AU642553B2 - Beta-hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, a process for their preparation and their use - Google Patents
Beta-hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, a process for their preparation and their use Download PDFInfo
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- AU642553B2 AU642553B2 AU88140/91A AU8814091A AU642553B2 AU 642553 B2 AU642553 B2 AU 642553B2 AU 88140/91 A AU88140/91 A AU 88140/91A AU 8814091 A AU8814091 A AU 8814091A AU 642553 B2 AU642553 B2 AU 642553B2
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- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/10—Antimycotics
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- 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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- 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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- 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
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- 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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- 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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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
P/00/011 28/5191 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: 0@3* 0 0*eO 0
S
S
S.
*0
SS
S 0
S.
Invention Title: 83 -HYDROXYETHYLAMINES HAVING CYCLOPROPYL RADICAL, A PROCESS FOR THEIR USE.
A 1, 1-DISUBSTITUTED THEIR PREPARATION AND The following statement is a full description of this invention, including the as.. S.
5055 55 S. S
S*
S
.b* best method of performing it known to US
S.
S
a .aa 55 a 0e a aS F02 9881 2711 91 HOECHST AKTIENGESELLSCHAFT HOE 90/F 356 Dr. v.F./St Description P-Hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, a process for their preparation and their use The invention relates to p-hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, their preparation and the use of p-hydroxyethylamines having a 1,1-disubstituted 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.
It is known of a few p-hydroxyethylamines, which are used as beta-blockers, that they indeed have a slight effect on the inhibition of liposomal phospholipase Al (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).
C
i OH
OH
dependin on te sructure of the resp C-CH tive subtituents, are inhibitors of the exoenzymes of fungi, NH 9 9 propranolol metoprolol It has now surprisingly been found that p-hydroxyethyl- 25 amines having a 1,1-disubstituted cyclopropyl radical, depending on the structure of the respective substituents, are inhibitors of the exoenzymes of fungi have 2 fungicidal and antimycotic action and are particularly outstanding growth inhibitors of the pathogenic phase of dimorphic yeast cells.
The invention relates to the compounds of the formula I, their preparation and their use as fungicides, as antimycotics 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: R(2) R(1) -XR(3) N R(4) in formula I: R(l) is t-butyl, phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, naph- .15 thyl, 1,2,3,4-tetrahydronaphthyl, indanyl, fluorenyl, thienyl, furyl, pyridyl, isoxazolyl, pyrazolyl, benzofuryl or ben2:othienyl, where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or different and which are F, Cl, Br, I, (Ci-C 18 )-alkyl (straight-chain or branched and unsubstituted or substituted by 1-9 F or Cl atoms), 1 )-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or mono- or disubstituted by C-C 4 )-alkyl (straight-chain or branched), (Ci-C 4 )-alkoxy (straight-chain or branched), CF 3
F,
Cl, Br, OH, such as, for example, norbornyl, adamantyl, decahydronaphthyl], Y-[Ci-C 18 )-alkyl 3 (straight-chain or branched), Y-(C 3 -Cia)-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or substituted as indicated above], (C 2
-C
15 )-alkenyl, (straight-chain or branched, mono- or polyunsaturated), Y-(C 2
-C
15 )-alkenyl (straight-chain or branched, mono- or polyunse.turated), Y-phenyl, Y- (Ci-C 4 -alkylphenyl, phenyl-(C,-C )-alkyl, phenyl, CN,
NO
2 CO2Z (where Z is phenyl (C.-C 5 )-alkyl or (C 2 Cs)-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, Cl, CF 3 and OH), where Y is oxygen, sulfur, sulfinyl or sulfonyl, R(2) is OH, F, Cl, Br, (Ci-C 10 )-alkylcarbonyloxy (straight-chain or branched), (CI-C 10 )-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or mono- or disubstituted by F, Cl, Br, CF 3 or
OCH
3 phenylcarbonyloxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, Cl, Br, CF 3 (Ci-C 4 alkyl (straight-chain or branched), *oo R(3) is (Ci-C 1 ,)-alkyl (straight-chain or branched, is unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or OCH 3
(C
2
-C
12 )-alkenyl (straight-chain or branched, mono- or polyunsaturated, in the form of the pure E- or Z-diastereomers or as an E/Z-diastereomer mixture, unsubstituted or mono- to nona- :substituted by F, Cl, Br, I and/or OCH 3
(C
2 -C2)alkynyl (straight-chain or branched, having one or more triple bonds, unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or OCH 3
(C
3
-C
12 alkenynyl (straight-chain or branched, containing one or more double and/or triple bonds, in the form of the pure E- or Z-diastereomers or as an E/Z-dia- .35 stereomer mixture, unsubstituted or mono to nonasubstituted by F, Cl, Br, I and/or OCH 3 -4-
(C
3 -Cl)cycloalkyl (unsubstituted or mono- to nonasubstituted by F, Cl, Br, I, OCH, and/or CH.), (C3-C, 2 -cycloalkyl-(Ci-Ca) -alkyl (unsubstituted or mono- to nonasubstituted by F, Cl, Br and/or CH.), phenyl, benzyl, phenyl-(C 2 -C,)-alkyl, phenoxyphenyl, phenyithiophenyl, phenylsulfinyiphenyl, phenylsulfonyiphenyl, phenoxyphenyl- -alkyl, phenylthiophenyl- (C 1
C
4 -alkyl, naphthyl, naphthyl- (C 1 alkyl, biphenylyl, biphenyl- (Cl-CA) -alkyl, hetaryl, hetaryl-(Cl-C 2 )-alkyl (where hetaryl is thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4oxadiazole, pyrimidine, pyrazine, benzothiofuran, benzothiazole, benzoxazole, indole, quinoline and isoquinoline), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- to trisubstituted by F, Cl, Br, CF., (C,-C,,)-alkyl (straight-chain or branched, unsubstituted or monoto trisubstituted by F, Cl and/or OCH 3
(C
3
-C
6 cycloalkyl (unsubstituted), or the aromatic 'ring systems or the hetaryl systems are substituted by phenyl (unsubstituted or mono- to trisubstituted by F, Cif OCH 3 CN, OH, NH 2 NR(6)R(7), N0 2 in which R(6) is (Cl-C 1 0 )-alkyl (straight-chain or .4.44:25branched, unsubstituted or mono- to nonasubstituted 4.*by F, Cl and/or OCH 3 and Z'I is oxygen or sulfur, or R(6) is (C 3
-C
12 )-alkenyl (s traight- chain or branc.hed, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3 or R(6) is benzyl, biphenylylmethyl, naphthylmethyl, phenyl, Sthienylmethyl, thienyl, (C 1
-C
10 -alkylcarbonyl (straight-chain or branched) or phenylcarbonyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- to trisubsti- 935 tuted by F, Cl, CF 3
(C
1
-C
4 -alkyl and/or (C 1
-C
4 **too.
alkoxy and R(7) is either hydrogen or def ined as where R(6) and R(7) can be identical or different, R(4) is H, (Cl-C, 8 )-alkyl (straight-chain or branched),
(C
2
-C.
10 )-alkenyl (straight-chain or branched, monoor polyunsaturated), benzyl (unsubstituted or monoor polysubstituted by F, Cl, Br, CF 3 1 (Cl-C 4 )-alkyl (straight-chain or branched), OCH 3 1 0-phenyl or phenyl), is H, (Cj-C 18 )-alhyI (straight-chain or branched),
(C
2 -Cl,)-alkenyl (straight-chain or branched, monoor polyunsaturated),, (C 3
-C
12 -cycloalkyl, (mono-, bior tricyclic, such as, for example, cyclohexyl, norbornyl or adamantyl),~ (Cj-CB) -alkyloxy- (C 2
-C
10 alkyl, phenyl- (Cl-C) -alkyl (straight-chain or branched), phenyloxy- (C 1
-C
6 -alkyl, phenylthio- -alkyl, phenyl-(C 2 -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl- -alkyl (straight-chain or branched), th-%enyl, thienylmethyl, phenyl, where the phenyl or thienyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents from the group comprising F, Cl, Br, (Cl-C 1 0 )-alkyl (s tra ight- chain or branched), -cycloalk-yl, OH, SH, (C 1 -Cl 0 )-alkoxy (straight-chain or branched), phenyl, benzyl, phenethyl, thiophenyl, where a 1-6, and -O(CH 2 2 0-, 25 or is a piperidin-4-yl radical which is unsubstituted or substituted by 1 to 4 methyl groups, or is an indoI-3-yl-(C 1
-C
4 )-alkyl radical (straightchain or branched) or '9 R(4) with R(5) forms a chain of units with m 4-6, 6 which chain can be interrupted by an oxygen, sulfur or nitrogen atom, where nitrogen as a further bonding component carries a hydrogen atom, or a CH 3 phenyl, benzyl or phenethyl group, and the heterocycle thus formed is unsubstituted on the CH 2 units or carries 1 to 4 CH, groups as substituents) and X is oxygen, sulfur, sulfinyl or sulfonyl, and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.
Preferred compounds of the formula I are those in which: R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, naphthyl, 1,2,3,4tetrahydronaphthyl, indanyl, fluorenyl, thienyl or pyridyl, where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or 20 different and which are F, Cl, (C 1
-C
12 )-alkyl (straight-chain or branched and unsubstituted or substituted by 1-6 fluorine or chlorine atoms), (C 3
-C
18 )-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or monosubstituted by 25 (Ci-C 4 )-alkyl (straight-chain or branched), (C 1
-C
4 alkoxy (straight-chain or branched), CF 3 F, Cl S* or OH), such as, for example, norbornyl, adamantyl or decahydronaphthyl], Y-(Ci-C, 0 )-alkyl (straightchain or branched), Y-(C 3
-C,
0 )-cycloalkyl [mono-, bi- 30 or multicyclic, unsubstituted or substituted as indicated above], (C 2
-C
1 0 ]-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-(C 2 -Cio)- S" alkenyl (straight-chain or branched, mono- or -7 *see 20* *.:so 6460 0 0 0 00S
'I@
polyunsaturated), Y-phenyl, Y- (Cl-C 2 -alkyiphenyl, phenyl-(C 1
-_C
2 )-alkyl, phenyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1 to 3 substituents from the series comprising F, Cl, CF 3 and OH, where Y is oxygen or sulfur, R(2) is OH, F, Cl, (Cl-Cl)-alkylcarbonyloxy (straightchain or branched), (Cl-C 1 )-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or mono- or disubstituted by F, Cl, CF 3 or 0CH 3 phenylcarbonyloxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, Cl, CF 3 and (Cl-C 4 )-alkyl (straightchain or branched), R(3) is -C 1 8 -alkyl (straight-chain or branched, unsubstituted or mono- to hexasubstituted by F, Cl, Br and/or OCH 3
(CZ-C
12 )-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH,,),
(C
2
_C
1 D)-alkyiyl (straight-chain or branched, having one or two triple bonds and unsubstituted) (C 3
-C
10 alkenynyl (straight-chain or branched, containing one or more double and/or triple bonds and unsubstituted), (C 3
-C
12 )-cycloalkyl (unsubstituted or monoto trisubstituted by F, Cl, Br and/or CHO., (C 3
-C
1 2 cycloalkyl-(Cl-C 3 )-alkyl (unsubstituted), phenyl, benzyl, phenyl- (C 2
-C
3 -alkyl, phenoxyphenyl, phenylthiophenyi, phenyisulfinylphenyl, phenylsulfonylphenyl, phenoxyphenyl- (C 1
-C
4 -alkyl, phenylthiophenyl- (C,-C 2 -alkyl, naphthyl, naphthyl- (C.-C 2 alkyl, biphenylyl, biphenylyl- (Cl-C 2 -alkyl, hetaryl, hetaryl- -alkyl [where hetaryl is thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, 1, 3,4-oxadiazole, pyrimidine, benzothiofuran, benzothiazoler benzoxazole, cuinoline and *we*e.
30
S
S
S
S..
5 4*
S
.5* 35 *5 4 *5
S.
-8isoquinoline], where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF 3 (Cl-Cl.)-alkyl (straightchain or branched, unsubstituted or mono- or disubstituted by F and Cl), (C 3 -C,)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or in which R(6) is (C,-C,,)-alkyl (straightchain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH.) and Z' is oxygen or sulfur, or R(6) is (C 3
-C
1 o)-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3 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, CF 3
(C
1
-C
4 )-alkyl and/or (C 1
-C
4 )-alkoxy and R(7) is either hydrogen or as defined for where R(6) and R(7) can be identical or different, R(4) is H, 10 )-alkyl (straight-chain or branched), benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF 3
(C,-C
4 )-alkyl (straight-chain or branched), OCH, O-phenyl or phenyl), *oo' 25 R(5) is H, (C 1 -Clr)-alkyl (straight-chain or branched),
(C
2
-C
16 )-alkenyl (straight-chain or branched, monoor diunsaturated), (C 3 -Cl 2 )-cycloalkyl, (mono-, bior tricyclic, such as, for example, cycloheryl, norbornyl or adamantyl), (Cj-C,)-alkyloxy-(C 2
-C
8 30 alkyl, phenyl-(C,-C 6 )-alkyl (straight-chain or branched), phenyl-(C 2
-C
6 -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(Cl-C6)- E alkyl (straight-chain or branched), phenyl, where :000: the phenyl systems mentioned with respect to are unsubstituted or mono- to trisubstituted by substituents from the group comprising F, Cl, (straight-chain or branched), 4 )-alkyl (straight-chain or branched), (C 3
-CB)-
cycloalkyl, (Ci-C, 0 )-alkoxy (straight-chain or branched), benzyl, phenethyl, thiophenyl or 1-2-0-, or R(5) is 2,2,6,6-tetramethylpiperidin-4-yl, or indol-3-yl- -alkyl, X is oxygen, sulfur, sulfinyl or sulfonyl, and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.
Particularly preferred compounds of the formula I are those in which: R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl or pyridyl, where said ring systems are unsubstituted or substituted by 1-3 substituents, which are identical or rdifferent and which are F, Cl, (Ci-C 10 )-alkyl (straight-chain or branched and :20 unsubstituted or substituted by 1-3 fluorine or chlorine atoms), (C 3 -Co 1 )-cycloalkyl (mono-, bi- or multicyclic and unsubstituted, such as, for example, norbornyl, adamantyl or decahydronaphthyl), Y-(Ci-C 1 0 )-alkyl (straight-chain or branched),
Y-(C
3 -Co)-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C 2
-C
10 )-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-(C 2
-C
1 0 alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, benzyl or phenyl, where 30 the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1 to 3 substituents from the series comprising F, Cl and CFa, 10 where Y is oxygen or sulfur, R(2) is OH, F, (Cl-C,)-alkylcarbonyloxy (straight-chain or branched), (C 1 -C.)-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or monosubstituted by F, Cl or CF 3 phenylcarbonyloxy, where the phenyl radical is unsubstituted or -ono- to trisubstituted by substituents from the series comprising F, Cl,, Br, CF, and (Cl-C 4 )-alkyl (straight-chain or branched), R(3) is (Cl-Cle)-alkyl (straight-chain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3
(C
2
-C
12 )-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubstituted), (C 3
-C,
2 )-cycloalkyl (unsubstituted), (C 3
-C
1 o)cycloalkyl- (C 1
-C
3 -alkyl (unsubstituted), phenyl, benzyl, phenoxyphenyl, phenyithiophenyl, phenoxyphenyl-(C 1 )-alkyl, phenylthiophenyl-(C,)-alkyl, naphthy.-(C 1 -alkyl, biphenylyl, biphenylyl- (C alkyl, hetaryl, hetarylmethyl (where hetaryl is thiophene, furan, pyridine, oxazole, isoxazole, ~thiazole, isothiazole, pyrimidine, benzothiazole and benzoxazole), where said aromatic ring systems and i hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF 3 1 )-alkyl (straightchain or branched and unsubstituted), (C 3 -C,)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or in which R(6) is (Cl-C,,)-alkyl (straight-chain or branched and unsubstituted) and Z' is oxygen or sulfur or R(6) is (C 3 -C,)-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubstituted) or R(6) is benzyl, phenyl, thienylmethyl or thienyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- or disubstituted by F, Cl, CF 3 4 )-alkyl and/or (Cl-C 4 )-alkoxy and R(7) is either hydrogen or as defined for where R(6) and R(7) 11 can be identical or different, R(4) is H, (Ci-Co 1 )-alkyl (straight-chain or branched), benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF 3
(CI-C
4 )-alkyl (straight-chain or branched), OCH 3 O-phenyl or phenyl), is H, (Ci-C 12 )-alkyl (straight-chain or branched), (Cz-C 12 )-alkenyl (straight-chain or branched, monoor diunsaturated), (C 3
-C
12 )-cycloalkyl, (mono-, bior tricyclic, such as, for example, cyclohexyl, norbornyl or adamantyl), phenyl-(Ci-C -alkyl (straight-chain or branched), phenyl-(C 2
-C
6 )-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(Ci-C 6 )-alkyl (straight-chain or branched), phenyl, where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents from the group comprising F, Cl, (Ci-C 4 )-alkyl (straight-chain or branched), (C 3
-C
6 )-cycloalkyl, (CI-CI 0 )-alkoxy (straight-chain or branched), benzyl and phenethyl, X is oxygen or sulfur, and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.
Very particularly preferred compounds of the formula I are those in which: S**o R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl or pyridyl, a where said ring systems are unsubstituted or substituted by 1-2 substituents, which are identical or :s different and which are F, Cl, (Ci-C 10 )-alkyl (straight-chain or branched and unsubstituted), '12
(C
3
-C
11 _cycloalkyl (mono-, bi- or multicyclic and unsubstituted, such as, for example, norbornyl, adamantyl or decahydronaphthyl), Y-(Cl-Cl 0 )-alkyl (straight-chain or branched), Y-(C 3
-C
1 ,)-cycloalkyl (mono-, bi- or multicyclic &nd unsubstituted),
(C
2 -Cl 0 )-alkenyl (straight-chain or branched, monoor diunsaturated), Y-(C 2
-C
1 0 )-alkenyl (straight-chain or branched, mono- or diunsaturated), Y-phenyl, benzyl or phenyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1 or 2 substituents from the series comprising F, Cl and where Y is oxygen or sulfur, R(3) is (C, 1
C
1 0 )-alkyl (straight-chain or branched and unsubstituted), (C 3
-C
12 )-alkenyl (straight-chain or branched, mono- or diunsaturated and unsubstituted),
(C
3
-C
6 -cycloalkyl (unsubstituted), phenyl, benzyl, phenoxyphenyl, phenyithiophenyl, phenoxyphenyl- (C 1 alkyl, phenyithiophenyl- (C 1 -alkyl,, naphthyl-(Cl)alkyl, biphenylyl, biphenylyl-(C 1 )-alkyl, hetaryl, hetarylinethyl (where hetaryl is thiophene, pyridine, oxazole, isoxazole), where said aronnttic ring systems and hetaryl systems are unsubstituted or tets 25 mono- or disubstituted by F, Cl, CF 3
(C
1
-C
1 0 )-alkyl i so too(straight-chain or branched and unsubstituted), (C.-C,,)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are unsubstituted or substituted by CN, NR(6)R(7) or ZIR(6), in which R(6) is (Cl-C 1 0 )-alkyl (straight-chain or *s~ebranched and unsubstituted) and Z is oxygen or 'a sulfur or R(6) is (C 3 -Cr 6 )-alkenyl (straight-chain or branched, 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,
CF
3
(CI-C
4 )-aikyl and/or (C 1
-C
4 )-alkoxy and R(7) is '13 either hydrogen or as defined for R(6), R(4) is H, is H, (Ci-Co 1 )-alkyl (straight-chain or branched),
(C.-C
10 )-alkenyl (straight-chain or branched, monoor diunsaturated), (C 3
-C
12 )-cycloalkyl, (mono-, bior tricyclic, such as, for example, cyclohexyl, norbornyl or adamantyl), phenyl-(Cl-C, -alkyl (straight-chain or branched), phenyl-(C 2 -C6)-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(Ci-Cs)-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 comprising F, Cl, (C 1
-C
4 )-alkyl (straight-chain or S 15 branched), -cycloalkyl, (Ci-C 4 )-alkoxy (straight-chain or branched), benzyl or phenethyl, and X is oxygen or sulfur,
C
and their salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharmaceutically acceptable derivatives.
Suitable physiologically hydrolyzable and pharmaceutically acceptable derivatives are, for example, derivatives esterified at the hydroxyl group, which are hydrolyzable 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.
The compounds have at least one asymmetric carbon atom and can therefore occur as enantiomers and diastereomers. 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 '14 solvents or by chromatography on silica gel or alumina.
Racemates can be separated into the enantiomers by customary methods, for example by salt formation with an optically active acid, separation of the diastereomeric salts and liberation of the pure enantiomers by means of a base.
The invention furthermore relates to a process for the preparation of compounds of the formula which comprises reacting a compound of the formula (II) 0 SR(1) X-R(3) 10 (II) '0 S S in which R(3) and X have said meanings, with a sulfur ylide of the formula III (H C) S=CH 3 2 Ii 2 (0) p III ee s in which p is zero or 1, 15 to give a compound of the formula IV 07 R(1)C X-R(3)
(IV)
and then reacting the compound 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 I where R(2) OH being formed, and, if desired, acylating or alkylating this compound I and 15 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 formula thus obtained in the form of the free base or of an acid addition salt.
To prepare the compounds of the formula in a first reaction step for the preparation of the compounds of the formula (IV) a ketone of the formula (II) in which R(1), 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, 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 D 1, a temperature range between 0" and 80", preferably between 20* and 20 is advantageous.
S
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.
The abovementioned reaction is carried out in a temperature range from 20-160 0 C, if appropriate in an inert solvent and if appropriate using a base.
Suitable solvents are, for example, 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 16 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.
Suitable bases are, for example, alkali metal or alkaline earth metal alcoholates or hydrides such as, for example, sodium methylate or sodium hydride.
The reaction of the compounds of the formula II with the compounds of the formula III to give the intermediates of 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.
To do this, as indicated above, a solution of a compound S 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 II'. An at least equivalent amount of a compound of the formula HNR(4)R(5) is then added to this solution.
20 Compounds of the formula I in which R(2) is (C 1
-C
1 o)alkoxy or benzyloxy (unsubstituted or mono- or disubsti- Stuted by F, Cl, Br, CF 3 or OCH,) 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°. 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, the abovementioned inorganic bases or organic bases such as tert-amines such as triethylamine, ethylmorpholine or, for example, DBU, imidazole or pyridine.
Compounds of the formula I in which R(2) is (Ci-Clo)alkylcarbonyloxy are prepared by reacting a compound of 17 the formula I where R(2) H with an appropriate alkylcarbonyl halide or phenylcarbonyl halide, preferably an alkylcarbonyl chloride, alkylcarboxylic anhydride, phenylcarbonyl chloride or anhydride, in the presence of a base, in an inert solvent and in a temperature range from -20 to 120 0
C.
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 bases, such as NEt 3 pyridine or DBU.
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 S 15 trifluoride (Et 2
NSF
3 in an inert solvent, if appropriate in the presence of a base, and in a temperature range from to Solvents and bases preferably used are those which have been 7iven for the reaction of compounds of the :20 formula IV with NMR(4)R(5) and, for example, bases such as NEt 3 ethylmorpholine, pyridine or DBU.
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 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 80 0 C. To prepare sulfoxides, a molar equivalent of oxidant is added to this compound, and to prepare sulfones two molar equivalents are added, and if appropriate even an excess.
Solvents used are preferably those which are given for the reaction of compounds of the formula (IV) with 18 Preparation of the starting substances To prepare compounds of the formula II in which R(1) and R(2) have the meanings indicated, processes according to those given in Patent Applications DE-OS 3,608,792 and DE-OS 3,608,727 are advantageously used.
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
O
I
R(1)-C XR(3) 10 in which R(3) and X have the meanings mentioned, is reacted with a phosphorus ylide to give a compound of the formula V CH2 XR(3) "and then the compound V is reacted with an organic 15 peroxide to give a compound of the formula IV o 4 4 R(1) XR(3)
(IV)
and IV, as already mentioned above, is further reacted with a nucleophile of the formula M-NR(4)R(5) in which R(5) and M have the meanings mentioned and M is hydrogen or a metal eqruivalent, a compound I where R(2) OH being formed, and, if desired, this compound I being acylated, alkylated or converted into a compound being acylated, alkylated or converted into a compound '19 where R(2) F, Cl or Br, and optionally being oxidized to the sulfoxide or sulfone on the sulphur of a thioether group, and optionally being converted into the salt using a physiologically tolerable acid.
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(3) and X have the abovementioned meanings, is reacted with a phosphorous ylide in an inert solvent and in a temperature range from -60 to +80 0
C.
The phosphorous ylide used in this reaction is prepared by reaction of a methyltriarylphosphonium salt, preferably methyltriphenylphosphonium chloride, bromide or 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 bistrimethylsilylamide or organolithium compounds such as, for example, n-butyllithium or phenyllithium.
20 Solvents used are those which are given for the reaction of compounds of the formula IV with o .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.
Suitable oxidants are, for example, H 2 0 2 or percarboxylic acids, such as, for example, peracetic acid, trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid.
Bases and solvents used are those which are given for the 20 reaction of compounds of the formula IV with 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 process.
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 sulfoxide or sulfone, and if appropriate can be converted into the salt with a physiologically tolerable acid, such as given in the above process.
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.
The examples which follow serve to characterize the 20 invention.
Example 1 Preparation of a compound of the formula I by reaction of an oxirane of the formula IV with an amine without further additional solvent Preparation of COH Cl N
S
N
CH
3 21 R(1) is 4-chlorophenyl, R(2) is OH, R(3) is 4-chlorobenzyl, R(4) is hydrogen, R(5) is n-butyl and X is sulfur.
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 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(1) is 4-chlorophenyl and R(2) is 4-chlorobenzyl and X is 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.
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.
The combined organic phases are washed three times with ml portions of water, dried over Na 2
SO
4 and filtered off from the drying agent, and the solvent is removed in ""vacuo.
According to the 'H-NMR spectrum, the oily residue has the structure of the formula IV, where R(1) is 4-chlorophenyl and R(2) is 4-chlorobenzylthio, and a purity of about 90 Yield: 3.52 g (pale yellow oil) 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/dichloromethane 1:3).
22 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 (eluent: ethyl acetate/dichloromethane 1:3).
Yield: 3.44 g (8.1 mmol, 81 of theory), colorless oil Elemental analysis C 22
H
27 C1 2
NOS:
C found: 62.4 calc.: 62.3 H found: 6.3 calc.: 6.4 N found: 3.2 calc.: 3.3 10 Example 2 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 Preparation of o* C cl (1.19) 0 R(1) is 4-chlorophenyl, R(2) is OH, R(3) is 2,4-dichlorobenzyl, R(4) is hydrogen, R(5) is isopropyl and X is sulfur.
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 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 23 (14 mmol) of the ketone of the formula II where R(1) 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 one hour at 40°C and then for six hours at room temperature.
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.
The combined organic phases are washed three times with ml portions of water, dried over Na 2
SO
4 and filtered off from the drying agent, and the solvent is removed in :vacuo.
*a *06*0* According to the H-NMR spectrum, the oily residue has 15 the structure of the formula IV, where R(1) is 4-chlorophenyl, R(2) is 2,4-dichlorobenzyl and X is sulfur, and a purity of about 95 Yield: 2.97 g (pale yellow oil, 55 of theory) 0.5 g of the oxirane (1.29 mmol) prepared in this way are 120 reacted for two hours at 140 0 C in an autoclave with 3 ml of isopropylamine in 20 ml of DMSO as solvent.
After completion of the reaction, excess isopropylamine is removed in a rotary evaporator under reduced pressure and the residue which remains is extracted with dichloromethane/water. After drying the organic phase by means of NazSO 4 separating off 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 A colorless oil is obtained; the product crystallizes from diethyl ether.
Yield: 370 mg (0.83 mmol, 65 of theory) Melting point: 128 0
C
Elemental analysis CziH 24 Cl 3 NOS: 444.85 g mol"' 24 found: found: found: 56.5 5.4 3.2 calc.: calc.: calc.: 56.7 5.4 3.1 Example 3 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 Preparation of owes a 0.00 *5*e
S
0, a a.
r a.
a a
C
CF
3 (1.25) 5 *r 0 a r R(1) R(2) R(3) R(4) R(5)
X
4-cyclohexylphenyl,
OH,
3-trifluoromethylbenzyl, hydrogen, phenylethyl and sulfur.
a "*15 0.5 g (1.16 mmol) of the oxirane of the formula II, where R(1) is 4-cyclohexylphenyl, R(3) is 3-trifluoromethylbenzyl and X is sulfur, prepared in the manner described in Example 1 is dissolved together with 1 ml of phenethylamine in 30 ml of ethanol and 2 ml of water and the mixture is stirred for 5 hours at 80°C; the reaction is monitored by thin layer chromatography (silica gel; eluent: dichloromethane).
After completion of the reaction, the solvent is removed under reduced pressure in a rotary evaporator and the residue which remains is extracted with 25 dichloromethane/water. After drying the organic phase by means of Na 2
SO
4 separating off the drying agent and removing the extracting agent in a rotary evaporator, an oily residue remains, which is purified by column chromatography (silica gel; eluent: dichloromethane). A colorless oil is obtained which crystallizes from diethyl ether: Yield: 428 mg (0.77 mmol, 67 of theory) Melting point: 81'C Elemental analysis C 33
H
3
,F
3 NOS: 553.73 g mol C found: 71.5 calc.: 71.6 H found: 6.8 calc.: 6.9 N found: 2.4 calc.: Example 4 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.
20 Variant 1, 2 or 3 distinguishes whether the reaction is carried out according to Example 1, 2 or 3.
S
Examples 1.41-1.95 were reacted according to the variant from Example 3.
-26 TABLE 1 M.P. oil Variant calc. found 1.1 C 57.27% 57.2 H 5.26% 5.2 C1 16 N 3.18% 3.2 0 3.63% S 14.56% M.P. oil Variant 1.2 calc. found: 3 1.2.C 61.76% 61.8 H H 5.68% C1 17.36% N 3.43 3.3 b 0 3.92 7.85 o"I Variant 1.3calc. found :1 66 C 63.71% 3.8 H 6.91% Cl 15.67% N 3.10% 0 3.54% S•s 7.09% M.p. oil Variar, 1.4 calc. found OH C 62.26% 62.3 H 6.41 6.4 Cl 16.71% N 3.30% 3.4 0 3.77% S 7.55% 27 Continuation of TABLE 1 b a 6*e* *4R*
S
*444
S
S
*5 4 *5 S .5 4 ft 4S 1.6 CH S-b M.p. oil calc. C 62.26% H 6.41% Cl 16.71% N 3.30% 0 3.77% S 7.55% oil cac. C 60.27% H 5.75% Cl 16.17% N 3.19 0 7.30 S 7.31 M.P. oil calc.
C 66.03% H 6.11% Cl 13.44% N 5.31% 0 3.03% S 6.08% M.p. oil talc. C 64.54% H 5.82 Cl 14.11% N 2.79% 0 6.37% S 6.38% found 62.3 3.3 found: 60.3 5.7 Variant 1 Variant 1 7.3 4 «4 4 St *4* 4.* tt 1.7 found found 64.6 5.7 2.9 Variant 2 Variant 3
JCH
28 Continuation of TABLE 1 1.9 M.P. :oil Variant 3 caic.: 63.99% 6.49% 15.74% 3.11% 3.55% 7.12% found 63.9 6.4 3.1 Variant M.P. oil calc.
1.10 e 4.0 ~4 0 q, .~h 4 dl
CH
a C 60.60% H 5.75% C1 17.89% N 3.53% 0 4.04 s 8.09 found 60.6 5.8 3.7 6 d 40 4 S
I
0 #46404 6 0 0 .46001 4 0 0* 4.
0 40 4 6 09 40 1. 11 Mi.P. 0.l calc.
Variant 3 63.71% 6.91% 15.67% 3.10% 3.54% 7.09% found 63.8 6.8 1.12 M.P. Oil caic.
Variant 3 69.87% 9.12% 7.64% 3 .02% 3.45% 6.91% found 69.9 -'29 Continuation of TABLE 1 oil calc.
C 68.85% H 8.78% CI 8.13% N 3.21% 0 ,3.67% S 7.35% Oil Va rian t found: 8.6 3.1 Np-t O V- tar.t
~CO
S
see
S
S.D.
S
OSOO*e
S
t 4,5
C
65
IS
a a 5* calc.
1.14 c
H
Cl
N
0
S
71. 95% 7 .91% 7.32% 2.89% 3.30% 6 .62%, found 71.8 7.2 2.9 M oil 1 V a r i ant 3 calt.
S
S
9* 6e C
U
S 00006 3 0
S
a CBS OS
S
'S
ma
SOS
Jg C a 68.30%, 8.60% 8.40% 3.32% 3 .79% 7.60% found 68.2 3.2 M. oil Variant 1.16 calc.
found: 62.26% 6.41% 16.71% 3.30% 3'.77% 7.55% 6.4 3.2 30 Continuation of TABLE 1 1.17 oil calc.
C 59.52% H 5.68% C1 7.99% F 12.84 N 63.15% 0 3.60% S 7.22% Variant found 59.6 5.7 3.1 a -Q -t F 14; oil V a rian t 3 calc.
1.18 61.78% 6.43% 7.29% 11.73 2.88% 3.29% 6 found 61.9 6.3 I. oil
S.SSS
S
S S
SS
S.
5 6
S.
S
555555 1.19 1.20
OHQS<
56. 70% 5.44% 23. 91% 3.15% 3. 7.21% Vr iant 2 calc.: found 56.6 5.6 3.1 oil Variant 2 Caic.
5555 *5
S
S.
S
5 @55 *5 S S
*S
60.92% 4.91% 21. 58% 2.84% 3.25% 6.51% f ound 60.8 4.8 2.7 31 Continuation of TABLE 1 1.21 a~QJ~~ 1.22 M.P. oil calc.
C 57.58% H 5.71% C1 23.18% N 3.05% 0 3,.49% S 6.99% oil calc.: C 75.31% H 7.22% C1 6.35% N 2.51% 0 2.87% S 5.74% oil talc.
C 68.887 H 7. 5 1 F 11.27% N 2.77% o 3.16% S *6.34% M.P. oil calc.: C 64.25% H 7.25% C1 6.54% F 10.51% N 2.58% o 2.95% S 5.91% V a rian t 3 0 0*.
000000 0 .0 0 0 *0 00 0 0 1.23 found 57.6 5.8 3.1 found 75.1 7.1 2.4 found 69.0 2.6 found 64.1 7.1 Variant 3 Va r.t 2 Variant 3 0 000000 0 *000 00 @0 0 00000.
0 000000 0 *0 0 000 00 0 0 0 1.24 H-bQ 2.7 H+ O 32 Continuation of TABLE 1 M.P. i Variant 1. 5calc. :found :3 C 71.58% 71.4 H 6.92% N 2.5 3% 2.
F o 2.89% s 5.79% oilVar an alc. :found: 3 1.26C 66.71% 66.9 CHH 6.47% 6.3 C1 6.15% X H CrF 9.-89% N 2.43% 2.4 bt o 2.78% oil Variant 1.27 calc. :found :3 HO C 73.07% 73.2 F H 6 .81% 6.9 0 t F F 9.63% 4 11N 2.37% 2.2 0 2.70% s 5.42% M oil fndVariant 1 .2 8 c l f u d3 7.3 H 70.48 09 2.64 Soo :t -O S 5.90% .33 Continuation of TABLE 1 oil Variant 3 1.29 t-buty 1 calc.
C 70.00% H 8 .13% C1 7.95% N 3.14% 0 3.59% S 7.19% M.Dp. oil calc.
C 69.73% H 8.89% N 6.50% 0 7.43% S 7.45% found 70.2 Variant 1.30 H3C HZ cQ found 69.7 6.4 M.P. oil Variant
S**
S S a.
a a 0 a.
a S a.
1.31 caic.
0
'N
69.73% 8.89% 6.50% 7.43% 7.457, found 69.9 6.4 Hc 1.32 oil caic.: C 72.38% H 7.815% N 6.03% 0 6.89% S 6.90% Variant 3 found 72.3 7.8 6.1 -34 Continuatio~n of TABLE 1 1.33
N
M.P. oil V ari~ant 3 calc.
C 69.73% H 8.89% N 6.50% 0 7.43% S 7.45% oil founid 69.7 6.7 ca.b .1 1 .34
H
69.50% 7 .93% 8.21% 3 .24% 3 7.42% found 69.6 3.1 *99999 0 9 9.
*9 9 9 1.35 M.P. oil calc.
Varant 3 68 .61% 8.23% 7.23% 2.86% 6.53% 6.54% found 68.6 8.3 2.7 1.36 *0*9 9O .9 9 90999 *00990
S
9.
9** 0 M.P. oil caic.
C 70.00% H 8.13% C1 7.95% N 3.14% 0 3.59% s 7.19% found 70.2 8.1 3.1 Va r ian t 35 Continuation of TABLE 1 M oil Variant 1.37 Icalc. found: 3 C 69.19% 69.2 H 8.71% .8.6 N 6.72% 6.8 w 07.68% S 7.70% M.P. oil Variant talC found 3 1.38 0 C 76.02% 76.2 H 7.80% 7.8 N 4.92% 4.8 0 5.63% S 5.64% p Oil Variant 1 .39 calp found 3 C 70.83% 71.0 HC H 7.93% 7.9 N 5.51% 5.6 0 9.43% S 6.40% S .SSIl S.P. oil Variant 5Calc.: found 3 55 e 1.40 C 70.00% 70.1 H 8.13% 8.2 CI 7.95% N 3.14% 3.2 0: S 3.59% 7.19%.
36 Continuation of TABLE 1 1 .41 M.P. 8 0
C
calc.
found: 1.42 c
H
Cl
F
N
0
S
M. P.
c a Ic
C
H
Cl
F
N
0 s 65. 52% 6.98% 5.23% 8.40% 2.06% 7.08% 4.73% 65.3 7.1 2.1 f ound 55. 18% 5.68% 22. 21% 3.97% 2.92% 3.34% 6.70% 55.1 5.6 2.9
S
S
550
S
S S *5 1 .43 OH F H+ a- 1.44 H+ a- 209-210 0
C
caic.
C 5
H
Cl 2
F
N
0
S
M.P.
caic.
C
H
Cl 2
F
N
0
S
found 5.18% 5.68% 2.21% 3.97% 2. 92% 3.34% 6.70% 55.1 5.8 2.9 55.5 *0
S
S S. a .555.
S.
0 *55 *5 45 188-190UC f ound: 5.18% 5. 684 p2.21% 3.97% 2.92% 3. 34% 6.70% C 55.0 H 5.8 N 2.8 I- 37 Continuation of TABLE 1 1 157-5c.
calc. found a- 60.81% 6. 59% 7.48% 12.02% 2.95% 3.38% 6.76% 6.6 6.7 1.46 M.P. 204 0
C
calc.
found: w a(- 63. 83% 5.75% 6.98% 11.22% 2.76% 3.15% 6.31% 63.6 5.8 2.7 6*6 6 66*@ .666 66.
*6tq*6 6 6
*W
6 9 *6 66 6 6 66 1 .47
M.P.
caic C 6
H
Cl F 1
N
0
S
1 53 0
C
found mK a- 4. 42% 5.99% 6.79% 0.92% 2.68% 3.06% 6.14% 64.3 6.2 2.7 6 6 *9 66 66
I
606696
S
6 666 6 *6 6 66, 6 6 6 *6 1 .48 188 0
C
C 60.81% H 6.59% Cl 7.48% F 12.02% N 2.95% 0 3.38% S 6.76% found 60.8 6.8 3.1 H+ a- 38 Continuation of TABLE I 1.49 Ol H+ a 1 50
M.P.
ca it.
H
cl
N
0
S
M.P..
ca it.
C
H
Cl
N
0
S
M calc
C
H
Cl
N
0 s found 56.09% 5.304s 20.70% 5.45% 6.23% 6. 24% 19 0 0
C
C
H
N
55.9 5.2 2 47 "C found 56. 88% 5.54% 20.15% 5.31% 6.06% 6. 07% 2242 C 56.9 5.4 5.2 a 4 a *4 a 4 a.
a a.
K 0- 1 .51 found: 59. 85% 4. 84% 18. 93% 4.98% 5.69% 5.71% 60.0 4.9 4.9 H 0 .4a4 a* a a a. a. a. a.
a *aa 644 a 66 6 *6.
a. 4a 1 .5? M. 217 0
C
C81c.
C 59.424 H 5.524 CI. 18.79% N 4.95% 0 5.65% s 5.67% found 59.5 5.6 39 Continuation of TABLE 1 1.53 M.P. 176 0
C
calc found 58.54% 23s 16.72% 4.40% 10.06% 5.04% 58.4 5.2 4.3 H C 1 .54 M. P. 13 9 0
C
cal c.* found 64. 254 7.25% 6. 54% 51% 2.58% 2.95% 5.91% 64.3 7.4 2.6 H+ a- 1.55 0*0@ 0~ a a 0 S S S
SO
S S
S.
55~55
S
50 *5 5
S
S SO S SS
S
S.
S
505 SS S a.
126 0
C
caic. found 64.65% 6.674 5.45% 8.77% 2.15% 7.38% 4.93% 64.7 6.6 2.2 1 .56 M. 2 4 0 C ceic.
found 66. 71% 6.47% 6.15% 9.89% 2.43% 2.78% 5. 574 66.8 6.4 40 Continuation of TABLE 1 1 .57 21 0 0
C
found-' 66. 25% 7.12%6 6.11% 9.82% 2.41% 2.76% 5.53% 66.4 -j .0 1.58 224 0
C
c a Ic found 62.63% 6.71% 6.37% 2.52% 5.75% 5.77% 62.7 6.8 2.4 a..
a a..
a a a a a.
a a eal., a.
1.59 M.P. 52 0
C
calc found: 43cy 71.,75% 8.83% 7.06% 2.79% 3.19% 6.38% 71.8 8.9 2.9
H
4
O
1.60
I-
Sa I a..
a.
a a..
a. a a a a.
M. P. 220 0
C
calc. found 73. 92% 7.89% 6.61% 2.61% 2. 98% 5.98% 73.8 7.8 2.6
H
4 Or 41 Continuation of TABLE 1 1 .61 oil c a Ic.
found 85% 7.93% 5.81% 2.30% 7.86% 5.25% 71.0 7.9 2.3 1.62
M.P.
calc.
C
H
Cl
N
0
S
115 0
C
found 68. 25% 8.27% 7.46% 5.90% 3.37% 6.75% 68.1 8.3 Wf ae.g
C
CCC
0 *0
S
*0
CC
0 0
SC
0
C
C. C
C
*00*OC 0 0 060S0
S
00 *0* S. C C 1 .63
M.P.
celc c
H
Cl
N
0
S
21 8 0
C
found 70. 77% 7.32% 6.96% 5.50% 3.14% 6.30% 70.9 7.4 5.4 H+ 0- 1 .64 M.P. 259 0
C
caic.
found: 70. 21% 8.05% 6.91% 5.46% 3.12% 6.25% 70.1 8.1 H+ 0- 42 Continuation of TABLE I 1.65 M.P. oil C8a.1C found: 63.08% 6.86% 6.904 11.09% 2.72% 3.11% 6. 24% 63.0 6.9 2.8 1 .66 M.P. ,resin Calc. found H+ a- 74% 6.07% 6.47% 10. 2.56% 2.92% 65.8 6.1 S. S
SSS
S
555*** 5 *5 S C
OS
*4 S S
S.
9S*OCS
S
555.
S S S 0b S 0 0*SS*u
S
S
S. SOC
S
S.
S..
S. S C S
SS
1.67 1.68 M.P. :oil caic. f o und.
H C 67. 12% 8.21% 5.66% 9.10% 2.24% 2.55% 5.12% 67.0 8.2 2.3 cabc.
found: 62. 84% 7.23% 6.87% 11. 04% 2.71% 3.10% 6.21% 62.6 7.1 2.8 a- c 43 Continuation of TABLE 1 1.69 M.P. :oil calc.
found 71.03% 8.86% 9.63% 2.37% 2.70% 5.42% 71.0 8.7 2.2 S S
S
0Ss6
S
GE 5555 S S
SO
ES S 8 55
SE
S .5 1.70 1 .71 1.72 It4t calc..
72. 55% 7.14% 7.38% 2.92% 3.33% 6.68% 72.4 7.1 2.9 found: M.P. found:
C
H
cl
N
0
S
M.P.
69. 50% 7. 93% 8.21% 3. 24% 3.70% 7.42% 69.5 9 5556
S.
S
S
S
S
55
S
S
Es.
.5 5 5E 5 oil calc.
found: 73. 14% 9.39s; 6.35% 2. 51% 2.87% 5. 74% 44 Continuation of TABLE 1 cii 1.73 SM.. ceic.: found: C 76.06% C 76.0 HN H 7.25% H 7.3 Cl 6.07% N 2.3 N 2.40% 0 2.74% S 5.49% oi] M.p.: 1.74 round calc.
0H C 72.12% C 72.0 H 7.83% H 7.9 Cl 6.26% N N 2.47% O 5.65% S 5.66% Ric* oil *t 1.75 found calc.
C 68.93% C 68.9 *6 m H 7.09% H 7.1 Cl 6.56% N 2.6 N 2.59% 0 8.89% H; S 5.94% M oil 1.76 calc. found C 70.93% C 70.0 85.64*0 H 8.50% H 8.3 Cl 7.48% N 2.9 N 2.95% I 0 337% 33 .~~vN~P%4 3 S 6.76% 45 Continuation of TABLE 1 1 .77 M0P oi Cfl1c.
found 74.22% 8.06% 6.44% 2.55% 2.91% 5.83% 74.2 8, 1 2.4 1.78 M. o i found: 73.32% 8.08% 6.76% 2.67% 3.05% 6.12% 73.1 2.7 .4.
qee.
S
~Sw n~s~ 4 S
S.
I.
S..
a 6 6. *8 a r as...
.8 S
S
j B
S
6.6.6.5 *9 a 4..
6.
US S S
SI
1 .79 1 M. .:oil cabc.
f ou nd.
68. 75% 6. 54% 6.76% 2.67% 9.16% 6.12% 68.7 6.6 2.7 M p oil caic found 73. 60.% 7.72% 6.79% 2.681k 3.06% 6.14% 73.7 7.8 2.8 46 Continuation of TABLE 1 oil 1.81 Cal C found CHC 62.66% C 62.7 H 5.94% H HNCl 5.97% N 2.3 F 9.59% N 2.36% F 0 2.69%1 s 10.79%c OH calc. found 1.82 1 .82- NC 76.99 C 76.2 HN bH 8.22 H 8.1 43K 5.44 N 5.4
H
5 0 0 3.11 CS 6.23 0*Oa OH Caelc. f o u n '1.83 -jI c 78.73 c 78.6 H 6.61 H 14N N 5.40 N 5.4 0 3.08 s/ 6.'18 Vs
OS...
S
a *r
S
r 47 Continuation of TABLE 1 1.84
H
CC:%
1.85
MN
1.86 oil calc.
found: 52.53 5.10 3.22 16.32 3.68 4 .37 14.76 52.4 3.3 M...oil C 81.95 H 8.54 N 2.90 0 6.61 found C 88.1 H N
S
S
6*SS o *5
S
*5 *5 S .5 oil calc.: C 71.93 H 6.68 N 2.99 0 10.27 found: C 72.1 H 6.6 N 3.1
S
es.. 0@
S
55.5 S. S 55
S
S
S
OSS
S. S S S
OS
1.87 C443
ON
HC
resin caic.: C 74.02 H 10.68 N 3.45 0 3.94 S 7.90 found C 74.2 H 10.6 N 3.6 48 Continuationi of TABLE 1 1 .88 114. P. 011 caj.c C 65.94 H 5.53 N 2.96 0 6.76 S 6.77 F 12.04 found C 65.8 H N 2.9 1.89
HN
CH,
a.
S00 M.P. oil calc C 67.49 H 6.95 N 3.58 F 9.70 0 4.09 S 8.19 M. oil C 78.61 H 8.30 N 2.96 o 10.13 found C 67.6 H N found C 78.5 H 8.4 N 3.1 1.90 *aa. a.
a *9*S
*S
S. S 5*0@55
S*.S*
a a a..
*0 S a a a.
1 .91 resin calc.
C 60.92 H 6. 88 N 2.73 0 3.12 C1. 13.83 S 12.51 found C 61.1 H 6.9 N 2.7 49 Continuation of TABLE 1 1.92 OH
PH
2
MN
oil C 67.77 H 7.24 N 3.59 Cl 9.09 0 4.10 S 8.22 found: C 67.6 H 7.2 N 3.7 1.93 M-P. resin caic.: C 59.67 H 5.92 N 3.16 C1 24.02 0 7.23 found C 59. 8 H N 3.2
S
*5*
S
S
0S
S.
HN'
CH,
'1.94 M1.P. oil caic, C 62.27 H 6.41 N 3.30 0 11.31 C1 16.71 found: C 62.4 H N 3.3 .5555.
6 S S 5* 5
S~
S
SS
S
0S 11, OF6 1.95 I1. Oil cslc. C 64.56 H 8.02 N 6.02 C1 7.62 0 6.88 S 6.89 found C 64.5 H 8. 2 N 50 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 niger or against yeasts, such as, for example, Candida albicans, C. tropicalis, Torulopsis glabrata and Trichosporon cutaneum or against protozoa such as Trichomonas vaginalis or T. fetus, or alternatively against grampositive and gram-negative bacteria.
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 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 administration.
2 Examples of indication areas in human medicine which may .be mentioned are: Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, 25 Microspora species, Epidermophyton floccosum, and biphasic 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.
30 Examples of indication areas in veterinary medicine which may be mentioned are: All dermatomycoses and systemic mycoses, in particular those which are caused by the abovementioned pathogens.
51 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 used according to the invention, and processes for the production of these preparations.
Non-toxic, inert pharmaceutically suitable excipients are understood as meaning solid, semisolid or liquid diluents, fillers and formulation auxiliaries of any type.
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 substances have to be administered in a concentration which has previously proved effective in animal experiments.
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 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.
Suitable candidates for prophylaxis are primarily immunocompromised patients, who are in this situation owing to 52 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 long-term ventilation etc.
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 as a rule be below that which would be necessary for a pure antimycotic therapy.
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 parenchyma. 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 o 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 attachment is prevented by phospholipase inhibitors, the other pathomechanisms are unable to act completely.
Possible administration forms are, for example, tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, lotions, sprays etc.
The prophylactically and therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95 by weight of 53 the total mixture.
The abovementioned pharmaceutical preparations can also contain other pharmaceutical active compounds in addition to the active compounds used according to the invention.
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.
The present invention includes the use of the active 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.
*.15 The active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and/or rectally.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active 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 of several individual doses to achieve tne desired results. The total amount is administered in 1 to 8, preferably in 1 to 3, individual doses, but in deepseated mycoses over substantially longer periods of time (up to 6 weeks).
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 54 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, 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.
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 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 compoundL I oo includes a large number of different phytopathogenic 20 fungi, such as, for example, Piricularia oryzae, Plasmopara viticola and various rust species, but especially Venturia inaequalis, Cercospora beticola and powdery mildew fungi in fruit, vegetable, cereal and decorative plant cultivation.
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.
Wettable powders are understood as meaning preparations 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, polyoxyethylated fatty alcohols, alkyl- or alkylphenylsulfonates and dispersing agents, for example sodium ligninsulfonate, sodium 2,2'-dinaphthylmethane-6,6'-disulfonate, sodium 55 dibutylnaphthalenesulfonate or, alternatively, sodium oleoylmethyYtauride. They are prepared in a customary manner, for example by grinding and mixing the components.
Emulsifiable concentrates can be prepared, for example, by dissolving the active compound in an inert organic solvent, for example butanol, cyclohexanone, dimethylformamide, xylene or, alternatively, higher-boiling aromatics or hydrocarbons with the addition of one or more emulsifiers. In the case of liquid active compounds, the solvent component can also be entirely or partially omitted. Examples of emulsifiers which can be used are: calcium alkylarylsulfonates, such as Ca dodecylbenzenesulfonate, or nonionic emulsifiers such as fatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide/ ethylene oxide condensation products, fatty alcohol/ propylene oxide/ethylene oxide condensation products, alkyl polyglycol ethers, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters or polyoxy- 20 ethylene sorbitol esters.
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.
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 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.
In wettable powders, the active compound concentration is, for example, about 10-90 by weight, the remainder 56 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 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.
In addition, said active compound formulations optionally contain the adhesives, wetting agents, dispersants, emulsifers, penetrants, solvents, fillers or carrier substances customary in each case.
For application, the concentrates present in commercial form are diluted, if appropriate, in a customary manner, 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.
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.
Some formulation examples may be mentioned in the following: 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.
A wettable powder which is easily dispersible in water is obtained by mixing 25 parts by weight of active compound, 57 parts by weight of kaolin-containing quartz as an inert substance, 10 parts by weight of potassium ligninsulfonate and 1 part by weight of sodium oleoylmethyltauride as a wetting agent and dispersant and grinding in a pinned-disk mill.
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 polyglycol ether (8 EO) and 71 parts by weight of paraffinic 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.
An emulsifiable concentrate can be prepared from 15 parts by weight of active compound, 75 parts by weight of cyclohexanone as a solvent and 10 parts by weight of xyethylated nonylphenol (10 EO) as an emulsifier.
0** As an example of the inhibition of the pathogenic phase of dimorphic yeast cells, results of an in vitro enzyme 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.
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 4*o 30 a) 100 pl of preparation solution (suspension) 900 pl of bacterial suspension b) 100 pl of solvent 900 pl of bacterial suspension 58 pl each of the blastoconidia suspension which had been incubated at 21 0 C for 30 min were added dropwise to an agar plate (Sabouraud agar with the addition of 8 egg yolk, 1 M NaC1, 5 mM CaCl 2 The plate thus inoculated was incubated at 37 0 C for 3 days.
Evaluation was carried out by 1. determining the diameter (mm) of the Candida albicans colony (treated and untreated) and 2. determining the total diameter of colony and turbidity halo which was caused by exoenzymes (treated and untreated).
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.
S* As can be seen from Table 2, the compounds according to the invention inhibit the exoenzymes released substantially more strongly than propranolol.
Propranolol is described in the literature (Pappu A.S. et 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.
The prior art is surprisingly clearly surpassed by the 25 compounds I according to the invention.
e 0° 59 Table 2 Phospholipase inhibition of some compounds of the formula I Compound Concentration Inhibition op...
0* p.
*e p (micrograms/mi) 1.4 100 100 100 100 100 s0 100 1.15 100 100 100 1.24 100 100 100 1 1.2S 100 100 50 100 10 68 5 1 22 1.26 100 100 s0 100 5 s0 1,27 100 100 100 10 87 5 62 1 11 1.29 100 100 50 100 67 0 S. *P Ot SO S 0 0S@@S*
S
S
S. 555 0S 0
OS.
5* 4 50 60 Continuation of Table 2 Compound Concentration (micrograms/mi) Inhibition 1.34 100 100 1.00 100 Propranolol 100 9SeS a a
S
a& a
S.
fr S S a.
a SeI*1 a S. S a
S
0
*SSS**
a Ii a ape *6 0 a a C.
61 Systemic Candida albicans infection in the mouse is used as an example of the systemic in vivo activity of the compounds.
It is the aim of this method to determine the effect of preparations on a systemic Candida albicans infection.
The infection leads to the death of the animals within 2-4 days.
Description of the method: Albino mice (NMRI, male, 15-20 g bodyweight) are infected intravenously with 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 mouse.
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 S. the substance group, oral administration being given Spreference. 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 other. Group size is on average 10 animals.
The mean values are compared using the Students T test.
Oe9.
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 U, mice infected with Candida is increased by 57 (The survival time of the animals treated by means of flucona- S* zole monotherapy was defined as 100, whereupon 157 resulted for the combination therapy).
62 Table 3 Survival times of mice infected with Candida in combination therapy with fluconazole Compound Survival time (relative to fluconazole 100 Fluconazole 100 Fluconazole Compound 1.4 157 Dosages: Fluconazole in each case 9 x p.o. 50 mg/kg/day Combination partner in each case 14 x p.o. 50 mg/kg/day 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 Trichophyton mentagrophytes in distilled water overnight.
After washing the preparation (cf. H. Hanel and W. Raether in Mycoses 31 148-154 (1988)), testing is carried out for survival of the fungi.
Some values determined in this way are reproduced in r* .20 Table 4 (the comparison preparation is rilopirox).
The compounds according to the invention are thus in the range of the highly active rilopirox with respect to their fungicidal activity.
I
6,3 Table 4 Compound 14g/ml 1.17 100 100 100 96.9 1.29 100 100 100 99.66 1.35 100 100 100 100 99.29 1.36 100 100 100 96.47 1.44 100 100 100 99.09 1.48 100 100 100 99.44 Rilopirox 100 100 100 100 96.2 aoes *:go so )0 wo 0 a so
Claims (9)
1. A compound of the formula I R(2) R(1) XR(3) R(4) in which: R(1) is t-butyl, phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenyithiophenyl, phenylsulfinyiphenyl, phenylsulfonyiphenyl, naphthyl, 1,2,3,4 -tetrahydronaphthyi, indanyl, see: 10 fluorenyl, thienyl, furyl, pyridyl, isoxazolyl, :9..:pyrazolyl, benzofuryl or benzothienyl, 0 990 where said ring systems are unsubstituted or substi- tuted by 1-3 substituents, which are identical or different and which are F, Cl, Br, I, (Cj-C 1 8 )-alkyl (straight-chain or branched and unsubstituted or substituted by 1-9 F or Cl atoms), (C 3 -C 1 )-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or mono- or disubstituted by (C 1 -C 4 -alkyl (straight-chain or branched), (C,-C 4 )-alkoxy (straight-chain or branched), CF 3 1 F, Cl, Br, OH, -alkyl (straight-chain or *branched), Y-(C 3 -C 1 8 )-cycloalkyl [mono-, bi- or .multicyclic, unsubstituted or substituted as indicated above], (C 2 -C, 5 )-alkenyl, (straight-chain or branched, mono- or polyunsaturated), Y-(C 2 -Cl 5 alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-phenyl, Y- (C 1 -C 2 -alkyiphenyl, phenyl- (Cl-C 2 -alkyl, phenylyl, CN, NO 2 CO 2 Z (where 65 15 C ~20 .25 00 S. 2 is phenyl, (Ci-C 1 ,)-alkyl or (C 2 -Cl,)-alkenyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubsti- tuted or carries 1-3 substituents from the series comprising F, C1, CF 3 and OH), where Y is oxygen, sulfur, sulfinyl or sulfonyl, R(2) is OH, F, Cl, Br, (Ci-C 1 o)-alkylcarbonyloxy (straight-chain or branched), (Ci-C 1 o)-alkyloxy (straight-chain or branched), benzyloxy (unsubsti- tuted or mono- or disubstituted by F, Cl, Br, CF 3 or OCH 3 phenylcarbonyloxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, Cl, Br, CF 3 (Ci-C 4 alkyl (straight-chain or branched), R(3) is (Ci-C 1 e)-alkyl (straight-chain or branched, is unsubstituted or mono- to nonasubstituted by F, Cl, Br, I and/or OCH 3 (C 2 -C 12 )-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 nona- substituted by F, Cl, Br, I and/or OCH 3 (C 2 -C 12 alkynyl (straight-chain or branched, having one or more triple bonds, unsubstituted or mono- to nona- substituted by F, Cl, Br, I and/or OCH 3 (C 3 -C 2 alkenynyl (straight-chain or branched, containing one or more double and/or 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 OCH 3 (C 3 -Cl)cycloalkyl (unsubstituted or mono- to nona- substituted by F, Cl, Br, I, OCH 3 and/or CH 3 (C 3 -C 12 -cycloalkyl-(Ci-C 3 -alkyl (unsubstituted or mono- to nonasubstituted by F, Cl, Br and/or CH 3 phenyl, benzyl, phenyl-(C 2 -C 4 )-alkyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenyl- sulfonylphenyl, phenoxyphenyl-(Ci-C 4 )-alkyl, phenyl- 66 255 thiophenyl- (Cl-C 4 -alkyl, naphthyl, naphthyl- (Cl-C 4 alkyl, biphenylyl, biphenyl- (Cl-C 4 -alkyl, hetaryl, hetaryl-(Cl-C 2 )-alkyl (where hetatyi is thiophene, furan, pyridine, oxezole, isoxazole, thiazole, isothiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4- oxadiazole, pyrimidine, pyrazine, benzothiofuran, benzothiazole, benzoxazole, indole, quinoline and isoquinoline), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- to trisubstituted by F, Cl, Br, CF 3 (Cl-Cl)-alkyl (straight-chain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3 (C 3 -C 6 cycloalkyl (unsubstituted), or the aromatic ring systems or the hetaryl systems are substituted by phenyl (unsubstituted or mono- -to trisubstituted by F, Cl, OCH 3 CN, OH, NH 2 NR(6)R(7), NO 2 in which R(6) is (Cl-Cl 0 )-alkyl (straight-chain or branched, unsubstituted or mono- to nonasubstituted by F, Cl and/or OCH.) and Z'I is oxygen or sulfur, or R(6) is (C 3 -C 12 )-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3 or R(6) is benzyl, biphenylylmethyl, naphthylmethyl, phenyl, thienylmethyl, thienyl, -alkylcarbonyl (straight-chain or branched) or phenylcarbonyl, where the ring systems mentioned here for R(6) are for their part unsubstituted or mono- to trisubsti- tvutrt. by F, Cl, CF 3 1 (Cl-C 4 )-alkyl and/or 4 alkoxy and R(7) is either hydrogen or defined as where R(6) and R(7) can be identical or different, R(4) is H, 1 8 )-alkyl (straight-chain ior branched), (C 2 -C,,)-alkenyl (straight-chain or branched, mono- or polyunsaturated), benzyl (unsubstituted or mono- or polysubstituted by F, Cl, Br, CF 3 1 (Cl-C 4 )-alkyl (straight-chain or branched), OCH 3 1 0-phenyl or phenyl), is H, (C 1 -C 18 )-alkyl (straight-chain or branched), (C 2 -C 1 8 )-alkenyl (straight-chain or branched, mono- or polyunsaturated), (C 3 -C 12 )-cycloalkyl, (mono-, bi- or tricyclic), (Ci-C) -alkyloxy- (C 2 -C 1 alkyl, phenyl-(Ci-Cs)-alkyl (straight-chain or branched), phenyloxy-(Ci-C) -alkyl, phenylthio- (Ci-C 6 -alkyl, phenyl- (C 2 -C 8 -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl- (Ci-C 6 )-alkyl (straight-chain or branched), thienyl, thienylmethyl, phenyl, where the phenyl or thienyl systems mentioned with respect to R(5) are unsubsti- tuted or mono- to trisubstituted by substituents from the group comprising F, Cl, Br, (Ci-C,,)-alkyl (straight-chain or branched), (C 3 -Cs)-cycloalkyl, OH, SH, (Ci-Co 1 )-alkoxy (straight-chain or branched), phenyl, benzyl, phenethyl, thiophenyl, CF,+ 1 where oe a 1-6, and -O(CH 2 1 2 0-, or S 20 R(5) is a piperidin-4-yl radical which is unsubstituted or substituted by 1 to 4 methyl groups, or R(5) is an indol-3-yl-(Cj-C 4 )-alkyl radical (straight- chain or branched) or R(4) with R(5) forms a chain of (CH 2 units with m 4-6, which chain can be interrupted by an oxygen, sulfur or nitrogen atom, where nitrogen as a further bonding component carries a hydrogen atom, or a CH 3 phenyl, benzyl or phenethyl group, and the hetero- cycle thus formed is unsubstituted on the CH 2 units or carries 1 to 4 CH 3 groups as substituents and X is oxygen, sulfur, sulfinyl or sulfonyl, 68 and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharma- ceutically acceptable derivatives.
2. A compound I as claimed in claim 1, in which: R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, phenylsulfinyl- phenyl, phenylsulfonylphenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, indanyl, fluorenyl, thienyl or pyridyl, where said ring systems are unsubstituted or substi- tuted by 1-3 substituents, which are identical or different and which are F, Cl, (Ci-C 1 2 )-alkyl (straight-chain or branched and unsubstituted or substituted by 1-6 fluorine or 15 chlorine atoms), (C 3 -C 18 )-cycloalkyl [mono-, bi- or multicyclic, unsubstituted or monosubstituted by (Ci-C 4 )-alkyl (straight-chain or branched), (C 1 -C 4 alkoxy (straight-chain or branched), CF 3 F, Cl or OHj, f-(C 1 -Co 1 )-alkyl (straight-chain or branched), Y-(C 3 -C 1 o)-cycloalkyl [mono-, bi- or multicyclic, unsubstitutsd or substituted as indicated above], (C 2 -C 10 ]-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-(C 2 -C 10 )-alkenyl (straight- chain or branched, mono- or polyunsaturated), 25 Y-phenyl, Y-(Ci-C 2 )-alkylphenyl, phenyl-(Ci-C 2 )-alkyl, phenylyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1 to 3 substituents from the series comprising F, Cl, CF 3 and OH, where Y is oxygen or sulfur, R(2) is OH, F, Cl, (Ci-C 1 o)-alkylcarbonyloxy (straight- chain or branched), (Ci-C 1 o)-alkyloxy (straight-chain V or branched), benzyloxy (unsubstituted or mono- or 6'9- 20 egg6 00ee. 3e e 0 disubstituted by F, Cl, CF 3 or OCH 3 phenylcarbonyl- oxy, where the phenyl radical is unsubstituted or substituted by 1-3 substituents from the series comprising F, Cl, CF. anc: (Cl-C 4 )-alkyl (straight- chain or branched), R(3) is (Cl-C 18 -alkyl (straight-chain or branched, unsubstituted or mono- to hexasubstituted by F, Cl, Br and/or OCH.), (C 2 -C 12 )-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted or mono- to trisubstituted by F, C1 and/or OCH 3 (C 2 -C 10 ),%-alkynyl (straight-chain or branched, having one or two triple bonds and unsubstituted) (C 3 -C 10 alkenynyl (straight-chain or branched, containing one or more double and/or triple bonds and unsubsti- tuted) (C 3 -C 12 )-cycloalkyl (unsubstituted or mono- to trisubstituted by F, Cl, Br and/or CHOI, (C 3 -C 12 cycloalkyl- (C,-C 3 -alkyl (unsubstituted), phenyl, benzyl, phenyl- (C 2 -C 3 -alkyl, phenoxyphenyl, phenyl- thiophenyl, phenylsulfinyiphenyl, phenylsulfonyl- phenyl, phenoxyphenyl- (C 1 -C 4 -alkyl, phenylthio- phenyl- (C,-C 2 )-alkyl, naphthyl, naphthyl- (Cl-C 2 alkyl, biphenylyl, biphenylyl- (Cl-C 2 -alkyl, hetaryl, hetaryl- (C,-C 2 -alkyl [where hetaryl is thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, 1, 3,4-oxadiazole, pyrnnidine, benzo- thiofuran, benzothiazole, benzoxazole, quinoline and isoquinoline], where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF 3 (Cl-Cl 0 )-alkyl (straight- chain or branched, unsubstituted or mono- or disub- stituted by F and Cl), (C 3 -cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or in which R(6) is (Cl-Cl 0 )-alkyl (straight- chain or branched, unsubstituted or mono- to trisub- stituted by F, and/or 0CH 3 and Z I is oxygen or sulfur, or R(6) is (C 3 -C 1 0 )-alkenyl (straight-chain or branched, mono- or polyunsaturated, unsubstituted 15 see* so a 2 0 S or mono- to trisubstituted by F, Cl and/or OCH 3 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, CF 3 1 (Cl-C 4 )-alkyl and/or (CI-C 4 )-alkoxy and R(7) is either hydrogen or as defined for where R(6) and R(7) can be identical or different, R(4) is H, (Cl-C 1 0 )-alkyl (straight-chain or branched), benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF 3 1 (C 1 -C 4 -alkyl (straight-chain or branched), OCH 3 0-phenyl or phenyl), is H, (C,-C 1 6 )-alkyl (straight-chain or branched), (C 2 -Clr 6 )-alkenyl (straight-chain or branched, mono- or diunsaturated), (C 3 -Cl 2 )-cycloalkyl, (mono-, bi- or tricycli), -alkyloxy- (C 2 -C 8 -alkyl, phenyl- (Cl-C).alkyl (straight-chain or branched), phenyl- (C 2 -C 6 -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(Cj-C,)-alky_!. (straight- chain or branched), phenyl, where the phenyl systems mentioned with respect to R(5) are unsubstituted or mono- to trisubstituted by substituents from the group comprising F, Cl, (Cl-C 4 )-alkyl (straight-chain or branched), (C 3 -cycloalkyl, (Cl-C 10 -alkoxy (straight-chain or branched), benzyl, phenethyl, thiophenyl or (CH 2 or is 2,2,6,6-tetramethylpiperidin-4-yl, or indol-3-yl- (C.-C 4 -alkyl, X is oxygen, sulfur, sulfinyl or sulfonyl, and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharma- ceutically acceptable derivatives. 71 S0 S C 20 5
3. A compound I as claimed in claim 1, in which: R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl or pyridyl, where said ring systems are unsubstituted or substi- tuted by 1-3 substituents, which are identical or different and which are F, Cl, (Ci-Co 1 )-alkyl (straight-chain or branched and unsubstituted or substituted by 1-3 fluorine or chlorine atoms), (C 3 -C 1 0 )-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), Y-(Ci-Ci 0 -alkyl (straight-chain or branched), Y-(C 3 -C 10 )-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C 2 -C 10 )-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y-(C 2 -C 0 )-alkenyl (straight- chain or branched, mono- or polyunsaturated), Y-phenyl, benzyl or .phenylyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsubstituted or carries 1 to 3 substituents from the series comprising F, Cl and CF 3 where Y is oxygen or sulfur, R(2) is OH, F, (C2-Cs)-alkylcarbonyloxy (straight-chain or branched), (Ci-C 6 )-alkyloxy (straight-chain or branched), benzyloxy (unsubstituted or monosubsti- tuted by F, Cl or CF 3 phenylcarbonyloxy, where the phenyl radical is unsubstituted or mono- to trisub- stituted by substituents from the series comprising F, Cl,, Br, CF 3 and (Ci-C 4 )-alkyl (straight-chain or branched), R(3) is (Ci-C 1 s)-alkyl (straight-chain or branched, unsubstituted or mono- to trisubstituted by F, Cl and/or OCH 3 (C 2 -C 1 2 )-alkenyl (straight-chain or branched, mono-orpolyunsaturated and unsubstituted), S 5055 S S 30 7 a (C 3 -C 12 )-cycloalkyl (unsubstituted), (C 3 -C' 0 )-CYClo- alkyl-(Cl-C 3 )-alkyl (unsubstituted), phenyl, benzyl, phenoxyphenyl, phenyithiophenyl, phenoxyphenyl- (C 1 alkyl, phenyithiophenyl- (C 1 -alkyl, naphthyl- (C 1 alkyl, biphenylyl, biphenylyl-(Cl)-alkyl, hetaryl, hetarylmethyl (where hetaryl is thiophene, furan, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyrimidine, benzothiazole and benzoxazole), where said aromatic ring systems and hetaryl Systems are unsubstituted or mono- or disubstituted by F, Cl, CF 3 -alkyl (straight-chain or branched and unsubstituted), (C 3 -C)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are substituted by CN, NR(6)R(7) or in which R(6) is (Cl-C 1 0 )-alkyl (straight-chain or branched and unsubstituted) and Z' is oxygen or sulfur or R(6) is (C 3 -C)-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubstituted) or R(6) is benzyl, phenyl, thienylmethyl or thienyl, where the ring systems mentioned here for R(6) are for C their part unsubstituted or mono- or disubstituted sees.'by F, Cl, CF., (Cl-C 4 )-alkyl and/or (Cl-C 4 )-alkoxy and *oo R(7) is either hydrogen or as defined for R(6), where R(6) and R(7) can be identical or different, R(4) is H, (C3 1 -C 1 0 )-alkyl (straight-chain or branched), benzyl (unsubstituted or mono- or disubstituted by F, Cl, CF 3 1 (C 1 -C 4 -alkyl (straight-chain or branched), OCH 3 0-phenyl ox~ phenyl), 0:000eR(5) is H, (C 1 -C 1 2 )-alkyl (straight-chain or branched), S (C 2 -C 12 )-alkenyl (straight-chain or branched, mono- V or diunsaturated), (C 3 -C 12 )-cycloalkyl, (mono-, bi- or tricyclic), phenyl- (Cl-C 6 -alkyl (straight-chain or branched), phenyl-(C 2 -C 6 )-alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl- -alkyl (straight-chain or branched), phenyl, where the phenyl systems mentioned with respect to are unsubstituted or mono- to trisubstituted by 13 substituents from the group comprising F, Cl, (C 1 -C 4 )-alkyl (straight-chain or branched), (C 3 -C 5 cycloalkyl, (Ci-C 10 )-alkoxy (straight-chain or branched), benzyl and phenethyl, X is oxygen or sulfur, and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharma- ceutically acceptable derivatives.
4. A compound I as claimed in claim 1, in which R(1) is phenyl, biphenylyl, phenoxyphenyl, benzylphenyl, benzyloxyphenyl, phenylthiophenyl, naphthyl or pyridyl, 0060 s '0 s to* 0. 25 *:soot A' so: 00 0 0 where said ring systems are unsubstituted or substi- tuted by 1-2 substituents, which are identical or different and which are F, Cl, (Ci-C 10 )-alkyl (straight-chain or branched and unsubstituted), (C 3 -C 10 )-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), Y-(Ci-C,,)-alkyl (straight-chain or branched), Y-(C 3 -C 1 )-cycloalkyl (mono-, bi- or multicyclic and unsubstituted), (C 2 -C 10 )-alkenyl (straight-chain or branched, mono- or diunsaturated), Y-(C 2 -C 1 o)-alkenyl (straight-chain or branched, mono- or diunsaturated), Y-phenyl, benzyl or phenylyl, where the alkyl and alkenyl substituents mentioned are straight-chain or branched and phenyl is unsub- stituted or carries 1 or 2 substituents from the series comprising F, Cl and CF,), where Y is oxygen or sulfur, R(3) is (CI-Ci,)-alkyl (straight-chain or branched and unsubstituted), (C 3 -C 1 2 )-alkenyl (straight-chain or branched, mono- or diunsaturated and unsubstituted), (C 3 -C,)-cycloalkyl (unsubstituted), phenyl, benzyl, 74 phenoxyphenyl, phenylthiophenyl, phenoxyphenyl- alkyl, phenylthiophenyl-(C) -alkyl, naphthyl-( C) alkyl, biphenylyl, biphenylyl-(C 1 )-alkyl, hetaryl, hetarylmethyl (where hetaryl is thiophene, pyridine, oxazole, isoxazole), where said aromatic ring systems and hetaryl systems are unsubstituted or mono- or disubstituted by F, Cl, CF 3 (Cl-Cl 0 )-alkyl (straight-chain or branched and unsubstituted), (C 3 -C)-cycloalkyl (unsubstituted) or the aromatic ring systems or the hetaryl systems are unsubsti- tuted or substituted by CN, NR(6)R(7) or in which R(6) is (Cl-C 10 )-alkyl (straight-chain or branched and unsubstituted) and Z' is oxygen or sulfur or R(6) is (C 3 -C,)-alkenyl (straight-chain or branched, mono- or polyunsaturated and unsubsti- tuted) or R(6) is benzyl or phenyl, where the ring 0404systems mentioned here for R(6) are for their part S unsubstituted or mono- or disubstituted by F, Cl, CF 3 (C-C 4 )-alkyl and/or (Cl-C 4 )-alkoxy and R(7) is either hydrogen or as defined for R(6), *o. R(4) is H, is H, (C 1 -Clo)-alkyl (straight-chain or branched), (C 2 -Cl,)-alkenyl (straight-chain or branched, mono- or diunsaturated), (C 3 -C)-cycloalkyl, (mono-, bi- 25 or tricyclic), phenyl-(Cl-C)-alkyl (straight-chain or branched), phenyl-(C 2 -alkenyl (straight-chain or branched, mono- or diunsaturated), diphenyl-(C,- C )-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 comprising F, Cl, 05 (Cl-C 4 )-alkyl (straight-chain or branched), (C 3 cycloalkyl, 4 )-alkoxy (straight-chain or branched), benzyl or phenethyl, and X is oxygen or sulfur, and its salts with pharmaceutically acceptable acids and in the form of physiologically hydrolyzable and pharma- ceutically acceptable derivatives.
A process for preparing a compound I as claimed in claim 1, which comprises reacting a compound of the formula (II) 0 R(1 X-R(3) (II) in which R(3) and X have the meanings mentioned, with a sulfur ylide of the formula III (H C) S CH 3 2 I 2 10 III P 4 *S a a in which p is zero or 1, S* to give a compound of the formula IV S* R(1)C X-R(3) (IV) 6 and then reacting the compound 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 equi- valent, a compound I where R(2) OH being formed, and, if desired, acylating or alkylating this compound I and 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 formula thus obtained in the form of the free base or of an acid addition salt.
6. A method of preparation of an antimycotic comprising admixing an effective amount of a compound as claimed in claim 1 with suitable carriers or excipients.
7. A method of treating mycotic infections comprising administering to a mammal requiring such treatment an effective amount of a compound as claimed in claim 1.
8. An antimycotic preparation which comprises an effective content of a compound of the formula I as claimed in claim 1 and pharmaceutically acceptable additives.
9. A method of inhibiting the pathogenic phase of dimorphous yeasts comprising administering an effective amount of a compound as claimed in claim 1. DATED this 23rd day of July, 1993. HOECHST AKTIENGESELLSCHAFT S WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA DBM:CJH:ML VAX doc 037 AU8814091.WPC *o o HOE 90/F 356 Abs tract ,-Hydroxyethylamines having a 1,1-disubstituted cyclo- propyl radical, a process for their preparation and their use Compounds I R(2) R(1) R(3) R(4) where R(l) is t-butyl or an aromatic compound, R(2) is OH, Hal, alkyl(phenyl)carbonyioxy, alkyloxy or benzyloxy, R(3) is (cyclo)alk(en)(yn)yl or an aromatic compound, R(4) is H, alk(en)yl or benzyl, is H, (cyclo)alk(en)yl or phenylalk(en)yl or R(4) and R(5) are a (CH 2 4 6 chain, and X is 0, S, SO, or SO, have antimycotic activity, and are also used for prophy- laxis and exhibit inhibition of the phospholipase of Candida albicans. S ,Thr
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4037819 | 1990-11-28 | ||
| DE4037819 | 1990-11-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8814091A AU8814091A (en) | 1992-06-04 |
| AU642553B2 true AU642553B2 (en) | 1993-10-21 |
Family
ID=6419070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU88140/91A Expired - Fee Related AU642553B2 (en) | 1990-11-28 | 1991-11-27 | Beta-hydroxyethylamines having a 1,1-disubstituted cyclopropyl radical, a process for their preparation and their use |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0488169A1 (en) |
| JP (1) | JPH04290853A (en) |
| KR (1) | KR920009787A (en) |
| AU (1) | AU642553B2 (en) |
| CA (1) | CA2056311A1 (en) |
| FI (1) | FI915566A (en) |
| HU (1) | HUT62265A (en) |
| IE (1) | IE914129A1 (en) |
| IL (1) | IL100167A0 (en) |
| NO (1) | NO914654L (en) |
| NZ (1) | NZ240727A (en) |
| PT (1) | PT99619A (en) |
| ZA (1) | ZA919356B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9198429B2 (en) * | 2011-11-25 | 2015-12-01 | Bayer Intellectual Property Gmbh | Heterocyclic alkanol-derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3608792A1 (en) * | 1986-03-15 | 1987-09-24 | Hoechst Ag | 1,1-DISUBSTITUTED CYCLOPROPANE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| DE3732388A1 (en) * | 1987-09-25 | 1989-04-06 | Bayer Ag | AZOLYLMETHYLCYCLOPROPYL CARBINOLE CONTAINING ANTIMYCOTIC AGENTS |
-
1991
- 1991-11-26 NZ NZ240727A patent/NZ240727A/en unknown
- 1991-11-26 FI FI915566A patent/FI915566A/en unknown
- 1991-11-26 EP EP91120186A patent/EP0488169A1/en not_active Withdrawn
- 1991-11-26 KR KR1019910021205A patent/KR920009787A/en not_active Application Discontinuation
- 1991-11-27 IE IE412991A patent/IE914129A1/en not_active Application Discontinuation
- 1991-11-27 IL IL100167A patent/IL100167A0/en unknown
- 1991-11-27 ZA ZA919356A patent/ZA919356B/en unknown
- 1991-11-27 AU AU88140/91A patent/AU642553B2/en not_active Expired - Fee Related
- 1991-11-27 CA CA002056311A patent/CA2056311A1/en not_active Abandoned
- 1991-11-27 NO NO91914654A patent/NO914654L/en unknown
- 1991-11-27 PT PT99619A patent/PT99619A/en not_active Application Discontinuation
- 1991-11-27 JP JP3335822A patent/JPH04290853A/en active Pending
- 1991-11-28 HU HU913710A patent/HUT62265A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA919356B (en) | 1992-08-26 |
| NO914654D0 (en) | 1991-11-27 |
| IL100167A0 (en) | 1992-08-18 |
| PT99619A (en) | 1992-10-30 |
| CA2056311A1 (en) | 1992-05-29 |
| EP0488169A1 (en) | 1992-06-03 |
| JPH04290853A (en) | 1992-10-15 |
| AU8814091A (en) | 1992-06-04 |
| FI915566A0 (en) | 1991-11-26 |
| HU913710D0 (en) | 1992-02-28 |
| HUT62265A (en) | 1993-04-28 |
| KR920009787A (en) | 1992-06-25 |
| NZ240727A (en) | 1994-04-27 |
| IE914129A1 (en) | 1992-06-03 |
| NO914654L (en) | 1992-05-29 |
| FI915566A (en) | 1992-05-29 |
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