, benzimidazolyl, benzotriazolyl, indazolyl, purinyl, a phenyl radical substitued by R22 and/or R23, a phenoxy radical substituted by R24 and/or R25, or a coumarinyloxy radical substituted by R26, in which R22 is hydrogen, halogen,
  • R5 is R6 or -C p H 2p -Ar, in which R6 is hydrogen, 1-8C-alkyl, 3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 7-10C-polycycloalkyl, pyridyl, or an unsubstituted or by R61 and/or R62 substituted phenyl radical, in which R61 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, nitro or halogen, and R62 is 1-4C-alkyl, nitro or halogen, Ar is an unsubstituted phenyl, naphthyl or pyridyl radical, or a phenyl radical substituted by R7 and/or R8, in which R7 is hydroxyl, halogen, nitro, 1-4C-al
  • 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkoxy is a radical, which, in addition to the oxygen atom contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy and in particular the isopropoxy, ethoxy and methoxy radicals.
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples are the methoxycarbonyl [CH 3 0-C(0)-] and the ethoxycarbonyl [CH 3 CH 2 0-C(0)-] radical.
  • 1-4C-Alkylcarbonyloxy stands for a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded.
  • An example is the acetoxy radical [CH 3 C(0)-0-].
  • Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals. Examples, which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino radical.
  • An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C 3 H 7 C(0)NH-] and the acetyl- amino radical [CH 3 C(0)NH-].
  • Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropylamino- carbonyl radical.
  • Mono- or Di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino radicals is bonded. Examples which may be mentioned are the methyl- aminosulfonyl, the dimethylaminosulfonyl and the ethylaminosulfonyl radical.
  • Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
  • Carboxy-1-4C-alkyl radicals are, for example, the carboxymethyl (-CH 2 COOH) and the carboxyethyl (-CH 2 CH 2 COOH) radical.
  • 3-10C-Cycloalkyl radicals are, for example, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl and the cyclooctyl radical.
  • 3-7C-Cycloalkylmethyl stands for a methyl radical, which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclobutyl- methyl and the cyclopentylmethyl radicals.
  • 7-10C-Polycycloalkyl stands for 7-10C-bicycloalkyl or 7-10C-tricycloalkyl groups, such as for example, bornyl, norbornyl or adamantyl.
  • Possible groups -C r H 2r - and -C p H 2p - are straight chain or branched groups.
  • Examples which may be mentioned for the -C r H 2r - group are the octylene, heptylene, isoheptylene (2-methylhexylene), hexylene, isohexylene (2-methylpentylene), neohexylene (2,2-dimethylbutylene), pentylene, isopentylene (2-methylbutylene), neopentylene (2,2-dimethylpropylene), butylene, iso- butylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene and the methylene group.
  • Examples which may be mentioned for the -C p H 2p - group are the butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene and the methylene group.
  • Aza-heterocycles which are a component (R21 ) of the group of substituents defined as -0-C r H 2r -R21 and contain the grouping -NH- (imino), such as for example, pyrrole, imidazole, benzimidazole, benzotriazole or purine, are preferably bonded via their imino-nitrogen to the -C r H 2r - group.
  • coumarinyloxy preferably stands for coumarinyl-4-oxy or coumarinyl-7-oxy.
  • Suitable salts for compounds of the formula I - depending on substitution - are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts with the inorganic and organic acids and bases customarily used in pharmacy.
  • water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.
  • acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid
  • salts with bases are - depending on substitution - also suitable.
  • salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • Pharmacologically intolerable salts which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
  • R1 is 1-4C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is chlorine, bromine, hydroxyl, carboxyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkyl- carbonyloxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, indolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which
  • R22 is hydrogen, halogen, carboxyl, carboxy-1-4C-alkyl or 1-4C-alkoxycarbonyl,
  • R24 is hydrogen, nitro, cyano, halogen, carboxyl, carboxy-1-4C-a!kyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, tetrazolyl, imidazolyl or 4-methyI-6-oxo-1 ,4,5,6- tetrahydropyridazin-3-yl,
  • R26 is hydrogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or carboxy-1-2C-alkyl,
  • R3 and R4 are both hydrogen or together form an additional bond
  • R5 is R6 or -C p H 2p -Ar, in which
  • R6 is hydrogen, 1-8C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloaIkylmethyl, bornyl, norbornyl, adamantyl, pyridyl, or an unsubstituted or by R61 substituted phenyl radical, in which
  • R61 is 1-2C-alkyl, 1-2C-alkoxy, carboxyl, 1-2C-alkoxycarbonyl or halogen,
  • Ar is an unsubstituted or by R7 substituted phenyl radical, in which
  • R7 is hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, carboxy-1-4C-alkyI, 1-4C-alkylcarbonyl- oxy or 1-4C-alkoxycarbonyl and p is an integer from 1 to 2, r is an integer from 1 to 8, and the salts of these compounds.
  • R1 is 1-4C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein R21 is chlorine, bromine, hydroxyl, carboxyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkyl- carbonyloxy, amino, mono- or di-1-4C-alkylamino, 1-4C-aIkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, indolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which
  • R22 is hydrogen, halogen, carboxyl, carboxy-1-4C-alkyl or 1-4C-alkoxycarbonyl,
  • R24 is hydrogen, nitro, cyano, halogen, carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, tetrazolyl or imidazolyl,
  • R26 is hydrogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or carboxy-1-2C-alkyl,
  • R3 and R4 are both hydrogen or together form an additional bond
  • R5 is R6 or -C p H 2p -Ar, in which
  • R6 is hydrogen, 1-8C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, bornyl, norbornyl, adamantyl, pyridyl, or an unsubstituted or by R61 substituted phenyl radical, in which
  • R61 is 1-2C-alkyl, 1-2C-alkoxy, carboxyl, 1-2C-alkoxycarbonyl or halogen,
  • Ar is an unsubstituted or by R7 substituted phenyl radical, in which
  • R7 is hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, carboxy-1-4C-alkyl, 1-4C-alkylcarbonyl- oxy or 1-4C-alkoxycarbonyl and p is an integer from 1 to 2, r is an integer from 1 to 8, and the salts of these compounds.
  • R1 is methoxy, ethoxy, difluoromethoxy or trifluoromethoxy
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is chlorine, bromine, hydroxyl, carboxyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylami- no, 1-4C-alkyicarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, indolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which
  • R22 is hydrogen, carboxyl or carboxy-1-2C-alkyl
  • R24 is hydrogen, cyano, carboxyl, carboxy-1-2C-alkyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, tetrazolyl, imidazolyl or 4-methyl-6-oxo-1 ,4,5,6-tetrahydropyridazin- 3-yl,
  • R26 is hydrogen, 1 -2C-alkyl or carboxy-1 -2C-alkyl
  • R5 is R6 or -C p H 2p -Ar, in which
  • R6 is 3-7C-cycloalkyl or an unsubstituted or by R61 substituted phenyl radical, in which
  • R61 is carboxyl or 1-2C-alkoxycarbonyl
  • Ar is an unsubstituted or by R7 substituted phenyl radical, in which R7 is carboxyl, carboxy-1-2C-alkyl or 1-2C-alkoxycarbonyl, p is 1 , r is an integer from 1 to 6, and the salts of these compounds.
  • R1 is methoxy, ethoxy, difluoromethoxy or trifluoromethoxy
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is chlorine, bromine, hydroxyl, carboxyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylami- no, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, indolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which
  • R22 is hydrogen, carboxyl or carboxy-1-2C-alkyl
  • R24 is hydrogen, cyano, carboxyl, carboxy-1-2C-aikyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, tetrazolyl or imidazolyl,
  • R26 is hydrogen, 1-2C-alkyl or carboxy-1-2C-alkyl
  • R5 is R6 or -C p H 2p -Ar, in which
  • R6 is 3-7C-cycloalkyl or an unsubstituted or by R61 substituted phenyl radical, in which
  • R61 is carboxyl or 1-2C-alkoxycarbonyl
  • Ar is an unsubstituted or by R7 substituted phenyl radical, in which
  • R7 is carboxyl, carboxy-1-2C-alkyl or 1-2C-alkoxycarbonyl
  • P is 1
  • r is an integer from 1 to 6, and the salts of these compounds.
  • Preferred compounds of the formula I are those in which
  • R1 is methoxy
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is bromine, hydroxyl, carboxyl, dimethylamino, imidazolyl, benzimidazolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which R22 is carboxymethyl, R24 is hydrogen, carboxyl, carboxymethyl, aminocarbonyl, cyano, tetrazolyl, imidazolyl or 4-methyl-6- oxo-1 ,4,5,6-tetrahydropyridazin-3-yl, R26 is hydrogen, methyl or carboxymethyl, R3 and R4 form together an additional bond R5 is 5-7C-cycloalkyl or phenyl, r is an integer from 1 to 6, and the salts of these compounds.
  • R1 is methoxy
  • R2 is hydroxyl or stands for -0-C r H 2r -R21 , wherein
  • R21 is bromine, hydroxyl, carboxyl, dimethylamino, imidazolyl, benzimidazolyl, purinyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which R22 is carboxymethyl,
  • R24 is hydrogen, carboxyl, carboxymethyl, aminocarbonyl, cyano, tetrazolyl or imidazolyl
  • R26 is hydrogen, methyl or carboxymethyl
  • R3 and R4 form together an additional bond
  • R5 is 5-7C-cycloalkyl or phenyl
  • r is an integer from 1 to 6, and the salts of these compounds.
  • R1 is methoxy
  • R2 stands for -0-C r H 2r -R21 , wherein
  • R21 is hydroxyl, imidazolyl, a phenyl radical substituted by R22, a phenoxy radical substituted by R24, or a coumarinyloxy radical substituted by R26, in which R22 is carboxymethyl,
  • R24 is hydrogen, carboxyl, carboxymethyl, aminocarbonyl, cyano or imidazolyl
  • R26 is hydrogen, methyl or carboxymethyl
  • R3 and R4 form together an additional bond
  • R5 is cyclopentyl, cycloheptyl or phenyl
  • r is an integer from 1 to 6, and the salts of these compounds.
  • the compounds of formula I are chiral compounds with chiral centers in the positions 4a and 8a.
  • the invention includes all conceivable pure diastereomers and pure enantiomers, as well as all mixtures thereof independent from the ratio, including the racemates.
  • Preferred are those compounds, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
  • Especially preferred are in this connection those compounds, in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a. Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art.
  • the racemic mixtures are separated into two diastereomers with the help of an optical active separation agent on the stage of the cyclohexanecarboxylic acids (for example, starting compound B1) or the 1 ,2,3,6-tetrahydrobenzoic acids (for example, starting compound A1 ).
  • an optical active separation agent on the stage of the cyclohexanecarboxylic acids (for example, starting compound B1) or the 1 ,2,3,6-tetrahydrobenzoic acids (for example, starting compound A1 ).
  • optical active amines such as the (+)- and (-)-forms of ⁇ -phenylethylamin and ephedrine, or the optical active alkaloids cinchonine, cinchonidine and brucine.
  • the Keto acids of formula II in which R1 , R2, R3 and R4 have the abovementioned meanings can, for example, be prepared from compounds of the formula III, in which R1 and R2 have the abovementioned meanings and Z represents hydrogen (H) by a Friedel-Crafts acylation with compounds of the formula IV, in which R3 and R4 have the abovementioned meanings.
  • the Friedel-Crafts acylation is carried out in a manner which in known by the skilled person (for example as described in M. Yamaguchi et al., J. Med. Chem. 36: 4052-4060, 1993) in presence of a suitable catalyst, such as for example, AICl 3 , ZnCI 2 , FeCI 3 or iodine, in an appropriate inert solvent, such as methylene chloride or nitrobenzene or another inert solvent such as diethylether, preferably at raised temperature, especially at the boiling point of the solvent being used.
  • a suitable catalyst such as for example, AICl 3 , ZnCI 2 , FeCI 3 or iodine
  • an appropriate inert solvent such as methylene chloride or nitrobenzene or another inert solvent such as diethylether, preferably at raised temperature, especially at the boiling point of the solvent being used.
  • the compounds of formula II in which R1 , R2, R3 and R4 have the abovementioned meanings
  • R1 , R2, R3 and R4 have the abovementioned meanings
  • Z represents a halogen atom through reaction with compounds of the formula IV, in which R3 and R4 have the abovementioned meanings.
  • the reaction is carried out in a manner which is known by a person skilled in the art, for example
  • the compounds of formula I can be prepared by
  • these compounds can be further reacted with alkylating agents of formula R5-X, in which R5 has the abovementioned meanings [exception: R5 does not represent hydrogen (H)] and X represents a leaving group to give further compounds of formula I, in which R1 , R2, R3, R4 and R5 have the abovementioned meanings [exception: R5 does not represent hydrogen (H)].
  • inert solvents are preferably used alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamylalcohol, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or monoethyl ether, carboxylic acids such as formic acid, acetic or propionic acid, suitable mixtures of the abovementioned solvents, as well as mixtures with water, for example aqueous ethanol, further ethers, especially water soluble ethers such as tetrahydrofuran, dioxane or ethylene glycol dimethylether; further toluene or benzene, especially when the method of azeotropic destination is used to remove the reaction water.
  • alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamylalcohol
  • glycols and their ethers such as ethylene glycol, diethylene glycol,
  • the reaction temperatures are suitably between 0 and 200°C, preferably between 20 and 100°C; the reaction times are preferably between 1 and 48 hours.
  • Suitable reactive derivatives of the keto acids of formula II which may be mentioned in this context are, for example, esters, especially methyl and ethyl esters, nitrils and acid halides, such as acid chlorides or acid bromides. They can be prepared, for example, starting from the corresponding keto acids of formula II, by methods which are known by the person skilled in the art.
  • the hydrogen atom (H) of the NH-group of the compounds of formula I, in which R5 represents a hydrogen atom (H) is removed by a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolate, sodium ethanolate or buthyllithium in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or diethylether.
  • a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolate, sodium ethanolate or buthyllithium in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or diethylether.
  • a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolate, sodium ethanolate or buthyllithium in a suitable inert solvent such as dimethylformamide, dimethylsulfox
  • the bases are preferably used in more than an equimolar ratio; the reaction temperature is preferably between 0 and 150°C.
  • Suitable leaving groups X which may be mentioned are halogen atoms, especially chlorine, or hydroxyl groups activated by esterification (for example with p-toluenesulfonic acid).
  • halogen atoms especially chlorine
  • hydroxyl groups activated by esterification for example with p-toluenesulfonic acid.
  • suitable temporary protection groups in this connection may be mentioned, for example, the 2-tetrahydropyranyl, t-butyl, isopropyl, allyl, benzyloxymethyl, methoxyethoxyethyl, methylthiomethyl, methoxymethyl, cyclopropylmethyl, cyclopentyl and the cyclohexyl group.
  • the compounds of formula la can be obtained starting from the compounds of formula V through a selective ether cleavage reaction.
  • the ether cleavage reaction can be performed, for example, using a strong acid like sulphuric acid, hydrochloric acid or p-toluenesulphonic acid, in an inert solvent, such as for example, benzene or toluene, preferably at raised temperature, especially at the boiling temperature of the solvent being used.
  • a strong acid like sulphuric acid, hydrochloric acid or p-toluenesulphonic acid
  • an inert solvent such as for example, benzene or toluene, preferably at raised temperature, especially at the boiling temperature of the solvent being used.
  • the alkylation reactions are carried out using standard conditions which are familiar to the person skilled in the art.
  • compounds of formula I (lb), in which R21 comprises an ester can be converted by acidic or alkaline saponification to the corresponding carboxylic acid or by reaction with a suitable amine to the corresponding amide.
  • compounds of formula I (lb), in which R21 comprises a reactive leaving group such as, for example, a halogen atom can be converted to the corresponding amines by reaction with an appropriate amine.
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g. 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 base, or to which the desired acid or base is then added.
  • a suitable solvent e.g. 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 base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent.
  • Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologically non-tolerable salts can be converted into pharmacological
  • the compounds according to the invention have useful pharmacological properties which make them industrially utilizable.
  • selective cyclic nucleotide phosphodiesterase (PDE) inhibitors specifically of type 4
  • they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions on account of their dilating action but also on account of their respiratory rate- or respiratory drive-increasing action) and for the removal of erectile dysfunction on account of their vascular dilating action, but on the other hand especially for the treatment of disorders, in particular of an inflammatory nature, e.g.
  • the compounds according to the invention are distinguished by a low toxicity, a good enteral absorption (high bioavailability), a large therapeutic breadth and the absence of significant side effects.
  • the compounds according to the invention can be employed in human and veterinary medicine as therapeutics, where they can be used, for example, for the treatment and prophylaxis of the following illnesses: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of varying origin (bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea and other prolife
  • the compounds of the invention are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; and also illnesses of the central nervous system, such as depressions or arteriosclerotic dementia.
  • cerebral metabolic inhibition such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia
  • illnesses of the central nervous system such as depressions or arteriosclerotic dementia.
  • the invention further relates to a method for the treatment of mammals, including humans, which are suffering from one of the abovementioned illnesses.
  • the method is characterized in that a therapeuti- cally active and pharmacologically effective and tolerable amount of one or more of the compounds according to the invention is administered to the ill mammal.
  • the invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, especially the illnesses mentioned.
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the illnesses mentioned.
  • the invention furthermore relates to medicaments for the treatment and/or prophylaxis of the illnesses mentioned, which contain one or more of the compounds according to the invention.
  • the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for antagonizing the effects of the cyclic nucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptoms of an PDE4-mediated disorder, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating PDE4-mediated disorders, and wherein said pharmaceutical agent comprises one or more compounds of formula I according to the invention.
  • the packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.
  • the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on account of his expert knowledge.
  • gel formers for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters
  • active compound excipients for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters
  • the compounds according to the invention are preferably also administered by inhalation. To do this, these are either administered directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions which contain them.
  • European Patent 163 965 With respect to the preparations and administration forms, reference is made, for example, to the details in European Patent 163 965.
  • the compounds according to the invention are in particular administered in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • the medicaments according to the invention are prepared by processes known per se.
  • the dosage of the active compounds is carried out in the order of magnitude customary for PDE inhibitors.
  • Topical application forms (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for example, 0.1-99%.
  • the dose for administration by inhalation is customarly between 0.1 and 3 mg per day.
  • the customary dose in the case of systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg/kg per day.
  • FMLP N-formyl-methionyl-leucyl-phenylalanine
  • Mc Phail LC Strum SL, Leone PA and Sozzani S, The neutrophil respiratory burst mechanism.
  • Coffey RG Marcel Decker, Inc., New York- Basel-Hong Kong
  • Substances which inhibit chemiluminescence and cytokine secretion and the secretion of proinflamma- tory mediators on inflammatory cells are those which inhibit PDE 4.
  • This isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation. PDE 4 inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes.
  • the activity test was carried out according to the method of Bauer and Schwabe, which was adapted to microtitre plates (Naunyn-Schmiederberg ' s Arch. Pharmacol. 311 , 193-198, 1980).
  • the PDE reaction is carried out in the first step.
  • the resultant 5 ' -nucleotide is cleaved to the uncharged nucleoside by a snake venom 5 ' -nucleotidase from Crotalus Atrox.
  • the nucleoside is separated from the remaining charged substrate on ion exchange columns. The columns are eluted directly into minivials using 2 ml of 30 mM ammonium formate (pH 6.0), to which a further 2 ml of scintillation fluid is added for counting.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Les composés de formule (I), dans laquelle R1, R2, R3, R4 et R5 ont les significations données dans la description, sont des agents thérapeutiques pour les bronches, nouveaux et efficaces.
PCT/EP1998/008015 1997-12-15 1998-12-09 Nouveaux phtalazinones WO1999031071A1 (fr)

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AU17603/99A AU1760399A (en) 1997-12-15 1998-12-09 New phthalazinones

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EP97122038 1997-12-15
EP97122038.9 1997-12-15

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WO2001030777A1 (fr) * 1999-10-25 2001-05-03 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives tetrahydrothiopyranphthalazinone utilises comme inhibiteurs de pde4
WO2001030766A1 (fr) * 1999-10-25 2001-05-03 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de phthalazinone, utilises comme inhibiteurs de pde4
WO2001094319A1 (fr) * 2000-06-05 2001-12-13 Altana Pharma Ag Composes efficaces comme agonistes du recepteur beta 2-adrenergique et comme inhibiteurs de pde4
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4
WO2002085906A2 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Phtalazinones
WO2002085885A1 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Derives piperazines et leur utilisation en tant qu'inhibiteurs de pde4
WO2004018449A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4)
WO2004018450A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de n-oxyde de piperidine
KR100426534B1 (ko) * 2001-09-03 2004-04-28 한올제약주식회사 아젤라스틴의 개선된 합성방법
US7220746B2 (en) 2002-08-10 2007-05-22 Altana Pharma Ag Pyrrolidinedione substituted piperidine-phthalazones as PDE4 inhibitors
US7494990B2 (en) 2004-02-04 2009-02-24 Nycomed Gmbh 2-(piperidin-4-yl)-4,5-dihydro-2H-pyridazin-3-one derivatives as PDE4 inhibitors
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
CN102964340A (zh) * 2012-12-12 2013-03-13 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation

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EP0634404A1 (fr) * 1993-07-13 1995-01-18 Rhone Poulenc Agriculture Ltd. Dérivés de phtalazine et leur utilisation comme pesticides

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WO1994012461A1 (fr) * 1992-12-02 1994-06-09 Pfizer Inc. Diethers de pyrocatechine utilises comme inhibiteurs selectifs de la pde¿iv?
EP0634404A1 (fr) * 1993-07-13 1995-01-18 Rhone Poulenc Agriculture Ltd. Dérivés de phtalazine et leur utilisation comme pesticides

Cited By (33)

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EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US6756371B1 (en) 1999-10-25 2004-06-29 Altana Pharma Ag Phthalazinone derivatives as PDE4 inhibitors
WO2001030766A1 (fr) * 1999-10-25 2001-05-03 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de phthalazinone, utilises comme inhibiteurs de pde4
WO2001030777A1 (fr) * 1999-10-25 2001-05-03 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives tetrahydrothiopyranphthalazinone utilises comme inhibiteurs de pde4
US6846821B2 (en) 1999-10-25 2005-01-25 Altana Pharma, Ag Tetrahydrothiopy ranphthalazinone derivatives as PDE4 inhibitors
US6544993B1 (en) 1999-10-25 2003-04-08 Altana Pharma Ag Tetrahydrothiopyranphthalazinone derivatives as PDE4 inhibitors
WO2001094319A1 (fr) * 2000-06-05 2001-12-13 Altana Pharma Ag Composes efficaces comme agonistes du recepteur beta 2-adrenergique et comme inhibiteurs de pde4
US6933296B2 (en) 2000-06-05 2005-08-23 Altana Pharma B.V. Compounds effective as β2-adrenoreceptor agonists as well as PDE4-inhibitors
US7179810B2 (en) 2001-02-15 2007-02-20 Altana Pharma Ag Phthalazinone-piperidino-derivatives as PDE4 inhibitors
US6953853B2 (en) 2001-02-15 2005-10-11 Altana Pharma Ag Phthalazinone-piperidino-derivatives as PDE4 inhibitors
HRP20030636B1 (en) * 2001-02-15 2012-05-31 Nycomed Gmbh Phthalayinone-piperidino-derivatives as pde4 inhibitors
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4
US7531540B2 (en) 2001-02-15 2009-05-12 Nycomed Gmbh Phthalazinone-piperidino-derivatives as PDE4 inhibitors
AU2002234634B2 (en) * 2001-02-15 2007-07-26 Takeda Gmbh Phthalayinone-piperidino-derivatives as PDE4 inhibitors
CZ299347B6 (cs) * 2001-04-25 2008-06-25 Altana Pharma Ag Ftalazinonové deriváty, jejich použití a léciva sjejich obsahem
WO2002085906A3 (fr) * 2001-04-25 2002-12-19 Altana Pharma Ag Phtalazinones
WO2002085906A2 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Phtalazinones
US7186710B2 (en) 2001-04-25 2007-03-06 Altana Pharma Ag Phthalazinones
US7022696B2 (en) 2001-04-25 2006-04-04 Altana Pharma Ag Piperazino-derivatives and their use as PDE4 inhibitor
WO2002085885A1 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Derives piperazines et leur utilisation en tant qu'inhibiteurs de pde4
AU2002315311B2 (en) * 2001-04-25 2007-12-06 Altana Pharma Ag Piperazino-derivatives and their use as PDE4 inhibitor
KR100426534B1 (ko) * 2001-09-03 2004-04-28 한올제약주식회사 아젤라스틴의 개선된 합성방법
WO2004018450A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de n-oxyde de piperidine
US7220746B2 (en) 2002-08-10 2007-05-22 Altana Pharma Ag Pyrrolidinedione substituted piperidine-phthalazones as PDE4 inhibitors
WO2004018449A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4)
US7494990B2 (en) 2004-02-04 2009-02-24 Nycomed Gmbh 2-(piperidin-4-yl)-4,5-dihydro-2H-pyridazin-3-one derivatives as PDE4 inhibitors
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
US8247414B2 (en) 2006-07-25 2012-08-21 Cephalon, Inc. Pyridizinone derivatives and the use thereof as H3 inhibitors
US8586588B2 (en) 2006-07-25 2013-11-19 Cephalon, Inc. Aryl pyridazinone derivatives and their use as H3 receptor ligands
US8673916B2 (en) 2006-07-25 2014-03-18 Cephalon, Inc. Methods of treating disorders mediated by histamine H3 receptors using pyridazinone derivatives
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation
CN102964340A (zh) * 2012-12-12 2013-03-13 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂
CN102964340B (zh) * 2012-12-12 2015-10-07 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂

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