EP1076643A1 - Biphenyl derivatives - Google Patents

Biphenyl derivatives

Info

Publication number
EP1076643A1
EP1076643A1 EP99920646A EP99920646A EP1076643A1 EP 1076643 A1 EP1076643 A1 EP 1076643A1 EP 99920646 A EP99920646 A EP 99920646A EP 99920646 A EP99920646 A EP 99920646A EP 1076643 A1 EP1076643 A1 EP 1076643A1
Authority
EP
European Patent Office
Prior art keywords
formula
biphenyl
compounds
group
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99920646A
Other languages
German (de)
French (fr)
Inventor
Joachim Di Gante
Dieter Dorsch
Horst Juraszyk
Werner Mederski
Hanns Wurziger
Hans-Peter Buchstaller
Sabine Bernotat-Danielowski
Guido Melzer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1076643A1 publication Critical patent/EP1076643A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines

Definitions

  • the invention relates to compounds of the formula
  • R 2 , R 3 , R ö each independently of one another H, A, OR 6 , N (R 6 ) 2 , NO 2l CN, Hai, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) n A, S (O) n Ar, -O- [C (R 6 ) 2 ] m -COOR 6 , - [C (R 6 ) 2 ] p -COOR 6 , -O- [C (R 6 ) 2 ] m - CON (R 6 ) 2l - [C (R 6 ) 2 ] p -CON (R 6 ) 2 , -O- [C (R 6 ) 2 ] m -CONHAr, or - [C (R 6 ) 2 ] p -CONHAr,
  • R b H, A or benzyl, - 2 -
  • a alkyl with 1-20 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms or by -CR 6 CR 6 groups and / or 1-7 H atoms by F,
  • NHSO 2 A NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2l CONHAr', COR 6 , COAr ', S (O) n A or S (O) n Ar' substituted phenyl or 0 naphthyl,
  • p denotes 1 or 2, 5 and their salts.
  • the invention relates to the hydrates and solvates of these encryption "n bonds.
  • 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. 35 - 3 -
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermittently.
  • Aromatic amidine derivatives with antithrombotic activity are e.g. known from EP 0 540 051 B1.
  • Cyclic guanidines for the treatment of thromboembolic diseases are e.g. described in WO 97/08165.
  • Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022.
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory effect against the activated coagulation protease, known under the name factor Xa.
  • Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to thrombin, which in turn contributes to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. Inhibition of factor Xa can thus prevent thrombin from being formed.
  • the compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
  • the inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 63, 220-223 (1990).
  • the measurement of the inhibition of factor Xa can, for example, by the method of T. Hara et al. in thromb. Haemostas. 71, 314-319 (1994).
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate.
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
  • Hydrates and solvates are e.g. the hemi, mono- or dihydrates, among solvates e.g. Alcohol addition compounds such as with methanol or ethanol.
  • A means alkyl, is linear or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyi, 1, 1-, 1, 2 - or 2,2-dimethylpropyl, 1-ethyl propyl, 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, heptyl, Octyl, nonyl or decyl.
  • A also means e.
  • COR 6 is acyl and preferably means formyl, acetyl, propionyl, but also butyryl, pentanoyl or hexanoyl.
  • COOR 6 preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.
  • R 2 , R and R are each, independently of one another, preferably H, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfonamido, methylsulfonamido , Phenylsulfonamido, methylthio, ethylthio,
  • R 2 , R 5 mean H.
  • R 3 in particular denotes, for example, H, COOA or -OCH 2 COOR 6 , where R 6 denotes H or alkyl having 1-4 C atoms.
  • R represents H, A or benzyl, but especially H or alkyl with 1-4 C-
  • Ar preferably denotes unsubstituted phenyl or naphthyl, further preferably, for example, by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyioxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, Ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propyls
  • Ar therefore preferably means, for example, o-, m- or p-tolyi, 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-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, - or p- ( N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-,
  • Ar 'means in particular, for example, phenyl or naphthyl, further preferably, for example, o-, m- or p-tolyl, 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-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o -, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamido phenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,
  • 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.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 3 is H, COOR 6 or -O- (CH 2 ) COOR 6
  • A is alkyl with 1-4 carbon atoms. - 10 -
  • 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.
  • Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a soivolysing or hydrogenolysing agent.
  • 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 instead of an HN
  • Group carry an R'-N group, in which R 'represents an amino protecting group and / or those which carry a hydroxy protecting group instead of the H atom of a hydroxy group, e.g. those which correspond to the formula I, but carry parts of a group -COOH a group -COOR ", in which R" denotes a hydroxy protective group.
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • the oxadiazole group can be introduced, for example, by reacting the cyano compounds with hydroxylamine and reaction with phosgene, dialkylamine. - 11 -
  • 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 (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, 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 at other locations in the molecule. Typical of such groups are those above - 12 -
  • 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 reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr 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 e.g. CBZ, benzyl or the liberation of the amidino group from their oxadiazolde vat
  • a catalyst z. B. a noble metal catalyst such as palladium, suitably on a support such as coal or like wet Raney nickel with the addition of, for example, acetic acid - 13 -
  • Suitable solvents are the above, especially z.
  • 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
  • CBZ Group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • the conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C or Raney nickel.
  • a catalyst such as e.g. Pd / C or Raney nickel.
  • 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 in turn reacts with NH 3 to form the amidine, b) converting the nitrile with an alcohol, for example ethanoi in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • the cyan compounds are prepared by methods known per se.
  • Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • 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
  • the reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium , Calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula II or the alkylation derivative of the formula III can also be favorable.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
  • 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 - 15 -
  • hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
  • chlorinated hydrocarbons such as
  • glycol dimethyl ether diglyme
  • Ketones such as acetone or butanone
  • Amides such as acetamide, dimethylacetamide, N-methyipyrrolidone (NMP) or dimethylformamide (DMF)
  • Nitriles such as acetonitrile
  • Sulfoxides such as dimethyl sulfoxide (DMSO)
  • Carbon disulfide Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene; Esters like
  • a base of the formula I can be converted into the associated acid addition acid using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanoi and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • 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.
  • Physiologically harmless organic bases such as ethanol amine, can also be used. - 16 -
  • the invention further 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 optionally 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 which are suitable for enteral (for example 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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries 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.
  • auxiliaries 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 the formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclero- - 17 -
  • 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 wide 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 and combination of drugs and severity of the disease to which the therapy applies. Oral application is preferred.
  • a solution of 2.06 g of 3-bromobenzonitrile and 1.50 g of 3-tolylboronic acid in 50 ml of dimethoxyethane is mixed with 247 mg of palladium (II) acetate, 335 mg of tri-o-toiylphosphine, 20 ml of water and 954 mg of anhydrous sodium carbonate added and heated with stirring at 100 ° C for 18 hours.
  • the mixture is worked up in the customary manner, the residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate 9: 1 and 3'-methylbiphenyl-3-carbonitrile is obtained as a colorless solid ("A”), El 193.
  • the compound 3'-cyano-5-methyl-biphenyl-3-carboxylic acid methyl ester is obtained by reacting 3-cyanophenylboronic acid with methyl 3-bromo-5-methylbenzoate. Bromination with NBS and reaction with 3-hydroxybenzonitrile gives 3'-cyan-5- (3-cyanophenoxymethyl) biphenyl-3-carboxylic acid methyl ester. Reaction with hydroxyiamine and reduction with H 2 / Ra-Ni gives the compound 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid methyl ester. - 20th
  • tert-butyl ester are cleaved with trifluoroacetic acid and the corresponding carboxylic acids are obtained
  • a solution of 5.0 g of 3'-bromomethyl-biphenyl-3-carbonitrile and 5 ml of triethyl phosphite are combined and slowly heated to 150 °.
  • the mixture is subsequently stirred at 150 ° for 6 h and, after customary working up, 6.05 g of diethyl 3-cyano-biphenyl-3-ylmethylphosphonate ("BA”) are obtained.
  • 150 mg of sodium hydride are added to a solution of 1.0 g of “BA” and 3-cyanobenzaldehyde in 20 ml of ethylene glycol dimethyl ether with ice cooling and nitrogen.
  • the mixture is stirred for 4 hours, worked as usual and 0.93 g of 3 '- [2- (3-cyanophenyl) vinyl] biphenyl-3-carbonitrile (“BB”) is obtained.
  • 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 is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O 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.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • 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.

Abstract

The invention relates to novel compounds of formula (I), wherein X, R?1, R2, R3, R4 and R5¿ have the meanings cited in Patent Claim No. 1. Said compounds are inhibitors of the coagulation factor Xa and can be used for prophylaxis and/or for treating thromboembolic disorders.

Description

1 - 1 -
BiphenylderivateBiphenyl derivatives
ie Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
R .R.
worin wherein
R1, R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch -COA, -CO-[C(R6)2]n-Ar, -COOA,R 1 , R 4 each independently of one another -C (= NH) -NH 2 , which can also be obtained simply by -COA, -CO- [C (R 6 ) 2 ] n -Ar, -COOA,
-OH oder durch eine konventionelle Aminoschutzgruppe substituiert sein kann,-OH or can be substituted by a conventional amino protecting group,
NH-C(=NH)-NH2, -CO-N=C(NH2)2,NH-C (= NH) -NH 2 , -CO-N = C (NH 2 ) 2 ,
N. *- ON. * - O
HΛ °der { N =HΛ ° the { N =
O CH,O CH,
R2, R3, Rö jeweils unabhängig voneinander H, A, OR6, N(R6)2, NO2l CN, Hai, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA, S(O)nAr, -O-[C(R6)2]m-COOR6, -[C(R6)2]p-COOR6, -O-[C(R6)2]m- CON(R6)2l -[C(R6)2]p-CON(R6)2, -O-[C(R6)2]m-CONHAr, oder -[C(R6)2]p-CONHAr,R 2 , R 3 , R ö each independently of one another H, A, OR 6 , N (R 6 ) 2 , NO 2l CN, Hai, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) n A, S (O) n Ar, -O- [C (R 6 ) 2 ] m -COOR 6 , - [C (R 6 ) 2 ] p -COOR 6 , -O- [C (R 6 ) 2 ] m - CON (R 6 ) 2l - [C (R 6 ) 2 ] p -CON (R 6 ) 2 , -O- [C (R 6 ) 2 ] m -CONHAr, or - [C (R 6 ) 2 ] p -CONHAr,
-[C(R6)2]n-, -CR6=CR6-, -[C(R6)2]n-O-, -O-[C(R6)2]n-, -COO-, -OOC-, -CONR6- oder -NR6CO-,- [C (R 6 ) 2 ] n-, -CR 6 = CR 6 -, - [C (R 6 ) 2 ] n -O-, -O- [C (R 6 ) 2 ] n -, -COO -, -OOC-, -CONR 6 - or -NR 6 CO-,
Rb H, A oder Benzyl, - 2 -R b H, A or benzyl, - 2 -
A Alkyl mit 1-20 C-Atomen, worin eine oder zwei CH2-Gruppen durch O- oder S-Atome oder durch -CR6=CR6-Gruppen und/oder 1-7 H-Atome durch F ersetzt sein können,A alkyl with 1-20 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms or by -CR 6 = CR 6 groups and / or 1-7 H atoms by F,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch A, Ar',Ar unsubstituted or single, double or triple by A, Ar ',
OR6, OAr', N(Rδ)2, NO2, CN, Hai, NHCOA, NHCOAr',OR 6 , OAr ', N (R δ ) 2 , NO 2 , CN, shark, NHCOA, NHCOAr',
NHSO2A, NHSO2Ar', COOR6, CON(R6)2l CONHAr', COR6, COAr', S(O)nA oder S(O)nAr' substituiertes Phenyl oder 0 Naphthyl,NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2l CONHAr', COR 6 , COAr ', S (O) n A or S (O) n Ar' substituted phenyl or 0 naphthyl,
Ar' unsubstituiertes oder ein-, zwei- oder dreifach durch A, OR6,Ar 'unsubstituted or single, double or triple by A, OR 6 ,
N(R6)2, NO2, CN, Hai, NHCOA, COOR6, CON(R6)2, COR6 _ oder S(O)πA substituiertes Phenyl oder Naphthyl,N (R 6 ) 2 , NO 2 , CN, shark, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 _ or S (O) π A substituted phenyl or naphthyl,
Hai F. CI, Br oder I,Hai F. CI, Br or I,
n 0, 1 oder 2, 0 m 1 oder 2,n 0, 1 or 2, 0 m 1 or 2,
p 1 oder 2 bedeutet, 5 sowie deren Salze.p denotes 1 or 2, 5 and their salts.
Gegenstand der Erfindung sind auch die Hydrate und Solvate dieser Ver- „n bindungen.The invention relates to the hydrates and solvates of these encryption "n bonds.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können. 35 - 3 -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. 35 - 3 -
Es wurde gefunden, daß die Verbindungen der Formel I und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakoiogische Eigenschaften besitzen. Insbesondere zeigen sie Faktor Xa inhibierende Eigenschaften und können daher zur Bekämpfung und Verhütung von thromboembolischen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angioplastie und Claudicatio intermittens eingesetzt werden.It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermittently.
Aromatische Amidinderivate mit antithrombotischer Wirkung sind z.B. aus der EP 0 540 051 B1 bekannt. Cyclische Guanidine zur Behandlung thromboemboiischer Erkrankungen sind z.B. in der WO 97/08165 beschrieben. Aromatische Heterocyclen mit Faktor Xa inhibitorischer Aktivität sind z.B. aus der WO 96/10022 bekannt.Aromatic amidine derivatives with antithrombotic activity are e.g. known from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are e.g. described in WO 97/08165. Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022.
Der antithrombotische und antikoagulierende Effekt der erfindungsgemäßen Verbindungen wird auf die inhibierende Wirkung gegenüber der aktivierten Gerinnungsprotease, bekannt unter dem Namen Faktor Xa, zurückgeführt. Faktor Xa ist eine der Proteasen, die in den komplexen Vorgang der Blut- gerinnung involviert ist. Faktor Xa katalysiert die Umwandlung von Pro- thrombin in Thrombin, das seinerseits zur Thrombusbildung beiträgt. Eine Aktivierung von Thrombin kann zum Auftreten von thromboembolischen Erkrankungen führen. Eine Inhibierung des Faktors Xa kann somit verhindern, daß Thrombin ge- bildet wird.The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory effect against the activated coagulation protease, known under the name factor Xa. Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to thrombin, which in turn contributes to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. Inhibition of factor Xa can thus prevent thrombin from being formed.
Die erfindungsgmäßen Verbindungen der Formel I sowie ihre Salze greifen durch Inhibierung des Faktors Xa in den Blutgerinnungsprozeß ein und hemmen so die Entstehung von Thromben.The compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
Die Inhibierung des Faktors Xa durch die erfindungsgemäßen Verbindungen und die Messung der antikoagulierenden und antithrombotischen Aktivität kann nach üblichen in vitro- oder in vivo-Methoden ermittelt werden. Ein geeignetes Verfahren wird z.B. von J. Hauptmann et al. in Thrombosis and Haemostasis 63, 220-223 (1990) beschrieben. Die Messung der Inhibierung von Faktor Xa kann z.B. nach der Methode von T. Hara et al. in Thromb. Haemostas. 71, 314-319 (1994) erfolgen.The inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 63, 220-223 (1990). The measurement of the inhibition of factor Xa can, for example, by the method of T. Hara et al. in thromb. Haemostas. 71, 314-319 (1994).
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden, insbesondere zur Bekämpfung und Verhütung von thromboembolischen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angioplastie und Claudicatio in- termittens.The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate.
Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß manThe invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
a) sie aus einem ihrer funktionellen Derivate durch Behandeln mit einem soivolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt, indem mana) liberates them from one of their functional derivatives by treatment with a soivolysing or hydrogenolysing agent by
i) eine Amidinogruppe aus ihrem Oxadiazolderivat durch Hydrogenoly- se freisetzt,i) releases an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) eine konventionelle Aminoschutzgruppe durch Behandeln mit einem soivolysierenden oder hydrogenolysierenden Mittel durch Wasserstoff ersetzt oder eine durch eine konventionelle Schutzgruppe geschützte Aminogrup- pe in Freiheit setzt,ii) replacing a conventional amino protecting group with hydrogen by treatment with a soivolysing or hydrogenolysing agent or releasing an amino group protected by a conventional protecting group,
oderor
b) in einer Verbindung der Formel I einen oder mehrere Rest(e) Y, R1, R2, R3, R4 und/oder R5 in einen oder mehrere Rest(e) R1, R2, R3, R4 und/oder R5 umwandelt,b) in a compound of the formula I one or more radicals Y, R 1 , R 2 , R 3 , R 4 and / or R 5 into one or more radicals R 1 , R 2 , R 3 , Converts R 4 and / or R 5 ,
indem man beispielsweisefor example by
i) eine Estergruppe zu einer Carboxygruppe hydrolysiert, ii) eine hydroxyiierte Amidinogruppe in eine Amidinogruppe umwandelt,i) hydrolyzing an ester group to a carboxy group, ii) converting a hydroxylated amidino group into an amidino group,
ii) eine Nitrogruppe reduziert,ii) reducing a nitro group,
iii) eine Aminogruppe acyliert,iii) acylating an amino group,
und/oderand or
c) eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.c) converts a base or acid of the formula I into one of its salts.
Für alle Reste, die mehrfach auftreten, wie z.B. R6, gilt, daß deren Bedeutungen unabhängig voneinander sind.For all radicals that occur more than once, such as R 6 , the meanings are independent of one another.
Unter Hydraten und Solvaten versteht man z.B. die Hemi-, Mono- oder Dihydrate, unter Solvaten z.B. Alkoholadditionsverbindungen wie z.B. mit Methanol oder Ethanol.Hydrates and solvates are e.g. the hemi, mono- or dihydrates, among solvates e.g. Alcohol addition compounds such as with methanol or ethanol.
In den vorstehenden Formeln bedeutet A Alkyl, ist linear oder verzweigt, und hat 1 bis 20, vorzugsweise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 oder 12 C-Atome. A bedeutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Iso- propyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyi, 1 ,1- , 1 ,2- oder 2,2-Dimethylpropyl, 1-Ethyipropyl, He- xyl, 1- , 2- , 3- oder 4-Methylpentyl, 1 ,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- oder 3,3- Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methylpropyl, 1-Ethyl-2- methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl, Heptyl, Octyl, Nonyl oder Decyl. A bedeutet weiterhin z.B. Trifluormethyl, Pentafluorethyl, Allyl oder Crotyl.In the above formulas, A means alkyl, is linear or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyi, 1, 1-, 1, 2 - or 2,2-dimethylpropyl, 1-ethyl propyl, 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, heptyl, Octyl, nonyl or decyl. A also means e.g. Trifluoromethyl, pentafluoroethyl, allyl or crotyl.
COR6 ist Acyl und bedeutet vorzugsweise Formyl, Acetyl, Propionyl, ferner auch Butyryl, Pentanoyl oder Hexanoyl.COR 6 is acyl and preferably means formyl, acetyl, propionyl, but also butyryl, pentanoyl or hexanoyl.
COOR6 bedeutet vorzugsweise Methoxycarbonyl, Ethoxycarbonyl, Pro- poxycarbonyl oder Butoxycarbonyl.COOR 6 preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auch I. R2, R und R bedeuten, jeweils unabhängig voneinander, vorzugsweise H, Fluor, Chlor, Brom, lod, Hydroxy, Methoxy, Ethoxy, Propoxy, Nitro, Amino, Methylamino, Dimethylamino, Ethylamino, Diethylamino, Acetamido, Sul- fonamido, Methylsulfonamido, Phenylsulfonamido, Methylthio, Ethylthio,Shark preferably means F, Cl or Br, but also I. R 2 , R and R are each, independently of one another, preferably H, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfonamido, methylsulfonamido , Phenylsulfonamido, methylthio, ethylthio,
Methylsulfinyl, Ethylsulfinyl, Methylsulfonyl, Ethylsulfonyl, Phenylsulfinyl, Phenylsulfonyl, Cyan, Carboxy, Methoxycarbonyl, Ethoxycarbonyl, Car- boxymethoxy, Methoxycarbonylmethoxy, Carboxymethyl, Methoxycar- bonylmethyl, Aminocarbonylmethoxy, Aminocarbonylmethyl, N-Phenyl- aminocarbonylmethoxy, N-Phenylaminocarbonylmethyl, ferner auch Acyl oder Benzoyl.Methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxylic boxymethoxy, bonylmethyl methoxycarbonylmethoxy, carboxymethyl, Methoxycar-, aminocarbonylmethoxy, aminocarbonylmethyl, N-phenyl aminocarbonylmethoxy, N-phenylaminocarbonylmethyl, furthermore also acyl or Benzoyl.
Insbesondere bedeuten R2, R5 H.In particular, R 2 , R 5 mean H.
R3 bedeutet insbesondere z.B. H, COOA oder -OCH2COOR6, wobei R6 H oder Alkyl mit 1-4 C-Atomen bedeutet.R 3 in particular denotes, for example, H, COOA or -OCH 2 COOR 6 , where R 6 denotes H or alkyl having 1-4 C atoms.
R bedeutet H, A oder Benzyl, insbesondere jedoch H oder Alkyl mit 1-4 C-R represents H, A or benzyl, but especially H or alkyl with 1-4 C-
Atomen.Atoms.
X bedeutet vorzugsweise z.B. -CH2-, -CH=CH-, -CH2O-, -O-CH2-, -COO-,X preferably denotes, for example, -CH 2 -, -CH = CH-, -CH 2 O-, -O-CH 2 -, -COO-,
-OOC-, -CONH- oder -NHCO-; ganz besonders bevorzugt ist -CH2O-, -O--OOC-, -CONH- or -NHCO-; -CH 2 O-, -O- is very particularly preferred
CH2- oder -CH2-CH2-.CH 2 - or -CH 2 -CH 2 -.
Ar bedeutet vorzugsweise unsubstituiertes Phenyl oder Naphthyl, weiterhin vorzugsweise z.B. durch A, Fluor, Chlor, Brom, lod, Hydroxy, Methoxy, Ethoxy, Propoxy, Butoxy, Pentyloxy, Hexyioxy, Benzyloxy, Phenethyloxy, Methylthio, Ethylthio, Methylsulfinyl, Ethylsulfinyl, Methylsulfonyl, Ethylsulfonyl, Phenylsulfinyl, Phenylsulfonyl, Nitro, Amino, Methylamino, Ethylamino, Dimethylamino, Diethylamino, Formamido, Acetamido, Propionyl- amino, Butyrylamino, Methylsulfonamido, Ethylsulfonamido, Propylsulfon- amido, Butylsulfonamido, Phenylsulfonamido, (4-Methylphenyl)-sulfon- amido, Carboxymethoxy, Carboxyethoxy, Methoxycarbonylmethoxy, Me- thoxycarbonylethoxy, Hydroxymethoxy, Hydroxyethoxy, Methoxyethoxy, Carboxy, Methoxycarbonyl, Ethoxycarbonyl, Cyan, Phenylaminocarbonyl, Acyl oder Benzoyl mono-, di- oder trisubstituiertes Phenyl oder Naphthyl, ferner auch Biphenyl. Ar bedeutet daher bevorzugt z.B. o-, m- oder p-Tolyi, o-, m- oder p-Ethyl- phenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylpheπyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitro- phenyl, o-, m- oder p-Aminophenyl, o-, - oder p-(N-Methylamino)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Carboxyphenyl, o-, m- oder p-Methoxycar- bonylphenyl, o-, m- oder p-(N,N-Dimethylamiπo)-phenyl, o-, m- oder p-(N- Ethylamino)-phenyl, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Acetylphenyl, o-, m- oder p-Formylphenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-Methyl- sulfonylphenyl, o-, m- oder p-(Phenylsulfonamido)-pheπyl, o-, m- oder p- (Methylsulfonamido)-phenyl, o-, m- oder p-Methylthiophenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2.3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibrom- phenyl, 2,4- oder 2,5-Dinitrophenyl, 2,5- oder 3,4-Dimethoxyphenyl, 3-Ar preferably denotes unsubstituted phenyl or naphthyl, further preferably, for example, by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyioxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, Ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamonido, butylsulfonamonido, butylsulfonamonido, Carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl mono-, di- or tri-substituted phenyl or naphthyl, also also biphenyl. Ar therefore preferably means, for example, o-, m- or p-tolyi, 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-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, - or p- ( N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p - (N, N-Diethylamino) phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl , o-, m- or p- chlorophenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p- (phenylsulfonamido) -phenyl, o-, m- or p- (methylsulfonamido) -phenyl , o-, m- or p-methylthiophenyl, 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, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-
Nitro-4-chlorphenyl, 3-Amino-4-chlor-, 2-Amino-3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oder 2-Amino-6-chloφhenyl, 2-Nitro-4-N,N-dimethyl- amino- oder 3-Nitro-4-N,N-dimethylaminophenyl, 2,3-Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Trichlorphenyl, 2,4,6-Trimethoxy- phenyl, 2-Hydroxy-3,5-dichlorphenyl, p-lodphenyl, 3,6-Dichlor-4-amino- phenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4-bromphenyl, 2,5-Difluor-4-brom- phenyl, 3-Broπv6-methoxyphenyl, 3-Chlor-6-methoxyphenyl, 3-Chlor-4- acetamidophenyl, 3-Fluor-4-methoxyphenyl, 3-Amino-6-methylphenyl, 3- Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4-chlorphenyl.Nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3 , 6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4 -aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-broπv6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chlorine -4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Ar' bedeutet insbesondere z.B. Phenyl oder Naphthyl, ferner bevorzugt z.B. o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propyl- phenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-Amino- phenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p-Acetamido- phenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Carboxyphenyl, o-, m- oder p-Methoxycarbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p-(N-Ethylamino)-phenyi, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Acetylphenyl, o-, m- oder p-Formylphenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl oder o-, m- oder p-Methyisulfonylphenyl. - 8 -Ar 'means in particular, for example, phenyl or naphthyl, further preferably, for example, o-, m- or p-tolyl, 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-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o -, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamido phenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N-ethylamino) -phenyi , o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o -, m- or p-bromophenyl, o-, m- or p-chlorophenyl or o-, m- or p-methyisulfonylphenyl. - 8th -
Dementsprechend sind Gegenstand der Erfindung insbesondere diejenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la bis li ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochAccordingly, 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. Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in la R'. R jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch OH substituiert sein kann oder -CO-N=C(NH2)2 bedeuten; in Ib R2, R5 H bedeuten; in Ic R1, R4 jeweils unabhängig voneinander -C(=NH)-NH2) das auch einfach durch OH substituiert sein kann oderin la R '. R in each case independently of one another —C (= NH) —NH 2 , which can also be simply substituted by OH or —CO — N = C (NH 2 ) 2 ; in Ib R 2 , R 5 are H; in Ic R 1 , R 4 each independently of one another —C (= NH) —NH 2) which can also be simply substituted by OH or
-CO-N=C(NH2)2, R2, R5 H und-CO-N = C (NH 2 ) 2 , R 2 , R 5 H and
R3 H oder COOR6, bedeuten; in Id R1, R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch OH substituiert sein kann oderR 3 is H or COOR 6 ; in Id R 1 , R 4 each independently of one another —C (= NH) —NH 2 , which can also be simply substituted by OH or
-CO-N=C(NH2)2,-CO-N = C (NH 2 ) 2 ,
R2, R5 H undR 2 , R 5 H and
R3 H, COOR6 oder -O-(CH2)COOR6, bedeuten; in le X -CH2-O- oder -O-CH2- bedeuten; in lf R1, R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch OH substituiert sein kann oder -CO-N=C(NH2)2, R2, R5 H, - 9 -R 3 is H, COOR 6 or -O- (CH 2 ) COOR 6 ; in le X represents -CH 2 -O- or -O-CH 2 -; in each case R 1 , R 4 independently of one another —C (= NH) —NH 2 , which can also be simply substituted by OH or —CO-N = C (NH 2 ) 2 , R 2 , R 5 H, - 9 -
R3 H oder COOR6 undR 3 H or COOR 6 and
X -CHz-O- oder -O-CH2- bedeuten; in Ig R1 , R4 jeweils unabhängig vo auch einfach durch OH substituiert sein kann oder -CO-N=C(NH2)2, R2, R5 H,X represents -CHz-O- or -O-CH 2 -; in Ig R 1 , R 4 can in each case independently of one another also be simply substituted by OH or -CO-N = C (NH 2 ) 2 , R 2 , R 5 H,
R3 H, COOR6 oder -O-(CH2)COOR6,und X -CH2-O-, -O-CH2- oder -CH2-CH2- bedeuten; in Ih R1 , R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch OH substituiert sein kann oder -CO-N=C(NH2)2,R 3 is H, COOR 6 or -O- (CH 2 ) COOR 6 , and X is -CH 2 -O-, -O-CH 2 - or -CH 2 -CH 2 -; in Ih R 1 , R 4 each independently of one another —C (= NH) —NH 2 , which can also be simply substituted by OH or —CO-N = C (NH 2 ) 2 ,
R2, R5 H, ι3R 2 , R 5 H, ι3
Rύ H, COOR°, -O-CH2-COOR°, CH2-COOR0, -O-CH2-R ύ H, COOR °, -O-CH 2 -COOR °, CH2-COOR 0 , -O-CH 2 -
CON(R6)2, CH2-CON(R6)2, -O-CH2-CONHAr oderCON (R 6 ) 2 , CH 2 -CON (R 6 ) 2 , -O-CH 2 -CONHAr or
CH2-CONHAr, X -CH2-O-, -O-CH2- oder -CH2-CH2-,CH 2 -CONHAr, X -CH 2 -O-, -O-CH 2 - or -CH 2 -CH 2 -,
R6 H oder A,R 6 H or A,
A Alkyl mit 1-4 C-Atomen, bedeuten; in li R1 , R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch OH substituiert sein kann oderA is alkyl with 1-4 C atoms; in li R 1 , R 4 each independently of one another —C (= NH) —NH 2 , which can also be simply substituted by OH or
-CO-N=C(NH2)2, R2, R5 H,-CO-N = C (NH 2 ) 2 , R 2 , R 5 H,
R3 H, COOR6, -O-CH2-COOR6, CH2-COOR6, -O-CH2-R 3 H, COOR 6 , -O-CH 2 -COOR 6 , CH 2 -COOR 6 , -O-CH 2 -
CON(R6)2, oder CH2-CON(R6)2l X -CH2-O-, -O-CH2- oder -CH2-CH2-,CON (R 6 ) 2 , or CH 2 -CON (R 6 ) 2l X -CH 2 -O-, -O-CH 2 - or -CH 2 -CH 2 -,
R6 H oder A,R 6 H or A,
A Alkyl mit 1-4 C-Atomen, bedeuten. - 10 -A is alkyl with 1-4 carbon atoms. - 10 -
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Hersteilung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Veriag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Veriag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.If desired, 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.
Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel l aus einem ihrer funktioneilen Derivate durch Behandeln mit einem soivolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt.Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a soivolysing or hydrogenolysing agent.
Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die sonst der Formel I entsprechen, aber anstelle einer oder mehrerer freier Amino- und/oder Hydroxygruppen entsprechende geschützte Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die anstelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Ami- noschutzgruppe tragen, insbesondere solche, die anstelle einer HN-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 instead of an HN
Gruppe eine R'-N-Gruppe tragen, worin R' eine Aminoschutzgruppe bedeutet, und/oder solche, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z.B. solche, die der Formel I entsprechen, jedoch ansteile einer Gruppe -COOH eine Gruppe -COOR" tragen, worin R" eine Hydroxyschutzgruppe bedeutet.Group carry an R'-N group, in which R 'represents an amino protecting group and / or those which carry a hydroxy protecting group instead of the H atom of a hydroxy group, e.g. those which correspond to the formula I, but carry parts of a group -COOH a group -COOR ", in which R" denotes a hydroxy protective group.
Bevorzugte Ausgangsstoffe sind auch die Oxadiazolderivate, die in die entsprechenden Amidinoverbindungen überführt werden können.Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
Die Einführung der Oxadiazolgruppe gelingt z.B. durch Umsetzung der Cyanverbindungen mit Hydroxylamin und Reaktion mit Phosgen, Dialkyla- - 11 -The oxadiazole group can be introduced, for example, by reacting the cyano compounds with hydroxylamine and reaction with phosgene, dialkylamine. - 11 -
carbonat, Chlorameisensäureester, N,N'-Carbonyldiimidazol oder Acetan- hydrid.carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.
Es können auch mehrere - gleiche oder verschiedene - geschützte Amino- und/oder Hydroxygruppen im Molekül des Ausgangsstoffes vorhanden sein. Falls die vorhandenen Schutzgruppen voneinander verschieden sind, können sie in vielen Fällen selektiv abgespalten werden.Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.
Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Umsetzungen zu schützen (zu blockieren), die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind insbesondere unsubstituierte oder substituierte Acyl-, Aryl-, Aralkoxymethyl- oder Aralkylgruppen. Da die Aminoschutzgruppen nach der gewünschten Reaktion (oder Reaktionsfolge) entfernt werden, ist ihre Art und Größe im übrigen nicht kritisch; bevorzugt werden jedoch solche mit 1-20, insbesondere 1-8 C-Atomen. Der Ausdruck "Acylgruppe" ist im Zusammenhang mit dem vorliegenden Verfahren in weitestem Sinne aufzufassen. Er um- schließt von aliphatischen, araliphatischen, aromatischen oder hetero- cyclischen Carbonsäuren oder Sulfonsäuren abgeleitete Acylgruppen sowie insbesondere Alkoxycarbonyl-, Aryloxycarbonyl- und vor allem Aral- koxycarbonylgruppen. Beispiele für derartige Acylgruppen sind Alkanoyl wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Ben- zoyl oder Toluyl; Aryloxyalkanoyl wie POA; Alkoxycarbonyl wie Methoxycarbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, BOC (tert.-Butyl- oxycarbonyl), 2-lodethoxycarbonyl; Aralkyloxycarbonyl wie CBZ ("Carbo- benzoxy"), 4-Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl wie Mtr. Bevorzugte Aminoschutzgruppen sind BOC und Mtr, ferner CBZ, Fmoc, Ben- zyl und Acetyl.The term "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. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such 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 (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
Der Ausdruck "Hydroxyschutzgruppe" ist ebenfalls allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Hydroxygruppe vor chemischen Umsetzungen zu schützen, die aber leicht entfernbar sind, nach- dem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind die oben - 12 -The term "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 at other locations in the molecule. Typical of such groups are those above - 12 -
genannten unsubstituierten oder substituierten Aryl-, Aralkyl- oder Acylgruppen, ferner auch Alkylgruppen. Die Natur und Größe der Hydroxy- schutzgruppen ist nicht kritisch, da sie nach der gewünschten chemischen Reaktion oder Reaktionsfolge wieder entfernt werden; bevorzugt sind Gruppen mit 1-20, insbesondere 1-10 C-Atomen. Beispiele für Hydroxy- schutzgruppen sind u.a. Benzyl, p-Nitrobenzoyl, p-Toluolsuifonyl, tert.- Butyl und Acetyl, wobei Benzyl und tert.-Butyl besonders bevorzugt sind.mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size of the hydroxyl protective groups is 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. Examples of hydroxy protecting groups include Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
Das In-Freiheit-Setzen der Verbindungen der Formel I aus ihren funktionel- len Derivaten gelingt - je nach der benutzten Schutzgruppe - z. B. mit starken Säuren, zweckmäßig mit TFA oder Perchlorsäure, aber auch mit anderen starken anorganischen Säuren wie Salzsäure oder Schwefelsäure, starken organischen Carbonsäuren wie Trichloressigsäure oder Sulfonsäu- ren wie Benzol- oder p-Toluolsulfonsäure. Die Anwesenheit eines zusätzli- chen inerten Lösungsmittels ist möglich, aber nicht immer erforderlich. Als inerte Lösungsmittel eignen sich vorzugsweise organische, beispielsweise Carbonsäuren wie Essigsäure, Ether wie Tetrahydrofuran oder Dioxan, Amide wie DMF, halogenierte Kohlenwasserstoffe wie Dichiormethan, ferner auch Alkohole wie Methanol, Ethanol oder Isopropanol, sowie Wasser. Ferner kommen Gemische der vorgenannten Lösungsmittel in Frage. TFA wird vorzugsweise im Überschuß ohne Zusatz eines weiteren Lösungsmittels verwendet, Perchlorsäure in Form eines Gemisches aus Essigsäure und 70 %iger Perchlorsäure im Verhältnis 9:1. Die Reaktionstemperaturen für die Spaltung liegen zweckmäßig zwischen etwa 0 und etwa 50°, vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. 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 reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
Die Gruppen BOC, OBut und Mtr können z. B. bevorzugt mit TFA in Dichiormethan oder mit etwa 3 bis 5n HCI in Dioxan bei 15-30° abgespalten werden, die FMOC-Gruppe mit einer etwa 5- bis 50 %igen Lösung von Dimethylamin, Diethylamin oder Piperidin in DMF bei 15-30°.The groups BOC, OBut and Mtr 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 °.
Hydrogenolytisch entfembare Schutzgruppen (z. B. CBZ, Benzyl oder die Freisetzung der Amidinogruppe aus ihrem Oxadiazolde vat)) können z. B. durch Behandeln mit Wasserstoff in Gegenwart eines Katalysators (z. B. eines Edelmetallkatalysators wie Palladium, zweckmäßig auf einem Träger wie Kohle oder wie feuchtes Raney-Nickel unter Zusatz von z.B. Essigsäu- - 13 -Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the liberation of the amidino group from their oxadiazolde vat) can be used e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, suitably on a support such as coal or like wet Raney nickel with the addition of, for example, acetic acid - 13 -
re) abgespalten werden. Als Lösungsmittel eignen sich dabei die oben angegebenen, insbesondere z. B. Alkohole wie Methanol oder Ethanoi oder Amide wie DMF. Die Hydrogenolyse wird in der Regel bei Temperaturen zwischen etwa 0 und 100° und Drucken zwischen etwa 1 und 200 bar, be- vorzugt bei 20-30° und 1-10 bar durchgeführt. Eine Hydrogenolyse derre) be split off. Suitable solvents are the above, especially z. B. alcohols such as methanol or Ethanoi 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
CBZ-Gruppe gelingt z. B. gut an 5 bis 10 %igem Pd/C in Methanol oder mit Ammoniumformiat (anstelle von Wasserstoff) an Pd/C in Methanol/DMF bei 20-30°.CBZ Group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
Verbindungen der Formel I, worin R1 und R4 -C(=NH)-NH2 bedeuten, können vorzugsweise aus der entsprechenden Cyanverbindung erhalten werden.Compounds of the formula I in which R 1 and R 4 are -C (= NH) -NH 2 can preferably be obtained from the corresponding cyano compound.
Die Umwandlung einer Cyangruppe in eine Amidinogruppe erfolgt durch Umsetzung mit z.B. Hydroxylamin und anschließender Reduktion des N- Hydroxyamidins mit Wasserstoff in Anwesenheit eines Katalysators wie z.B. Pd/C oder Raney-Nickel.The conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C or Raney nickel.
Zur Herstellung eines Amidins der Formel I (R = -C(=NH)-NH2) kann man an ein Nitrit der Formel I (R1 = CN) auch Ammoniak anlagern. Die Anlagerung erfolgt bevorzugt mehrstufig, indem man in an sich bekannter Weise a) das Nitril mit H2S in ein Thioamid umwandelt, das mit einem Alkylie- rungsmittel, z.B. CH3I, in den entsprechenden S-Alkyl-imidothioester übergeführt wird, welcher seinerseits mit NH3 zum Amidin reagiert, b) das Nitril mit einem Alkohol, z.B. Ethanoi in Gegenwart von HCI in den entsprechenden Imidoester umwandelt und diesen mit Ammoniak behandelt, oder c) das Nitril mit Lithium-bis-(trimethylsilyl)-amid umsetzt und das Produkt anschließend hydrolysiert.To produce an amidine of the formula I (R = -C (= NH) -NH 2 ), ammonia can also be added to a nitrite of the formula I (R 1 = CN). 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 in turn reacts with NH 3 to form the amidine, b) converting the nitrile with an alcohol, for example ethanoi in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
Herstellung der Cyanverbindungen erfolgt nach an sich bekannten Methoden.The cyan compounds are prepared by methods known per se.
Verbindungen der Formel I, worin R1 und R4 -CON(=NH)-NH2 bedeuten, können vorzugsweise aus den entsprechenden Alkoxycarbonylverbindun- gen erhalten werden, indem man mit Guanidin umsetzt.Compounds of the formula I in which R 1 and R 4 are -CON (= NH) -NH 2 can preferably be obtained from the corresponding alkoxycarbonyl compounds by reacting with guanidine.
Es ist ferner möglich, eine Verbindung der Formel I in eine andere Verbindung der Formel I umzuwandeln, indem man einen oder mehrere - 14 -It is also possible to convert a compound of formula I into another compound of formula I by using one or more - 14 -
Rest(e), R1 , R2, R3, R4 und/oder R5 in einen oder mehrere Rest(e) R1, R2, R3, R4 und/oder R5 umwandelt, z.B. indem man eine Aminogruppe acyliert oder Nitrogruppen (beispielsweise durch Hydrierung an Raney-Nickel oder Pd-Kohle in einem inerten Lösungsmittel wie Methanol oder Ethanoi) zu Aminogruppen reduziert.Conversion of residue (s), R 1 , R 2 , R 3 , R 4 and / or R 5 into one or more residue (s) R 1 , R 2 , R 3 , R 4 and / or R 5 , for example by acylated an amino group or reduced nitro groups (for example by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanoi) to amino groups.
Ester können z.B. mit Essigsäure oder mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift werden.Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
Ferner kann man freie Aminogruppen in üblicher weise mit einem Säurechlorid oder -anhydrid acyiieren oder mit einem unsubstituierten oder substituierten Alkylhalogenid alkylieren, zweckmäßig in einem inerten Lösungsmittel wie Dichlormethan oder THF und /oder in Gegenwart einer Base wie Triethylamin oder Pyridin bei Temperaturen zwischen -60 undFurthermore, 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°.+ 30 °.
Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, in Gegenwart eines säurebindenden Mittels vorzugsweise eines Alkali- oder Er- dalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums, Calciums oder Cäsiums. Auch der Zusatz einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinolin oder eines Überschusses der Aminkomponente der Formel II bzw. des Alkylierungsderivates der Formel III kann günstig sein. Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwa 0° und 150°, normalerweise zwischen 20° und 130°.The reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium , Calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of the formula II or the alkylation derivative of the formula III can also be favorable. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanoi, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Te- trahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen- - 15 -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 - 15 -
glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methyipyrrolidon (NMP) oder Dime- thylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Es- sigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wieglycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methyipyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters like
Ethylacetat oder Gemische der genannten Lösungsmittel.Ethyl acetate or mixtures of the solvents mentioned.
Eine Base der Formel I kann mit einer Säure in das zugehörige Säure- additionssaiz übergeführt werden, beispielsweise durch Umsetzung äqui- valenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanoi und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwas- serstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Ortho- phosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascor- binsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfonsäure, p- Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Laurylschwefel- säure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der Formel I verwendet werden.A base of the formula I can be converted into the associated acid addition acid using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanoi and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or hydroxysulfonic acid, ethane-sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, and ethane sulfonic acid, , p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
Andererseits können Verbindungen der Formel I mit Basen (z.B. Natrium- oder Kaliumhydroxid oder -carbonat) in die entsprechenden Metall-, insbesondere Alkalimetall- oder Erdalkalimetall-, oder in die entsprechenden Ammoniumsalze umgewandelt werden.On the other hand, compounds of formula I with bases (e.g. sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
Auch physiologisch unbedenkliche organische Basen, wie z.B. Ethanol- amin können verwendet werden. - 16 -Physiologically harmless organic bases, such as ethanol amine, can also be used. - 16 -
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nicht-chemischem Wege. Hierbei können sie zusammen mit mindestens einem fe- sten, flüssigen und/oder halbflüssigen Träger- oder Hiifsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.The invention further 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. Here, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzyl- alkohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyo- philisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffer- Substanzen, Färb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example 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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries 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.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung und Verhütung von thromboemboli- sehen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklero- - 17 -The compounds of the formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclero- - 17 -
se, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angiopla- stie und Claudicatio intermittens verwendet werden.se, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
Dabei werden die erfindungsgemäßen Substanzen in der Regel vorzugs- weise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der einge- setzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.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. However, the specific dose for each patient depends on a wide 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 and combination of drugs and severity of the disease to which the therapy applies. Oral application is preferred.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethyla- cetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation. Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ All temperatures above and below are given in ° C. In the examples below, "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, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ Beispiel 1FAB (Fast Atom Bombardment) (M + H) + Example 1
Eine Lösung von 2,06 g 3-Brombenzonitril und 1 ,50 g 3-Tolylboronsäure in 50 ml Dimethoxyethan wird mit 247 mg Palladium(ll)acetat, 335 mg Tri-o- toiyl-phosphin, 20 ml Wasser und 954 mg wasserfreiem Natriumcarbonat versetzt und unter Rühren 18 Stunden bei 100° C erhitzt. Man arbeitet wie üblich auf, chromatographiert den Rückstand an einer Kieselgelsäule mit Petrolether/Ethylacetat 9:1 und erhält 3'-Methylbiphenyl-3-carbonitril als farblosen Feststoff ("A"), El 193. Eine Lösung von 1 ,17 g "A" in 10 ml Tetrachlorkohlenstoff wird mit 1 ,09 g N-Bromsuccinimid (NBS) und 60 mg Azobisisobutyronitril versetzt und 18 Stunden bei 70° C erhitzt. Man arbeitet wie üblich auf, chromatographiert - 18 -A solution of 2.06 g of 3-bromobenzonitrile and 1.50 g of 3-tolylboronic acid in 50 ml of dimethoxyethane is mixed with 247 mg of palladium (II) acetate, 335 mg of tri-o-toiylphosphine, 20 ml of water and 954 mg of anhydrous sodium carbonate added and heated with stirring at 100 ° C for 18 hours. The mixture is worked up in the customary manner, the residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate 9: 1 and 3'-methylbiphenyl-3-carbonitrile is obtained as a colorless solid ("A"), El 193. A solution of 1.17 g "A 1.09 g of N-bromosuccinimide (NBS) and 60 mg of azobisisobutyronitrile are added to 10 ml of carbon tetrachloride and the mixture is heated at 70 ° C. for 18 hours. One works up as usual, chromatographed - 18 -
den Rückstand an einer Kieselgelsäule mit Petrolether/Ethylacetat 9:1 und erhält 3'-Brommethylbiphenyl-3-carbonitril als farblosen Feststoff ("B"). Eine Lösung von 500 mg "B" und 238 mg 3-Hydroxybenzonitrii in 10 ml Acetonitril wird mit 652 mg Cäsiumcarbonat versetzt und 40 Stunden bei Raumtemperatur gerührt. Nachüblicher Aufarbeitung wird der Rückstand an einer reversed-phase-Säule mit Acetonitril/Wasser 65:35 chromatographiert. Man erhält als farblosen Feststoff 3'-(3-Cyanphenoxymethyl)- biphenyl-3-carbonitril ("C"), FAB 311. Eine Lösung von 90 mg "C" und 125 mg Hydroxylammoniumchlorid in 10 ml Ethanoi wird mit 1 ,2 g polymergebundenem Dimethylaminopyridinthe residue on a silica gel column with petroleum ether / ethyl acetate 9: 1 and receives 3'-bromomethylbiphenyl-3-carbonitrile as a colorless solid ("B"). A solution of 500 mg "B" and 238 mg 3-hydroxybenzonitrii in 10 ml acetonitrile is mixed with 652 mg cesium carbonate and stirred for 40 hours at room temperature. After the usual work-up, the residue is chromatographed on a reversed-phase column with acetonitrile / water 65:35. The colorless solid obtained is 3 '- (3-cyanophenoxymethyl) biphenyl-3-carbonitrile ("C"), FAB 311. A solution of 90 mg "C" and 125 mg of hydroxylammonium chloride in 10 ml of ethanoi is mixed with 1.2 g polymer-bound dimethylaminopyridine
(DMAP) versetzt und 18 Stunden bei Raumtemperatur gerührt. Man filtriert ab, entfernt das Lösungsmittel und erhält N-Hydroxy-3'-[3-(N-hydroxy- carbamimidoyl)-phenoxymethyl]-biphenyl-3-carboxamidin ("D") als farblosen Feststoff, FAB 377. Eine Lösung von 76 mg "D" in 10 ml Methanol wird mit 100 mg wasserfeuchtem Raney-Nickel und 30 mg Essigsäure versetzt und 18 Stunden bei Raumtemperatur und Normaldruck hydriert. Man filtriert ab, entfernt das Lösungsmittel und erhält 3'-(3-Carbamimidoyl-phenoxymethyl)- biphenyl-3-carboxamidin, Acetat, El 327 (M+ - NH3), 310 (M+ - 2 NH3)(DMAP) were added and the mixture was stirred at room temperature for 18 hours. It is filtered off, the solvent is removed and N-hydroxy-3 '- [3- (N-hydroxycarbamimidoyl) phenoxymethyl] biphenyl-3-carboxamidine ("D") is obtained as a colorless solid, FAB 377. A solution of 76 mg "D" in 10 ml methanol are mixed with 100 mg water-moist Raney nickel and 30 mg acetic acid and hydrogenated for 18 hours at room temperature and normal pressure. The mixture is filtered off, the solvent is removed and 3 '- (3-carbamimidoylphenoxymethyl) biphenyl-3-carboxamidine, acetate, El 327 (M + - NH 3 ), 310 (M + - 2 NH 3 )
Analog erhält man die VerbindungenThe connections are obtained analogously
3'-(3-Carbamimidoyl-phenoxymethyl)-biphenyl-4-carboxamidin, Di- acetat, FAB 345;3 '- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxamidine, diacetate, FAB 345;
3'-(4-Carbamimidoyl-phenoxymethyl)-biphenyl-4-carboxamidin, Di- acetat, FAB 345;3 '- (4-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxamidine, diacetate, FAB 345;
3'-(4-Carbamimidoyl-phenoxymethyl)-biphenyl-3-carboxamidin, Di- acetat, FAB 345;3 '- (4-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxamidine, diacetate, FAB 345;
4'-(4-Carbamimidoyl-phenoxymethyl)-biphenyl-4-carboxamidin, 4'-(4-Carbamimidoyl-phenoxymethyl)-biphenyl-3-carboxamidin, 4'-(3-Carbamimidoyl-phenoxymethyl)-biphenyl-3-carboxamidin und4 '- (4-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxamidine, 4' - (4-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxamidine, 4 '- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxamidine and
4'-(3-Carbamimidoyl-phenoxymethyl)-biphenyl-4-carboxamidin. 194 '- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxamidine. 19
Beispiel 2Example 2
Analog Beispiel 1 erhält man durch Umsetzung von 3-Brombenzonitril mitAnalogously to Example 1, 3-bromobenzonitrile is also used to react
3-Methoxyphenylboronsäure die Verbindung 3'-Methoxybiphenyl-3- carbonitril.3-methoxyphenylboronic acid the compound 3'-methoxybiphenyl-3-carbonitrile.
Durch anschließende Etherspaltung mit Aluminiumthiodid in Acetonitril undSubsequent ether cleavage with aluminum thiodide in acetonitrile and
Umsetzung mit 3-Brommethyi-benzonitril erhält man 3'-(3-Cyan- benzyloxy)-biphenyl-3-carbonitril.Reaction with 3-bromomethyl benzonitrile gives 3 '- (3-cyano-benzyloxy) biphenyl-3-carbonitrile.
Durch Umsetzung mit Hydroxyiamin und Reduktion mit Wasserstoff unterBy reaction with hydroxyiamine and reduction with hydrogen under
Ra-Ni-Katalyse erhält man 3'-(3-Carbamimidoyl-benzyloxy)-biphenyl-3- carboxamidinRa-Ni catalysis gives 3 '- (3-carbamimidoyl-benzyloxy) biphenyl-3-carboxamidine
Analog erhält manYou get analog
4'-(4-Carbamimidoyl-benzyloxy)-biphenyl-4-carboxamidin, Diacetat, FAB4 '- (4-carbamimidoyl-benzyloxy) biphenyl-4-carboxamidine, diacetate, FAB
345;345;
4'-(3-Carbamimidoyl-benzyloxy)-biphenyl-4-carboxamidin, Diacetat, FAB4 '- (3-carbamimidoyl-benzyloxy) biphenyl-4-carboxamidine, diacetate, FAB
345.345.
Beispiel 3Example 3
Analog Beispiel 1 erhält man durch Umsetzung von 3-Cyanphenylboron- säure mit 3-Brom-5-methyl-benzoesäuremethylester die Verbindung 3'- Cyan-5-methyl-biphenyl-3-carbonsäuremethylester. Durch Bromierung mit NBS und Umsetzung mit 3-Hydroxybenzonitril erhält man 3'-Cyan-5-(3- Cyan-phenoxymethyl)-biphenyl-3-carbonsäuremethylester. Reaktion mit Hydroxyiamin und Reduktion mit H2/Ra-Ni ergibt die Verbindung 3'-Carbamimidoyl-5-(3-carbamimidoyl-phenoxymethyl)-biphenyl-3- carbonsäuremethylester. - 20Analogously to Example 1, the compound 3'-cyano-5-methyl-biphenyl-3-carboxylic acid methyl ester is obtained by reacting 3-cyanophenylboronic acid with methyl 3-bromo-5-methylbenzoate. Bromination with NBS and reaction with 3-hydroxybenzonitrile gives 3'-cyan-5- (3-cyanophenoxymethyl) biphenyl-3-carboxylic acid methyl ester. Reaction with hydroxyiamine and reduction with H 2 / Ra-Ni gives the compound 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid methyl ester. - 20th
Durch Verseifung des Esters mit wässriger NaOH erhält man daraus 3'-Saponification of the ester with aqueous NaOH gives 3'-
Carbamimidoyl-5-(3-carbamimidoyl-phenoxymethyl)-biphenyl-3- carbonsäure.Carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid.
HO^OHO ^ O
Durch Chromatographie an reversed-phase-Säule mit Acetoni- tril/Wasser/TFA-Gemisch erhält man 3'-Carbamimidoyl-5-(3- carbamimidoyl-phenoxymethyl)-biphenyl-3-carbonsäure, Bistrifluoracetat.Chromatography on a reversed-phase column with an acetonitrile / water / TFA mixture gives 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid, bistrifluoroacetate.
Analog erhält man die VerbindungenThe connections are obtained analogously
4'-Carbamimidoyl-4-(4-carbamimidoyl-phenoxymethyl)-biphenyl-3- carbonsäuremethylester, FAB 403;4'-Carbamimidoyl-4- (4-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid methyl ester, FAB 403;
4'-Carbamimidoyl-4-(3-carbamimidoyl-phenoxymethyl)-biphenyl-2- carbonsäuremethylester, FAB 403;4'-Carbamimidoyl-4- (3-carbamimidoyl-phenoxymethyl) biphenyl-2-carboxylic acid methyl ester, FAB 403;
3'-Carbamimidoyl-4-(4-carbamimidoyl-phenoxymethyl)-biphenyl-2- carbonsäuremethylester, FAB 403;3'-Carbamimidoyl-4- (4-carbamimidoyl-phenoxymethyl) biphenyl-2-carboxylic acid methyl ester, FAB 403;
3'-Carbamimidoyl-4-(3-carbamimidoyl-phenoxymethyl)-biphenyl-2- carbonsäuremethylester, FAB 403;3'-Carbamimidoyl-4- (3-carbamimidoyl-phenoxymethyl) biphenyl-2-carboxylic acid methyl ester, FAB 403;
4'-Carbamimidoyl-5-(3-carbamimidoyl-phenoxymethyl)-biphenyl-4- carbonsäuremethylester, FAB 403;4'-Carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxylic acid methyl ester, FAB 403;
3'-Carbamimidoyl-5-(3-carbamimidoyl-phenoxymethyl)-biphenyl-4- carbonsäuremethylester, FAB 403.3'-Carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxylic acid methyl ester, FAB 403.
Beispiel 4 - 21 -Example 4 - 21 -
Analog Beispiel 1 erhält man durch Umsetzung von 3-Brombenzoesäure- methylester mit 3-Tolylboronsäure 3'-Methylbiphenyi-3-carbonsäuremethyl- ester. Durch Bromierung mit NBS und Umsetzung mit 3-Hydroxybenzoe- säuremethylester erhält man daraus 3'-(3-Methoxycarbonyl-phenoxy- methyl)-biphenyl-3-carbonsäuremethylester. Durch Umsetzung mit Guaπi- dinhydrochlorid in methanolischer Natriummethanolatlösung erhält man daraus N-[3'-(3-Guanidinocarbonyl-phenoxymethyl)-biphenyl-3-carbonyl]- guanidinAnalogously to Example 1, 3'-methylbiphenyi-3-carboxylic acid methyl ester is obtained by reacting methyl 3-bromobenzoate with 3-tolylboronic acid. By bromination with NBS and reaction with 3-hydroxybenzoic acid methyl ester, 3 '- (3-methoxycarbonyl-phenoxymethyl) biphenyl-3-carboxylic acid methyl ester is obtained therefrom. By reaction with guanidine hydrochloride in methanolic sodium methoxide solution, N- [3 '- (3-guanidinocarbonylphenoxymethyl) biphenyl-3-carbonyl] guanidine is obtained therefrom
Analog erhält man die Verbindung N-[4'-(4-Guanidinocarbonyl- phenoxymethyl)-biphenyl-4-carbonyl]-guanidin.The compound N- [4 '- (4-guanidinocarbonylphenoxymethyl) biphenyl-4-carbonyl] guanidine is obtained analogously.
Beispiel 5Example 5
Eine Lösung von 7,0 g 3-Brom-5-methyiphenol und 5,97 g Bromessigsäuremethylester sowie 13 g Cäsiumcarbonat in 100 ml Acetonitril wird bei Raumtemperatur über Nacht gerührt. Nach üblicher Aufarbeitung erhält man 9,70 g (3-Brom-5-methylphenoxy)-essigsäuremethylester ("AB"). Eine Suspension von 2,0 g "AB", 100 mg Tetrakis(triphenylphosphin)- Palladium und 0,85 g Natriumcarbonat in 50 ml Toluol wird zum Sieden erhitzt. Dann wird eine Lösung von 2,94 g 3-Cyanphenylboronsäure in 30 ml Methanol zugetropft und 14 Stunden unter Rückfluß erhitzt. Man arbeitet wie üblich auf und erhält 2,17 g (3'-Cyan-5-methyl-biphenyl-3-yloxy)- essigsäuremethylester ("AC").A solution of 7.0 g of 3-bromo-5-methyiphenol and 5.97 g of methyl bromoacetate and 13 g of cesium carbonate in 100 ml of acetonitrile is stirred at room temperature overnight. After the usual work-up, 9.70 g of (3-bromo-5-methylphenoxy) -acetic acid methyl ester ("AB") are obtained. A suspension of 2.0 g of "AB", 100 mg of tetrakis (triphenylphosphine) palladium and 0.85 g of sodium carbonate in 50 ml of toluene is heated to boiling. A solution of 2.94 g of 3-cyanophenylboronic acid in 30 ml of methanol is then added dropwise and the mixture is heated under reflux for 14 hours. The mixture is worked up as usual and 2.17 g of (3'-cyano-5-methyl-biphenyl-3-yloxy) methyl acetate ("AC") are obtained.
Eine Lösung von 1 ,2 g "AC" und 0,765 g NBS in 50 ml Tetrachlorkohlenstoff wird bei Raumtemperatur mit UV-Licht bestrahlt. Nach üblicher Aufarbeitung erhält man 1 ,54 g (3'-Cyan-5-brommethyl-biphenyl-3-yloxy)- essigsäuremethylester ("AD").A solution of 1.2 g of "AC" and 0.765 g of NBS in 50 ml of carbon tetrachloride is irradiated with UV light at room temperature. After customary working up, 1.54 g of (3'-cyano-5-bromomethyl-biphenyl-3-yloxy) methyl acetate ("AD") are obtained.
Eine Lösung von 185 mg "AD", 63,1 mg 4-Hydroxybenzonithl und 172,7 mg Cäsiumcarbonat in 10 ml Acetonitril wird bei Raumtemperatur 4 Tage 22A solution of 185 mg "AD", 63.1 mg 4-hydroxybenzonithl and 172.7 mg cesium carbonate in 10 ml acetonitrile is at room temperature for 4 days 22
gerührt. Nach üblicher Aufarbeitung erhält man [3'-Cyan-5-(4- cyanphenoxymethyl)-biphenyl-3-yloxy]-essigsäuremethylester ("AE"). Eine Lösung von 60 mg "AE", 69,5 mg Hydroxylammoniumchlorid und 101 mg Triethylamin in 10 ml Methanol wird 14 Stunden unter Rückfluß erhitzt. Nach Entfernen des Lösungsmittels wird in Wasser aufgenommen. Man trennt ab und erhält 70 mg [3'-N-Hydroxyamidino-5-(4-N-hydroxyamidino- phenoxymethyl)-biphenyl-3-yloxy]-essigsäuremethylester ("AF"). Durch Reduktion mit H2/Raney-Nickel erhält man daraus [3'-Amidino-5-(4- amidinophenoxymethyl)-biphenyl-3-yloxy]-essigsäuremethylester, FAB 433touched. After customary working up, [3'-cyan-5- (4-cyanophenoxymethyl) biphenyl-3-yloxy] acetic acid methyl ester ("AE") is obtained. A solution of 60 mg "AE", 69.5 mg hydroxylammonium chloride and 101 mg triethylamine in 10 ml methanol is heated under reflux for 14 hours. After removing the solvent, it is taken up in water. It is separated off and 70 mg of [3'-N-hydroxyamidino-5- (4-N-hydroxyamidino-phenoxymethyl) biphenyl-3-yloxy] acetic acid methyl ester ("AF") is obtained. Reduction with H 2 / Raney nickel gives methyl [3'-amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid, FAB 433
Analog erhält man die VerbindungenThe connections are obtained analogously
[4'-Amidino-5-(4-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäuremethylester, FAB 433[4'-Amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] methyl acetate, FAB 433
[3'-Amidino-5-(3-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäuremethylester, FAB 433[3'-Amidino-5- (3-amidinophenoxymethyl) biphenyl-3-yloxy] methyl acetate, FAB 433
[4'-Amidino-5-(3-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäuremethylester, FAB 433.[4'-Amidino-5- (3-amidinophenoxymethyl) biphenyl-3-yloxy] methyl acetate, FAB 433.
Ersetzt man in der ersten Stufe Bromessigsäuremethylester durch Brom- essigsäure-tert.-butylester so können die in der letzten Stufe erhaltenen - 23 -If in the first stage methyl bromoacetate is replaced by tert-butyl bromoacetate, those obtained in the last stage can be obtained - 23 -
tert.-Butylester mit Trifluoressigsäure gespalten werden und man erhält die entsprechenden Carbonsäurentert-butyl ester are cleaved with trifluoroacetic acid and the corresponding carboxylic acids are obtained
[3'-Amidino-5-(4-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsaure, Bistrifluoracetat, FAB 419;[3'-Amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid, bistrifluoroacetate, FAB 419;
[4'-Amidino-5-(4-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäure;[4'-Amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid;
[3'-Amidino-5-(3-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäure;[3'-Amidino-5- (3-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid;
[4'-Amidino-5-(3-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäure.[4'-Amidino-5- (3-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid.
Beispiel 6Example 6
Eine Lösung von 5,0 g 3'-Brommethyl-biphenyl-3-carbonitril und 5 ml Tri- ethylphosphit werden zusammengegeben und langsam auf 150° erhitzt. Man rührt 6 h bei 150° nach und erhält nach üblicher Aufarbeitung 6,05 g (3'-Cyan-biphenyl-3-ylmethyl)-phosphonsäurediethylester ("BA"). Zu einer Lösung von 1 ,0 g "BA" und 3-Cyanbenzaldehyd in 20 ml Ethy- lenglycoldimethylether gibt man unter Eiskühlung und Stickstoff 150 mg Natriumhydrid. Man rührt 4 Stunden nach, arbeitet wie Üblichauf und erhält 0,93 g 3'-[2-(3-Cyanphenyl)-vinyl]-biphenyl-3-carbonitril ("BB").A solution of 5.0 g of 3'-bromomethyl-biphenyl-3-carbonitrile and 5 ml of triethyl phosphite are combined and slowly heated to 150 °. The mixture is subsequently stirred at 150 ° for 6 h and, after customary working up, 6.05 g of diethyl 3-cyano-biphenyl-3-ylmethylphosphonate ("BA") are obtained. 150 mg of sodium hydride are added to a solution of 1.0 g of “BA” and 3-cyanobenzaldehyde in 20 ml of ethylene glycol dimethyl ether with ice cooling and nitrogen. The mixture is stirred for 4 hours, worked as usual and 0.93 g of 3 '- [2- (3-cyanophenyl) vinyl] biphenyl-3-carbonitrile ("BB") is obtained.
Nach Hydrierung von 360 mg "BB" mit Pd-C-5 % in Methanol erhält man 360 mg 3'-[2-(3-Cyanphenyl)-ethyl]-biphenyl-3-carbonitril ("BC"). Nach Umsetzung mit Hydroxylammmoniumchlorid und Hydrierung mit Raney- Nickel erhält man analog Beispiel 1 die Verbindung 3'-[2-(3-Amidino- phenyl)-ethyl]-biphenyl-3-carboxamidin, FAB 343 - 24After hydrogenation of 360 mg "BB" with Pd-C-5% in methanol, 360 mg of 3 '- [2- (3-cyanophenyl) ethyl] biphenyl-3-carbonitrile ("BC") are obtained. After reaction with hydroxylammmonium chloride and hydrogenation with Raney nickel, the compound 3 '- [2- (3-amidino-phenyl) -ethyl] -biphenyl-3-carboxamidine, FAB 343 is obtained analogously to Example 1 - 24th
H2N^ .NHH 2 N ^ .NH
Analog erhält man die Verbindung 3'-[2-(4-Amidinophenyl)-ethyl]-biphenyl- 3-carboxamidin, FAB 343. The compound 3 '- [2- (4-amidinophenyl) ethyl] biphenyl-3-carboxamidine, FAB 343 is obtained analogously.
- 25 -- 25 -
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt er- kalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O 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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: TablettenExample E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält. - 26 -A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. - 26 -
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatine- kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

- 27Patentansprüche - 27 patent claims
1. Verbindungen der Formel I1. Compounds of formula I.
worin wherein
R1, R4 jeweils unabhängig voneinander -C(=NH)-NH2, das auch einfach durch -COA, -CO-[C(R6)2]n-Ar, -COOA, -OH oder durch eine konventionelle Aminoschutzgruppe substituiert sein kann, NH-C(=NH)-NH2, -CO-N=C(NH2)2, > ,NN R 1 , R 4 each independently of one another -C (= NH) -NH 2 , which is also simply by -COA, -CO- [C (R 6 ) 2 ] n -Ar, -COOA, -OH or by a conventional amino protecting group may be substituted, NH-C (= NH) -NH 2 , -CO-N = C (NH 2 ) 2 ,>, N N
'/'/
*- 0 O oder* - 0 O or
HN-^ N: HN- ^ N :
O CH,O CH,
R2, R3, R5 jeweils unabhängig voneinander H, A, OR6, N(R6)2, NO2, CN, Hai, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA CON(R6)2, CONHAr, COR6, COAr, S(O)nA, S(O)nAr, -O-[C(R6)2]m-COOR6, -[C(R6)2]p-COOR6, -O-[C(R6)2]m- CON(R6)2, -[C(R6)2]p-CON(R6)2, -O-[C(R6)2]m-CONHAr, oder -[C(R6)2]p-CONHAr,R 2 , R 3 , R 5 each independently of one another H, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hai, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) n A CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) n A, S (O) n Ar, -O- [C (R 6 ) 2 ] m -COOR 6 , - [C (R 6 ) 2 ] p -COOR 6 , -O- [C (R 6 ) 2 ] m - CON (R 6 ) 2 , - [C (R 6 ) 2 ] p -CON (R 6 ) 2 , -O- [C (R 6 ) 2 ] m -CONHAr, or - [C (R 6 ) 2 ] p -CONHAr,
X -[C(R6)2]n-, -CR6=CR6-, -[C(R6)2]n-O-, -O-[C(R6)2]n-, -COO-, -OOC-, -CONR6- oder -NR6CO-, - o -X - [C (R 6 ) 2 ] n-, -CR 6 = CR 6 -, - [C (R 6 ) 2 ] n -O-, -O- [C (R 6 ) 2 ] n -, - COO-, -OOC-, -CONR 6 - or -NR 6 CO-, - o -
R6 H. A oder Benzyl,R 6 H. A or benzyl,
A Alkyl mit 1-20 C-Atomen, worin eine oder zwei CH2-A alkyl with 1-20 C atoms, in which one or two CH 2 -
Gruppen durch O- oder S-Atome oder durch -CR6=CR6- Gruppen und/oder 1-7 H-Atome durch F ersetzt sein können,Groups can be replaced by O or S atoms or by -CR 6 = CR 6 groups and / or 1-7 H atoms by F,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch A, 0 Ar', OR6, OAr', N(R6)2, NO2, CN, Hai, N IHHCCOOAA,, NHCOAr', NHSO2A, NHSO2Ar', COOR6, CON(R6)2, C COONNHHAArr'',, CCOORR66,, CCOOAArr'',, SS((CO)πA oder S(O)nAr' substitu- iertes Phenyl oder Naphthyl,Ar unsubstituted or single, double or triple by A, 0 Ar ', OR 6 , OAr', N (R 6 ) 2 , NO 2 , CN, Hai, N IHHCCOOAA ,, NHCOAr ', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , C COONNHHAArr'',, CCOORR 66 ,, CCOOAArr'',, SS ((CO) π A or S (O) n Ar' substituted phenyl or naphthyl,
55
Ar' unsubstituiertes oder ein-, zwei- oder dreifach durch A,Ar 'unsubstituted or single, double or triple by A,
OR6, N(R6)2, NO2, CN, Hai, NHCOA, COOR6, CON(R6)2, COR6 oder S(O)nA substituiertes Phenyl oder Naphthyl,OR 6 , N (R 6 ) 2 , NO 2 , CN, shark, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) n A substituted phenyl or naphthyl,
0 Hai F, Cl, Br oder I, 0 shark F, Cl, Br or I,
n 0, 1 oder 2,n 0, 1 or 2,
5 m 1 oder 2,5 m 1 or 2,
p 1 oder 2 bedeutet,p means 1 or 2,
_n sowie deren Salze._ n and their salts.
2. Verbindungen gemäß Anspruch 12. Compounds according to claim 1
a) 3'-(3-Carbamimidoyl-phenoxymethyl)-biphenyl-3- 35 carboxamidin; b) 3'-(3-Carbamimidoyl-benzyloxy)-biphenyl-3-carboxamidin; - 29 -a) 3 '- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-35 carboxamidine; b) 3 '- (3-carbamimidoyl-benzyloxy) biphenyl-3-carboxamidine; - 29 -
c) 3'-Carbamimidoyl-5-(3-carbamimidoyl-phenoxymethyl)- biphenyl-3-carbonsäure; d) N-[3'-(3-Guanidinocarbonal-phenoxymethyl)-biphenyl-3- carbonylj-guanidin; e) [3'-Amidino-5-(4-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäuremethylester; f) [3'-Amidino-5-(4-amidinophenoxymethyl)-biphenyl-3-yloxy]- essigsäurec) 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-3-carboxylic acid; d) N- [3 '- (3-guanidinocarbonalphenoxymethyl) biphenyl-3-carbonylj-guanidine; e) [3'-Amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] methyl acetate; f) [3'-Amidino-5- (4-amidinophenoxymethyl) biphenyl-3-yloxy] acetic acid
sowie deren Salze.as well as their salts.
3. Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß man3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that
a) sie aus einem ihrer funktionellen Derivate durch Behandeln mit einem soivolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt, indem mana) liberates them from one of their functional derivatives by treatment with a soivolysing or hydrogenolysing agent by
i) eine Amidinogruppe aus ihrem Oxadiazolderivat durch Hydrogenolyse freisetzt,i) releases an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) eine konventionelle Aminoschutzgruppe durch Behandeln mit einem soivolysierenden oder hydrogenolysierenden Mittel durch Wasserstoff ersetzt oder eine durch eine konventionelle Schutzgruppe geschützteii) replacing a conventional amino protecting group with hydrogen by treatment with a soivolysing or hydrogenolysing agent, or one protected by a conventional protecting group
Aminogruppe in Freiheit setzt,Sets amino group free,
oderor
b) in einer Verbindung der Formel I einen oder mehrere Rest(e) Y,b) one or more radical (s) Y in a compound of the formula I,
R1, R2, R3, R4 und/oder R5 in einen oder mehrere Rest(e) R1 ,R 1 , R 2 , R 3 , R 4 and / or R 5 into one or more radicals R 1 ,
R2, R3, R4 und/oder R5 umwandelt,Converts R 2 , R 3 , R 4 and / or R 5 ,
indem man beispielsweisefor example by
i) eine Estergruppe zu einer Carboxygruppe hydrolysiert, ii) eine hydroxylierte Amidinogruppe in eine Amidinogruppe umwandelt,i) hydrolyzing an ester group to a carboxy group, ii) converting a hydroxylated amidino group into an amidino group,
ii) eine Nitrogruppe reduziert,ii) reducing a nitro group,
iii) eine Aminogruppe acyliert,iii) acylating an amino group,
und/oderand or
c) eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.c) converts a base or acid of the formula I into one of its salts.
4. Verfahren zur Herstellung pharmazeutischer Zubereitungen, dadurch gekennzeichnet, daß man eine Verbindung der Formel I nach Anspruch 1 und/oder eines ihrer physiologischen unbedenklichen Salze zusammen mit mindestens einem festen, flüssigen oder halbflüssigen Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.
5. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I nach Anspruch 1 und/oder einem ihrer physiologisch unbedenklichen Salze.5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.
6. Verbindungen der Formel I nach Anspruch 1 und ihre physiologisch unbedenklichen Salze zur Bekämpfung von Thrombosen, myocar- dialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angioplastie und Claudicatio intermittens.6. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
7. Arzneimittel der Formel I nach Anspruch 1 und ihre physiologisch unbedenklichen Salze als Inhibitoren des Koagulationsfaktors Xa.7. Medicament of the formula I according to claim 1 and their physiologically acceptable salts as inhibitors of the coagulation factor Xa.
8. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze zur Herstellung ei- nes Arzneimittels. - 31 -8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament. - 31 -
Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihrer physiologisch unbedenklichen Salze bei der Bekämpfung von Thrombosen, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angiopla- stie und Claudicatio intermittens. Use of compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for combating thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
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