NZ240727A - Beta-hydroxyethylamine derivative, preparation and pharmaceutical compositions thereof - Google Patents

Beta-hydroxyethylamine derivative, preparation and pharmaceutical compositions thereof

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Publication number
NZ240727A
NZ240727A NZ240727A NZ24072791A NZ240727A NZ 240727 A NZ240727 A NZ 240727A NZ 240727 A NZ240727 A NZ 240727A NZ 24072791 A NZ24072791 A NZ 24072791A NZ 240727 A NZ240727 A NZ 240727A
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New Zealand
Prior art keywords
chain
straight
branched
unsubstituted
alkyl
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NZ240727A
Inventor
Heinz Hanel
Reinhard Kirsch
Hariolf Kottmann
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Hoechst Ag
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Publication of NZ240727A publication Critical patent/NZ240727A/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £40727 <br><br> '240 7 2 7 <br><br> Patents Form 5 <br><br> CwnyiCw^ -ViC^ £ \\ <br><br> r~— Co-iC3^^l3sp/.C9^&lt;^nU?,7&lt;P,'.. CvriDZJDjIl^CalW.tdtt;, <br><br> CRl PA-M.jp.*; C°^O^fhl: C9J/&amp;VJ2K - <br><br> 2 7 APR 1994 <br><br> i.^ia <br><br> MfrS",.S"^.53S7; <br><br> COMPLETE SPECIFICATION <br><br> MO DRAWINGS <br><br> 26 NOV 1991 <br><br> R-TL;«. <br><br> N.Z. No. <br><br> NEW ZEALAND Patents Act 1953 <br><br> fl-HYDROXYETHYLAMINES HAVING A T. 1 -DISUBSTITUTEP CYCLOPROPYL RADICAL. A PROCESS FOR THEIR PREPARATION AND THEIR USE <br><br> We, HOECHST AKTIENGESELLSHAFT, a Joint Stock Company existing under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- <br><br> -1 - (Followed by 1A) <br><br> £4072 <br><br> ~1A- <br><br> W J'Jf* <br><br> Description <br><br> /9-Hydroxyethyl amines having a 1,1-disubstituted cyclo-propyl radical, a process for their preparation and their use <br><br> The invention relates to £-hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, their preparation and the use of /9-hydroxyethylamines having a 1,1-di-substituted cyclopropyl radical and of pharmaceutical compositions containing such compounds as pharmaceuticals, in particular as growth inhibitors of the pathogenic phase of amorphous yeast cells, as antimycotics and as plant protection agents, for example fungicides and growth regulators, the use of the compounds being possible both in prophylaxis and in therapy. <br><br> It is known of a few ^-hydroxyethylamines, which are used as beta-blockers, that they indeed have a slight effect on the inhibition of liposomal phospholipase A1 (cf. K.Y. Hostetler et al., Biochemical Pharmacology 34, 521-524 (1985)). However, the potency and tolerability of these compounds are unsatisfactory (examples are, for example, propranolol or metoprolol). <br><br> It has now surprisingly been found that |9-hydroxyethyl-amines having a 1,1-disubstituted cyclopropyl radical, depending on the structure of the respective substitu-ents, are inhibitors of the exoenzymes of fungi, have <br><br> propranolol metoprolol <br><br> l y y <br><br> - 2 - <br><br> fungicidal and antiiaycotic action and are particularly outstanding growth inhibitors of the pathogenic phase of dimorphic yeast cells. <br><br> The invention relates to the compounds of the formula I, <br><br> their preparation and their use as fungicides, as anti-mycotics and as growth inhibitors of the pathogenic phase of dimorphic yeast cells for the prophylaxis and therapy of fungal diseases. The invention furthermore relates to pharmaceutical compositions containing these compounds: <br><br> R(2) <br><br> R(l&gt; T <br><br> 10 <br><br> R(4) R(5) <br><br> in formula Is <br><br> R( 1) is t-butyl, phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, <br><br> phenylsul f inylphenyl, phenylsul f onylphenyl, naph-15 thyl, 1,2,3,4-tetrahydronaphthyl, indanyl, fluor- <br><br> enyl, thienyl, furyl, pyridyl, isoxazolyl, pyrazo-lyl, benzofuryl or benzothienyl, <br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or 20 different and which are <br><br> F, CI, Br, I, (Ci-CiaJ-alkyl (straight-chain or branched and unsubstituted or substituted by 1-9 F or CI atoms), (C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or mono- or disubstituted 25 by (CX-CA) -alkyl (straight-chain or branched), <br><br> (Ci-C*)-alkoxy (straight-chain or branched), CF3, F, _ <br><br> CI, Br, or OH, such as, for example, norbornyl, adc!^i ^ ? c; <br><br> * <br><br> mantyl, decahydronaphthyl], ^-CCi-C^)-alkyl <br><br> J <br><br> 7C JUL:?" <br><br> 240727 <br><br> (straight-chain or branched), Y-(C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or substituted as indicated above], (C2-C15) -alkenyl, (straight-chain or branched, mono- or polyunsaturated), Y-(C2-C15)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, Y-(Ci-C*)-alkylphenyl, phenyl-(Cj-C^J-alkyl, phenyl, CN, N02, or C02Z (where Z is phenyl), (Ci-C^)-alkyl or (C2-C15)-alkenyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1-3 substituents from the series comprising F, CI, CF3 and OH), <br><br> where Y is oxygen, sulfur, sulfinyl or sulfonyl, <br><br> R(2) is OH, F, CI, Br, (C^CujJ-alkylcarbonyloxy (straight-chain or branched), (Ci-CmJ-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or mono- or disubstituted by F, CI, Br, CF3 or OCH3) , phenylcarbonyloxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, CI, Br, CF3, and (Cj-C*) - alley 1 (straight-chain or branched), <br><br> R(3) is (Ci-Cia)-alkyl (straight-chain or branched, <br><br> unsubstituted or mono- to nonasubstituted by F, CI, Br, I and/or OCH3),. (C2-C12)-alkenyl (straight-chain or branched, mono- or polyunsaturated, in the form of the pure E- or Z-diastereomers or as an E/Z-dia-stereomer mixture, unsubstituted or mono- to nonasubstituted by F, CI, Br, I and/or OCH3), (C^C^)-alkynyl (straight-chain or branched, having one or more triple bonds, unsubstituted or mono- to nona- ^ L K ' 0 substituted by F, Cl, Br, I and/or OCH3), (Ca-C^)^ <br><br> alkenynyl (straight-chain or branched, containing <br><br> , kl . + . , u « £11 JAN 1094 <br><br> one or more double and triple bonds, in the form of the pure E- or Z-diastereomers or as an E/Z-dia-stereomer mixture, unsubstituted or mono to nonasubstituted by F, Cl, Br, I and/or OCH3), <br><br> 24 07 27 <br><br> (C^-C^)cycloalkyl (unsubstituted or mono- to nonasubstituted by F, Cl, Br, I, OCH3 and/or CH3), (Ca-C^)-cycloalkyl-(Ci-Ca)-alkyl (unsubstituted or mono- to nonasubstituted by F, Cl, Br and/or CH3), <br><br> phenyl, benzyl, phenyl-(C2-CJ-alkyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsul-fonylphenyl, phenoxyphenyl-(Cj-C^)-alkyl, phenyl-thiophenyl-(C1-CA)-alIcyl, naphthyl, naphthyl- (Ci-C*) -alkyl, biphenylyl, biphenyl-(C!-CA)-alkyl, hetaryl or hetaryl- (Ci-Cj) -alkyl (where hetaryl is a radical derived from thiophene, <br><br> furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyrimidine, pyrazine, benzothiofuran, benzothiazole, benzoxazole, indole, quinoline or isoquinoline), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- to trisubstituted by F, Cl, Br, CF3, ()-alley 1 (straight-chain or branched, unsubstituted or mono-to trisubstituted by F, Cl and/or OCH3), (C3-C6)-cycloalkyl (unsubstituted), or the aromatic *ing systems or the hetaryl systems are substituted by phenyl (unsubstituted or mono- to trisubstituted by F, Cl, OCH3), CN, OH, NH2, NR(6)R(7), N02, or Z'R(6), <br><br> in which Z' is oxygen or sulfur, R(6) is (Ci-C10)-alkyl (straight-chain or branched, unsubstituted or mono- to nonasubstituted by F, Cl and/or OCH3) , or R(6) is (C3-Cu)-alkenyl (straight-chain or branched, <br><br> mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or QCH3), or R(6) is benzyl, biphenylylmethyl, naphthylmethyl, phenyl, thienylmethyl, thienyl, (C^C^) -alkylcarbonyl (straight-chain or branched) or phenylcarbonyl, <br><br> where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- to trisubstituted by F, Cl, CF3, (Ci-CJ-alkyl and/or (Cl-C*)-alkoxy and R(7) is either hydrogen or defined '% <br><br> R(6), where R(6) and R(7) can be identical different, /f'Y <br><br> &gt; » r,t <br><br> \ "JIN 1394 "if <br><br> V, .o/ <br><br> - 5 - <br><br> 24 0727 <br><br> R(4) is H, (Ci-C^)-alkyl (straight-chain or branched), (C2-C10)-alkenyl (straight-chain or branched, mono-or polyunsaturated), or benzyl (unsubstituted or mono-or polysubstituted by F, Cl, Br, CF3, (Cj-C*)-alkyl 5 (straight-chain or branched), OCH3, O-phenyl or phenyl), <br><br> R(5) is H, (Ci-Cia)-alkyl (straight-chain or branched), (C2-C18)-alkenyl (straight-chain or branched, mono-or polyunsaturated)(C^C^)-cycloalkyl (mono-, bi-10 or tricyclic, such as, for example, cyclohexyl, <br><br> norbornyl or adamantyl), (Ci-CaJ-alkyloxy-^-Cm)-alkyl, phenyl-(Ci-Cg)-alkyl (straight-chain or branched), phenyloxy- (Ci-Cg) -alkyl, phenylthio-(Ci-Cg)-alkyl, phenyl-(C2-C6)-alkenyl (straight-chain 15 or branched, mono- or diunsaturated), diphenyl- <br><br> (Ci—C6) —alkyl (straight-chain or branched), thienyl, thienylmethyl, or phenyl, where the phenyl or thienyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents 20 from the group comprising F, Cl, Br, (C^Cm)-alkyl <br><br> (straight-chain or branched), (C3-CB)-cycloalkyl, OH, SH, (Ci-Cio) -alkoxy (straight-chain or branched), <br><br> phenyl, benzyl, phenethyl, thiophenyl, CaFa+1 where a = 1-6, and -0(CH2) j_20-, <br><br> 25 or <br><br> R(5) is a piperidin-4-yl radical which is unsubstituted or substituted by 1 to 4 methyl groups, <br><br> or <br><br> R(5) is an indol-3-yl-(C1-C4)-alkyl radical (straight-30 chain or branched), <br><br> or &lt; <br><br> // c <br><br> ,;-V <br><br> R(4) with R(5) forms a chain of (CH2)B units with m = 4-6,' <br><br> '"20 JUL;:::. <br><br> 25 <br><br> - 6 - <br><br> 4 0/27 <br><br> which chain can be interrupted by an oxygen, sulfur or nitrogen atom, which nitrogen as a further bonding component carries a hydrogen atom, or a CH3, phenyl, benzyl or phenethyl group, and the hetero-cycle thus formed is unsubstituted on the CHZ units or carries 1 to 4 CH3 groups as substituents) <br><br> and <br><br> X is oxygen, sulfur, sulfinyl or sulfonyl, <br><br> and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives. <br><br> Preferred compounds of the formula I are those in which: <br><br> R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinyl-„ phenyl, phenylsulfonylphenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, fluorenyl, thienyl or pyridyl, <br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are <br><br> F, Cl, (Ci-Cj^)-alley 1 (straight-chain or branched and unsubstituted or * substituted by 1-6 fluorine or chlorine atoms), (C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or monosubstituted by (CL—CA) —alkyl (straight-chain or branched), (Ci-C*)-alkoxy (straight-chain or branched), CF3, F, Cl or OH , such as, for example, norbomyl, adamantyl or decahydronaphthyl ], Y- (Cx-C10) -alkyl (straight-chain or branched) / Y-(C3-C10) -cycloalkyl [mono-, bi-or multicyclic, unsubstituted or substituted as indicated above], (C2-C10) -alkenyl (straight-chain or <br><br> — - - - <br><br> branched, mono- or polyunsaturated), Y-(C2-C10WO6N r &lt;, <br><br> •7Q <br><br> alkenyl (straight-chain or branched, mono- or <br><br> "2 0 JULC?3 <br><br> - 7 - <br><br> 4 0 7 2? <br><br> polyunsaturated), Y-phenyl, Y-(C1-C2) -alley lphenyl, phenyl-(Ci-Cj)-alkyl, or biphenylyl, <br><br> where Y is oxygen or sulfur, <br><br> R(2) is OH, F, Cl, (Ci-CioJ-alkylcarbonyloxy (straight-chain or branched) , (C1-C10)-alkyloxy (straight-chain 10, or branched), benzyloxy (unsubstituted or mono- or disubstituted by F, Cl, CF3 or OCH3), or phenylcarbonyl-oxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, Cl, CF3 and (Cx-C4)-alkyl (straight-15 chain or branched), <br><br> R(3) is (Ci-Cxa)-alkyl (straight-chain or branched, unsubstituted or mono- to hexasubstituted by F, Cl, <br><br> Br and/or OCH3), (C^-C^)-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or 2 0 mono- to trisubstituted by F, Cl and/or 0CH3), <br><br> (C2-C10)-alkynyl (straight-chain or branched, having one or two triple bonds and unsubstituted), (C3-C10)-alkenynyl (straight-chain or branched, containing one or more double and/or triple bonds and unsubsti-25 tuted), (Ca-C^)-cycloalkyl (unsubstituted or mono- <br><br> to trisubstituted by F, Cl, Br and/or CH3), (Cj-C^)-cycloalkyl- (C1-C3) -alkyl (unsubstituted), phenyl, <br><br> benzyl, phenyl-(C2-C3)-alkyl, phenoxyphenyl, phenyl-thiophenyl, phenylsulfinylphenyl, phenylsulfonyl-30 phenyl, phenoxyphenyl-(C^C*) -alkyl, phenylthio- <br><br> phenyl-(C1-C2)-alkyl, naphthyl, naphthyl-(Ci-Cj,)- <br><br> alkyl, biphenylyl, biphenylyl-(Cx-C2)-alkyl, hetaryl'pr • " ' <br><br> '/'X <br><br> hetaryl- (Ci-Ca) -alkyl [where hetaryl is a radical derived from thiophene, <br><br> furan, pyridine, oxazole, isoxazole, thiazole, <br><br> A 11 ' * \! 1QQ4 <br><br> 35 isothiazole, 1,3,4-oxadiazole, pyrimidine, benzo- J,u" / <br><br> A --v /y thiofuran, benzothiazole, benzoxazole, quinoline or o <br><br> -s- 240727 <br><br> isoquinoline], where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF3, (Ci-C^)-alkyl (straight-chain or branched, unsubstituted or mono- or disubstituted by F or Cl) , (C3-C6)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or Z*R(6), in which Z' is oxygen or sulfur, R(6) is (C,-C10)-alkyl (straight-chain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH3) , <br><br> or R(6) is (C3-Cl0)-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or 0CH3), or R(6) is benzyl, phenyl, thienylmethyl, thienyl or phenylcarbonyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- or disubstituted by F, Cl, CF3, -alley 1 <br><br> and/or (C^C*)-alkoxy and R(7) is either hydrogen or as defined for R(6), where R(6) and R(7) can be identical or different, <br><br> R(4) is H, (Cx-C10)-alkyl (straight-chain or branched), or benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF3, (Ci-CJ-alkyl (straight-chain or branched), OCH3, 0-phenyl or phenyl), <br><br> R(5) is H, (Ci-Cig)-alkyl (straight-chain or branched), (C2-C16)-alkenyl (straight-chain or branched, mono-or diunsaturated), (Ca-C^)-cycloalkyl (mono-, bi-or tricyclic), such as, for example, cyclohexyl, <br><br> norbornyl or adamantyl), (Cj-Ce) -alkyloxy-(C2-CB) -alkyl, phenyl- (C1-C6) -alkyl (straight-chain or branched), phenyl-(C2-C6)-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(C1-C6)-alkyl (straight-chain or branched), or phenyl, where <br><br> , ^ ' 1J d' <br><br> the phenyl systems mentioned with respect to R(5) .' o% <br><br> / ' ^ <br><br> are unsubstituted or mono- to trisubstituted by <br><br> • ,, c, <br><br> substituents from the group comprising F, C1': ^ <br><br> (Ci-CJ-alkyl (straight-chain or branched), (Ca-Ca)--,. ^ J <br><br> • .H «" ? ^ <br><br> - 9 - <br><br> 24 0727 <br><br> cycloalkyl, (Ci-Cu) -alkoxy (straight-chain or branched), benzyl, phenethyl, thiophenyl and -O-fCHah-a-O-, <br><br> or <br><br> 5 R(5) is 2,2,6,6-tetramethylpiperidin-4-yl, or indol-S-yl-fCi-CJ-alkyl, and <br><br> X is oxygen, sulfur, sulfinyl or sulfonyl, <br><br> and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and 10 pharmaceutically acceptable derivatives. <br><br> Particularly preferred compounds of the formula I are those in which: <br><br> R(l) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl, 15 1,2,3,4-tetrahydronaphthyl, indanyl or pyridyl, <br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are <br><br> F, Cl, (Ci-Cio) -alkyl (straight-chain or branched and 20 unsubstituted or substituted by 1-3 fluorine or chlorine atoms), (C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted, such as, for example, norbornyl, adamantyl or decahydxonaphthyl), Y- (Ci-Cio) -alkyl (straight-chain or branched), 25 Y- (C3-C10) -cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C2-C10)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y- (C2-C10) -alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, benzyl or biphenylyl, <br><br> £ •« /' <br><br> ,y't V <br><br> 2 0 JUL 1593"! <br><br> 24 07 27 <br><br> where Y is oxygen or sulfur, <br><br> R(2) is OH, F, (Cj-CgJ-alkylcarbonyloxy (straight-chain or branched), (Ci-Cg) -alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or monosubsti-5 tuted by F, Cl or CF3), or phenylcarbonyloxy, where the phenyl radical is unsubstituted or mono- to trisubstituted by substituents from the series comprising F, Cl , Br, CF3 and (Ci-C*)-alley 1 (straight-chain or branched), <br><br> 10 R(3) is (Cj-Cja)-alkyl (straight-chain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH3), (Ca-C^)-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubstituted), (Cg-Cia)-cycloalkyl (unsubstituted), (C3-C10)-15 cycloalkyl-(C^C^-allcyl (unsubstituted), phenyl, <br><br> benzyl, phenoxyphenyl, phenylthiophenyl, phenoxyphenyl- (Cx) -alkyl, phenylthiophenyl-(Cx)-alkyl, <br><br> naphthyl- (Cx) -alkyl, biphenylyl, biphenylyl- (Cj.) -alkyl, hetaryl or hetarylmethyl (where hetaryl is 20 a radical derived from thiophene, furan, pyridine, oxazole, isoxazole, <br><br> thiazole, isothiazole, pyrimidine, benzothiazole and benzoxazole), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF3, ()-alkyl (straight-25 chain or branched and unsubstituted), (C3-C6)-cyclo alkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or Z'R(6), in which Z1 is oxygen or sulfur, R(6) is (C^-Cjo) -alkyl (straight-chain or branched 30 and unsubstituted), or R(6) is (C3-C6)-alkenyl <br><br> (straight-chain or branched, mono- or polyunsaturated^ i,, and unsubstituted) or R(6) is benzyl, phenyl, / <br><br> thienylmethyl or thienyl, where the ring systems ^ 7. <br><br> mentioned here for R(6) are for their part unsubsti- <br><br> &lt; J.1.V 1034 <br><br> 35 tuted or mono- or disubstituted by F, Cl, CF3,„ f x, *5^ <br><br> (Ci-CJ-alkyl and/or (Ci-CJ-alkoxy and R(7) is either hydrogen or as defined for R(6), where R(6) and R(7) <br><br> 240727 <br><br> - 11 - <br><br> can be identical or different, <br><br> R(4) is H, (Ci-Cj,,)-alkyl (straight-chain or branched), or benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF3, (Cj-C*) -alkyl (straight-chain or 5 branched), OCH3, O-phenyl or phenyl), <br><br> R(5) is H, (C^C^)-alkyl (straight-chain or branched), (C2-C12)-alkenyl (straight-chain or branched, mono-or diunsaturated), (Gj-C^)-cycloalkyl (mono-, bi-or tricyclic, such as, for example, cyclohexyl, 10 norbornyl or adamantyl), or phenyl-{Ci-Cg)-alkyl <br><br> (straight-chain or branched), phenyl-(C2-C6)-alkenyl (straight-chain or branched, mono- or diunsaturated ), diphenyl- (Cx-C6) -alkyl (straight-chain or branched), phenyl, where the phenyl systems 15 mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents from the group comprising F, Cl, (Cx-C4)-alkyl (straight-chain or branched), (C3-C6)-cycloalkyl, (C^C^) -alkoxy (straight-chain or branched), benzyl and phenethyl, and <br><br> 20 X is oxygen or sulfur, <br><br> and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives. <br><br> Very particularly preferred compounds of the formula I 25 are those in which: <br><br> R( 1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl or pyridyl, <br><br> where said ring systems are unsubstituted or substi-30 tuted by 1-2 substituents, which are identical or different and which are F, Cl, (Cx-C^,)-alkyl^ £ ' o <br><br> ■ ^ * . <br><br> (straight-chain or branched and unsubstituted), <br><br> .0 JUL:?93 <br><br> - 12 - <br><br> 0727 <br><br> (C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted, such as, for example, norbornyl, adamantyl or decahydronaphthyl), Y- (Ci-Cuj) -alkyl (straight-chain or branched), Y-(C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C2-C10)-alkenyl (straight-chain or branched, mono-or diunsaturated), Y-(C2-C10)-alkenyl (straight-chain or branched, mono- or diunsaturated), Y-phenyl, benzyl or phenyl, where the alkyl and alkenyl substituents mentioned are straightrchain or branched and phenyl is unsubstituted or carries 1 or 2 substituents from the series comprising F, Cl and CF3), <br><br> where Y is oxygen or sulfur, <br><br> R(3) is (C1-C10)-alkyl (straight-chain or branched and unsubstituted) , (C3-C12)-alkenyl (straight-chain or branched, mono- or diunsaturated and unsubstituted), (C3-C6)-cycloalkyl (unsubstituted), phenyl, benzyl, phenoxyphenyl, phenylthiophenyl, phenoxyphenyl- (Cx) -alkyl, phenylthiophenyl-(C^-alkyl, naphthyl- (C^ -alkyl, biphenylyl, biphenylyl-(CJ-alkyl, hetaryl, <br><br> hetarylmethyl (where hetaryl is a radical derived from thiophene, pyridine, <br><br> oxazole, isoxazole), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF3, (Cx-C10)-alkyl (straight-chain or branched and unsubstituted), (C3-C6)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are unsubstituted or substituted by CN, NR(6)R(7) or Z'R(6), in which Z' is oxygen or sulfur, R(6) is (C,-C10)-alkyl (straight-chain or branched and unsubstituted) or R(6) is (C3-C6)-alkenyl (straight-chain or , <br><br> branched, mono- or polyunsaturated and unsubstituted) .• <br><br> or R(6) is benzyl or phenyl, where the ring . J pi systems mentioned here for R(6) are for their ^aiti.-.i'\ IGJ4 i unsubstituted or mono- or disubstituted by F, <br><br> X i» | , r,- <br><br> CF3, (C-l-CJ-alkyl and/or (Ci-CJ-alkoxy and R(7) is - - - <br><br> - 13 - <br><br> 24 07 27 <br><br> either hydrogen or as defined for 11(6), <br><br> R(4) is H, <br><br> R(5) is H, (Cx-C10)-alkyl (straight-chain or branched), (C2-C10)-alkenyl (straight-chain or branched, mono-5 or diunsaturated), (Cs-C^)-cycloalkyl (mono-, bi- <br><br> or tricyclic, such as, for example, cyclohexyl, norbornyl or adamantyl), phenyl-(Cj-Cg) -alkyl (straight-chain or branched), phenyl-(C2-C6)-alkenyl (straight-chainor branched, mono- or diunsaturated), 10 diphenyl-(C1-Cs)-alkyl (straight-chain or branched) <br><br> or phenyl, where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- or disubstituted by substituents from the group comprising F, Cl, (Cx-Ct)-alkyl (straight-chain or 15 branched), (C3-C6)-cycloalkyl, (Ci-CJ-alkoxy <br><br> (straight-chain or branched), benzyl and phenethyl, and <br><br> X is oxygen or sulfur, <br><br> and their salts with pharmaceutically acceptable acids 20 and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives. <br><br> Suitable physiologically hydrolyzable and pharmaceutically acceptable derivatives are, for example, derivatives esterified at the hydroxyl group, which are hydrolyzable 25 under physiological conditions to give the free acids, which for their part are in turn physiologically acceptable, i.e. are non-toxic in the necessary doses. <br><br> The compounds (I) have at least one asymmetric carbon atom and can therefore occur as enantiomers and dia-30 stereomers. The invention includes both the pure isomers and their mixtures. The mixtures of diastereomers can be separated into the components by conventional methods, for example by selective crystallization from suitable,^--- <br><br> £ I'J Y <br><br> ■vi &gt; 0 <br><br> r\ <br><br> '20JUL:-??3 <br><br> 24 07 27 <br><br> solvents or by chromatography on silica gel or alumina. <br><br> Racemates can be separated into the enantiomers by customary methods, i.e., for example by salt formation with an optically active acid, separation of the dia-stereomeric salts and liberation of the pure enantiomers by means of a base. <br><br> The invention furthermore relates to a process for the preparation of compounds of the formula (I), which comprises reacting a compound of the formula (II) <br><br> R(l)^,lV^-X-R(3) 10 ZT (II) <br><br> in which R(l), R(3) and X have said meanings, with a sulfur ylide of the formula III <br><br> (H C) S=CH 3 2 li 2 <br><br> (0) TTT <br><br> P III <br><br> in which p is zero or 1, <br><br> 15 to give a compound of the formula IV <br><br> °~7 <br><br> R(1)C' X-R(3) <br><br> (IV) <br><br> ,/q' <br><br> ■f - <br><br> \ " <br><br> rv; <br><br> J <br><br> O ■&gt; <br><br> 20 <br><br> and then reacting the compound of the formula IV with a nucleophile of the formula MNR(4)R(5) in which R(4) and R(5) have the meanings mentioned and M is hydrogen or a metal equivalent, a compound of the formula I where R(2) = OH being formed, and, if desired, acylating or alkylating this compound of the formula I and <br><br> - 15 <br><br> 24 0 7 <br><br> optionally oxidizing to the sulfoxide or sulfone on the sulfur of a thioether group and optionally converting the compound I where R(2) = OH into a compound where R(2) = F, Cl or bromine and isolating a compound of the 5 formula (I) thus obtained in the form of the free base or of an acid addition salt. <br><br> To prepare the compounds of the formula (I), in a first reaction step for the preparation of the compounds of the formula (IV) a ketone of the formula (II) in which R(l), 10 R(3) and X have the abovementioned meanings is reacted with a sulfur ylide of the formula (III) in an inert solvent, preferably dimethyl sulfoxide, or in mixtures of dimethyl sulfoxide with other inert solvents, for example tetrahydrofuran. In this reaction when using 15 a sulfur ylide of the formula (III), for which p = zero, <br><br> a temperature range between -10° and 50°C, preferably between 0° and 30°C, is advantageous; when using a sulfur ylide of the formula (III) for which p = 1, a temperature range between 0° and 80°, preferably between 20° and 60°, 20 is advantageous. <br><br> The conversion of the intermediates of the formula IV into the final products of the formula I where R(2) = OH is carried out in a second reaction step by reaction with a compound of the formula NR(4)R(5)-M, in which R(4), 25 R(5) and M have the abovementioned meanings. <br><br> The abovementioned reaction is carried out in a temperature range from 20-160°C, if appropriate in an inert solvent and if appropriate using a base. <br><br> Suitable solvents are, for example, 30 N,N~dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetonitrile, 4-methyl-2-pentanone, methanol, ethanol, isopropyl alcohol, propanol, butanol, pentanol, tert-butyl alcohol, methylglycol, methylene <br><br> - 16 - <br><br> 240 7 2 7 <br><br> chloride or an aromatic hydrocarbon such as benzene, chlorobenzene, nitrobenzene, toluene or xylene or water. Mixtures of the solvents mentioned by way of example can also be used. <br><br> 5 Suitable bases are, for example, alkali metal or alkaline earth metal alcoholates or hydrides such as, for example, sodium methylate or sodium hydride. <br><br> The reaction of the compounds of the formula II with the compounds of the formula III to give the intermediates of 10 the formula IV and reaction of this with those of the formula MNR(3)R(4) to give compounds of the formula I where R(3) = OH can also be carried out in a one-pot process. <br><br> To do this, as indicated above, a solution of a compound 15 of the formula IV in one of the abovementioned inert solvents is initially prepared by reaction of a compound of the formula II with a compound of the formula III. An at least equivalent amount of a compound of the formula HNR(4)R(5) is then added to this solution. <br><br> 20 Compounds of the formula I in which R(2) is (Ci-C^)-alkoxy or benzyloxy (unsubstituted or mono- or disubstituted by F, Cl, Br, CF3 or OCH3) are prepared by reacting a compound of the formula I where R(2) = OH with an appropriate alkyl or benzyl halide, preferably a chlor-25 ide, bromide, tosylate or mesylate, in the presence of a base, in an inert solvent and in a temperature range from 0 to 100°C. Solvents used are preferably those which are given for the reaction of compounds of the formula IV with M-NR(3)R(4), and suitable bases are, for example, 30 the abovementioned inorganic bases or organic bases such as tert-amines such as triethylamine, ethylmorpholine or, for example, DBU, imidazole or pyridine. <br><br> Compounds of the formula I in which R(2) is (Ci-Cm)-alkylcarbonyloxy are prepared by reacting a compound of <br><br> - 17 - <br><br> '240 7 2 7 <br><br> the formula I where R(2) = H with an appropriate alkyl-carbonyl halide or phenylcarbonyl halide, preferably an alkylcarbonyl chloride, alkylcarboxylic anhydride, phenylcarbonyl chloride or anhydride, in the presence of 5 a base, in an inert solvent and in a temperature range from -20 to 120°C. <br><br> Solvents and bases used are preferably those which have been given for the reaction of compounds of the formula IV with MNR(4)R(5) or alternatively organic 10 bases, such as NEt3, pyridine or DBU. <br><br> Compounds of the formula I in which R(2) is F, Cl or bromine are prepared by reacting a compound of the formula I where R(2) = OH with thionyl chloride, thionyl bromide, sulfur tetrafluoride or diethylaminosulfur 15 trifluoride (Et2NSF3), in an inert solvent, if appropriate in the presence of a base, and in a temperature range from (-40) to (+80)°C. <br><br> Solvents and bases preferably used are those which have been given for the reaction of compounds of the 20 formula IV with NMR(4)R(5) and, for example, bases such as NEt3, ethylmorpholine, pyridine or DBU. <br><br> Compounds of the formula I which contain a thioether group can be oxidized on the sulfur to a sulfoxide or sulfone. To do this, compounds of the formula I of this 25 type are reacted with an oxidant, such as, for example, hydrogen peroxide or m-chloroperbenzoic acid, in an inert solvent and in a temperature range from -10 to 80eC. To prepare sulfoxides, a molar equivalent of oxidant is added to this compound, and to prepare sulfones two molar 30 equivalents are added, and if appropriate even an excess. <br><br> Solvents used are preferably those which are given for the reaction of compounds of the formula (IV) with M-NR(4)R(5). <br><br> 240 7 <br><br> Preparation of the starting substances <br><br> To prepare compounds of the formula II in which R(l) and <br><br> R(2) have the meanings indicated, processes according to corresponding to New Zealand Patent Application N(^ 219606 those given m Patent Applications DEr-OS 3,608,792kana <br><br> DE-OS 3,608,727/are advantageously used. <br><br> corresponding to New Zealand Patent Application No. 219605 <br><br> The invention furthermore relates to a process for the preparation of the compounds of the formula I, according to which a compound of the formula II <br><br> 0 it <br><br> R(l)-C XR(3) <br><br> V (II) <br><br> in which R(l), R(3) and X have the meanings mentioned, is reacted with a phosphorus ylide to give a compound of the formula V <br><br> CH2 <br><br> R(l)-C . XR(3) <br><br> V &lt;7&gt; <br><br> and then the compound V is reacted with an organic peroxide to give a compound of the formula IV <br><br> 0—7 <br><br> R(1)&gt;C X*(3) (IV) <br><br> and IV, as already mentioned above, is further reacted with a nucleophile of the formula M-NR(4)R(5) in which R(4), R(5) and M have the meanings mentioned and M is hydrogen or a metal equivalent, a compound I where R(2) = OH being formed, and, if desired, this compound I being acylated, alkylated or converted into a compound <br><br> - 19 - <br><br> 240727 <br><br> where R(2) = F, Cl or Br, and optionally being oxidized to the sulfoxide or sulfone on the sulphur of a thioether group, <br><br> and optionally being converted into the salt using a 5 physiologically tolerable acid. <br><br> To prepare the compounds of the formula I, in a first reaction step for the preparation of compounds of the formula V a ketone of the formula II, in which R(l), R(3) and X have the abovementioned meanings, is reacted with 10 a phosphorous ylide in an inert solvent and in a temperature range from -60 to +80°C. <br><br> The phosphorous ylide used in this reaction is prepared by reaction of a methyltriarylphosphonium salt, preferably methyltriphenylphosphonium chloride, bromide or 15 iodide, with a strong base in an inert solvent. Suitable bases are, for example, alkali metal or alkaline earth metal hydrides, amides or alcoholates, sodium bistri-methylsilylamide or organolithium compounds such as, for example, n-butyllithium or phenyllithium. <br><br> 20 Solvents used are those which are given for the reaction of compounds of the formula IV with M-NR(4)R(5). <br><br> In a second reaction step for the preparation of compounds of the formula IV a compound of the formula V is reacted with an oxidant, in an inert solvent and in a 25 temperature range from -10 to 80°C, if appropriate in the presence of a base, or of a base and a nitrile such as, for example, benzonitrile, or thionyl-bis-imidazole or -triazole. <br><br> Suitable oxidants are, for example, H202 or percarboxylic 30 acids, such as, for example, peracetic acid, trifluoro-peracetic acid, perbenzoic acid or m-chloroperbenzoic acid. <br><br> Bases and solvents used are those which are given for the <br><br> - 20 - <br><br> £40727 <br><br> reaction of compounds of the formula IV with M-NR(4)R(5). <br><br> In a third reaction step for the preparation of compounds of the formula I where R(2) = OH from compounds of the formula IV, the procedure is as given in the above 5 process. <br><br> These compounds of the formula I where R(2) = OH can, of desired, be acylated, alkylated or converted into a compound where R(2) = F, Cl or Br, and if appropriate oxidized on the sulfur of a thioether group to give the 10 sulfoxide or sulfone, and if appropriate can be converted into the salt with a physiologically tolerable acid, such as given in the above process. <br><br> The compounds of the formula I, their acid addition salts and their physiologically hydrolyzable derivatives are 15 useful pharmaceuticals. They have, in particular, antimicrobial action and are suitable for the prevention and treatment of fungal infections in humans and in various mammalian species. <br><br> The examples which follow serve to characterize the 20 invention. <br><br> Example 1 <br><br> Preparation of a compound of the formula I by reaction of an oxirane of the formula IV with an amine without further additional solvent <br><br> 25 <br><br> Preparation of <br><br> - 21 - <br><br> 240727 <br><br> R( l) <br><br> is <br><br> 4-chlorophenyl, <br><br> R(2) <br><br> is <br><br> OH, <br><br> R(3) <br><br> is <br><br> 4-chlorobenzyl, <br><br> R(4) <br><br> is hydrogen, <br><br> R(5) <br><br> is n-butyl and <br><br> X <br><br> is sulfur. <br><br> 2.64 g of trimethylsulfoxonium iodide (12 mmol, 1.2 equivalents) are dissolved in 30 ml of abs. DMS and treated in portions with 0.39 g of NaH (80 % strength suspension 10 in paraffin oil, 13 mmol, 1.3 equivalents) and the reaction mixture is stirred for three hours at room temperature until evolution of gas is complete. 3.37 g (10 mmol) of the ketone of the formula II where R(l) is 4-chlorophenyl and R(2) is 4-chlorobenzyl and X is 15 sulfur, dissolved in 10 ml of abs. DMSO, are then added to this solution, and the reaction solution is stirred for four hours at room temperature. <br><br> For working-up, the reaction solution is poured into 200 ml of ice-water and the aqueous phase is extracted 20 four times with 100 ml of dichloromethane in each case. <br><br> The combined organic phases are washed three times with 50 ml portions of water, dried over Na2S04 and filtered off from the drying agent, and the solvent is removed in vacuo. <br><br> 25 According to the XH-NMR spectrum, the oily residue has the structure of the formula IV, where R(l) is 4-chloro-phenyl and R(2) is 4-chlorobenzylthio, and a purity of about 90 %: <br><br> Yield: 3.52 g (pale yellow oil) <br><br> 30 20 ml of n-butylamine are then added to this intermediate and the mixture is heated under reflux for four hours. The course of the reaction is monitored by thin layer chromatography (silica gel, eluent: ethyl acetate/di-chloromethane = 1:3). <br><br> - 22 - <br><br> 24-07 27 <br><br> For working-up, excess n-butylamine is removed in vacuo in a rotary evaporator and the crude product is purified by means of chromatography on a silica gel column (elu-ent: ethyl acetate/dichloromethane = 1:3). <br><br> 5 Yield: 3.44 g (8.1 mmol, 81 % of theory), colorless oil <br><br> Elemental analysis C22H27CI2NOS: <br><br> c found: <br><br> 62.4 <br><br> calc.: <br><br> 62.3 <br><br> H <br><br> found: <br><br> 6.3 <br><br> calc.: <br><br> 6.4 <br><br> N <br><br> found; <br><br> 3.2 <br><br> calc.: <br><br> 3.3 <br><br> 10 Example 2 <br><br> Preparation of a compound of the formula I by reaction of an oxirane of the formula IV with an amine in an autoclave in DMSO as solvent <br><br> Preparation of <br><br> : R (1) <br><br> is <br><br> 4-chlorophenyl, <br><br> R(2) <br><br> is <br><br> OH, <br><br> R(3) <br><br> is <br><br> 2,4-dichlorobenzyl <br><br> R(4) <br><br> is hydrogen, <br><br> R(5) <br><br> is isopropyl and <br><br> X <br><br> is sulfur. <br><br> 3.08 g of trimethylsulfoxonium iodide (14 mmol, 1 equivalent) are dissolved in 35 ml of abs. DMSO and treated in portions with 0.46 g of NaH (80 % strength suspension 25 in paraffin oil, 11 mmol, 1.1 equivalents) and the reaction mixture is stirred for four hours at room temperature until evolution of gas is complete. 5.2 g <br><br> £40 7 2 7 <br><br> (14 mmol) of the ketone of the formula II where R(l) is 4-chlorophenyl, R(2) is 2,4-dichlorobenzyl and X is sulfur, dissolved in 10 ml of abs. DMSO, are then added to this solution and the reaction solution is stirred for 5 one hour at 40°C and then for six hours at room temperature . <br><br> For working-up, the reaction solution is poured into 200 ml of ice-water and the aqueous phase is extracted four times with 100 ml of dichloromethane in each case. 10 The combined organic phases are washed three times with 50 ml portions of water, dried over Na2S0A and filtered off from the drying agent, and the solvent is removed in vacuo. <br><br> According to the ^-NMR spectrum, the oily residue has 15 the structure of the formula IV, where R(l) is 4-chlorophenyl, R(2) is 2,4-dichlorobenzyl and X is sulfur, and a purity of about 95 %. <br><br> Yield: 2.97 g (pale yellow oil, 55 % of theory) <br><br> 0.5 g of the oxirane (1.29 mmol) prepared in this way are 20 reacted for two hours at 140°C in an autoclave with 3 ml of isopropylamine in 20 ml of DMSO as solvent. <br><br> After completion of the reaction, excess isopropylamine is removed in a rotary evaporator under reduced pressure and the residue which remains is extracted with dichloro-25 methane/water. After drying the organic phase by means of Na2S0M separating of f the drying agent and removing the solvent in a rotary evaporator, an oily residue remains which is purified by column chromatography (silica gel; eluent: dichloromethane/ethyl acetate = 1:1). A colorless 30 oil is obtained; the product crystallizes from diethyl ether. <br><br> Yield: 370 mg (0.83 mmol, 65 % of theory) <br><br> Melting point: 128°C <br><br> Elemental analysis C21H2AC13N0S: 444.85 g mol"1 <br><br> - 24 - <br><br> 240727 <br><br> C found: 56.5 calc.: 56.7 H found: 5.4 calc.: 5.4 N found: 3.2 calc.: 3.1 <br><br> Example 3 <br><br> 5 Preparation of a compound of the formula I by reaction of an oxirane of the formula IV with an amine in ethanol/-water as reaction medium <br><br> Preparation of <br><br> (1.25) <br><br> i.e.: R(l) is 4-cyclohexylphenyl, <br><br> 10 R(2) is OH, <br><br> R(3) is 3-trifluoromethylbenzyl, <br><br> R(4) is hydrogen, <br><br> R(5) is phenylethyl and <br><br> X is sulfur. <br><br> 15 0.5 g (1.16 mmol) of the oxirane of the formula II, where R( 1) is 4-cyclohexylphenyl, R(3) is 3-trifluoromethyl-benzyl and X is sulfur, prepared in the manner described in Example 1 is dissolved together with 1 ml of phen-ethylamine in 30 ml of ethanol and 2 ml of water and the 20 mixture is stirred for 5 hours at 80°C; the reaction is monitored by thin layer chromatography (silica gel; eluent: dichloromethane). <br><br> After completion of the reaction, the solvent is removed under reduced pressure in a rotary evaporator and the 25 residue which remains is extracted with <br><br> - 25 <br><br> 240727 <br><br> dichloromethane/water. After drying the organic phase by means of Na2S04, separating off the drying agent and removing the extracting agent in a rotary evaporator, an oily residue remains, which is purified by column chroma-5 tography (silica gel; eluents dichloromethane). A colorless oil is obtained which crystallizes from diethyl ether: <br><br> Yield: 428 mg (0.77 mmol, 67 % of theory) <br><br> Melting point: 81°C <br><br> 10 Elemental analysis C33H3eF3NOS: 553.73 g mol"1 <br><br> c found: <br><br> 71.5 <br><br> calc.: <br><br> 71.6 <br><br> H <br><br> found: <br><br> 6.8 <br><br> calc.: <br><br> 6.9 <br><br> N <br><br> found: <br><br> 2.4 <br><br> calc.: <br><br> 2.5 <br><br> Example 4 <br><br> 15 The compounds of the formula I where R(2) is OH shown in Table 1 can also be prepared analogously to Example 1, 2 or 3, but using appropriate compounds of the formula II and M-NR(4)R(5). Examples 1, 2 and 3 are also contained in Table 1. <br><br> 20 Variant 1, 2 or 3 distinguishes whether the reaction is carried out according to Example 1, 2 or 3. <br><br> Examples 1.41-1.95 were reacted according to the variant from Example 3. <br><br> - 26 - <br><br> 2 40 7 2 7 <br><br> TABLE 1 <br><br> 1.1 <br><br> &lt;* S- <br><br> M-p- : oil calc. : <br><br> C 57.27% <br><br> H 5.26% <br><br> Cl 16.10% <br><br> N 3.18% <br><br> 0 3.63% <br><br> S 14.56% <br><br> found * <br><br> 57.2 5.2 <br><br> 3.2 <br><br> Variant <br><br> 1 <br><br> 1.2 <br><br> OH S' <br><br> M.p. : Oil calc. ; <br><br> C 61.76% H 5.68% Cl 17.36% N 3.43 0 3.92 S 7.85 <br><br> Variant found • <br><br> 61.8 5.5 <br><br> 3.3 <br><br> r.3 <br><br> 1.4 <br><br> w s- <br><br> 0H S- <br><br> M-p-: oil calc. ; <br><br> C 63.71% H 6.91% Cl 15.67% N 3.10% 0 3.54% S 7.09% <br><br> M.p.: oil calc. <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> s <br><br> 62.26% 6.41 16.71% 3.30% 3.77% 7.55% <br><br> found <br><br> 3.8 7.0 <br><br> 7.0 <br><br> found I <br><br> 62.3 6.4 <br><br> 3.4 <br><br> 'Variant. 1 <br><br> Variant <br><br> 1 <br><br> 27 - <br><br> 2 7 2 7 <br><br> Continuation of TABLE 1 <br><br> 1.5 <br><br> w s- <br><br> m-P- : on calc <br><br> • • <br><br> found c <br><br> 62 <br><br> .26% <br><br> 62.3 <br><br> H <br><br> 6 <br><br> .41% <br><br> 6.5 <br><br> Cl <br><br> 16 <br><br> .71% <br><br> N <br><br> 3 <br><br> .30% <br><br> 3.3 <br><br> O <br><br> 3 <br><br> .77% <br><br> s <br><br> 7 <br><br> .55% <br><br> Variant <br><br> 1 <br><br> 1.6 <br><br> 1.7 <br><br> 1.8 <br><br> &lt;* s- <br><br> m s- <br><br> M.p. : oil calc . ; <br><br> C 60.27% H 5.75% Cl 16.17% N 3.19 0 7.30 S 7.31 <br><br> M,p- : oil calc. . <br><br> • <br><br> C 66.03% H 6.11% Cl 13.44% N 5.31% 0 3.03% S 6.08% <br><br> M.p. ; oil calc. : <br><br> C 64.54% <br><br> H 5.82 <br><br> Cl 14.11% <br><br> N 2.79% <br><br> O 6.37% <br><br> S 6.38% <br><br> found! <br><br> 60.3 5.7 <br><br> 7.3 <br><br> found ! <br><br> found: <br><br> 64.6 5.7 <br><br> 2.9 <br><br> Variant <br><br> 1 <br><br> Variant <br><br> Variant <br><br> 3 <br><br> 440 7 2 7 <br><br> - 28 - <br><br> Continuation of TABLE 1 <br><br> M.p. ; oil <br><br> 1.9 <br><br> 1.10 <br><br> * <br><br> calc.j found <br><br> C 63.99% <br><br> 63.9 <br><br> H 6.49% <br><br> 6.4 <br><br> Cl 15.74% <br><br> N 3.11% <br><br> 3.1 <br><br> 0 3.55% <br><br> S 7.12% <br><br> M.p.; oil calc. • <br><br> C <br><br> 60.60% <br><br> 60.6 <br><br> H <br><br> 5.75% <br><br> 5.8 <br><br> Cl <br><br> 17.89% <br><br> N <br><br> 3.53% <br><br> 3.7 <br><br> 0 <br><br> 4.04 <br><br> S <br><br> 8.09 <br><br> Variant 3 <br><br> found • <br><br> Variant <br><br> 2 <br><br> 1.11 <br><br> M.p-: Oil calc. ; <br><br> C 63.71% H 6.91% Cl 15.67% N 3.10% 0 3.54% S 7.09% <br><br> found S <br><br> 63.8 6.8 <br><br> 3.0 <br><br> Variant <br><br> 3 <br><br> 1.12 <br><br> M.p.; oil calc. ; <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 69.87% 9.12% 7.64% 3.02% 3.45% 6.91% <br><br> found &lt; <br><br> I <br><br> 69.9 9.0 <br><br> 3.0 <br><br> Variant <br><br> 3 <br><br> - 29 <br><br> 2407 27 <br><br> Continuation of TABLE 1 <br><br> M-p-: on <br><br> 1.13 <br><br> « .S <br><br> calc. <br><br> c <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 68.85% 8.78% 8.13% 3.21% 3.67% 7.35% <br><br> found ; <br><br> 68.7 8.6 <br><br> 3.1 <br><br> Variant 3 <br><br> 1.14 <br><br> 1.15 <br><br> « s <br><br> M.p ■ <br><br> oil <br><br> Variant calc. I <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 71.95% 7.-91% 7.32% 2.89% 3.30% 6.62% <br><br> M.p. • calc. ; <br><br> oil c <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 68.30% 8.60% 8.40% 3.32% 3.79% 7.60% <br><br> found ; <br><br> 71.8 <br><br> 7.2 2.9 <br><br> found <br><br> 68.2 8.5 <br><br> 3.2 <br><br> Variant 3 <br><br> 1.16 <br><br> OH s- <br><br> M.p. : oii calc. : <br><br> C 62.26% H 6.41% Cl 16.71% N 3.30% O 3.77% S 7.55% <br><br> found J <br><br> 62.1 6.4 <br><br> 3.2 <br><br> Variant <br><br> 3 <br><br> - 30 - <br><br> Continuation of TABLE 1 <br><br> £40 7 2 <br><br> 1.17 <br><br> 1.18 <br><br> 1.19 <br><br> 1.20 <br><br> « s- <br><br> « S- <br><br> I.p. <br><br> ; oil <br><br> calc <br><br> • * <br><br> • <br><br> found : <br><br> c <br><br> 59.52% <br><br> 59.6 <br><br> H <br><br> 5.68% <br><br> 5.7 <br><br> Cl <br><br> 7.99% <br><br> F <br><br> 12.84 <br><br> N <br><br> 3.15% <br><br> 3.1 <br><br> 0 <br><br> 3.60% <br><br> s <br><br> 7.22% <br><br> M.p. <br><br> , * oil <br><br> calc. : <br><br> found . <br><br> c <br><br> 61.78% <br><br> 61.9 <br><br> H <br><br> 6.43% <br><br> 6.3 <br><br> Cl <br><br> 7.29% <br><br> F <br><br> 11.73 <br><br> N <br><br> 2.88% <br><br> 3.0 <br><br> 0 <br><br> 3.29% <br><br> S <br><br> 6.60% <br><br> M.p. <br><br> : on <br><br> calc. ; <br><br> found i <br><br> C <br><br> 56.70% <br><br> 56.6 <br><br> H <br><br> 5.44% <br><br> 5.6 <br><br> Cl <br><br> 23.91% <br><br> N <br><br> 3.15% <br><br> 3.1 <br><br> 0 <br><br> 3.60% <br><br> S <br><br> 7.21% <br><br> M.p <br><br> •: oil <br><br> calc. J <br><br> found <br><br> C <br><br> 60.92% <br><br> 60.8 <br><br> H <br><br> 4.91% <br><br> 4.8 <br><br> Cl <br><br> 21.58% <br><br> N <br><br> 2.84% <br><br> 2.7 <br><br> 0 <br><br> 3.25% <br><br> S <br><br> 6.51% <br><br> Variant 2 <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 2 <br><br> Variant <br><br> 2 <br><br> - 31 <br><br> Continuation of TABLE 1 <br><br> M.p. <br><br> oil <br><br> 1.21 <br><br> 1.22 <br><br> 1.23 <br><br> HO <br><br> / <br><br> HO <br><br> kJi <br><br> 1.24 <br><br> —J Qf <br><br> H£ <br><br> k* cr calc. <br><br> found : <br><br> C 57.58% <br><br> 57.6 <br><br> H 5.71% <br><br> 5.8 <br><br> Cl 23.18% <br><br> N 3.05% <br><br> 3.1 <br><br> 0 3.49% <br><br> S 6.99% <br><br> M.p. calc. <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> oil <br><br> 75.31% 7.22% 6.35% 2.51% 2.87% 5.74% <br><br> M.p. <br><br> oil found ! <br><br> 75.1 7.1 <br><br> 2.4 <br><br> M.p. <br><br> : oil <br><br> calc <br><br> . a • • <br><br> found • <br><br> c <br><br> 68.88% <br><br> 69.0 <br><br> H <br><br> 7.57% <br><br> 7.5 <br><br> F <br><br> 11.27% <br><br> N <br><br> 2.77% <br><br> 2.6 <br><br> 0 <br><br> 3.16% <br><br> S <br><br> •6.34% <br><br> calc <br><br> , • • <br><br> found <br><br> C <br><br> 64.25% <br><br> 64.1 <br><br> H <br><br> 7.25% <br><br> 7.1 <br><br> Cl <br><br> 6.54% <br><br> F <br><br> 10.51% <br><br> N <br><br> 2.58% <br><br> 2.7 <br><br> 0 <br><br> 2.95% <br><br> S <br><br> 5.91% <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> Va-iant <br><br> Variant <br><br> 3 <br><br> - 32 - 2 f:: 7 <br><br> r- ▼ V J (c, <br><br> Continuation of TABLE 1 <br><br> 1.25 <br><br> 1.26 <br><br> 1.27 <br><br> 1.28 <br><br> M.p. <br><br> . oil • <br><br> calc <br><br> • • <br><br> found ; <br><br> c <br><br> 71.58% <br><br> 71.4 <br><br> H <br><br> 6.92% <br><br> 7.0 <br><br> F <br><br> 10.29% <br><br> . <br><br> N <br><br> 2.53% <br><br> 2.5 <br><br> 0 <br><br> 2.89% <br><br> S <br><br> 5.79% <br><br> :H.P' <br><br> oil <br><br> calc <br><br> • • <br><br> found &lt; <br><br> c <br><br> 66.71% <br><br> 66.9 <br><br> H <br><br> 6.47% <br><br> 6.3 <br><br> Cl <br><br> 6.15% <br><br> F <br><br> 9.89% <br><br> N <br><br> 2.43% <br><br> 2.4 <br><br> 0 <br><br> 2.78% <br><br> S <br><br> 5.57% <br><br> M.p. <br><br> : oil <br><br> calc. ; <br><br> found <br><br> C <br><br> 73.07% <br><br> 73.2 <br><br> H <br><br> 6.81% <br><br> 6.9 <br><br> F <br><br> 9.63% <br><br> N <br><br> 2.37% <br><br> 2.2 <br><br> 0 <br><br> 2.70% <br><br> S <br><br> 5.42% <br><br> M.p <br><br> .. oil • <br><br> calc <br><br> * « <br><br> f ound c <br><br> 70.69% <br><br> 70.4 <br><br> H <br><br> 7.425% <br><br> 7.3 <br><br> F <br><br> 10.48% <br><br> N <br><br> 2.58% <br><br> 2.6 <br><br> 0 <br><br> 2.94% <br><br> S <br><br> 5.90% <br><br> Variant <br><br> 3 <br><br> Varian t <br><br> 3 <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> - 33 <br><br> 240727 <br><br> Continuation of TABLE 1 <br><br> M.p.: oil <br><br> 1.29 <br><br> -o&amp;b t-butyl <br><br> J.30 <br><br> HC <br><br> CH&gt; __ W s_/ V <br><br> 1.31 <br><br> 1.32 <br><br> H£ <br><br> calc. : <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 70.00% 8.13% 7.95% 3.14% 3.59% 7.19% <br><br> M.p. <br><br> oil calc. • <br><br> c <br><br> H N 0 S <br><br> 69.73% 8.89% 6.50% 7.43% 7.45% <br><br> found 1 <br><br> 70.2 8.0 <br><br> 2.5 <br><br> M.p. : Oil <br><br> calc. . • <br><br> found : <br><br> C 69.73% <br><br> 69.7 <br><br> H 8.89% <br><br> 9.0 <br><br> N 6.50% <br><br> 6.4 <br><br> 0 7.43% <br><br> S 7.45% <br><br> found . • <br><br> 69.9 9.0 6.4 <br><br> M.p. • oil <br><br> calc. ; <br><br> found <br><br> C 72.38% <br><br> 72.3 <br><br> H 7.815% <br><br> 7.8 <br><br> N 6.03% <br><br> 6.1 <br><br> 0 6.89% <br><br> S 6.90% <br><br> Variant. <br><br> 3 <br><br> Vflriant 3 <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> - 34 - <br><br> 14 0 7 2 " <br><br> Continuation of TABLE 1 <br><br> 1.33 <br><br> «5 y " S—'^ <br><br> 1.34 <br><br> HC <br><br> « .S <br><br> 1.35 <br><br> j . OH S—' <br><br> -oh _? <br><br> S«-\ <br><br> 1.36 <br><br> « .S <br><br> ir*5 <br><br> M.p. <br><br> ■ oil <br><br> calc <br><br> . ; <br><br> found &gt; <br><br> c <br><br> 69.73% <br><br> 69.7 <br><br> H <br><br> 8.89% <br><br> 9.0 <br><br> N <br><br> 6.50% <br><br> 6.7 <br><br> 0 <br><br> 7.43% <br><br> S <br><br> 7.45% <br><br> M.p. <br><br> . oil <br><br> caic <br><br> « • • <br><br> found ; <br><br> c <br><br> 69.50% <br><br> 69.6 <br><br> H <br><br> 7.93% <br><br> 8.0 <br><br> Cl <br><br> 8.21% <br><br> N <br><br> 3.24% <br><br> 3.1 <br><br> 0 <br><br> 3.70% <br><br> s <br><br> 7.42% <br><br> M.p. <br><br> oil <br><br> • <br><br> calc. : <br><br> found <br><br> C <br><br> 68.61% <br><br> 68.6 <br><br> H <br><br> 8.23% <br><br> 8.3 <br><br> Cl <br><br> 7.23% <br><br> N <br><br> 2.86% <br><br> 2.7 <br><br> 0 <br><br> 6.53% <br><br> S <br><br> 6.54% <br><br> M.p. <br><br> : oil <br><br> calc. . • <br><br> found c <br><br> 70.00% <br><br> 70.2 <br><br> H <br><br> 8.13% <br><br> 8.1 <br><br> Cl <br><br> 7.95% <br><br> N <br><br> 3.14% <br><br> 3.1 <br><br> 0 <br><br> 3.59% <br><br> S <br><br> 7.19% <br><br> Variant 3 <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> - 35 <br><br> '140? <br><br> Continuation of TABLE 1 <br><br> M.p.: oil <br><br> 1.37 <br><br> I <br><br> ■■J **1 r / <br><br> 1.38 <br><br> 1.39 <br><br> /S <br><br> 1.40 <br><br> icalc. • • <br><br> found : <br><br> C 69.19% <br><br> 69.2 <br><br> H 8.71% <br><br> .8.6 <br><br> N 6.72% <br><br> 6.8 <br><br> 0 7.68% <br><br> S 7.70% <br><br> M.p. <br><br> . oil « <br><br> colc • <br><br> • • <br><br> found c <br><br> 76.02% <br><br> 76.2 <br><br> H <br><br> 7.80% <br><br> 7.8 <br><br> N <br><br> 4.92% <br><br> 4.8 <br><br> 0 <br><br> 5.63% <br><br> S <br><br> 5.64% <br><br> M.p. <br><br> : 011 <br><br> calc <br><br> • • <br><br> found c <br><br> 70.83% <br><br> 71.0 <br><br> H <br><br> 7.93% <br><br> 7.9 <br><br> N <br><br> 5.51% <br><br> 5.6 <br><br> 0 <br><br> 9.43% <br><br> S <br><br> 6.40% <br><br> M.p.: oil <br><br> calc. ; <br><br> found <br><br> C 70.00% <br><br> 70.1 <br><br> H 8.13% <br><br> 8.2 <br><br> Cl 7.95% <br><br> N 3.14% <br><br> 3.2 <br><br> 0 3.59% <br><br> S 7.19% <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 ' <br><br> Variant <br><br> 3 <br><br> Variant <br><br> 3 <br><br> - 36 - <br><br> Continuation of TABLE 1 <br><br> .-) }. T~ '"i <br><br> 4r. Lf y / l <br><br> 1.41 <br><br> « s. <br><br> 1 .42 <br><br> _ OH s <br><br> -0-h£ <br><br> H+ <br><br> 1 .43 <br><br> Q- <br><br> h* &lt;r <br><br> 1 .44 <br><br> V M <br><br> &lt;r <br><br> M.p. <br><br> 80eC <br><br> calc. <br><br> • <br><br> C <br><br> 65.52% <br><br> H <br><br> 6.98% <br><br> Cl <br><br> 5.23% <br><br> F <br><br> 8.40% <br><br> N <br><br> 2.06% <br><br> 0 <br><br> 7.08% <br><br> S <br><br> 4.73% <br><br> M.p. . <br><br> oil calc. <br><br> : <br><br> C <br><br> 55.18% <br><br> H <br><br> 5.68% <br><br> Cl <br><br> 22.21% <br><br> F <br><br> 3.97% <br><br> N <br><br> 2.92% <br><br> 0 <br><br> 3.34% <br><br> s <br><br> 6.70% <br><br> M.p.; <br><br> 209-: <br><br> calc. <br><br> • <br><br> C <br><br> 55.18% <br><br> H <br><br> 5.68% <br><br> Cl <br><br> 22.21% <br><br> F <br><br> 3.97% <br><br> N <br><br> 2.92% <br><br> 0 <br><br> 3.34% <br><br> S <br><br> 6.70% <br><br> M.p. . <br><br> 188- <br><br> calc. <br><br> - <br><br> C <br><br> 55.18% <br><br> H <br><br> 5.68% <br><br> Cl <br><br> 22.21% <br><br> F <br><br> 3.97% <br><br> N <br><br> 2.92% <br><br> 0 <br><br> 3.34% <br><br> S <br><br> 6.70% <br><br> found c <br><br> H N <br><br> 65.3 7.1 2.1 <br><br> found• <br><br> c <br><br> 55.1 <br><br> H <br><br> 5.6 <br><br> N <br><br> 2.9 <br><br> °c* <br><br> found <br><br> : <br><br> c <br><br> 55.1 <br><br> H <br><br> 5.8 <br><br> N <br><br> 2.9 <br><br> found: <br><br> c <br><br> H N <br><br> 55.0 5.8 2.8 <br><br> - 37 - <br><br> ■2407 2 7 <br><br> Continuation of TABLE 1 <br><br> 1 .45 <br><br> 1.46 <br><br> HtC <br><br> 1 .47 <br><br> h+ or <br><br> 1 .48 <br><br> o4 <br><br> H* 0 <br><br> M. <br><br> p. <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 157-158°C <br><br> calc. <br><br> 60.81% 6.59% 7.48% 12.02% 2.95% 3.36% 6.76% <br><br> M.p. . calc. <br><br> c <br><br> H <br><br> Cl <br><br> F <br><br> H <br><br> 0 <br><br> S <br><br> M.p. . <br><br> calc . <br><br> 204°C <br><br> 63.83% 5.75% 6.98% 11.22% 2.76% 3.15% 6.31% <br><br> 1 53°C <br><br> 64.42% 5.99% 6.79% 10.92% 2.68% 3.06% 6.14% <br><br> m. p •; 188°C <br><br> calc. . <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 60.81% 6.59% 7.48% 12.02% 2.95% 3.38% 6.76% <br><br> found c <br><br> H N <br><br> o0.6 6.7 3.0 <br><br> found <br><br> C H N <br><br> 63.6 5.8 2.7 <br><br> found : <br><br> C H N <br><br> 64.3 6.2 2.7 <br><br> found c <br><br> H N <br><br> 60.8 <br><br> 6.8 <br><br> 3.1 <br><br> - 38 - <br><br> Continuation of TABLE 1 <br><br> r, -L, <br><br> 1.49 <br><br> H* Q- <br><br> M.p. . 247*C <br><br> calc. ; found • <br><br> c <br><br> 56.09% <br><br> C <br><br> H <br><br> 5.30% <br><br> H <br><br> Cl <br><br> 20.70% . <br><br> N <br><br> N <br><br> 5.45% ' <br><br> 0 <br><br> 6.23% <br><br> S <br><br> 6.24% <br><br> 55.9 5.2 5.5 <br><br> 1.50 <br><br> M,p-: 190°C calc. ; <br><br> tf* 0- <br><br> C <br><br> 56.88% <br><br> H <br><br> 5.54% <br><br> Cl <br><br> 20.15% <br><br> N <br><br> 5.31% <br><br> 0 <br><br> 6.06% <br><br> S <br><br> 6.07% <br><br> f ound c <br><br> H N <br><br> 56.9 5.4 5.2 <br><br> 1.51 <br><br> h+ 0' <br><br> M.p.: 224oc calc. : <br><br> C <br><br> 59.85% <br><br> H <br><br> 4.84% <br><br> Cl <br><br> 18.93% <br><br> N <br><br> 4.98% <br><br> 0 <br><br> 5.69% <br><br> S <br><br> 5.71% <br><br> found : <br><br> C 60.0 H 4.9 N 4.9 <br><br> K* 0' <br><br> M• p •: 217°C <br><br> calc. : <br><br> C <br><br> 59.42% <br><br> H <br><br> 5.52% <br><br> Cl <br><br> 18.79% <br><br> N <br><br> 4.95% <br><br> 0 <br><br> 5.65% <br><br> S <br><br> 5.67% <br><br> found c <br><br> H N <br><br> 59.5 <br><br> 5.6 <br><br> 5.0 <br><br> - 39 - <br><br> 2407 27 <br><br> Continuation of TABLE 1 <br><br> 1.53 <br><br> N W S <br><br> h* &lt;r uSC4 <br><br> 1 .54 <br><br> OOV&lt;i <br><br> Lki I <br><br> H£ <br><br> h+ cr <br><br> 1 .55 <br><br> 0^4 <br><br> W+ (T <br><br> 1 .56 <br><br> M.p. : 176°C <br><br> calc. . <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 58.54% 5.23% 16.72% 4.40% 10.06% 5.04% <br><br> m.p.: 139°C calc. : <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 64.25% 7.25% 6.54% 10.51% 2.58% 2.95% 5.91% <br><br> «.p.: 126°C calc. • <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 64.65% 6.67% 5.45% 8.77% 2.15% 7.38% 4.93% <br><br> M.p.. 240°C <br><br> calc. <br><br> c <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 66.71% 6.47% 6.15% 9.89% 2.43% 2.78% 5.57% <br><br> found • <br><br> c <br><br> H N <br><br> 58.4 <br><br> 5.2 <br><br> 4.3 <br><br> found • <br><br> c <br><br> H N <br><br> C H N <br><br> 64.3 7.4 2.6 <br><br> found . <br><br> c <br><br> H N <br><br> 64.7 6.6 <br><br> 2.2 <br><br> found . <br><br> 66.8 <br><br> 6.4 <br><br> 2.5 <br><br> - 40 - <br><br> Continuation of TABLE 1 <br><br> n <br><br> $ <br><br> *?• <br><br> 1 .57 <br><br> oo <br><br> H* 0- <br><br> : 21 0°C <br><br> calc,.: <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> S <br><br> 66.25% 7.12% 6.11% 9.82% 2.41% 2.76% 5.53% <br><br> found- s <br><br> C H n <br><br> 66.4 7.0 2.5 <br><br> 1.58 <br><br> 1 .59 <br><br> / \ —/ <br><br> H* T <br><br> M.p.: 224°C <br><br> calc. : found I <br><br> C <br><br> H <br><br> Cl <br><br> F <br><br> N <br><br> 0 <br><br> s <br><br> 62.63% 6.71% 6.37% 10.25% 2.52% 5.75% 5.77% <br><br> m.p.: 152°C <br><br> calc. I <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> s <br><br> 71.75% 8.83% 7.06% 2.79% 3.19% 6. 38% <br><br> C H N <br><br> 62.7 6.8 2.4 <br><br> found : <br><br> C H N <br><br> 71.8 8.9 2.9 <br><br> 1.60 <br><br> O^TK. <br><br> m.p,. : 220°C <br><br> calc. : <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 73.92% 7.89% 6.61% 2.61% 2.98% 5.98% <br><br> found c <br><br> H N <br><br> 73.8 7.8 2.6 <br><br> Continuation of TABLE 1 <br><br> - 41 - <br><br> 240727 <br><br> 61 <br><br> OH r <br><br> 1 .62 <br><br> H* (T <br><br> 1 .63 <br><br> 1 .64 <br><br> M.p.* <br><br> calc. <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> - - <br><br> C <br><br> H <br><br> Cl <br><br> K <br><br> 0 <br><br> s <br><br> M.p. : calc. <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> M.p. : <br><br> calc. <br><br> C <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> oil <br><br> 70.85% 7.93% 5.81% 2.30% 7.86% 5.25% <br><br> M.p. ; calc. <br><br> 115°C <br><br> 68.25% 8.27% 7.46% 5.90% 3.37% 6.75% <br><br> 218°C <br><br> 70.77% 7.32% 6.96% 5.50% 3.14% 6.30% <br><br> 259°C <br><br> 70.21% 8.05% 6.91% 5.46% 3.12% 6.25% <br><br> found <br><br> C H N <br><br> 71.0 7.9 2.3 <br><br> found c <br><br> H N <br><br> 68.1 8.3 6.0 <br><br> found c <br><br> H N <br><br> 70.9 7.4 5.4 <br><br> found ; <br><br> C H N <br><br> 70.1 <br><br> 8.1 <br><br> 5.5 <br><br> Continuation of TABLE 1 <br><br> - 42 - <br><br> 240 7 <br><br> 1.65 <br><br> 1 .66 <br><br> F <br><br> 1 .67 <br><br> , 68 <br><br> h* or <br><br> M.p. . <br><br> oil calc <br><br> • <br><br> C <br><br> 63.06% <br><br> H <br><br> 6.86% <br><br> Cl <br><br> 6.90% <br><br> F <br><br> 11.09% <br><br> N <br><br> 2.72 % <br><br> 0 <br><br> 3.11% <br><br> S <br><br> 6.24% <br><br> i-p- : <br><br> resin calc <br><br> . ; <br><br> c <br><br> 65.74% <br><br> H <br><br> 6.07% <br><br> Cl <br><br> 6.47% <br><br> F <br><br> 10.40% <br><br> N <br><br> 2.56% <br><br> 0 <br><br> 2.92% <br><br> S <br><br> 5.85% <br><br> • p. : <br><br> oil calc. <br><br> : <br><br> C <br><br> 67.12% <br><br> H <br><br> 8.21% <br><br> Cl <br><br> 5. 66% <br><br> F <br><br> 9.10% <br><br> N <br><br> 2.24% <br><br> 0 <br><br> 2.55% <br><br> S <br><br> 5.12% <br><br> p. . <br><br> oil calc. <br><br> c <br><br> 62.84% <br><br> H <br><br> 7.23% <br><br> Cl <br><br> 6.87% <br><br> F <br><br> 11.04% <br><br> N <br><br> 2.71% <br><br> 0 <br><br> 3.10% <br><br> S <br><br> 6.21% <br><br> found c <br><br> H N <br><br> 63.0 6.9 2.8 <br><br> found : <br><br> C H N <br><br> 65.8 6.1 2.5 <br><br> found . <br><br> c <br><br> H N <br><br> 67.0 <br><br> 8.2 <br><br> 2.3 <br><br> found <br><br> C <br><br> 62.6 <br><br> H <br><br> 7.1 <br><br> N <br><br> 2.8 <br><br> Continuation of TABLE 1 <br><br> 1.69 <br><br> HjC <br><br> 1 .70 <br><br> M.p. <br><br> oi; <br><br> calc. <br><br> found <br><br> C 71.03% <br><br> C <br><br> H 8.86% <br><br> H <br><br> F 9.63% <br><br> N <br><br> N 2.37% <br><br> 0 2.70% <br><br> S 5.42% <br><br> . p . ; lOi 1 <br><br> calc. ; <br><br> found! <br><br> C 72.55% <br><br> c <br><br> H 7.14% <br><br> H <br><br> Cl 7.38% <br><br> N <br><br> N 2.92% <br><br> 0 3.33% <br><br> S 6.68% <br><br> 71.0 8.7 2.2 <br><br> 72.4 7.1 2.9 <br><br> : on calc. : found : <br><br> C <br><br> 69.50% <br><br> C <br><br> H <br><br> 7.93% <br><br> H <br><br> Cl <br><br> 8.21% <br><br> N <br><br> N <br><br> 3.24% <br><br> 0 <br><br> 3.70% <br><br> S <br><br> 7.42% <br><br> 1.72 <br><br> M.p. <br><br> oil calc. ' <br><br> c <br><br> H <br><br> Cl <br><br> N <br><br> 0 <br><br> S <br><br> 73.14% 9.39% 6.35% 2.51% 2.87 % 5.74% <br><br> found ■ <br><br> - 44 - <br><br> Continuation of TABLE 1 <br><br> -r <br><br> 1 .73 <br><br> •p.: <br><br> oil <br><br> calc. <br><br> found <br><br> C <br><br> 76.06% <br><br> c <br><br> 76.0 <br><br> H <br><br> Cl <br><br> N <br><br> 7.25% 6.07% .. 2.40% <br><br> H N <br><br> 7.3 2.3 <br><br> 0 <br><br> 2.74% <br><br> S <br><br> 5.49% <br><br> 1.74 <br><br> .p.. <br><br> calc. <br><br> I <br><br> found <br><br> C <br><br> 72.12% <br><br> c <br><br> 72.0 <br><br> H <br><br> 7.83% <br><br> H <br><br> 7.9 <br><br> Cl <br><br> 6. 26% <br><br> N <br><br> 2.5 <br><br> N <br><br> 2.47% <br><br> 0 <br><br> 5.65% <br><br> S <br><br> 5.66% <br><br> 1 .75 <br><br> M.p. ; calc. <br><br> 02 2 <br><br> C <br><br> 68.93% <br><br> H <br><br> 7.09% <br><br> Cl <br><br> 6.56% <br><br> N <br><br> 2.59% <br><br> 0 <br><br> 8.89% <br><br> S <br><br> 5.94% <br><br> found <br><br> C H N <br><br> 68.9 7.1 2.6 <br><br> p. : <br><br> oil <br><br> calc. <br><br> found <br><br> : <br><br> c <br><br> 70.93% <br><br> c <br><br> 70.0 <br><br> H <br><br> 8.50% <br><br> H <br><br> 8.3 <br><br> Cl <br><br> 7.48% <br><br> N <br><br> 2.9 <br><br> N <br><br> 2.95% <br><br> 0 <br><br> 3.37% <br><br> s <br><br> 6.76% <br><br> Continuation of TABLE 1 <br><br> - 45 - <br><br> 240727 <br><br> 1.77 <br><br> k.P. : calc. <br><br> oil found c <br><br> 74.22% <br><br> C <br><br> 74.2 <br><br> H <br><br> 8.06% <br><br> H <br><br> 8.1 <br><br> Cl <br><br> 6.44% <br><br> N <br><br> 2.4 <br><br> N <br><br> 2.55% <br><br> 0 <br><br> 2.91% <br><br> S <br><br> 5.83% <br><br> 1 .78 <br><br> 1 .79 <br><br> 1.80 <br><br> «.p.; <br><br> calc. : <br><br> found • <br><br> C <br><br> 73.32% <br><br> C <br><br> 73.1 <br><br> H <br><br> 8.08% <br><br> H <br><br> 8.0 <br><br> Cl <br><br> 6.76% <br><br> N <br><br> 2.7 <br><br> N <br><br> 2.67% <br><br> 0 <br><br> 3.05% <br><br> s <br><br> 6.12% <br><br> p- : <br><br> oil <br><br> calc <br><br> .; <br><br> found. <br><br> C <br><br> 68.75% <br><br> c <br><br> 68.7 <br><br> H <br><br> 6.54% <br><br> H <br><br> 6.6 <br><br> Cl <br><br> 6.76% <br><br> N <br><br> 2.7 <br><br> N <br><br> 2.67% <br><br> 0 <br><br> 9.16% <br><br> S <br><br> 6.12% <br><br> • p-: <br><br> oil <br><br> calc <br><br> . ; <br><br> found ; <br><br> c <br><br> 73.60% <br><br> c <br><br> 73.7 <br><br> H <br><br> 7.72% <br><br> H <br><br> 7.8 <br><br> Cl <br><br> 6.79% <br><br> N <br><br> 2.8 <br><br> N <br><br> 2.68% <br><br> 0 <br><br> 3.06% <br><br> S <br><br> 6.14% <br><br> - 46 - <br><br> Continuation of TABLE 1 <br><br> .p. . <br><br> oil <br><br> calc. <br><br> : <br><br> found <br><br> : <br><br> C <br><br> 62.66% <br><br> C <br><br> 62.7 <br><br> H <br><br> 5.94% <br><br> H <br><br> 6.0 <br><br> Cl <br><br> 5.97% <br><br> N <br><br> 2.3 <br><br> F <br><br> 9.59% <br><br> N <br><br> 2.36% <br><br> 0 <br><br> 2.69% <br><br> S <br><br> 10.79% <br><br> calc. . found . <br><br> C <br><br> 78.73 <br><br> C <br><br> 78.6 <br><br> H <br><br> 6.61 <br><br> H <br><br> 6.5 <br><br> N <br><br> 5.40 <br><br> N <br><br> 5.4 <br><br> 0 <br><br> 3.08 <br><br> s <br><br> 6.18 <br><br> Continuation of TABLE 1 <br><br> 1 .84 <br><br> - 47 - <br><br> 240727 <br><br> M.p. . oil calc. . <br><br> found * <br><br> C 52.53 <br><br> H 5.10 <br><br> N 3.22 <br><br> Cl 16.32 <br><br> 0 3.68 <br><br> F 4.37 <br><br> S 14.76 <br><br> C H N <br><br> 52.4 5.0 3.3 <br><br> 1 .85 <br><br> M.p <br><br> h,c <br><br> 1 .86 <br><br> p. <br><br> • • <br><br> oil <br><br> calc <br><br> • <br><br> found . <br><br> • <br><br> c <br><br> 81 .95 <br><br> C 88 <br><br> H <br><br> 8.54 <br><br> H 8 <br><br> N <br><br> 2.90 <br><br> N 3 <br><br> 0 <br><br> 6.61 <br><br> • p. . <br><br> oil <br><br> calc <br><br> • • • <br><br> found • <br><br> c <br><br> 71 .93 <br><br> c 72 <br><br> H <br><br> 6.68 <br><br> H 6 <br><br> N <br><br> 2.99 <br><br> N 3 <br><br> 0 <br><br> 10.27 <br><br> CH, <br><br> 1 .87 <br><br> '''1 Tesin <br><br> calc.• <br><br> found • <br><br> c 74.02 <br><br> c 74 <br><br> H 10.68 <br><br> H 10 <br><br> N 3.45 <br><br> N 3 <br><br> 0 3.94 <br><br> S 7.90 <br><br> - 48 - -X <br><br> {C~, <br><br> Continuation of TABLE 1 <br><br> 1 .88 <br><br> .p. : <br><br> Oil <br><br> calc <br><br> • • <br><br> found . • <br><br> C <br><br> 65.94 <br><br> C <br><br> 65.8 <br><br> H <br><br> 5.53 <br><br> H <br><br> 5.5 <br><br> N <br><br> 2.96 <br><br> N <br><br> 2.9 <br><br> O <br><br> 6.76 <br><br> s <br><br> 6.77 <br><br> F <br><br> 12.04 <br><br> 1 .89 <br><br> M.p. ; oil calc. • <br><br> C H N F 0 S <br><br> 67.49 6.95 3.58 9.70 4.09 8.19 <br><br> found c <br><br> H N <br><br> 67.6 7.0 3.5 <br><br> 1 .90 <br><br> M.p. ; oil calc. : <br><br> found • <br><br> C 78.61 <br><br> C 78.5 <br><br> H 8.30 <br><br> H 8.4 <br><br> N 2.96 <br><br> N 3.1 <br><br> O 10.13 <br><br> *CHj <br><br> 1.91 <br><br> M.p. • resin calc. . <br><br> 60.92 6.B8 2.73 3.12 Cl 13.83 S 12.51 <br><br> found : <br><br> C H N <br><br> 61.1 6.9 2.7 <br><br> - 49 - <br><br> Continuation of TABLE 1 <br><br> 240 7 57 <br><br> 1 .92 <br><br> -OR/ <br><br> 1.93 <br><br> M.p. . oil <br><br> calc. • <br><br> found ; <br><br> C 67.77 <br><br> C <br><br> 67.6 <br><br> H 7.24 <br><br> H <br><br> 7.2 <br><br> N 3.59 <br><br> N <br><br> 3.7 <br><br> Cl 9.09 <br><br> 0 4.10 <br><br> S 8.22 <br><br> M.p- ; resin <br><br> calc.: <br><br> found • <br><br> C 59.67 <br><br> C <br><br> 59.8 <br><br> H 5.92 <br><br> H <br><br> 6.0 <br><br> N 3.16 <br><br> N <br><br> 3.2 <br><br> Cl 24.02 <br><br> 0 7.23 <br><br> 1 .94 <br><br> M.p. S <br><br> oil calc. • <br><br> found : <br><br> C 62.27 <br><br> C 62.4 <br><br> H 6.41 <br><br> H 6.5 <br><br> N 3.30 <br><br> N 3.3 <br><br> O 11.31 <br><br> Cl 16.71 <br><br> 1.95 <br><br> m.p* : <br><br> oil calc. : <br><br> found : <br><br> C 64.56 <br><br> C 64.5 <br><br> H 8.02 <br><br> H 8.2 <br><br> N 6.02 <br><br> N 6.0 <br><br> Cl 7.62 <br><br> 0 6.88 <br><br> S 6.89 <br><br> 9 - so - '24 0 7 ? <br><br> The compounds are very highly active in vitro against skin fungi such as, for example, Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum; against mold fungi, such as, for example, Aspergillus 5 nlger or against yeasts, such as, for example, Candida albicans, C. tropicalis, Tornlopsis glabrata and Tricho-sporon cutaneum or against protozoa such as Trichomonas vaginalis or T. fetus, or alternatively against gram-positive and gram-negative bacteria. <br><br> 10 In vivo as well, for example in experimental renal candidiasis of the mouse, the compounds have a very good systemic effect after oral or parenteral administration against, for example, Candida albicans. In this case, the exoenzyme system of the yeast Candida albicans is in 15 particular affected in such a way that the pathogenicity of the pathogens is distinctly reduced. There is likewise a very good effect against various pathogens of skin mycoses (for example Trichophyton mentagrophytes) in the guinea pig after oral, parenteral or local administra-20 tion. <br><br> Examples of indication areas in human medicine which may be mentioned ares <br><br> Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, 25 Microspora species, Epidermophyton floccosum, and bi-phasic fungi and mold fungi. In particular, deep-seated mycoses, which are caused by Candida albicans, are favorably affected, as in this case penetration of the fungi into the host cell is prevented or made difficult. <br><br> 30 Examples of indication areas in veterinary medicine which may be mentioned are: <br><br> All dermatomycoses and systemic mycoses, in particular those which are caused by the abovementioned pathogens. <br><br> The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients contain one or more active compounds or which comprise one or more active compounds 5 used according to the invention, and processes for the production of these preparations. <br><br> Non-toxic, inert pharmaceutically suitable excipients are understood as meaning solid, semisolid or liquid diluents, fillers and formulation auxiliaries of any 10 type. <br><br> An inhibitor for the different phospholipases of Candida albicans must be present in sufficient concentrations everywhere in the patient where the fungus can colonize the parenchyma. This fact assumes that the corresponding 15 substances have to be administered in a concentration which has previously proved effective in animal experiments . <br><br> In the case of the severe symptoms of deep-seated candidiasis, the patients are usually in a very poor general 20 condition. High fever and other disorders are frequently to be found. In the dosage instructions, a differentiation must be made between the prophylactic dose and the therapy in the case of established infection. In the case of prophylaxis, it is possible to start from a better 25 general condition of the patients which enables oral administration. In this case, tablets, solutions, gels or inspissated juice can be used. In forms having established deep-seated candidiases, treatment must often be started from the fact that controlled oral absorption of 30 the active compounds is not always ensured. Parenteral administration forms are then suitable for this purpose. In exceptional cases, subcutaneous administration can also be considered. <br><br> Suitable candidates for prophylaxis are primarily immuno-35 compromised patients, who are in this situation owing to <br><br> L. r. <br><br> ■u- ?? v ■ <br><br> - 52 - U <br><br> appropriate medicinal stress or owing to immune problems specific to the body. These are in particular transplant patients, diabetics and/or adipose patients, AIDS patients, patients under chemotherapy, those receiving 5 long-term ventilation etc. <br><br> The compounds show inhibitions of the phospholipase of Candida albicans which are far below the minimum inhibitory concentrations of the active compounds against Candida albicans found in vitro. The dosage can therefore 10 as a rule be below that which would be necessary for a pure antimycotic therapy. <br><br> The action in the patient is based on the fact that the active compounds induce two different effects in the Candida cells which are in the vicinity of the paren-15 chyma. On the one hand, the adhesion of the yeast cells to the body cells is prevented and, on the other hand, Candida albicans is as a result prevented from penetrating the body cells with germ tubes. As a result of this dual concept of action, the yeast cannot express its 20 pathogenicity completely. However, it must be mentioned that, apart from the phospholipases, Candida albicans additionally has other pathomechanisms such as, for example, protease. The attachment to the body's own cells is, however, the primary step for penetration. As this 25 attachment is prevented by phospholipase inhibitors, the other pathomechanisms are unable to act completely. <br><br> Possible administration forms are, for example, tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable 30 solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, lotions, sprays etc. <br><br> The prophylactically and therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 35 0.1 to 99.5, preferably of about 0.5 to 95 % by weight of <br><br> 53 - <br><br> 240 7 2 7 <br><br> the total mixture. <br><br> The abovementioned pharmaceutical preparations can also contain other pharmaceutical active compounds in addition to the active compounds used according to the invention. <br><br> 5 The abovementioned pharmaceutical preparations are prepared in a customary manner by known methods, for example by mixing the active compound or the active compounds with the excipient or the excipients. <br><br> The present invention includes the use of the active 10 compounds according to the invention and of pharmaceutical preparations, which contain one or more active compounds according to the invention, in human and veterinary medicine for the prevention, amelioration and/or cure of the abovementioned diseases. <br><br> 15 The active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and/or rectally. <br><br> In general, it has proved advantageous both in human and in veterinary medicine to administer the active 20 compound(s) used according to the invention in total amounts of at least about 0.05, preferably 0.1, in particular 0.5 mg/kg of bodyweight up to at most about 200, preferably up to 100, in particular up to 10 mg/kg of body weight every 24 hours, if appropriate in the form 25 of several individual doses to achieve the desired results. The total amount is administered in 1 to 8, preferably in 1 to 3, individual doses, but in deep-seated mycoses over substantially longer periods of time (up to 6 weeks). <br><br> 30 However, it may be necessary to depart from the dosages mentioned, in particular depending on the species and the bodyweight of the subject to be treated, the nature and the severity of the disease, the manner of preparation <br><br> - 54 - &amp; <br><br> and administration of the pharmaceutical and the period or interval within which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, 5 while in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage and manner of administration of the active compounds necessary in each case can easily be determined by any person skilled in the art on the basis of his expert knowledge. <br><br> 10 The compounds of the formula I are also active as biocides. They are distinguished in particular by their fungicidal activity in phytopathogenic fungi. Even fungal disease pathogens which have already penetrated into the plant tissue can be controlled successfully. This is 15 particularly important and advantageous in those fungal diseases which can no longer effectively be controlled using the otherwise customary fungicides after infection has set in. The spectrum of action of the compounds I includes a large number of different phytopathogenic 20 fungi, such as, for example, Piricularia oryzae, Plasmopara viticola and various rust species, but especially Venturia inaegualis, Cercospora beticola and powdery mildew fungi in fruit, vegetable, cereal and decorative plant cultivation. <br><br> 25 The compounds can be applied in the customary preparations as wettable powders, emulsifiable concentrates, sprayable solutions, dusting agents, seed treatment agents, dispersions, granules or microgranules. <br><br> Wettable powders are understood as meaning preparations 30 which can be uniformly dispersed in water, which apart from the active compound in addition, if appropriate, to a diluent or inert substance, also contain wetting agents, for example polyoxyethylated alkylphenols, polyoxy-ethylated fatty alcohols, alkyl- or alkylphenylsulfonates 35 and dispersing agents, for example sodium ligninsulfonate, sodium 2,2'-dinaphthylmethane-6,6'-disulfonate, sodium <br><br> 2 7 <br><br> from <br><br> &gt; . ss. 14 0/27 <br><br> dibutylnaphthalenesulfonate or, alternatively, sodium oleoylmethyltauride. They are prepared in a customary manner, for example by grinding and mixing the components. <br><br> Emulsifiable concentrates can be prepared, for example, 5 by dissolving the active compound in an inert organic solvent, for example butanol, cyclohexanone, dimethyl-formamide, xylene or, alternatively, higher-boiling aromatics or hydrocarbons with the addition of one or more emulsifiers. In the case of liquid active compounds, 10 the solvent component can also be entirely or partially omitted. Examples of emulsifiers which can be used are: <br><br> calcium alkylarylsulfonates, such as <br><br> Ca dodecylbenzenesulfonate, or nonionic emulsifiers such as fatty acid polyglycol esters, alkylaryl polyglycol 15 ethers, fatty alcohol polyglycol ethers, propylene oxide/ ethylene oxide condensation products, fatty alcohol/ propylene oxide/ethylene oxide condensation products, <br><br> alkyl polyglycol ethers, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters or polyoxy-20 ethylene sorbitol esters. <br><br> Dusting agents are obtained by grinding the active compound with finely divided solid substances, for example talc or natural clays such as kaolin, bentonite, pyrophillite or diatomaceous earth. <br><br> 25 Granules can be prepared either by spraying the active compound onto adsorptive granulated inert material or by applying active compound concentrates to the surface of carrier substances such as sand, kaolinite or of granulated inert material by means of binders, for example 30 polyvinyl alcohol, sodium polyacrylate or, alternatively, mineral oils. Suitable active compounds can also be granulated in the customary manner for the preparation of fertilizer granules - if desired mixed with fertilizers. <br><br> In wettable powders, the active compound concentration 35 is, for example, about 10-90 % by weight, the remainder <br><br> - 56 - <br><br> 240727 <br><br> to 100 % by weight comprising customary formulation components. In the case of emulsifiable concentrates, the active compound concentration may be about 10-80 % by weight of active compound, in sprayable solutions about 5 1-20 % by weight. In the case of granules, the active compound content partly depends on whether the active compound is present as a liquid or solid and which granulating auxiliaries, fillers etc. are used. <br><br> In addition, said active compound formulations optionally 10 contain the adhesives, wetting agents, dispersants, emulsifers, penetrants, solvents, fillers or carrier substances customary in each case. <br><br> For application, the concentrates present in commercial form are diluted, if appropriate, in a customary manner, 15 for example by means of water in the case of wettable powders, emulsifiable concentrates, dispersions and in some cases also in the case of microgranules. Dust-like and granulated preparations and also sprayable solutions are customarily not diluted further with other inert 20 substances before application. <br><br> Mixtures or mixed formulations with other active compounds, such as, for example, insecticides, acaricides, herbicides, fertilizers, growth regulators or other fungicides may also be possible, under certain circum-25 stances it also being possible to achieve synergistic increases in action. <br><br> Some formulation examples may be mentioned in the following: <br><br> A dusting agent is obtained by mixing 10 parts by weight 30 of active compound and 90 parts by weight of talc as an inert substance and comminuting in a hammer mill. <br><br> A wettable powder which is easily dispersible in water is obtained by mixing 25 parts by weight of active compound, <br><br> - 57 - <br><br> 24072 7 <br><br> 65 parts by weight of kaolin-containing quartz as an inert substance, 10 parts by weight of potassium lignin-sulfonate and 1 part by weight of sodium oleoylmethyl-tauride as a wetting agent and dispersant and grinding in 5 a pinned-disk mill. <br><br> A dispersion concentrate which is easily dispersible in water is prepared by mixing 20 parts by weight of active compound with 6 parts by weight of alkylphenol polyglycol ether (Triton X 207), 3 parts by weight of isotridecanol 10 polyglycol ether (8 EO) and 71 parts by weight of paraf-finic mineral oil (boiling range for example, about 255 to over 377°C) and grinding in a friction ball mill to a fineness of less than 5 microns. <br><br> An emulsifiable concentrate can be prepared from 15 parts 15 by weight of active compound, 75 parts by weight of cyclohexanone as a solvent and 10 parts by weight of oxyethylated nonylphenol (10 EO) as an emulsifier. <br><br> As an example of the inhibition of the pathogenic phase of dimorphic yeast cells, results of an in vitro enzyme 20 test are shown in which the percentage inhibition of exoenzymes released, in particular of lysophospholipase (phospholipase B) released, is determined as a measure of the activity. <br><br> To determine the enzyme inhibition, a suspension of 25 Candida albicans blastoconidia (strain 200/175), in which the bacterial density was adjusted photometrically to an absorption of 0.5 (500 nm), was mixed with preparation solution or, for the control, with solvent solution, to be precise <br><br> 30 a) 100 /jl of preparation solution (suspension) + 900 /il of bacterial suspension b) 100 pi of solvent <br><br> + 900 /il of bacterial suspension <br><br> - 58 - <br><br> £40711 <br><br> 5 each of the blastocoriidia suspension which had been incubated at 21 °C for 30 min were added' dropwise to an agar plate (Sabouraud agar with the addition of 8 % egg yolk, 1 M NaCi, 5 mM CaCl2). <br><br> 5 The plate thus inoculated was incubated at 37°C for 3 days. <br><br> Evaluation was carried out by <br><br> 1. determining the diameter (mm) of the Candida albicans colony (treated and untreated) and <br><br> 10 2. determining the total diameter of colony and turbidity halo which was caused by exoenzymes (treated and untreated). <br><br> A value which was to be regarded as a measure of the enzyme activity resulted from the determination of the 15 quotient of preparation and control group. <br><br> As can be seen from Table 2, the compounds according to the invention inhibit the exoenzymes released substantially more strongly than propranolol. <br><br> » <br><br> Propranolol is described in the literature (Pappu A.S. et 20 al. in Biochem. Pharmacol. 34, 521-24, 1985) as the most active substance which showed inhibitory action against phospholipase from liver cells in an appropriate in vitro test. <br><br> The prior art is surprisingly clearly surpassed by the 25 compounds I according to the invention. <br><br> 2407 <br><br> - 59 - <br><br> Table 2 Phospholipase inhibition of some compounds of the formula I <br><br> Compound Concentration % inhibition <br><br> (micrograms/ml) <br><br> 1.4 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 20 <br><br> 1.5 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 50 <br><br> 1.15 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 25 <br><br> 1.24 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 75 <br><br> 5 <br><br> 25 <br><br> 1 <br><br> 40 <br><br> 1.25 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 68 <br><br> 5 <br><br> 25 <br><br> 1 <br><br> 22 <br><br> 1.26 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 85 <br><br> 5 <br><br> 50 <br><br> 1.27 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 87 <br><br> 5 <br><br> 62 <br><br> 1 <br><br> 11 <br><br> 1.29 <br><br> 100 <br><br> 100 <br><br> 50 <br><br> 100 <br><br> 10 <br><br> 67 <br><br> 5 <br><br> 50 <br><br> 140 7 2 " <br><br> - 60 - <br><br> Continuation of Table 2 <br><br> Compound Concentration % Inhibition <br><br> (micrograms /ml) <br><br> 1.34 100 100 <br><br> 50 100 <br><br> 10 100 <br><br> 5 67 <br><br> Propranolol 100 <br><br> 30 <br><br> - 61 — <br><br> ai0 7 <br><br> Systemic Candida albicans infection in the mouse is used as an example of the systemic in vivo activity of the compounds. <br><br> It is the aim of this method to determine the effect of 5 preparations on a systemic Candida albicans infection. The infection leads to the death of the animals within 2-4 days. <br><br> Description of the methods Albino mice (NMRI, male, 15-20 g bodyweight) are infected intravenously with 10 Candida albicans yeast cells (strain 200/175) which have been recently precultured on malt agar and suspended in physiological saline solution. The infectious dose which leads to mortality within the timescale indicated was set photometrically and contained a million yeast cells per 15 mouse. <br><br> The compounds to be tested are administered either on their own or in combination with a standard antimycotic. In the test carried out, a combination preparation was used, fluconazole (Pfizer) being used as the standard 20 antimycotic. Administration routes differ depending on the substance group, oral administration being given preference. The mice are observed for 4 weeks, the mortality is recorded daily, and the survival times of the individual groups are averaged and compared with each 25 other. Group size is on average 10 animals. <br><br> The mean values are compared using the Students T test. <br><br> As Table 3 shows, on combination therapy with compound 1.4 (14 x 50 mg/kg p.o. 1 x daily) the survival time of mice infected with Candida is increased by 57 %. (The 30 survival time of the animals treated by means of fluconazole monotherapy was defined as 100, whereupon 157 resulted for the combination therapy). <br><br> m 240 7 2 <br><br> W - 62 - <br><br> Table 3 Survival times of mice infected with Candida in combination therapy with fluconazole <br><br> Compound Survival time (relative to fluconazole <br><br> = 100 %) <br><br> 5 : <br><br> Fluconazole 100 % <br><br> Fluconazole + Compound 1.4 157 % <br><br> Dosages: <br><br> 10 Fluconazole in each case 9 x p.o. 50 mg/kg/day <br><br> Combination partner in each case 14 x p.o. 50 mg/kg/day <br><br> The fungicidal effect of the compounds of the formula I type is determined by incubating resting stages (replication form is the same as microconidia) of the fungus 15 Trichophyton mentagrophytes in distilled water overnight. <br><br> After washing the preparation (cf. H. H&amp;nel and W. Raether in Mycoses 31 (3), 148-154 (1988)), testing is carried out for survival of the fungi. <br><br> Some values determined in this way are reproduced in 20 Table 4 (the comparison preparation is rilopirox). <br><br> The compounds according to the invention are thus in the range of the highly active rilopirox with respect to their fungicidal activity. <br><br></p> </div>

Claims (10)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> *<br><br> - 63 -<br><br> Table 4<br><br> Compound<br><br> 80<br><br> jug/ml 40 20<br><br> 10<br><br> 5<br><br> 1.17<br><br> 100<br><br> 100<br><br> 100<br><br> 96.9<br><br> 1.29<br><br> 100<br><br> 100<br><br> 100<br><br> 99.66<br><br> 1.35<br><br> 100<br><br> 100<br><br> 100<br><br> 100<br><br> 99.29<br><br> 1.36<br><br> 100<br><br> 100<br><br> 100<br><br> 96.47<br><br> 1.44<br><br> 100<br><br> 100<br><br> 100<br><br> 99.09<br><br> 10<br><br> 1.48<br><br> 100<br><br> 100<br><br> 100<br><br> 99.44<br><br> Rilopirox<br><br> 100<br><br> 100<br><br> 100<br><br> 100<br><br> 96.2<br><br> &lt;»<br><br> - 64 -<br><br> 2<br><br> WHAT WE CLAIM IS:<br><br>
1. A compound of the formula I<br><br> R(2)<br><br> Rd) ^ \X_-^XR(3)<br><br> R(4) R(5)<br><br> in which s<br><br> R(l) is t-butyl, phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, naphthyl, 1,2,3,4-tetrahydronaphthy1, indany1, fluorenyl, thienyl, furyl, pyridyl, isoxazolyl, pyrazolyl, benzofuryl or benzothienyl,<br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are<br><br> F, Cl, Br, I, (Cj-Cjs)-alkyl (straight-chain or branched and unsubstituted or substituted by 1-9 F or Cl atoms), (C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or mono- or disubstituted by (Ci-CJ -alkyl (straight-chain or branched), (Ci-CJ-alkoxy (straight-chain or branched), CF3, F, Cl, Br, or OH], Y- (Cj-C^) -alkyl (straight-chain or branched), Y-(C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or substituted as indicated above], (C2-C15)-alkenyl, (straight-chain or branched, mono- or polyunsaturated), Y-(C2-C15)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, Y-(C1-C2)-alkylphenyl, phenyl-(Ci-Cz)-alkyl, biphenylyl, CN, N02, or C02Z (whe?:e<br><br> - 65 -<br><br> 4 07 n<br><br> 2 is phenyl, (C^C^)-alkyl or (C2-C13)-alkenyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1-3 substituents from the series consisting of F, Cl, CF3 and OH),<br><br> where Y is oxygen, sulfur, sulfinyl or sulfonyl,<br><br> R(2) is OH, F, Cl, Br, (Cx—C10)-alkylcarbonyloxy (straight-chain or branched), (Ci-C^J-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or mono- or disubstituted by F, Cl, Br, CF3 or OCHj), or phenylcarbonyloxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series consisting of F, Cl, Br, CF3, and (Ci-C,)-alkyl (straight-chain or branched),<br><br> R(3) is -alkyl (straight-chain or branched,<br><br> unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or 0CH3), (Cj-C^)-alkenyl (straight-chain or branched, mono- or polyunsaturated, in the form of the pure E- or Z-diastereomers or as an E/Z-dia-stereomer mixture, unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or 0CH3), ,(C2-C12)-alkynyl (straight-chain or branched, having one or more triple bonds, unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or 0CH3), (Cj-C^)-alkenynyl (straight-chain or branched, containing one or more double and triple bonds, in the form of the pure E- or Z-diastereomers or as an E/Z-dia-stereomer mixture, unsubstituted or mono to nona-substituted by F, Cl, Br, I and/or 0CH3),;.^Vs (Ca-C^) cycloalkyl (unsubstituted or mono- to nonary substituted by F, Cl, Br, I, OCH3 and/or CH3)|Z j| j, (C3-C12)-cycloalkyl-(Cj-Ca)-alkyl (unsubstituted o&amp;\<br><br> A<br><br> mono- to nonasubstituted by F, Cl, Br and/or CH3), (yl phenyl, benzyl, phenyl-(C2-CJ-alkyl, phenoxyphenyl,<br><br> phenylthiophenyl, phenylsulfinylphenyl, phenyl-<br><br> sulfonylphenyl, phenoxyphenyl-(C^C*)-alkyl, phenyl-<br><br> - 66 -<br><br> 24 07 21<br><br> thiophenyl-(Ci-C*)-alkyl, naphthyl, naphthyl-(Cx-C*)-alkyl, biphenylyl, biphenyl-(C1-CJ-alkyl, hetaryl or hetaryl-(Ci-Cj)-alkyl (where hetaryl is a radical derived from thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, • pyrrole, l,2,4-oxadia2ole, 1,3,4-oxadiazole, pyrimidine, pyrazine, benzotliiofuran, benzothiazole, benzoxazole, indole, quinoline or isoquinoline), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- to trisubstituted by F, Cl, Br, CF3, (C^-C^) -alkyl (straight-chain or branched, unsubstituted or mono-to trisubstituted by F, Cl and/or OCH3), or (C3-Q)-cycloalkyl (unsubstituted), or the aromatic ring systems or the hetaryl systems are substituted by phenyl (unsubstituted or mono- to trisubstituted by F, Cl, or OCH3), CN, OH, NHj, NR(6)R(7), N02, or Z'R(S), in which Z' is oxygen or sulfur, R(6) is (Ci-C10)-alkyl (straight-chain or branched, unsubstituted or mono- to nonasubstituted by F, Cl and/or OCH3) , or R(6) is (C^C^)-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH3), or R(6) is benzyl, biphenylylmethyl, naphthylmethyl, phenyl, thienylmethyl, thienyl, (Ci-C^) -alkylcarbonyl (straight-chain or branched) or phenylcarbonyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- to trisubstituted by F, Cl, CF3, (Cx-CJ-alkyl and/or (Ct-CJ-alkoxy and R(7) is either hydrogen or defined as R(6), where R(6) and R(7) can be identical or different,<br><br> R(4) is H, (Ci-Cia) -alkyl (straight-chain or branched), (C2-C10)-alkenyl (straight-chain or branched, mono-or polyunsaturated), or benzyl (unsubstituted or or polysubstituted by F, Cl, Br, CF3, (Ci-C^-a^cy!*- °x.\s<br><br> (straight-chain or branched), OCH3, O-phenyl'jbr phenyl), and ^ 11 j.lft ]0Q4 -1'/<br><br> 240727<br><br> - 67 -<br><br> R(5) is H, (Cj.-C^)-alkyl (straight-chain or branched), (C2-C18)-alkenyl (straight-chain or branched, mono-or polyunsaturated), (Cg-C^)-cycloalkyl (mono-, bi-or tricyclic),<br><br> (Ci-C8) -alkyloxy- (C2-C1D) -alkyl, phenyl-(Ci-Cg)-allcyl (straight-chain or branched), phenyloxy- (C:-C6) -alkyl, phenylthio-(C1-C6) -alkyl, phenyl- (C2-C6) -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-10 (Cx—C6) -alkyl (straight-chain or branche'd), thienyl,<br><br> thienylmethyl, or phenyl, where the phenyl or thienyl systems mentioned with respect to R (5) are unsubstituted or mono- to trisubstituted by substituents from the group consisting of F, Cl, Br, ()-alkyl 15 (straight-chain or branched), (C3-C8)-cycloalkyl, OH,<br><br> SH, (Cx-Cia) -alkoxy (straight-chain or branched),<br><br> phenyl, benzyl, phenethyl, thiophenyl, where a = 1-6, and -0 (CH2) j_20-,<br><br> or<br><br> _20 R(5) is a piperidin-4-yl radical which is unsubstituted or substituted by 1 to 4 methyl groups,<br><br> or<br><br> R(5) is an indol-S-yl-fCj-CJ-alkyl radical (straight-chain or branched), or<br><br> 25 R(4) with R(5) forms a chain of (CH2)a units with m = 4-6,<br><br> which chain can be interrupted by an oxygen, sulfur or nitrogen atom, which nitrogen as a further bonding component carries a hydrogen atom, or a CH3,<br><br> phenyl, benzyl or phenethyl group, and the hetero-30 cycle thus formed is unsubstituted on the CH2 units or carries 1 to 4 CH3 groups as substituents<br><br> \ £ 'v /'<br><br> and ,, c r :<br><br> X is oxygen, sulfur, sulfinyl or sulfonyl, 8 SEP 1993 '<br><br> '' i<br><br> 68<br><br> 24 0727<br><br> and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.<br><br>
2 . A compound of the formula I as claimed in claim 1, in which:<br><br> R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinyl-phenyl, phenylsulfonylphenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, fluorenyl, thienyl or pyridyl,<br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are<br><br> F, Cl, (Cj-Cj^)-alkyl (straight-chain or branched and unsubstituted or substituted by 1-6 fluorine or chlorine atoms), (C3-C18)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or monosubstituted by (Ci-C^,)-alkyl (straight-chain or branched), (Ci-C*)-alkoxy (straight-chain or branched), CF3, F, Cl or OH], Y-(C1-C10)-alkyl (straight-chain or branched), Y-(C3-C10)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or substituted as indicated above], (C2-C10')-alkenyl (straight-chain or branched, mono-or polyunsaturated), Y-(C2-C10)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, Y-(Ci-C2)-alkylphenyl, phenyl-(Cj.-C2)-alkyl, or biphenylyl,<br><br> R(2) is OH, F, Cl, (Ci-CiQ)-alkylcarbonyloxy ('straight-*-; chain or branched), {Cx-Cia) -alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or mono- or<br><br> 1594<br><br> where Y is oxygen or sulfur<br><br> - 69 -<br><br> it 4 Q 7 2* 1A<br><br> disubstituted by F, Cl, CF3 or OCH3), or phenylcarbonyl-oxy, where the phenyl radical is unsubstituted or-substituted by 1-3 substituents from the series consisting of F, Cl, CF3 and (Cx-C&lt;) -alkyl (straight-chain or branched),<br><br> ) is (C^C^)-alkyl (straight-chain or branched, unsubstituted or mono- to hexasubstituted by F, Cl, Br and/or OCH3), (C2-C12)-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH3), (C2-C10)-alkynyl (straight-chain or branched, having one or two triple bonds and unsubstituted), (C3-C10)-alkenynyl (straight-chain or branched, containing one or more double and/or triple bonds and unsubstituted) , (C^-C^)-cycloalkyl (unsubstituted or mono-to trisubstituted by F, Cl, Br and/or CH3), (Cg-C^)-cycloalkyl-fCi-Cj) -alkyl (unsubstituted), phenyl, benzyl, phenyl-(C2-C3)-alkyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonyl-phenyl, phenoxyphenyl- (C^C*)-alkyl, phenylthiophenyl- (Ci-Cj) -alkyl, naphthyl, naphthyl-(Cx-C2)-alkyl, biphenylyl, biphenylyl-(C1-Cz)-alkyl, hetaryl or hetaryl-(CJ.-C2)-alkyl [where hetaryl is a radical derived from thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, pyrimidine, benzo-thiofuran, benzothiazole, benzoxazole, guinoline or isoquinoline], where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF3, (C^C^)-alkyl (straight-chain or branched, unsubstituted or mono- or disubstituted by F or Cl), or (C3-C8)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or ZrR(6), in which Z' is oxygen or sulfur, R(6) is (C,-<br><br> C,0)-alkyl (straight-chain or branched, unsubstituted<br><br> ,r \ £ ft /<br><br> or mono- to trisubstituted by F, Cl and/or OCH3)^'tor if<br><br> R(6) is (C,-Cio)~alkenyl (straight-chain or branched mono- or polyunsaturated, unsubstituted Is-<br><br> i nB04<br><br> --..if-0<br><br> - 70 -<br><br> 240727<br><br> or mono- to trisubstituted by P, Cl and/or 0CH3), or R(6) is benzyl, phenyl, thienylmethyl, thienyl or phenylcarbonyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- or disubstituted by F, Cl, CF3, (C1-C4)-alkyl and/or (Ci-C4)-alkoxy and R(7) is either hydrogen or as defined for R(6), where R(6) and R(7) can be identical or different,<br><br> R(4) is H, (Cj-Cio)-alkyl (straight-chain or branched), or benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF3, (Ci-C*) -alkyl (straight-chain or branched), 0CH3, O-phenyl or phenyl),<br><br> R(5) is H, (Cx-C16)-alkyl (straight-chain or branched), (C2-C16)-alkenyl (straight-chain or branched, mono-or diunsaturated), (C^C^)-cycloalkyl (mono-, bi-or tricyclic) , (Ci-CgJ-alkyloxy-(C2-C8) -alkyl, phenyl-(Cj.—C6)-alkyl (straight-chain or branched), phenyl-(C2-Cs)-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(C1-C6) -alkyl (straight-chain or branched), or phenyl, where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents from the group consisting of F, Cl, (C^C*)-alkyl (straight-chain or branched), (C3-C8)-cycloalkyl, (Ci-CmJ-alkoxy (straight-chain or branched), benzyl, phenethyl, thiophenyl and -0-(CH2) i-2-0-,<br><br> or<br><br> R (5) is 2,2,6,6-tetramethylpiperidin-4-yl, or indol-3-yl-(Ci-CJ-alkyl, and<br><br> X is oxygen, sulfur, sulfinyl or sulfonyl,<br><br> and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives. L ; c<br><br> . - 8 SEi-1993<br><br> 240727<br><br> 71 -<br><br>
3. A compound of the formula I as claimed in claim 1, in which:<br><br> R( 1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl or pyridyl,<br><br> where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are<br><br> F, Cl, (Ci-Cio)-alkyl (straight-chain or branched and unsubstituted or substituted by 1-3 fluorine or chlorine atoms), (C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), T-(C1-C10)-alkyl (straight-chain or branched), Y-(C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C2-Ci0)-alkenyl (straight-chain or branched, mono-or polyunsaturated), Y-(C2-C10)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, benzyl or biphenylyl,<br><br> where Y is oxygen or sulfur,<br><br> R(2) is OH, F, (Ci-Ce)-alkylcarbonyloxy (straight-chain or branched), (Cj-CgJ-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or monosubsti-tuted by F, Cl or CF3), or phenylcarbonyloxy, where the phenyl radical is unsubstituted or mono- to trisubstituted by substituents from the series consisting of Y&amp; N<br><br> &lt;2 ^ 0 \<br><br> F, Cl , Br, CF3 and (Cj^-C*)-alkyl (straight-chain or; 4 branched), i c<br><br> H JAM 1394 ""<br><br> R (3) is (Ci-Cia) -alkyl (straight-chain or branched, * v* ? ^ unsubstituted or mono- to trisubstituted by F, Cl ;-~-— and/or OCH3), (Cj-C^)-alkenyl (straight-chain or branched, mono-or polyunsaturated and unsubstituted),<br><br> - 72 -<br><br> 24 0727-<br><br> (Cg-C^)-cycloalkyl (unsubstituted), (C3-C10)-cycloalkyl-(Cx-C3)-alkyl (unsubstituted), phenyl, benzyl, phenoxyphenyl, phenylthiophenyl, phenoxyphenyl-methyl, phenylthiophenyl-methyl, naphthyl-methyl, biphenylyl,<br><br> 5 biphenylyl-methyl, hetaryl.or hetarylmethyl (where hetaryl is a radical derived from thiophene, furan,<br><br> pyridine, oxazole, isoxazole, thiazole, isothiazole, pyrimidine, benzothiazole or benzoxazole), where said aromatic ring systems and hetaryl systems are 10 unsubstituted or mono- or disubstituted by F, Cl,<br><br> CF3, (Ci-Cio)-alkyl (straight-chain or branched and unsubstituted), or (C3-C6)-cycloalkyl (unsubstituted) or r<br><br> the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or Z'R(6), in which 15 Z' is oxygen or sulfur, R(6) is (C,-C10)-alkyl (straight-<br><br> chain or branched and unsubstituted) , or R(6) is (C3-C6)-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubstituted) or R(6) is benzyl,<br><br> phenyl, thienylmethyl or thienyl, where 20 the ring systems mentioned here for R(6) are for their part unsubstituted or mono- or disubstituted by F, Cl, CF3, (Ci-C,,)-alkyl and/or (Cj-C^)-alkoxy and R(7) is either hydrogen or as defined for R(6),<br><br> where R(6) and R(7) can be identical or different,<br><br> 25 R(4) is H, (Cj.-C10)-alkyl (straight-chain or branched), or benzyl (unsubstituted or mono- or disubstituted by-1"'* • F, Cl, CF3, (Cx—C,,) -alkyl (straight-chain ;or branched), OCHa, 0-phenyl or phenyl), ; -, .,,, , c^\<br><br> « :J34 "/<br><br> "* "&gt; „ &lt;S //<br><br> R(5) is H, (Ci-Cia)-alkyl (straight-chain or branched)'\r? p: V*' 30 (C2-C12)-alkenyl (straight-chain or branched, mono-<br><br> or diunsaturated), (Cg-C^)-cycloalkyl (mono-, bi- •, or tricyclic), phenyl- (Cj.-Cg) -alkyl (straight-chain or branched), phenyl-(C2-C8)-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-35 (C^Cg)-alkyl (straight-chain or branched), or phenyl,<br><br> where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by o<br><br> - 73 -<br><br> 24 07 27<br><br> substituents from the group consisting of F, Cl, (Cj^-C^)-alkyl (straight-chain or branched), (C3-Cs)-cycloalkyl, (Ci-C1Q) -alkoxy (straight-chain or branched), benzyl and phenethyl, and<br><br> X is oxygen or sulfur,<br><br> and its salts with pharmaceutically acceptable acids and in ths form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.<br><br>
4 . A compound of the formula I as claimed in claim 1, in which<br><br> R( 1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl or pyridyl,<br><br> where said ring systems are unsubstituted or substituted by 1-2 substituents, which are identical or different and which are F, Cl, (C^C^)-alkyl (straight-chain or branched and unsubstituted), (C3-Cio)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), Y-(C1-C10)-alkyl (straight-chain or branched), Y-(C3-C10)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C2-C10)-alkenyl (straight-chain or branched, mono- or diunsaturated), Y-(C2-C10)-alkenyl (straight-chain or branched, mono-or diunsaturated) ■, Y-phenyl, benzyl or biphenylyl,<br><br> ■ ^HT n •<br><br> &gt; (J . v\<br><br> O A"<br><br> //<br><br> I2 11 JAN 1994 1<br><br> 'a i i j h i&lt; mot jj where Y is oxygen or sulfur,<br><br> R(3) is (Cj-Cio)-alkyl (straight-chain or branched. and'&gt;vte^ unsubstituted), (C3-C12)-alkenyl (straight-chain or branched, mono- or diunsaturated and unsubstituted), (c3-c6)-cycloalkyl (unsubstituted), phenyl, benzyl,<br><br> £ 25<br><br> 30<br><br> 24 0 7 27<br><br> phenoxyphenyl, phenylthiophenyl, phenoxyphenyl-methyl, phenylthiophenyl-methyl, naphthyl-methyl, biphenylyl,<br><br> biphenylyl-methyl&gt; hetaryl or hetarylmethyl (where hetaryl is a radical derived from thiophene, pyridine, oxazole, orisoxazole), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF3/ (Ci-C^)-alkyl (straight-chain or branched and unsubstituted), or (C3-C6)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are unsubstituted or substituted by CN, NR(6)R(7) or Z'R(6), in which Z' is oxygen or sulfur, R(6) is (Cj-Cjo)-alkyl (straight-chain or branched and unsubstituted) , or R(6) is (C3-C6)-alkenyl (straight-chain or branched,<br><br> mono- or polyunsaturated and unsubstituted) or R(6) ■ is benzyl or phenyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- or disubstituted by F, Cl, CF3, (Cj-CJ-alkyl and/or (C^C,,)-alkoxy and R(7) is either hydrogen or as defined for R(S),<br><br> R(4) is H,<br><br> R( 5) is H, (Cx-C10) -alkyl (straight-chain or branched), (C2-C10)-alkenyl (straight-chain or branched, mono-or diunsaturated), (Cg-C^)-cycloalkyl (mono-, bi-or tricyclic), phenyl-(Cj-Cg)-alkyl (straight-chain or branched), phenyl-(C2-C8)-alkenyl (straight-chain or branched, mono- or diunsaturated) , diphenyl-(C1-C8)-alkyl (straight-chain or branched) or phenyl, where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- or disubstituted by substituents from the group consisting of F, Cl, (Ci-C*)-alkyl (straight-chain or branched), (C3-C8)-cycloalkyl, (Cx-C4) -alkoxy (straight-chain-^ i ots r o branched) , benzyl and phenethyl, &gt;'<br><br> ;'-V t and is oxygen or sulfur, X.f c £ ?<br><br> y 11 JAN 1394 r'l f<br><br> a<br><br> 240721<br><br> and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.<br><br>
5 . A process for preparing a compound of the formula I as claimed in claim 1, which comprises reacting a compound of the formula (II)<br><br> R(l) X-R(3) (II)<br><br> in which R(l), R(3) and X have the meanings as defined in claim l, with a sulfur ylide of the formula III<br><br> (H C) S CH 3 2 II 2<br><br> 10 (0) III<br><br> P<br><br> in which p is zero or 1,<br><br> to give a compound of the formula IV m ~<br><br> I*<br><br> ' V<br><br> v7 'J<br><br> R(i)Cv^x-R(3) (iv) ^ 11J AH 130 4 r~!<br><br> V; C£! ;.-X<br><br> and then reacting the compound of the formula IV with a nucleophile of 15 the formula MNR(4)R(5) in which R(4) and R(5) have the meanings as defined in claim 1 and M is hydrogen or a metal equivalent, a compound of the formula I where R(2) = OH being formed/ and, if desired, acylating or alkylating this compound of the formula I and optionally oxidizing to the sulfoxide or sulfone on the 20 sulfur of a thioether group and optionally converting the compound of the formula I where R(2) = OH into a compound where R(2) = F, Cl or bromine and isolating a compound of the<br><br> 76<br><br> 24 0 7 27<br><br> formula (I) thus obtained in the form of the free base or of an acid addition salt.<br><br>
6. The use of a compound of the formula I as claimed in claim 1 for the production of an antimycotic preparation.<br><br>
7. An antimycotic preparation which comprises am effective content of a compound of the formula I as claimed in claim 1 and pharmaceutically acceptable additives.<br><br>
8- A compound according to claim 1 substantially as herein described or exemplified.<br><br>
9. A process according to claim 5 substantially as herein described or exemplified.<br><br>
10. An antimycotic preparation according to claim 7 substantially as herein described or exemplified.<br><br> L /<br><br> r<br><br> O<br><br> r.<br><br> c £ \ v y,<br><br> </p> </div>
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