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WO1998018764A1 - Dihydrobenzoanthracenone, -pyrimidinone ou dihydroanphtoquinolinone - Google Patents

Dihydrobenzoanthracenone, -pyrimidinone ou dihydroanphtoquinolinone Download PDF

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Publication number
WO1998018764A1
WO1998018764A1 PCT/EP1997/005592 EP9705592W WO9818764A1 WO 1998018764 A1 WO1998018764 A1 WO 1998018764A1 EP 9705592 W EP9705592 W EP 9705592W WO 9818764 A1 WO9818764 A1 WO 9818764A1
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Prior art keywords
formula
dihydro
compounds
group
shark
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PCT/EP1997/005592
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German (de)
English (en)
Inventor
Horst Juraszyk
Joachim Gante
Hanns Wurziger
Peter Raddatz
Sabine Bernotat-Danielowski
Guido Melzer
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Merck Patent Gmbh
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Priority to AU49466/97A priority Critical patent/AU4946697A/en
Publication of WO1998018764A1 publication Critical patent/WO1998018764A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings

Definitions

  • the invention relates to compounds of the formula I.
  • R 6 CN COOH, COOA, CONH 2 , CONHA or CONA 2 , R 7 CN, CF 3 , shark, OH, OA, Het or S-Het,
  • R 8 A Ar, A-CO, Ar-alk-CO, AO-CO or Ar-alk-O-CO,
  • R 3 and R 10 together also form a bond, the free valence of the R 10- bearing C atom being saturated by H,
  • Ring members where 1 or 2 N- and / or 1 or 2 S- or 0- Atoms can be present and the heterocyclic radical can be substituted once or twice by CN, shark, OH, OA, CF 3 , A, NH 2 1 NHA, NA 2 or N0 2
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts and solvates have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the ⁇ v integrin receptors with ligands.
  • the compounds are particularly effective in the case of the integrins ⁇ v ß 3 and ßs-
  • the compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor ⁇ v ß 3 .
  • the compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis in the pathological environment of the organism.
  • micro-aggregates microthroma ben
  • the tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.
  • the micro-aggregates can attach themselves to the walls of the vessels, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.
  • compounds of the formula I In addition to the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as vitonectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
  • other adhesive proteins such as vitonectin, collagen and laminin
  • Inhibition of fibrinogen binding to the fibrinogen receptor can be detected using the method specified in EP-A1-0 381 033.
  • the antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
  • the invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitors.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They act as adhesion receptor antagonists and are suitable for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as eg inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, infection, viral infection, angioplasty, viral acute kidney failure and in wound healing to support the healing processes. Furthermore, they can be used to coat artificial surfaces and can thus be used for the therapeutic purposes mentioned.
  • the compounds of the formula I in particular in the form of coating materials, can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They also have an antiseptic effect.
  • the effectiveness of the antimicrobial activity can be demonstrated by the method described by P.Valentin-Weigund et al., In Infection and Immunity, 2851-2855 (1988).
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and their salts, characterized in that
  • R 1 , R 2 , R 3 , R 4 and R 5 and Y have the meanings given in claim 1 and
  • R, R, R, R and R and X and Y have the meanings given in claim 1 and
  • R 1 and shark have the meanings given in claim 1.
  • R 1 , R 2 , R 3 and R 4 have the meanings given in claim 1 and
  • free amino groups can be provided as substituents of compounds of the formula I with corresponding protective groups known per se.
  • A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1 -, 1, 2- or 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1, 1 -, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl.
  • Alkyl also means cyclobutyl, methylene cyclobutyl, cyclopentyl, methylene cyclopentyl, cyclohexyl or methylene cyclohexyl, methylene cyclopropyl or cyclopropyl.
  • the remainder alk denotes alkylene and is preferably methylene, ethylene, propylene, but also butylene, pentylene or hexylene.
  • Alkanoyl preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, furthermore nonanoyl or
  • Ar is preferably phenyl, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p- Propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-aminocarbonylphenyl, o-, m- or p- nitrophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-brom
  • Ethoxycarbonylphenyl more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chlorine -3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl-4-chloro , 2-methyl-5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3 methyl, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2 -Methyl-5-
  • Aralkanoyl preferably means benzoyl, unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenylacetyl, o-, m- or p-methoxyphenyl acetyl, o-, o-, m- or p-ethoxyphenylacetyl, o-, m - or p-fluorophenylacetyl, o-, m- or p-bromophenylacetyl, o-, m- or p-chlorophenylacetyl, o-, m- or p-methylphenylacetyl, o-, m- or p-ethylphenylacetyl, o- , m- or p-aminophenyl acetyl, o-, m- or p-nitrophenylacetyl, o-, m
  • Alkoxycarbonyl preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and also isopropoxycarbonyl, tert. -Butoxycarbonyl or hexyloxycarbonyl.
  • Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4-or -5-yl, 1, 2,4-triazol-1- , -3- or -5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or -5-yl, 1 , 3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4
  • heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also mean, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, Tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, - 4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, - 2- or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-,
  • R 2 , R 3 , R 4 and R 5 are preferably different from one another, but two to three of the radicals can also have the same meaning.
  • one or two radicals mean H, while the others have different meanings.
  • R 6 preferably denotes COOH or COOA, in particular COOMe or COOEt.
  • R 7 preferably denotes Het or S-Het, where Het in particular denotes pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl or morphlidinyl in substituted or unsubstituted form.
  • Het is also preferably benzimidazolyl, benzodioxanyl, indolyl, quinolinyl or isoquinolinyl.
  • Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl or benzyl and will be explained in more detail later.
  • Shark is preferably F, Cl or Br.
  • X are N or CR 6
  • Y are N or CR 7
  • the following ring systems are intended to be included by the present invention through these definitions:
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • R 4 and R 7 together -CO-CH 2 -CH 2 -, -CO-CH 2 -CHA-,
  • R 3 and R 10 together form a bond, the free valence of the R 10- bearing C atom being saturated by H,
  • R 2 , R 3 and R 5 are hydrogen
  • R 2 , R 3 and R 5 are hydrogen.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an Hn group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr.
  • Preferred amino protecting groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. They are typical of such groups - 1 o -
  • hydroxyl protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the groups BOC and OBut can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
  • Hydrogenolytically removable protective groups can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, conveniently on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, conveniently on a support such as coal.
  • a solvent are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good at 5 to 10
  • Compounds of formula I can also preferably be obtained by cyclizing compounds of formula II or formula III.
  • the starting compounds of the formula II are generally known and are commercially available. However, the unknown compounds can be prepared by methods known per se.
  • the compounds of formula II are anthraquinone derivatives. They can be prepared in a conventional manner from anthraquinone or suitable derivatives by appropriate substitutions on the aromatic system. It is also possible to convert appropriately substituted anthracenes into the anthraquinones by oxidation.
  • the compounds of the formula III are quinazoline derivatives, which are also generally commercially available. Furthermore, these compounds can be prepared by reacting o-acylanilines with acid amides.
  • the cyclizations are usually carried out in an inert solvent, preferably in the presence of an acid.
  • the reaction time is between a few minutes and several days, the reaction temperature is between approximately 0 ° and 150 °, normally between 20 ° and 130 °.
  • the reactions can e.g. B. in analogy to those in U.S. 2, 15,445 specified methods are carried out.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Ni
  • the compounds of the formula IV are derived from the anthrone and can be prepared from appropriately substituted anthraquinones by reduction with tin and hydrochloric acid in glacial acetic acid under conditions known per se. Furthermore, the substituents R 2 to R 5 can also be introduced by substitutions on the aromatic. In many cases, however, it is advisable to introduce these substituents before the reduction.
  • halides of the formula V are generally known and their preparation is familiar to the person skilled in the art, so that a description of the
  • reaction of the compounds of formula IV with compounds of formula V is preferably carried out in an inert solvent
  • Suitable acid-binding agents are preferably alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium.
  • a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable.
  • Derivatives with a free primary or an additional secondary amino group are expediently used in protected form.
  • the aforementioned groups can be used as protective groups.
  • the compounds of formula VI are derived from binaphthyl and are known per se or can be prepared by synthetic methods known per se.
  • the substituents R 2 to R 5 can preferably be introduced by substitution on the aromatic.
  • the cyclization of the compounds of formula VI is preferably carried out in an inert solvent.
  • a base can be advantageous.
  • the preferred reaction temperatures and reaction times are given above.
  • Suitable base additives are preferably alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, and the others mentioned above.
  • the reactions can preferably be carried out in analogy to those in J. Amer. Chem. Soc. 53, 3104-3108 (1931).
  • a corresponding amino-substituted compound can be treated with an amidinating agent.
  • 1-Amidino-3,5-dimethylpyrazole (DPFN) which is used in particular in the form of its nitrate, is preferred as the amidizing agent.
  • DPFN 1-Amidino-3,5-dimethylpyrazole
  • an excess of an alcohol advantageously in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0 and 100 ° C, preferably between 20 and 50 ° C.
  • an ester of the formula I can be converted into the corresponding acid of the formula I, advantageously by solvolysis using one of the methods given above, for example using NaOH or KOH in water dioxane at temperatures between 0 and 40 ° C, preferably between
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn contains NH 3 reacts to the amidine, b) the nitrile is converted to the corresponding imidoester with an alcohol, for example ethanol in the presence of HCl, and treated with ammonia, or c) the nitrile is reacted with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • NH 3 alkylating agent
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone - or sulfuric acids, e.g.
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills,
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, e.g. one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, e.g. one or more vitamins.
  • the compounds of formula I and their physiologically acceptable salts and solvates act as adhesion receptor antagonists and can be used in the control of diseases, in particular for the treatment of thromboses, tumor diseases, arteriosclerosis, apoplexy, inflammation, ischemia, osteoporosis and heart failure.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred. All temperatures above and below are given in ° C.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, the isomers described below also being separated and / or by crystallization.
  • a suspension of 4.37 g of 4- (2- (4-methyl-piperazino) propenal-3-yl) anthraquinone in 180 ml of THF is prepared under the conditions of the McMurray reaction (Accounts Chem. Res. 16, 405 (1983 )), ie cyclized in the presence of potassium and TiCl 3 by refluxing for 12 hours. After 12
  • a suspension of 1.2 g of 1-amino-4-cyan-7-amidino-anthraquinone in 120 ml of THF is mixed with 2 equivalents of formamide and refluxed for 6 hours.
  • the mixture is allowed to cool and, after customary working up, 6-cyan-10-amidino-7a, 11-a-dihydro-benzo [e] pe ⁇ ' midin-7-one is obtained.
  • Example 4 Analogously to Example 4, starting from 1- (1-chlorocarbonylprop-2-yl) -3-methoxy-4-methyl-6,8,10-trihydroxy-7a, 11a-dihydrobenzo [de] anthracen-7-one [obtainable according to Example 1 by subsequent conversion of the ester into the acid chloride] by cyclization under Friedel-Crafts conditions 3,5,7-trihydroxy-10-methoxy-1, 1, 9-trimethyl-1 H-benzo [cd] pyrene-2,6-dione.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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

Abstract

L'invention concerne de nouveaux composés de la formule (I) dans laquelle X, Y, R?1, R2, R3, R4 et R5¿ ont la signification mentionnée dans la description, ainsi que leurs sels et solvates. Ces composés inhibent la liaison de fibrinogène sur le récepteur correspondant et s'utilisent par exemple pour traiter des thromboses, l'ostéoporose, des affections tumorales, l'apoplexie, l'infarctus du myocarde, des ischémies, des inflammations, l'artériosclérose et des affections ostéolytiques.
PCT/EP1997/005592 1996-10-28 1997-10-10 Dihydrobenzoanthracenone, -pyrimidinone ou dihydroanphtoquinolinone WO1998018764A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49466/97A AU4946697A (en) 1996-10-28 1997-10-10 Dihydrobenzoanthracenone, -pyrimidinone or dihydronaphtoquinolinone

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DE19644748 1996-10-28
DE19644748.8 1996-10-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032577A3 (fr) * 1998-11-25 2000-09-21 Merck Patent Gmbh Benzo[de]isoquinoline-1,3-diones substituees

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JPS5283652A (en) * 1976-01-01 1977-07-12 Mitsubishi Chem Ind Ltd Benzanthrone derivatives
JPS5295678A (en) * 1976-02-09 1977-08-11 Kawasaki Kasei Chem Ltd Preparation of 2-carboxy-1, 9-anthrapyrimidine
US4051138A (en) * 1975-12-08 1977-09-27 Dynapol Water-soluble amine-linked polymeric colorants
JPS52117133A (en) * 1976-03-26 1977-10-01 Fuji Photo Film Co Ltd Resist image formation by stripping
DE2722773A1 (de) * 1976-05-21 1977-12-08 Rhone Poulenc Ind Neue derivate des dibenzo eckige klammer auf de,h eckige klammer zu chinolins, ihre herstellung und die sie enthaltenden zusammensetzungen
DE2741452A1 (de) * 1976-09-14 1978-03-16 Fuji Photo Film Co Ltd Lichtempfindliche masse
US4088572A (en) * 1976-11-18 1978-05-09 Dynapol Ultrafiltration purification of solution of polymeric anthraquinone colorants
JPS5392841A (en) * 1977-01-25 1978-08-15 Teijirou Kitao Colored organic compound* method of making same and coloring method of high polymer material using same
EP0022062A1 (fr) * 1979-05-30 1981-01-07 Ciba-Geigy Ag Procédé électrochimique pour la préparation de benzanthrone
DE3001149A1 (de) * 1980-01-15 1981-07-16 Bayer Ag, 5090 Leverkusen Lichtsammelsysteme und die verwendung von anthrapyrimidinderivaten als energiewandler in ihnen
DE3001188A1 (de) * 1980-01-15 1981-07-16 Bayer Ag, 5090 Leverkusen Anthrapyrimidinderivate und ihre verwendung als farbstoffe
JPS5738704A (en) * 1980-08-21 1982-03-03 Asahi Chem Ind Co Ltd Antifouling agent
JPS5742605A (en) * 1980-08-28 1982-03-10 Asahi Chem Ind Co Ltd Treating agent against injurious plankton and treating method
JPS5931962A (ja) * 1982-08-17 1984-02-21 Canon Inc 有機光導電体
JPS61175644A (ja) * 1985-01-31 1986-08-07 Canon Inc 電子写真感光体
JPS61203193A (ja) * 1985-03-06 1986-09-09 Sumitomo Chem Co Ltd エレクトロクロミツク表示装置
JPS62153859A (ja) * 1985-12-27 1987-07-08 Toyo Ink Mfg Co Ltd 電子写真感光体
EP0246193A2 (fr) * 1986-05-15 1987-11-19 Ciba-Geigy Ag Procédé de préparation de produits intermédiares anthraquinoniques et de colorants de cuve
EP0301910A2 (fr) * 1987-07-31 1989-02-01 Mita Industrial Co. Ltd. Matériau organique, laminé, photosensible du type à chargement positif et procédé pour sa préparation
DE3902686A1 (de) * 1988-02-05 1989-08-17 Ciba Geigy Ag Borkomplexe
JPH01241564A (ja) * 1988-03-23 1989-09-26 Canon Inc 電子写真感光体
JPH02243662A (ja) * 1989-03-16 1990-09-27 Mitsui Toatsu Chem Inc アミノベンザントロン類の製造方法
JPH0713354A (ja) * 1993-06-21 1995-01-17 Ricoh Co Ltd 積層型電子写真感光体及びその製造方法
JPH0790257A (ja) * 1993-09-24 1995-04-04 Nisshinbo Ind Inc 有機電界発光素子
JPH07165685A (ja) * 1993-12-09 1995-06-27 Mitsui Toatsu Chem Inc ３，９−ジアミノベンザントロンの製造方法
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DE407838C (de) * 1922-05-20 1924-12-24 Basf Ag Verfahren zur Darstellung von Kondensationsprodukten der Benzanthronreihe
DE436888C (de) * 1924-10-26 1926-11-11 I G Farbenindustrie Akt Ges Verfahren zur Darstellung von Isodibenzanthronen
DE485961C (de) * 1927-03-09 1929-11-11 I G Farbenindustrie Akt Ges Verfahren zur Darstellung von Kuepenfarbstoffen der Anthanthronreihe
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DE533493C (de) * 1928-02-04 1931-09-15 I G Farbenindustrie Akt Ges Verfahren zur Darstellung schwefelhaltiger Farbstoffe und Zwischenprodukte der Anthanthronreihe
US1856710A (en) * 1928-05-02 1932-05-03 Gen Aniline Works Inc Process of preparing vat dyestuffs
DE559354C (de) * 1928-05-03 1932-09-20 I G Farbenindustrie Akt Ges Verfahren zur Darstellung von Kuepenfarbstoffen der 3, 4, 8, 9-Dibenzpyrenchinonreihe
US1876973A (en) * 1928-07-28 1932-09-13 Gen Aniline Works Inc Substitution products of anthanthrones
US2059647A (en) * 1935-05-25 1936-11-03 Du Pont Compounds of the benzanthrone series
BE657303A (fr) * 1963-12-19 1965-04-16
DE2200127A1 (de) * 1972-01-03 1973-07-12 Basf Ag Verfahren zur herstellung von dichlor1,1'-dianthrachinonylen und deren derivaten
JPS4876927A (fr) * 1972-01-17 1973-10-16
DE2246255A1 (de) * 1972-09-21 1974-03-28 Kalle Ag Elektrophotographisches aufzeichnungsmaterial
US3975285A (en) * 1972-10-30 1976-08-17 Hodogaya Chemical Co., Ltd. Liquid crystal composition
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JPS5063913A (fr) * 1973-10-08 1975-05-30
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JPS52117133A (en) * 1976-03-26 1977-10-01 Fuji Photo Film Co Ltd Resist image formation by stripping
DE2722773A1 (de) * 1976-05-21 1977-12-08 Rhone Poulenc Ind Neue derivate des dibenzo eckige klammer auf de,h eckige klammer zu chinolins, ihre herstellung und die sie enthaltenden zusammensetzungen
DE2741452A1 (de) * 1976-09-14 1978-03-16 Fuji Photo Film Co Ltd Lichtempfindliche masse
US4088572A (en) * 1976-11-18 1978-05-09 Dynapol Ultrafiltration purification of solution of polymeric anthraquinone colorants
JPS5392841A (en) * 1977-01-25 1978-08-15 Teijirou Kitao Colored organic compound* method of making same and coloring method of high polymer material using same
EP0022062A1 (fr) * 1979-05-30 1981-01-07 Ciba-Geigy Ag Procédé électrochimique pour la préparation de benzanthrone
DE3001149A1 (de) * 1980-01-15 1981-07-16 Bayer Ag, 5090 Leverkusen Lichtsammelsysteme und die verwendung von anthrapyrimidinderivaten als energiewandler in ihnen
DE3001188A1 (de) * 1980-01-15 1981-07-16 Bayer Ag, 5090 Leverkusen Anthrapyrimidinderivate und ihre verwendung als farbstoffe
JPS5738704A (en) * 1980-08-21 1982-03-03 Asahi Chem Ind Co Ltd Antifouling agent
JPS5742605A (en) * 1980-08-28 1982-03-10 Asahi Chem Ind Co Ltd Treating agent against injurious plankton and treating method
JPS5931962A (ja) * 1982-08-17 1984-02-21 Canon Inc 有機光導電体
JPS61175644A (ja) * 1985-01-31 1986-08-07 Canon Inc 電子写真感光体
JPS61203193A (ja) * 1985-03-06 1986-09-09 Sumitomo Chem Co Ltd エレクトロクロミツク表示装置
JPS62153859A (ja) * 1985-12-27 1987-07-08 Toyo Ink Mfg Co Ltd 電子写真感光体
EP0246193A2 (fr) * 1986-05-15 1987-11-19 Ciba-Geigy Ag Procédé de préparation de produits intermédiares anthraquinoniques et de colorants de cuve
EP0301910A2 (fr) * 1987-07-31 1989-02-01 Mita Industrial Co. Ltd. Matériau organique, laminé, photosensible du type à chargement positif et procédé pour sa préparation
DE3902686A1 (de) * 1988-02-05 1989-08-17 Ciba Geigy Ag Borkomplexe
JPH01241564A (ja) * 1988-03-23 1989-09-26 Canon Inc 電子写真感光体
JPH02243662A (ja) * 1989-03-16 1990-09-27 Mitsui Toatsu Chem Inc アミノベンザントロン類の製造方法
JPH0713354A (ja) * 1993-06-21 1995-01-17 Ricoh Co Ltd 積層型電子写真感光体及びその製造方法
JPH0790257A (ja) * 1993-09-24 1995-04-04 Nisshinbo Ind Inc 有機電界発光素子
JPH07165685A (ja) * 1993-12-09 1995-06-27 Mitsui Toatsu Chem Inc ３，９−ジアミノベンザントロンの製造方法
JPH0859520A (ja) * 1994-06-17 1996-03-05 Ricoh Co Ltd ベンズアンスロン誘導体及びそれを含有する電子写真感光体

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032577A3 (fr) * 1998-11-25 2000-09-21 Merck Patent Gmbh Benzo[de]isoquinoline-1,3-diones substituees

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