Title of Invention	"NEW PHENYLAMIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS PHARMACEUTICALS"
Abstract	The invention relates to new phenylamidine derivatives, processes for preparing them and their use as pharmaceutical compositions. The phenylamidines; according to the invention correspond to the general formula I

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New phenylamidine derivatives, processes for preparing them and their use as pharmaceutical compositions The invention relates to new phenylamidine derivatives, processes for preparing them and their use in pharmaceutical compositions. The phenylamidines according to the invention correspond to the general formula I (Formula Removed) wherein A denotes X1-CmH2m-X2-, in which m is an integer 2, 3, 4, 5 or 6 or and j denotes O, NH or NCH3 ; X2 denotes 0, NH, NCH3 or - 2 - X3 denotes -Xi-CnH2n- in which n is an integer 1 or 2; X4 denotes -Cn-Han-Xj.-, wherein n is an integer 1 or 2; R! denotes Cs.7-cycloalkyl, Arl7 OArlf CH2-Ar2; CR4R5Ar3, or C(CH3)2R6; R2 denotes H, Cx.6-alkyl; OH, halogen, or O-fCj.g)-alkyl; R3 denotes H, or C^.g-alkyl; R4 denotes C^-alkyl, CF3, CH2OH, COOH, or COO(C^4) -alkyl; R5 denotes H, Cx-4-alkyl, or CF3 and R4 and R5 may also together form a C4_6-alkylene group; R6 denotes CH2OH, COOH, COO (C^) alkyl, CONR9R10, or CH2NR9R10; R7 denotes H, halogen, OH, C^.g-alkyl or C^g R8 denotes H, halogen, OH, C^.g-alkyl or C-L.g R9 denotes H, Ci-g-alkyl, phenyl, phenyl- (C^ CORllf COORllf CHO, CONH2/ CONHRu, S02-(C^g- S02-phenyl, wherein the phenyl ring may be mono- or polysubstituted by halogen, CF3, C1.4-alkyl, OH, or C1_4-alkoxy; R10 denotes H or C-L.g-alkyl and R9 and R10 together may represent a C4.6-alkylene group; RH denotes Ci.g-alkyl, C5.7-cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl- (C^gwherein the aryl or heteroaryl groups may be monoor polysubstituted by Cl, F, CF3, C^-alkyl, OH or C^-alkoxy; denotes an optionally mono- or polysubstituted aryl group, with the exception of an unsubstituted phenyl group or a phenyl group which is monosubstituted by halogen, C-^-alkyl or C1_4-alkoxy; Ar2 denotes an optionally mono- or polysubstituted aryl group, with the exception of an unsubstituted phenyl group; Ar3 denotes an optionally mono- or polysubstituted aryl group with the proviso that R cannot represent an unsubstituted phenyl group bound via a C^-alkylene unit; optionally in the form of individual optical isomers, mixtures of the individual enantiomers, or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Preferred compounds according to general formula I are those wherein A denotes X1-Cm-H2m-X2 in which m is an integer 2 and is 0; X2 is X3 denotes -X.i-CnK2n- _ wherein n is an integer 1 or 2 ; X4 denotes -CnE2li-X.i- wherein n is an integer 1 or 2 ; R! denotes C5_7-cycloalkyl , Arl7 OArx, CH2-Ar2; CR4R5Ar3/ or C(CH3)2R6; R2 denotes H, C^g-alky!, OH, Cl , or 0- (C^) -alkyl ; R3 denotes H, or C^.g-alkyl; R4 denotes C1.4-alkyl, CF3, or CH2OH; R5 denotes H, C1.4-alkyl, CF3, or CH2OH and R4 and R5 together may also form a C4_6-alkylene group; R6 denotes CH2OH, COOH, COO (C^) alkyl, CONR9R10/ or CH2NR9R10; R7 denotes H, F, Cl , Br, OH, CVg-alkyI or C1_6- R8 denotes H, F, Cl, Br, OH, C^.g-alkyl or C1_6-alkoxy; R9 denotes H, or Cg-alkyl; R10 denotes H or C-g-alkyl and R9 and R10 together may also represent a C4_6-alkylene group ; Art denotes an optionally mono- or polysubstituted aryl group, other than an unsubstituted phenyl group or a phenyl group which is monosubstituted by halogen, Ci-4-alkyl or C1_4-alkoxy; Ar2 denotes an optionally mono- or polysubstituted aryl group, with the exception of an unsubstituted phenyl group; Ar3 denotes an optionally mono- or polysubstituted aryl group with the proviso that R! cannot represent an unsubstituted phenyl group bound via a C1.4-alkylene unit; optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Particularly preferred compounds of general formula I are those wherein and Xj is 0; X3 denotes X1-CH2; X4 denotes CE2-'K1; R! denotes C5.7-cycloalkyl , Arlf OArlf CH2-Ar2; CR4R5Ar3/ or C(CH3 ) 2R6 ; R2 denotes H, OH, or 0- (C^g) -alkyl ; fR3 denotes H; R4 denotes CH3, or CH2OH; R5 denotes H, CH3, or CH2OH and R4 and R5 together may also denote a C4.6-alkylene group; R6 denotes CH2OH, COOH, COO (C^) -alkyl , CONR9R10, or CH2NR9R10; R7 denotes H; R8 denotes H; R9 denotes H, or C^g-alkyl; R10 denotes H or C^.g-alkyl and R9 and R10 together may also denote a C4.6-alkylene group; -L denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and Ar2 denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and Cj _6 -alkyl; Ar3 denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Unless specifically stated otherwise, the general definitions are used as follows: C^-Alkyl, Ci.g-alkyl and C-^g-alkyl, respectively, generally denote branched or unbranched hydrocarbon groups having 1 to 4, 6 or 8 carbon atoms respectively. These may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different from one another. The following hydrocarbon groups are mentioned by way of example: methyl, ethyl, propyl, 1-methylethyl (isopropyl) , nbutyl, 1-methylpropyl, 2-methylpropyl, 1,1- dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl , 3- methylbutyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl , 2 , 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- methylpentyl, 2-methylphenyl, 3-methylpentyl, 4- methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1,3- dimethylbutyl, 2 , 2-dimethylbutyl, 2 , 3-dimethylbutyl , 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-lmethylpropyl and 1- ethyl -2-methylpropyl . Unless otherwise specified, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1- dimethylethyl are preferred. Aryl generally denotes an aromatic group having 6 to 10 carbon atoms, the aromatic group may also be substituted by one or more lower alkyl groups, trifluoromethyl groups, cyano groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms - which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen (such as fluorine, chlorine or bromine) and hydroxyl. Aralkyl generally denotes a C7.14-aryl group bound via an alkylene chain, in which the aromatic group may be substituted by one or more lower alkyl groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms, which may be identical or different. Aralkyl groups having 1 to 6 carbon atoms in the aliphatic part and 6 carbon atoms in the aromatic part are preferred. Unless otherwise stated, the preferred aralkyl groups are benzyl, phenethyl and phenylpropyl or 2-phenylisopropyl. Alkoxy generally represents a straight-chained or branched Cl.e-hydrocarbon group bound via an oxygen atom. A lower alkoxy group having 1 to 3 carbon atoms is preferred. The methoxy group is particularly preferred. Unless otherwise stated, amino denotes an NH2 function which may optionally be substituted by one or two Ci.e-alkyl, aryl or aralkyl groups, which may be identical or different. Alkylamino represents, by way of example, methylamino, ethylamino, propylamino, 1-methylene-ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1, l-dimethylethylamino. Dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di-(1- methylethyl)amino, di-(1-methylpropyl)amino, di - 2 - methylpropylamino, ethylmethylamino or methylpropylamino. Cycloalkyl generally denotes a saturated or unsaturated cyclic hydrocarbon group having 5 to 9 carbon atoms which may optionally be substituted by a halogen atom or a number of halogen atoms, preferably fluorine, which may be the same or different. Cyclic hydrocarbon groups having 3 to 6 carbon atoms are preferred. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl. Heteroaryl, within the scope of the above definition, generally represents a 5- to 6-membered ring which may contain oxygen, sulphur and/or nitrogen as heteroatoms and onto which another aromatic ring may be fused. 5- and 6-membered aromatic rings which contain an oxygen, a sulphur and/or up to two nitrogen atoms and which are optionally benzocondensed are preferred. Examples of particular heterocyclic systems include: acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl, benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, dibenzazapinyl, dibenzofuranyl, dibenzothiophenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihy^dropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, phenanthracquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrimidyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl, quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl, succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xanthydrolyl, adeninyl, alloxanyl, alloxazinyl, anthranilyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl, benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, pyrimidioriyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl, thiazepinyl, thiazinyl, thiazolidinonyl, thiazolidinyl, thiazolinonyl, thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl, azabenzonaphththenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, petrazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl. Particularly preferred heteroaryl groups include, for example, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl,, isoquinolyl, quinazolyl, quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, .oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl. The new compounds may be prepared by a variety of methods, which comprise a further feature of the invention. The following procedures may be used to prepare compounds of the invention: 1) Imidoesters of formula II (Figure Removed) (wherein Rx to R4, A and B are as hereinbefore defined and -OR or -SR denote the residue of an alcohol or thiol preferably in which R denotes a Ci.g-alkyl or benzyl group) may be reacted with ammonia. The reaction is conveniently carried out in an organic solvent at temperatures between about 0°C and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100°C or boiling temperature, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol and propanol. If the starting materials are sufficiently acidstable, the reaction may be carried out via the corresponding acid imide chlorides instead of the imido esters. 2) In order to prepare compounds of formula I wherein A is linked via 0 or S to at least one of the ring systems: (a) a phenol or thiophenol of formula III wherein Z denotes OH or SH and R17 R2 and R3 are as hereinbefore defined, is reacted with a compound of general formula IV [IV) wherein A is as hereinbefore defined and L denotes a nucleofugic leaving group, or (b) a phenol or thiophenol of formula V (Figure Removed) wherein Z is as hereinbefore defined, is reacted with a compound of formula VI: (Figure Removed) wherein A, Rt, R2, R3 and L are as hereinbefore defined. The reaction is carried out in aprotic solvents such as dimethylsulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol using a base (metal carbonate, metal hydroxide, metal hydride) at temperatures between about 0 and 140°C or the boiling temperature of the reaction mixture. The phenols or thiophenols may also be used in the form of salts, e.g. the alkali metal salts. The nucleofugic leaving group may be, for example, a halogen such as Br or Cl. 3) An amidoxime of formula VII NOH (VII) wherein A and Rt to R3 are as hereinbefore defined, is reduced. Catalytic hydrogenation, particularly with Raney nickel in a lower alcohol such as methanol, is preferred as a method for reducing the amidoxime. Appropriately, the amidoxime of the formula (VII) is dissolved in methanol with the addition of the calculated quantity of the particular acid the salt of which is desired as an end product, and hydrogenated at ambient temperature under slight pressure, e.g. 5 bar, until the uptake of hydrogen has ceased. The starting materials may be obtained from known compounds by conventional methods. Thus, the starting materials for process 1) may be obtained from the corresponding nitriles by reacting with HCl via the step of the imide chlorides or directly by reacting with C^g-alcohols or benzyl alcohol, for example, in the presence of an acid such as HCl. Reacting the nitriles with H2S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine with subsequent alkylation or benzylation also results in compounds of formula II. Starting from carboxylic acid amides, which moreover correspond to the compounds of formula II by reacting with a trialkyloxonium salt such as triethyloxoniumtetrafluoroborate in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures of between 0 and 50°C, preferably at ambient temperature, compounds of formula II are obtained. In order to prepare the starting materials of general formula VII, the corresponding amidoximes may be reacted instead of amidines in a process analogous to process 1) or 2), or by analogous reaction of corresponding nitriles, from which the starting materials of general formula VII are finally obtained by the addition of hydroxylamine. It has been found that the compounds of formula I are characterised by their versatility in therapeutic applications. Particular mention should be made of those applications in which the LTB4-receptorantagonistic properties play a part. These include, in particular, arthritis, asthma, chronic obstructive lung diseases, e.g. chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by non-steroidal antiphlogistics, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis and multiple sclerosis. The new compounds may also be used to treat illnesses or conditions in which the passage of cells from the blood through the vascular endothelium into the tissue is of importance (e.g. metastasis) or diseases and conditions in which the combination of LTB4 or another molecule (such as 12-HETE) with the LTB4-receptor affects cell proliferation (such as chronic myeloid leukaemia). The new compounds may be used in conjunction with other active substances, e.g. those used for the same indications, or with antiallergics, secretolytics, (32- adrenergics, steroids administered by inhalation, antihistamines and/or PAF-antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation. The activities may be investigated pharmacologically and biochemically using tests such as those described in WO 93/16036, pages 15 to 17, which are thus incorporated herein by reference. The therapeutic or prophylactic dose is dependent not only on the potency of the individual compounds and the body weight of the patient but also on the nature and gravity of the condition being treated. For oral use the dose is between 10 and 500 mg, preferably between 20 and 250 mg. For administration by inhalation, the dose given to the patient is between about 0.5 and 25, preferably between about 2 and 20 mg of active substance. Solutions for inhalation generally contain between about 0.5 and 5% of active substance. The new compounds may be administered in conventional preparations, e.g. as tablets, coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments and suppositories. The Examples which follow show some possible formulations for the preparations: Examples of formulations 1. Tablets Composition: Active substance according to the invention 20 parts by weight Stearic acid 6 parts by weight Glucose 474 parts by weight The ingredients are processed in the usual way to form tablets weighing 500 mg. If desired, the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly. 2. Suppositories Composition: Active substance according to the invention 1000 parts by weight Powdered lactose 45 parts by weight Cocoa butter 1555 parts by weight The ingredients are processed in the usual way to form suppositories weighing 1.7 g. 3. Powders for inhalation Micronised powdered active substance (compound of formula I; particle size approximately 0.5 to 7 /xm) are packed into hard gelatine capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722, to which reference is hereby made. (Figure Removed) Example of synthesis Amidoxime: X = para-C(=NOH)NH2 2.0 g of the nitrile of the above formula (X = para-CN) are placed in 40 ml of ethanol, refluxed and a mixture of 1 g of Na2C03 in 5 ml of water and 1.24 g of hydroxylamine x HCl is added dropwise. After 5 hours' refluxing the solvent is distilled off, the residue is stirred with 50 ml of water, extracted 3 x with 50 ml of ethyl acetate and the combined organic phases are dried. After filtering, the substance is evaporated down in vacuo and the residue is purified by flash chromatography (silica gel 60, CH2Cl2/methanol 9:1). The product is dissolved in ethanol, acidified with ethanolic HCl and precipitated as the hydrochloride using ether. The oil obtained is crystallised with ethyl acetate. Yield: 2.0 g of white crystals. 4-[[3-[[4-[1-(4-Hydroxyphenyl)-1-methylethyl]phenoxy]- methyl]phenyl]methoxy]benzolcarboximidamide hydrochloride (X = para-C(=NH)-NH2) 2.0 g of the amidoxime of the above formula (X = para- C(=NOH)~NH2) are dissolved in 50 ml of methanol and hydrogenated with 5 g of methanol-moistened Raney nickel with the addition of 1 ml of 20% ammonium chloride solution for 5 hours under normal pressure and at ambient temperature. The nickel is suction filtered and the solution is filtered through kieselguhr. After concentration by evaporation in vacuo, the residue is stirred with 50 ml of water. The crystals are suction filtered and recrystallised twice from ethanol/ether. Yield: 1.0 g of the amidine compound (the above formula, X = para-C(=NH)-NH2 as hydrochloride, m.p. 234-236°C. The following compounds are also obtained, inter alia, using this procedure: (Table Removed) Surprisingly, the compounds in the Example and in the Table have outstanding Kt values which are largely within the range from 0.2 to 0.7 nmol/1 (RB.LTB4/U937 cells). Claims 1. Compounds of general formula I NH, (Formula Removed) wherein A denotes X1-CmH2m-X2/ in which m is an integer 2, 3, 4, 5 or 6 or and x denotes 0, NH or NCH3; X2 denotes 0, NH, NCH3 or X3 denotes ~Xi-CnU2n- in which n is an integer 1 or 2 ; X4 denotes -Cn-H^-X!-, wherein n is an integer 1 or 2; R! denotes C5.7-cycloalkyl, Arl r OArl7 CH2-Ar2; CR4R5Ar3, or C(CH3 ) 2R6 ; R2 denotes H, C^g-alkyl, OH, halogen, or O- ( C alkyl; R3 denotes H, or C^g- R4 denotes C^-alkyl, CF3, CH2OH, COOH, or 000(0!. 4) -alkyl; R5 denotes H, C1_4-alkyl, or CF3 and ^,1 R4 and R5 may also together form a C4_6-alkylene group; R6 denotes CH2OH, COOH, COO (C^ ) -alkyl, CONR9R10, or CH2NR9R10; R7 denotes H, halogen, OH, C-^g-alkyl or C^.g-alkoxy; Re denotes H, halogen, OH, C-^g-alkyl or C^g- R9 denotes H, C^g-alkyl, phenyl, phenyl- (C-^g- CORu, COOR11; CHO, CONH2 , CONHRllf SO2- (C^g- SO2 -phenyl, wherein the phenyl ring may be mono- or polysubstituted by halogen, CF3, C1.4-alkyl/ OH, C1.4-alkoxy; R10 denotes H or C^.g-alkyl and R9 and R10 together may represent a C4.6-alkylene group; denotes Ci.g-alkyl, C5.7-cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl- (Ci^gwherein the aryl or heteroaryl groups may be monoor polysubstituted by Cl, F, CF3, Cx^-alkyl, OH or C1_4-alkoxy; denotes an optionally mono- or polysubstituted aryl group, with the exception of an unsubstituted phenyl group or a phenyl group which is monosubstituted by halogen, C1.4-alkyl or Ar2 denotes an optionally mono- or polysubstituted aryl group, with the exception of an unsubstituted phenyl group; Ar3 denotes an optionally mono- or polysubstituted aryl group ,t with the proviso that R! cannot represent an unsubstituted phenyl group bound via a C1_4-alkylene unit; optionally in the form of individual optical isomers, mixtures of individual enantiomers, or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. 2. Compounds according to general formula I wherein A denotes X1-Cm-H2m-X2 in which m is the integer 2 and Xj_ is O; X2 is X3 denotes X^Cy^ wherein n is the integer 1 or 2; X4 denotes C^n'^i wherein n is the integer 1 or 2; R! denotes C5.7-cycloalkyl, Arlf OAr^ CH2-Ar2; CR4R5Ar3, C(CH3)2R6; R2 denotes H, Ci.g-alkyi, OH, Cl, O- (d.6) -alkyl ; R3 denotes H, Ci. 6- alkyl; R4 denotes C^-alkyl, CF3/ CH2OH; R5 denotes H, C^-alkyl, CF3, CH2OH and R4 and R5 together may also form a C4_6-alkylene group; R6 denotes CH2OH, COOH, COO (^.4) alkyl, CONR9R10, CH2NR9R10; R7 denotes H, F, Cl, Br, OH, C^g-alkyl or C1_6-alkoxy; R8 denotes H, F, Cl, Br, OH, C^g-alkyl or C1_6-alkoxy; R9 denotes H, Ci.g-alkyl; R10 denotes H or Ci.g-alkyl and R9 and R10 together may also represent a C4_6-alkylene group ; x denotes an optionally mono- or polysubstituted aryl group, with the exception of the unsubstituted phenyl group and the phenyl group which is monosubstituted by halogen, C^-alkyl and monosubstituted by C1.4-alkoxy; Ar2 denotes an optionally mono- or polysubstituted aryl group, with the exception of the unsubstituted phenyl group ; Ar3 denotes an optionally mono- or polysubstituted aryl group with the proviso that R! cannot represent an unsubstituted phenyl group bound via a C1_4-alkylene unit; optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates and /• in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. 3. Compounds according to general formula I wherein A denotes and Xj. is O; X3 denotes X1-CE2; X4 denotes Rx denotes C5.7-cycloalkyl, Arl7 OAr^ CH2-Ar2; CR4R5Ar3, C(CH3)2R6; R2 denotes H, OH, 0- (C^g) -alkyl ; R3 denotes H; R4 denotes CH3, CH2OH; R5 denotes H, CH3 , CH2OH and R4 and R5 together may also denote a C4_6-alkylene group; R6 denotes CH2OH, COOH, COO (C^) -alkyl , CONR9R10/ R7 denotes H; R8 denotes H; R9 denotes H, Ci.g- R10 denotes H or C^.g-alkyl and R9 and R10 together may also denote a C4_6-alkylene group; x denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and Ar2 denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and Ar3 denotes an aryl group optionally mono- or polysubstituted by hydroxy or by hydroxy and optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. 4 . A process for preparing compounds according to general formula I, as claimed in claim 1, which comprises either a) reacting an imido ester of general formula II (Formula Removed) wherein Rx to R4 and A are defined as in claim 1 and -OR represents the residue of an alcohol with ammonia. or b) where it is desired to form a compound in which A is linked to at least one of the ring systems via 0 or S, either (i) reacting a phenol or thiophenol of formula III (Formual Removed) wherein Z denotes OH or SH and R1; R2 and R3 are as defined in claim 1, with a compound of general formula IV (Formula Removed) wherein A is defined as in claim 1 and L denotes a nucleofugic leaving group; or ii) reacting a phenol or thiophenol of general formula V (Figure Removed) wherein z is defined as in (i) above with a compound of formula VT (Formula Removed) wherein A, R17 Rj, R3 and L are defined as in claim 1; or c) reducing an amidoxime of general formula (Formula Removed) wherein A and Rt to R3 are defined as in claim 1; followed where necessary or desired, by separation of any mixture of optical isomers into individual isomers, and formation of any acid-addition salt or free base from the free base or acid-addition salt respectively- 5. A process according to part a) of claim 4, wherein the reaction takes place in a polar organic solvent, at (Figure Removed) a temperature between about 0*C and the boiling ' temperature of the reaction mixture. I ' S. A process as claimed in claim 5 wherein the reaction is carried out in methanol, ethanol orlpropanol at between ambient temperature and about 10()"C or the boiling temperature of the;reaction mixture, if I this is lower 7. A process according to part b)(i) or b}(iij of claim 4, wherein the reaction is carried out in^an aprotic solvent in the presence of a base. i 8. A process as claimed in claim 7 wherein the reaction is carried out in dimethylsulphoxide, dimethylformamide, acetonitrile or a lower alkahol, and the base is a metal carbonate, metal hydroxide p:r metal hydride. i 9. A process according to any of claims 4 b), 7 or 8, which is carried out at a. tempeirature b«=>t-.weaii Qi ,ind 140°C or between, 0"C and the boiling temperature of the reaction mixture if this is lower. : 10. A process according to any of claims 4 b) or 7 to 9, wherein the phenols or thiophenols axe used in the form of their alkali metal salts, and where necessary or desired, a halogen is used as the nucleofugic leaving group. XI. A process according to part c) of claim 4/; wherein the reduction is carried out in the presence of a Raney nickel catalyst in a lower alkanol solvent, under ah elevated pressure of approximately 5 bar. 12. A process according to claim 4 a) or claim 5 in which, instead of an imidq ester of general formula II, a corresponding acid imide chloride is used as starting material. 13. Pharmaceutical preparation which comprises a compound according to any one of claims X to 3 or an acid addition salt thereof together with a pharmaceutically acceptable carrier, excipient or diluent. 14. Use of a compound according to any one of claims 1 to 3 in a pharmaceutical composition. 15. Use of compounds according to claim 14 as a pharmaceutical having LTB4-antagonistic activity. 16. Use of a. compound of gene,ral formula. I ap claimed in claim 1, their stereoisomers and the acid addition salts thereof for preparing.a drug for the therapeutic treatment of arthritis, asthma, chronic obstructive lung disease such as chronic bronchitis, psoriasis?/ ulcerative colitis, gastropathy or enteropathy induced by non-steroidal antiphlogistics, cystic fibrosis,. Alzheimer's disease, shock,:reperfusion damage/ischaemia, atherosclerosis and multiple sclerosis. 17. A method of treating- a condition requiring LTB4-antagonistic activity which comprises administering to a subject an effective amount: of a compound oi: formula (I) as claimed in claim 1 or a stereoisomer or acid-addition salt thereof. 18. Compounds of general formula I substantially as hereinbefore described with reference to the foregoing examples. 19. A process for preparing compounds substantially as hereinbefore described with reference to the foregoing examples. 20. Pharmaceutical preparation substantially as herein described with reference to the foregoing examples.

Documents:

2669-DEL-1996-Abstract-04-03-2008.pdf

2669-del-1996-abstract-24-04-2008.pdf

2669-del-1996-abstract.pdf

2669-DEL-1996-Claims-04-03-2008.pdf

2669-del-1996-claims-24-04-2008.pdf

2669-del-1996-claims.pdf

2669-DEL-1996-Correspondence-Others-04-03-2008.pdf

2669-del-1996-correspondence-others-15-04-2008.pdf

2669-del-1996-correspondence-others-24-04-2008.pdf

2669-del-1996-correspondence-others.pdf

2669-del-1996-correspondence-po.pdf

2669-DEL-1996-Description (Complete)-04-03-2008.pdf

2669-del-1996-description (complete)-24-04-2008.pdf

2669-del-1996-description (complete).pdf

2669-del-1996-form-1-24-04-2008.pdf

2669-del-1996-form-1.pdf

2669-del-1996-form-18.pdf

2669-del-1996-form-2-24-04-2008.pdf

2669-del-1996-form-2.pdf

2669-del-1996-form-3.pdf

2669-del-1996-form-4.pdf

2669-del-1996-form-5.pdf

2669-del-1996-form-6.pdf

2669-DEL-1996-GPA-04-03-2008.pdf

2669-del-1996-gpa.pdf

2669-DEL-1996-Other Document-04-03-2008.pdf

2669-DEL-1996-Petition-137-04-03-2008.pdf

2669-DEL-1996-Petition-138-04-03-2008.pdf

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