CA2078057A1 - Substituted aminopropanes, processes for their preparation, and their use - Google Patents
Substituted aminopropanes, processes for their preparation, and their useInfo
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- CA2078057A1 CA2078057A1 CA002078057A CA2078057A CA2078057A1 CA 2078057 A1 CA2078057 A1 CA 2078057A1 CA 002078057 A CA002078057 A CA 002078057A CA 2078057 A CA2078057 A CA 2078057A CA 2078057 A1 CA2078057 A1 CA 2078057A1
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- alkyl
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- 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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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/44—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
- C07C2601/20—Systems containing only non-condensed rings with a ring being at least seven-membered the ring being twelve-membered
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Hydrogenated Pyridines (AREA)
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Abstract
Abstract of the disclosure Substituted aminopropanes, processes for their preparation, and their use Compounds of the formula I
can be used for the treatment and for the prophylaxis of fungal diseases. They are obtained by reacting II
II
with III
III
to give IV
can be used for the treatment and for the prophylaxis of fungal diseases. They are obtained by reacting II
II
with III
III
to give IV
Description
2~780S7 I~OECHST A~TIENGESE~LLSCW'T HOE 91/F 287 Dr.vF/PL
Description Substituted aminopropanes, proco~ses for their prepara-tion, and their use The invention relates to ~ubstituted ~;nopropane~ of the formula I, to processes for th~ir preparation, and to pharmaceutical compositions containing ~uch compounds, and to their use a8 pharmaceuticals, in particular as growth inhibitors of the pathogenic pha~e of dimorphic yeast cells and as anti-ycoties, it being poesible for the compound~ according to the invention to be u~ed in prophylaxis as well a~ in therapy.
German Offenlegungsschrift DE 3,330,005 Al mentions compounds of the formula A
R ( 3 )~ R ( ~ ) R ( 2 ) ~ C ~ ( CH2 ) n ~ CH
\ N ~ R ( S ) R ( 1 )R ( 6 ) In this Offenlegungsschrift, R(3) i~ generally defined as aryl, alkyl or cycloalkyl, it being possible for each of these radicals to be substituted, and hydrogen. ~owever, nothing iB mentioned in the description and in the examples about compounds where R(3) is aryl, alkyl or cycloalkyl, and only tartaric acid derivatives of those compounds in which R(3) is hydrogen are described.
In contrast, compounds of the formula I in which the amine component has aliphatic, cycloaliphatic or aromatic radicals and the substituent R(7) in formula I is simul-taneously a group bonded via carbon, as well as the use 2078~
of such compounds as inhibitors of the exoenzymes (fac-tors of pathogenicity) of fungi and as antimycotics, are as yet unknown.
The invention therefore relates to substituted aminoprop-anes of the formula I
o ( R I ) ~ R ( 2 ) - X - C ~ ~ - C -- C ~
( 7 ~ R ( 3 ) to their preparation and to their use as antimycotics as well as growth inhibitors of the pathogenic phase of dimorphic yeast cells. The compounds can therefore be used for the prophylaxis and treatment of fungal dis-eases. The invention furthermore relates to pharmaceuti-cal preparations containing these compounds and to their salts with pharmaceutically acceptable acids and to their physiologically hydrolyzable derivatives.
Unless specifically mentioned otherwise, alkyl, alkoxy, alkylthio, alkylene and alkenyl groups in any form are straight-chain or branched; alkenyl chains are monoun-saturated or polyunsaturated. Aryl is phenyl or naphthyl.
However, phenanthryl, fluorenyl and anthracenyl can also act as aryl radicals.
In formula I:
R(1) is H, (Cl-Cl0)-alkyl, (C2-Cl0)-alkenyl, benzyl, [unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl or phenyl], C(O)-(Cl-C3)-alkyl, C(O)-phenyl 2~78a~7 R(2) is H, (cl-cla)-alkyll ~C1-C6)-alkyl-oxy-(C1-c8) alkyl, (cl-c6)-alkyl-thio-phen (C1-C6)-alkyl-oxy-phenyl, (c2-c~s)-alkenyll (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaPhthyl), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or di~ubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubsti-tuted by substituents selected from the group comprising F, Cl, Br, (Cl-Cl0)-alkyl~ (C3-C10)-cycloalkyl, OH, SH, (C,-C10)-alkoxy, (C1-C4)-alkylenedioxy, (C1-C~0)-alkylthio, dimethylamino-ethoxy, ( Cl-C4 ) -alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, C~F2~, (where a equals 1 - 6), or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by F, Cl, (C1-C4)-alkyl, O( Cl-C4 ) -alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or R(2) together with R(3) forms a chain -(CH2)~- where m equals 4 - 6 and in which a CH2 group can be replaced by oxygen or sulfur, A is (C1-C18)-alkyl, (c2-cl8)-alkenyl or a group 2078~5~
R ( 4 ) ,~, R(5) R ( 6 ) in which the radicals R(4), R(5) Pnd R(6) have the following meaning:
R(4) is H, ( C1-C1B ) -alkyl, (c2-cl8)-alkenyl/ (C3-C20)~
cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C20)-alkyl, Y-(C2-ClB)-alkenyl, Y-(C3-C20)-cycloalkyl (mono-, bi- or multicyclic), phenyl, Y-phenyl, phenyl-(C~-C~)-alkyl, phenyl-( C~-C4 ) -alkoxy, biphenylyl, F, Cl, Br, C~F2~t~ (where a equals 1 to 8), CC13, YH, naphthyl, CN, NO2, the phenyl systems being unsubstituted or monosubsti-tuted or disubstituted by F, Cl, CF3, ( C~-C4 ) -alkyl, ( C~-c4 ) -alkoxy, CN, -O-(CH2) 1-2--where Y equals oxygen or sulfur, SO, SO2, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded to the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, or an O(CH2)~2-O- chain, 20 R(6) is H, (C1-C15)-alkyl, (C2-C~5)-alkenyl, Y-( C,-C,5)-alkyl, Y-(C2-C~5)-alkenyl, phenyl, Y-phenyl, 207~
benzyl, biphenylyl, F, C.l, Br, I, C~F2~t1 (where a equals 1 - 8), CCl3, naphthyl, YH, X is oxygen or sulfur, R(7) is (Cl-C12J-alkyl, (C3-C12)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, naph-thyl, phenyl, thienyl, pyridyl, the aromatic and heteroaromatic ring systems mentioned being unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, (C1-C1B)-alkyl, (C1-C18)-alkoxy, (C2-C1a)-alkenyloxy, CF3, C2F5~ CN, (C1-C18)-alkylthio.
Preferred compounds of the formula I are those in which 15 R( 1 ) is H, (Cl-C6) -alkyl, benzyl, [unsubstituted or monosubstituted or disubstituted by F, Cl, Br, CF3 , ( cl-c4 ) -alkyl ~ OCH3 , O-phenyl or phenyl], C(O)-(C1-C3)-alkyl, C(O)-phenyl R(2) is H, ( Cl-Cl9 ) -alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-oxy-phenyl, (C2-Cl~)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or disubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubstituted by substituents selected from the group comprising F, Cl, Br, (C1-C1O)-alkyl, (C3-C10)-cycloalkyl, (Cl-C10)-alkoxy, (Cl-C4)-alkylenedioxy, (Cl-C4)-alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, ~ 207~57 or R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by Cl, (C1-C4)-alkyl, O( Cl-C4 ) -alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or A is (Cl-Cl3)-alkyl, (C2-C16)-alkenyl or a group R ( 4 ) ~, /= ' R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (Cl-C16)-alkyl, tc3-cl6)-alkenyl~ (C3~cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C16)-alkyl, Y-(C3-Cl6)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi- or multicyclic)~ phenyl, Y -p he ny l, ph eny l - (Cl- C 6 ) - al ky l, 2 ~ 7 ~ 7 phenyl-( C~-C4 ) -alkoxy, biphenylyl, F, Cl, CF3, naphthyl, CN, the phenyl systems being unsubsti-tuted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, ( Cl-C4 ) -alkoxy, -O-(CH2)1-2--, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded on the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2) r chain where r equals 3 or 4, R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl, CF3, X is oxygen or sulfur, R(7) is (C~-C12)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-or multicyclic, such a~ norbornyl or adamantyl), (C3-C~2)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl,phenyl, thienyl, the aromatic ring systems mentioned and the heteroaromatic ring 6ystem mentioned being unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, (C,-C1B)-alkyl, (C1-C1B)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, (C1-C1a)-alkylthio.
Particularly preferred compounds of the formula I are those in which R(l) is H, C(O)-(C1-C4)-alkyl, C(O)-phenyl R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-(C~-C6)-alkyl, (C~-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-2~780~7 oxy-phenyl, (C2-Cls)-alkenyl, (C3-Cl2)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(Cl-C6)-alkyl, diphenyl-(Cl-C6)-alkyl, phenyl, the phenyl systems being unsub~tituted or monosubstituted or disubstituted by substituents selected from the group comprising F, Cl, (Cl-C6)-alkyl, (C3-C6)-cycloalkyl,(Cl-C~O)-alkoxy,(Cl-C4)-alkylenedioxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or thien-ylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is (Cl-Cl8)-alkyl, (C2-ClB)-alkenyl or a group R ( 4 ) ,~
R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
207~7 g R(4) is H, (Cl-Cl2)-alkyl, (C3-Cl2)-alkenyl, (C3~Cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-(Cl-Cl2)-alkyl, Y-(c3-cl2)-alkenyll Y-(C3-C~2)-cycloalkyl (mono-, bi- or multicyclic), phenyl, Y-phenyl, phenyl-(Cl-C6)-alkyl, phenyl-(Cl-C4)-alkoxy, biphenylyl, F, Cl, CF3, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C,-C4)-alkyl, (Cl-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) i 6 defined as R(4), R(4) and R(5) being identical or different, or R(6) is ~ ( Cl-C4 ) -alkyl, Y-( Cl-c4 ) -alkyl, F, Cl, X is oxygen or sulfur, R(7) is (Cl-C~O)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-yl, phenyl-methyl-phenyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, (Cl-C4)-alkyl, (Cl-C4)-alkoxy, CF3, ( C~-C4 ) -alkylthio.
Very particularly preferred compounds of the formula I
are those in which 25 R(l) is H, R(2) is H, (C,-C,5)-alkyl, (C,-C6)-alkyl-oxy-(C,-C6)-alkyl, (C,-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-oxy-phenyl, (C3-Cl2)-alkenyl, (c3-clo)-cycloalk (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(Cl-C4)-2078a~7 alkyl, diphenyl-(Cl-C6)-alkyl, the phenyl systems being unsubstituted or monosubstituted or disub-stituted by substituents selected from the group comprising F, Cl, (C,-C6)-alkyl, (C3-C6)-cycloal-kyl, (C1-C1O)-alkoxy, (C1-Cz)-alkylenedioxy~
phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thien-ylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is a group R ~ 4 ) ,~, R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
2 ~ 7 ~ 7 R(4) is H~ (Cl-Cl2)-alkyl~ (C3-C12)-alkenyl, ~C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(Cl-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-~C3-cl2) cycloalkyl (mono-, bi- or multicycliC), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-~Cl-C4)-alkoxy, F, Cl, the phenyl systems being unsubsti-tuted or monosubstitutecl or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y ecluals oxygen or sulfur, 0 R(5) is defined as R(4), R(4) and R(5) being identical or different, R(6) is H, (C1-C4)-alkyl, Y-( C~-C4 ) -alkyl, X is oxygen, R(7) is (C,-C4)-alkyl, (C3-Cl2)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-yl, phenyl, the aromatic ring 6ystems mentioned being unsubstituted or monosubstituted or disub-stituted by F, Cl, (Cl-C4)-alkyl, (Cl-C4)-alkoxy, CF3, ( C~-C4 ) -alkylthio.
Racemates can be resolved into the enantiomers by custom-ary 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. Moreover, the enantiomers can also be resolved by means of chromatography on chiral phases or enzymatically.
The invention furthermore relates to a process for the preparation of compounds of the formula (I), which comprises reacting a compound of the formula (II) 2078~7 // (II) A - X - CH2 -'~
R ( 7 ) in which R(7), A and x have the meanings mentioned, with a sulfur ylide of the formula III
(H3C)2S = CHi~
ll (III) (O)p in which p is zero or 1, to give a compound of the formula IV
A - X - CH2 V R ( 7 ) (IV), and subsequently reacting the compound IV with a nucleophile of the formula M~R(2)R(3) in which R(2) and R(3) have the meanings mentioned and M i8 hydrogen or a metal equivalent, giving a compound I where R(1) = H, which is isolated in the form of the free base, of an acid addition salt or of a physiologically hydrolyzable derivative.
2a78~
To prepare the compounds of the formula (I), a ketone of the formula (II) in which R(7), .A and X have the above-mentioned meanings is reacted, in a first reaction step for the preparation of the compou,nds of the formula (IV), with a sulfur ylide of the formula (III) in an inert solvent, preferably dimethyl sulfoxide or tetrahydrofur-an, or in mixtures of dimethyl sulfoxide with other inert solvents, for example tetrahydrofuran. A temperature range of from -10 to 50C, preferably from 0 to 30C, is expedient if a sulfur ylide of the formula (III) is used where p = zero; if a sulfur ylide of the form-ula (III) is used where p = 1, then a temperature range of from 0 to 80C, preferably from 20 to 60C, is expedient.
The intermediates of the formula IV are converted into the end products of the formula I where R(1) = H in a second reaction step by reaction with a compound of the formula MNR(2)R(3) in which R(2), R(3) and M have the abovementioned meanings.
This reaction is effected in a temperature range of from 20 - 160C, if appropriate in an inert solvent.
Examples of suitable solvents are N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetoni-trile, 4-methyl-2-pentanone, methanol, ethanol, isopropyl alcohol, propanol, butanol, pentanol, tert-butyl alcohol, methyl glycol, methylene chloride or an aromatic hydro-carbon such as benzene, chlorobenzene, nitrobenzene, toluene or xylene, or water. Mixtures of the solvents which have been mentioned by way of example can also be used.
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 their reaction with compounds of the 2078~.57 formula MNR(2)R(3) to give compounds of the formula I
where R(l) = H can also be carried out in the form of a one-pot process.
To this end, a solution of a compound of the formula IV
in one of the abovementioned inert solvents is first prepared as indicated above by reacting a compound of the formula II with a compound of the formula III. At least an equivalent amount of a compound of the formula HNR(2)R(3) is subsequently added to this solution.
Compounds of the formula I in which R(l) has the meanings mentioned and is not hydrogen, are prepared by reacting a compound of the formula where R(l) = H with a corresponding alkyl halide, alkenyl halide or henzyl halide, preferably a chloride, bromide or a tosylate or mesylate, in the presence of a base, in an inert solvent, in a temperature range of from 0 - 100C. The solvents used are preferably those which are indicated for the reaction of compounds of the formula IV with M-NR(2)R(3), and bases which are suitable are, for example, inorganic bases such as carbonates, hydrogen carbonates, hydrox-ides, alcoholates or hydrides of alkali metals or alkal-ine earth metals, for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydrox-ide, sodium methylate or sodium hydride, or organic bases such as tert-amines, such as triethylamine, ethylmor-pholine or, for example, DBU, imidazole or pyridine.
Compounds of the formula I in which R(l) has the meaning of C(0)-(Cl-C8)-alkyl or -C(0)-phenyl are prepared by reacting a compound of the formula I where R(l) equals H
with a compound of the formula Va or Vb R(l)-Q R(l)-0-R(l) Va Vb 2078~)~7 where Q equals hydroxyl, halogen, such as chlorine or bromine, or an imidazolide. To do so, a procedure is best followed in which equimolar amountg or an up to 50-fold excess of a compound of the formula I where R(l) equals H, if appropriate in an inert, aprotic solvent such as chloroform, dichloromethane, tetrahydrofuran (THF) or dioxane, are reacted with a compound of the formula Va until the reaction is complete, if appropriate in the presence of a base, preferably pyridine or triethylamine. If a compound of the formula Va where Q equals OH is employed, then it is recommended that dicyclohexylcarbodiimide (DCC), if appropriate in the presence of a catalyst such as N,N-dimethylaminopyridine (DMAP) is added. If Vb tan acid anhydride) is used, R(l)-O-R(1) Vb then the process can be carried out without or with a catalyst such as DMAP or 4-pyrrolidinopyridine (PPY). The reaction temperatures here are between -70C and +120C, preferably, if a solvent is used, between the melting point and the boiling point of the solvent, in particular between -30 and +60C. The reaction times are 1 to 180 hours, preferably 1 to 48 hours, particularly prefer-ably 1 to 8 hours.
Compounds of the formula I which contain a thioether group can be oxidized on the sulfur to give a sulfoxide or sulfone. To this end, such compounds of the formula I
are reacted in an inert solvent and in a temperature range of from -10 to 80C with an oxidant, for example hydrogen peroxide or m-chloroperbenzoic acid. To prepare sulfoxides, one mole equivalent of oxidant is employed for this purpose, and for the preparation of sulfones two mole equivalents, or, if appropriate, an excess.
2378a~7 Solvents which are preferably uied are tho~e indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
The invention furthermore relates to a process for the preparation of the compounds of the formula I, in which a compound of the formula II
ll (II) A-X-CH2-C-R(7) in which R(7), X and A have the meanings mentioned, is reacted with a phosphorus ylide to give a compound of the formula VI
A - X - CH2 - ~ (VI) R ( 7 ) and the compound VI is subsequently reacted with a peroxide to give a compound of the formula IV
A - X - CH2 V R ( 7 ) (IV) and IV is reacted further as already mentioned above with a nucleophile of the formula M-NR(2)R(3) in which R(2) and R(3) have the meanings mentioned and M is hydrogen or a metal equivalent, giving a compound I where R(1) equals 207~57 hydrogen, and, if desired, this compound I is alkylated, alkenylated, benzylated or esterified and, if appropriate, oxidized on the sulfur of a thioether group to give the sulfoxide or sulfone, and, if appropriate, the product iB converted into the salt with a physiologically acceptable acid, or into a physiologically hydrolyzable derivative.
To prepare the compound~ of the formula I, a ketone of the formula II in which A, X and R(7) have the abovementioned meanings i8 reacted, in a first reaction step to prepare compounds of the formula V, with a phosphorus ylide in an inert solvent at a temperature of from -60 to +80C.
The phosphorus ylide used here is prepared by reacting a methyltriarylphosphonium salt, preferably methyltriphenylphosphonium chloride, methyltriphenyl-phosphonium bromide or methyltriphenylphosphonium iodide, with a strong base in an inert solvent. Examples of suitable bases are alkali metal hydrides, alkali metal amides, alkali metal alcoholates, alkaline earth metal hydrides, alkaline earth metal amides or alkaline earth metal alcoholates, sodium bistrimethylsilylamide or lithium organyls such as n-butyllithium or phenyllithium.
The solvents used are those indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
In a second reaction step for the preparation of com-pounds of the formula IV, a compound of the formula VI is reacted with an oxidant in an inert solvent at a tempera-ture of from -10 to +80C, if appropriate in the presence of a base and of a nitrile, for example benzonitrile, or thionylbisimidazole or -triazole.
Examples of suitable oxidants are HzO2 or percarboxylic acids such as, for example, peracetic acid, trifluoroper-2~78a~r~
acetic acid, perbenzoic acid or m-chloroperbenzoiC acid.
The solvents used are those indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
In a third reaction step for the preparation of compounds of the formula I where R(1) c ~I from compounds of the formula IV, the procedure is as indicated in the process above.
These compounds of the formula I where R(1) ~ H can, if desired, be alkylated, alkenylated, benzylated or esteri-fied and oxidized to give compounds where R(1) isnot equal to H, and, if appropriate, converted with a physiologically acceptable acid into the salt as indicated in the process above.
Preparation of the starting substances The preparation of compounds of the formula II i8 known from the literature. For example, an ~-haloketone of the formula VII:
,1~
¦ R(7) (VII) Hsl is reacted with a phenol or thiophenol in an inert solvent such as acetone, using a base (for example X2CO3).
Examples of suitable bases are carbonates, hydrogen carbonates, hydroxides or hydrides of alkali metals or alkaline earth metals such as, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbon-ate, sodium hydroxide or sodium hydride.
2078~7 The compounds of the formula VII are either commercially available or can be synthesized by halogenating the corresponding aryl methyl ketones by processes known from the literature.
The compounds of the formula I, their acid addition salts and their physiologically hydrolyzable derivatives are valuable pharmaceuticals. They have, in particular, an antimicrobial action and are suitable for preventing and treating fungal infections in humans and in various mammalian specie6.
The invention also relates to the preparation and the use of the compounds of the type I in the form of the free bases or of an acid addition salt as potent inhibitors of the exoenzymes of fungi, or as antimycotics.
Examples of pharmaceutically acceptable salt-forming acids are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, ~ulfuric acid, phos-phoric acid or nitric acid, or organic acids such as malonic acid, oxalic acid, gluconic acid, camphorsulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, p-toluenesulfonic acid or salicylic acid.
The compounds I have at least one asymmetrical C atom and can therefore exist in the form of enantiomers and diastereomers. The invention embraces the preparation and the use of the pure isomers as well as their mixtures.
Mixtures of diastereomers can be resolved into the components by customary methods, for example by selective crystallization from suitable solvents or by chromato-graphy on silica gel or aluminum oxide.
The compounds of the formula I, their acid addition salts and their physiologically hydrolyzable derivatives are valuable pharmaceuticals. They have, in particular, an antimicrobial action and are suitable for preventing and 2~781~
treating fungal infections in humans and in various mammallan specles.
The compounds have a very good in vitro activity against dermatomycetes such as, for example, Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum; against molds such as, for example, Aspergillus niger, or against yeasts such as, for example, Candida albicans, C. tropicalis, Torulopsis glabrata and Trichosporon cutanuem or against Protozoa such as Trichomonas vaginalis or T. fetus, or else against Gram-positive and Gram-negative bacteria.
After oral or parenteral administration, the compounds also have a very good systemic effect in vitro, for example against Candida albicans, for example in experi-mental renal candidosis in mice. In this case, in parti-cular the exoenzyme system of the yeast Candida albicans is affected in such a way that the pathogenicity of the pathogens is markedly reduced. There is also a very good effect against various pathogens of dermatomycoses (for example Trichophyton mentagrophytes) in guinea-pigs after oral, parenteral or local administration.
- Examples of indication areas in human medicine which may be mentioned are: dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporon species, Epidermophyton floccosum, and biphasic fungi, as well as molds.
In particular, deep mycoses caused by Candida albicans are affected favorably since penetration of the fungi into the host cell is prevented or hindered.
Examples of indication areas in veterinary medicine which - may be mentioned are:
2~78~7 All dermatomycoses and systemic mycoses, in particular those caused by the abovementioned pathogens.
The present invention includes pharmaceutical prepara-tions which contain one or more active ~ubstances in addition to non-toxic, inert pharmaceutically suitable carriers, or which are composed of one or more active substances used according to the invention, and processe~
for manufacturing these preparations.
Non-toxic, ~nert pharmaceutically suitable carriers are to be understood as meaning solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any type.
An inhibitor for the various phospholipases of Candida albicans must be present in adequate concentrations in the patient in all regions where the fungus can colonize the parenchyma. A precondition for this is the fact that the appropriate substances must be administered in a concentration which has previously proven effective in animal experiments.
When patients show severe symptoms of deep candidosis, they are frequently in a very poor general state. ~igh temperature and other diseases can frequently be found.
When deciding on the dosage rate, a difference must be made between prophylactic administration and therapy in the case where an infection has been established. In prophylaxis, it can be assumed that the general state of the patients is better, which allows oral administration.
Tablets, solutions, gels or inspissated juice can be used. In forms where deep candidoses have been estab-lished, it must frequently be assumed that controlledoral resorption of the active substances is not always guaranteed. In this case, parenteral administration forms are suitable. In exceptional cases, subcutaneous administration may also be considered.
207~a57 Candidates for prophylaxis are mainly immunocompressed patients who are in this situation due to strain caused by medicaments or due to endogenous immunity problems.
These are, in particular, transplant patients, diabetics and/or patients suffering from adiposis, AIDS patients, patients under chemotherapy, long-term ventilation patients, and others.
Some of the compounds inhibit the phospholipase of Candida albicans to an extent which is far below the minimum inhibitory concentrations of the active substanc-es to Candida albicans which have been determined in vitro. The dosage rate can therefore in many cases be below the rate which would be necessary for a purely antimycotic therapy.
The action within the patient is based on the fact that the active substances have two different effects on the Candida cells in the vicinity of the parenchyms. On the one hand, adhesion of the yeast cells to the somatic cells is prevented and, on the other hand, Candida albicans is prevented from penetrating the somatic cells with germination tubes.
This dual concept of action prevents the yeast from fully exploiting its pathogenicity. However, it must be men-tioned that in addition to the phospholipases Candida albicans also has other pathogenicity mechanisms such as, for example, the protease. Adhesion to endogenous cells is, however, the first step towards penetration. Since this adhesion is prevented by phospholipase inhibitors, the other pathogenicity mechanisms cannot be utilized fully.
Suitable formulations are, for example, tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile solutions for injec-tion, non-aqueous emulsions, suspensions and solutions, 2~7~.57 ointments, creams, pastes, lotions, gprays etc.
The abovementioned pharmaceutical preparations should contain the prophylactically ancl therapeutiCallY active compounds preferably in a concentration of about 0.1 to 99.5, preferably approximately 0.5 to 95, % by weight of the total mixture.
The abovementioned pharmaceutical preparations can also contain other pharmaceutical active substances in addi-tion to the active substances used according to the lQ invention.
The abovementioned pharmaceutical preparations are prepared in the customary manner by known methods, for example by mixing the active substance, or active sub-stances, with the carrier, or carriers.
The present invention includes the use of the active substances according to the invention and the pharmaceut-ical preparations which contain one or more active substances according to the invention in human and veterinary medicine for preventing, alleviating and/or curing the abovementioned diseases.
The active substances or the pharmaceutical preparations can be aclministered locally, orally, parenterally, intraparenterally and/or rectally.
In general, it has proved advantageous in both human and veterinary medicine to administer the active substance, or active substances, used according to the invention in total amounts of from at least about 0.05, preferably 0.1, in particular 0.5, mg/kg of body weight up to not more than about 200, preferably up to 100, in particular up to 10, mg/kg of body weight per 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. The total amount is 2~78~.~7 administered in 1 to 8, preferabLy in 1 to 3, individual doses, but over considerably longer period~ (up to 6 weeks) in the case of deep mycoses.
However, it may be necessary to deviate from the dosage rates mentioned, namely as a function of the species and the body weight of the subject to be treated, the nature and severity of the disea~e, the nature of the prepara-tion and administration of the pharmaceutical, and the period or interval within which the administration is effected. Thus, in some cases it may suffice to make do with less than the abovementioned amount of active -- substance, while in other cases the abovementioned amount of active substance must be exceeded. The decision with regard to optimum dosage rate and type of application of the active substances which are necessary in each case can be made easily by anyone skilled in the art due to his expert knowledge.
Example 1 Synthesisof2-t-butyl-1-(2,4-dichlorophenoxy)-3-isoprop-yl-amino-2-propanol (I.7) C i o Cl ~~ V~ (CH~)~5 (O) I, NaH ~~
/~ ! DVSO, 25 'C ~J
I . 7 IV.7 ClOH
isopropylamine o ~ NH
ethanol, H20 Cl l 7 (2 steps) 2~78i~.57 a) Preparation of the oxirane :rv. 7 1.5 g of trimethylsulfoxonium iodide (6.8 mmol) are dissolved in 30 ml of ab~olute ~MSO, 0.195 g (6.5 mmol) of sodium hydride ~80 % suspens:ion in mineral oil) are added, and the mixture iB stirred until the evolution of gas has ceased (approx. 30 minutes). 1.51 g (5.8 mmol) of 1-(2,4-dichlorophenoxy)-~,3-dimethyl-2-butanone~ di~-solved in 5 mi of absolute DMSO, are subsequently added at 25C, and the reaction mixture is stirred for 1 hour at 25C and for 2 hours at 40C.
For work-up, the reaction mixture is poured into water (400 ml), and the aqueous phase i9 extracted four times using 100 ml portions of dichloromethane. The combined organic phases are washed four times with 100 ml portions of water and dried over Na2SO4, the drying agent is filtered off, and the mixture is concentrated on a rotary evaporator under reduced pressure.
Yield: 1.24 g (78 %, 4.5 mmol, colorless oil).
The crude product is reacted directly, without further purification steps.
b) Reaction with isopropylamine 1 g of the oxirane prepared under a) t3.63 mmol) are dissolved in 30 ml of ethanol, and 6.38 ml (4.43 g, 75 mmol) of isopropylamine and l ml of water are added.
The reaction mixture is refluxed for 12 hours. The course of the reaction is monitored by thin-layer chromatography (silica gel plates, mobile phase: dichloromethane/ethyl acetate = 1/1).
For work-up, the solvent is removed on a rotary evaporat-or under reduced pressure, and the crude product obtained is chromatographed over silica gel (Silica Gel 60, manufactured by Merck 0.043 - 0.060 mm, mobile phase:
CH2Cl2/methanol z 19/1).
2~78~7 Yield: 0.972 g (2.9 mmol, 80 % of theory), colorless oil.
RF (CHzCl2/ethyl acetate = 1:1 silica gel glass plates) = 0.18.
Example 2 Synthesis of 3-N-benzylamino-2-t-butyl-l-(4-hept phenyloxy)-2-propanol (I.l9) (2 steps) C H 3 - ( C H 2 ) 6 - ~ ~( C H ~ S ( O ) I
I I .19 7 benzylamine CH~-(CH2)6-0 ~ ~ l20C
IV.l9 O H
CH3- ( CH~ ) 6- ~ O ~NH,J3 I . 19 2~78~57 a) Preparation of the oxirane IV.l9 7.37 g (33.5 mmol) of trimethylsulfoxonium iodide are introduced into 150 ml of absolute tetrahydrofuran, and 0.88 g (29 mmol) of sodium hydride (80 % ~uspension in paraffin oil) i8 added in portion6 under an N2 protective gas atmosphere. To deprotonate the mixture completely, it is refluxed for 2 hours, with stirring. 7.67 g (25 mol) of 3~3-dimethyl-l-(4-heptyloxy-phenyloxy)-2-butanone~
dissolved in 40 ml of absolute THF, are subseguently added, and the reaction solution i~ heated for 6 hours at 40C.
For work-up, the reaction mixture is poured into 400 ml of ice-water, and, after phase separation, the aqueous phase is extracted using 4 x 100 ml of ethyl acetate. The combined organic phases are washed with 4 x 100 ml of water and dried over Na2S04. After the drying agent has been removed by filtration, the solvent is removed under reduced pressure.
According to lH NMR spectra, the yellow solid residue has the structure indicated and a purity of approx. 96 %.
Yield 6.9 g (87 ~), yellow solid RF (silica gel glass plates, mobile phase CH2Cl2): 0.42 b) Reaction of the oxirane IV.19 with benzylamine 1 g (3.14 mmol) of the oxirane from a) is dissolved in 6 ml of benzylamine and heated for 2 hours at 120C.
After most of the benzylamine has been removed by means of bulb tube distillation under an oil pump vacuum (0.1 mbar), the product is chromatographed over a silica gel column (mobile phase: CH2Cl2/MeOH = 40:1).
The reaction product is subsequently recrystallized from heptane.
2 0 7 ~
Yield: 1.002 g (2.3 mmol, 75 ~) Melting point: 52C
Other compounds of the formula I where R(l) - H which were prepared analogously to Examples 1 and 2, but using corresponding compounds of the formula IV and MNR(2)R(3), are those listed in Table 1. ExampleQ 1 and 2 are con-tained in ~able 1 under I.7 and I.l9.
2~78~7 M.p.: oil OH CH, EA: calc . f ound:
Cl--~3 ~`'~ CH3 C 66.06% C 6 5 0 H 8.99% H8 9 J Cl 11.30%
N 4.46% N4 . 5 O 10.19%
H C
M . p .: oil OH CH3 EA: calc .: f ound :
--CH3 C 684 79% 8 8 HN Cl 11.82%
N 4 67% 4 . 8 O 1067%
H3C\ CH3 M.p.: oil OH CH, EA: calc .: f ound :
Description Substituted aminopropanes, proco~ses for their prepara-tion, and their use The invention relates to ~ubstituted ~;nopropane~ of the formula I, to processes for th~ir preparation, and to pharmaceutical compositions containing ~uch compounds, and to their use a8 pharmaceuticals, in particular as growth inhibitors of the pathogenic pha~e of dimorphic yeast cells and as anti-ycoties, it being poesible for the compound~ according to the invention to be u~ed in prophylaxis as well a~ in therapy.
German Offenlegungsschrift DE 3,330,005 Al mentions compounds of the formula A
R ( 3 )~ R ( ~ ) R ( 2 ) ~ C ~ ( CH2 ) n ~ CH
\ N ~ R ( S ) R ( 1 )R ( 6 ) In this Offenlegungsschrift, R(3) i~ generally defined as aryl, alkyl or cycloalkyl, it being possible for each of these radicals to be substituted, and hydrogen. ~owever, nothing iB mentioned in the description and in the examples about compounds where R(3) is aryl, alkyl or cycloalkyl, and only tartaric acid derivatives of those compounds in which R(3) is hydrogen are described.
In contrast, compounds of the formula I in which the amine component has aliphatic, cycloaliphatic or aromatic radicals and the substituent R(7) in formula I is simul-taneously a group bonded via carbon, as well as the use 2078~
of such compounds as inhibitors of the exoenzymes (fac-tors of pathogenicity) of fungi and as antimycotics, are as yet unknown.
The invention therefore relates to substituted aminoprop-anes of the formula I
o ( R I ) ~ R ( 2 ) - X - C ~ ~ - C -- C ~
( 7 ~ R ( 3 ) to their preparation and to their use as antimycotics as well as growth inhibitors of the pathogenic phase of dimorphic yeast cells. The compounds can therefore be used for the prophylaxis and treatment of fungal dis-eases. The invention furthermore relates to pharmaceuti-cal preparations containing these compounds and to their salts with pharmaceutically acceptable acids and to their physiologically hydrolyzable derivatives.
Unless specifically mentioned otherwise, alkyl, alkoxy, alkylthio, alkylene and alkenyl groups in any form are straight-chain or branched; alkenyl chains are monoun-saturated or polyunsaturated. Aryl is phenyl or naphthyl.
However, phenanthryl, fluorenyl and anthracenyl can also act as aryl radicals.
In formula I:
R(1) is H, (Cl-Cl0)-alkyl, (C2-Cl0)-alkenyl, benzyl, [unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl or phenyl], C(O)-(Cl-C3)-alkyl, C(O)-phenyl 2~78a~7 R(2) is H, (cl-cla)-alkyll ~C1-C6)-alkyl-oxy-(C1-c8) alkyl, (cl-c6)-alkyl-thio-phen (C1-C6)-alkyl-oxy-phenyl, (c2-c~s)-alkenyll (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaPhthyl), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or di~ubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubsti-tuted by substituents selected from the group comprising F, Cl, Br, (Cl-Cl0)-alkyl~ (C3-C10)-cycloalkyl, OH, SH, (C,-C10)-alkoxy, (C1-C4)-alkylenedioxy, (C1-C~0)-alkylthio, dimethylamino-ethoxy, ( Cl-C4 ) -alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, C~F2~, (where a equals 1 - 6), or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by F, Cl, (C1-C4)-alkyl, O( Cl-C4 ) -alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or R(2) together with R(3) forms a chain -(CH2)~- where m equals 4 - 6 and in which a CH2 group can be replaced by oxygen or sulfur, A is (C1-C18)-alkyl, (c2-cl8)-alkenyl or a group 2078~5~
R ( 4 ) ,~, R(5) R ( 6 ) in which the radicals R(4), R(5) Pnd R(6) have the following meaning:
R(4) is H, ( C1-C1B ) -alkyl, (c2-cl8)-alkenyl/ (C3-C20)~
cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C20)-alkyl, Y-(C2-ClB)-alkenyl, Y-(C3-C20)-cycloalkyl (mono-, bi- or multicyclic), phenyl, Y-phenyl, phenyl-(C~-C~)-alkyl, phenyl-( C~-C4 ) -alkoxy, biphenylyl, F, Cl, Br, C~F2~t~ (where a equals 1 to 8), CC13, YH, naphthyl, CN, NO2, the phenyl systems being unsubstituted or monosubsti-tuted or disubstituted by F, Cl, CF3, ( C~-C4 ) -alkyl, ( C~-c4 ) -alkoxy, CN, -O-(CH2) 1-2--where Y equals oxygen or sulfur, SO, SO2, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded to the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, or an O(CH2)~2-O- chain, 20 R(6) is H, (C1-C15)-alkyl, (C2-C~5)-alkenyl, Y-( C,-C,5)-alkyl, Y-(C2-C~5)-alkenyl, phenyl, Y-phenyl, 207~
benzyl, biphenylyl, F, C.l, Br, I, C~F2~t1 (where a equals 1 - 8), CCl3, naphthyl, YH, X is oxygen or sulfur, R(7) is (Cl-C12J-alkyl, (C3-C12)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, naph-thyl, phenyl, thienyl, pyridyl, the aromatic and heteroaromatic ring systems mentioned being unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, (C1-C1B)-alkyl, (C1-C18)-alkoxy, (C2-C1a)-alkenyloxy, CF3, C2F5~ CN, (C1-C18)-alkylthio.
Preferred compounds of the formula I are those in which 15 R( 1 ) is H, (Cl-C6) -alkyl, benzyl, [unsubstituted or monosubstituted or disubstituted by F, Cl, Br, CF3 , ( cl-c4 ) -alkyl ~ OCH3 , O-phenyl or phenyl], C(O)-(C1-C3)-alkyl, C(O)-phenyl R(2) is H, ( Cl-Cl9 ) -alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-oxy-phenyl, (C2-Cl~)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or disubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubstituted by substituents selected from the group comprising F, Cl, Br, (C1-C1O)-alkyl, (C3-C10)-cycloalkyl, (Cl-C10)-alkoxy, (Cl-C4)-alkylenedioxy, (Cl-C4)-alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, ~ 207~57 or R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by Cl, (C1-C4)-alkyl, O( Cl-C4 ) -alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or A is (Cl-Cl3)-alkyl, (C2-C16)-alkenyl or a group R ( 4 ) ~, /= ' R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (Cl-C16)-alkyl, tc3-cl6)-alkenyl~ (C3~cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C16)-alkyl, Y-(C3-Cl6)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi- or multicyclic)~ phenyl, Y -p he ny l, ph eny l - (Cl- C 6 ) - al ky l, 2 ~ 7 ~ 7 phenyl-( C~-C4 ) -alkoxy, biphenylyl, F, Cl, CF3, naphthyl, CN, the phenyl systems being unsubsti-tuted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, ( Cl-C4 ) -alkoxy, -O-(CH2)1-2--, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded on the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2) r chain where r equals 3 or 4, R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl, CF3, X is oxygen or sulfur, R(7) is (C~-C12)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-or multicyclic, such a~ norbornyl or adamantyl), (C3-C~2)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl,phenyl, thienyl, the aromatic ring systems mentioned and the heteroaromatic ring 6ystem mentioned being unsubstituted or monosubstituted or polysubsti-tuted by F, Cl, Br, (C,-C1B)-alkyl, (C1-C1B)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, (C1-C1a)-alkylthio.
Particularly preferred compounds of the formula I are those in which R(l) is H, C(O)-(C1-C4)-alkyl, C(O)-phenyl R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-(C~-C6)-alkyl, (C~-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-2~780~7 oxy-phenyl, (C2-Cls)-alkenyl, (C3-Cl2)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(Cl-C6)-alkyl, diphenyl-(Cl-C6)-alkyl, phenyl, the phenyl systems being unsub~tituted or monosubstituted or disubstituted by substituents selected from the group comprising F, Cl, (Cl-C6)-alkyl, (C3-C6)-cycloalkyl,(Cl-C~O)-alkoxy,(Cl-C4)-alkylenedioxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(Cl-C4)-alkyl, thienyl or thien-ylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is (Cl-Cl8)-alkyl, (C2-ClB)-alkenyl or a group R ( 4 ) ,~
R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
207~7 g R(4) is H, (Cl-Cl2)-alkyl, (C3-Cl2)-alkenyl, (C3~Cl2)~
cycloalkyl (mono-, bi- or multicyclic), Y-(Cl-Cl2)-alkyl, Y-(c3-cl2)-alkenyll Y-(C3-C~2)-cycloalkyl (mono-, bi- or multicyclic), phenyl, Y-phenyl, phenyl-(Cl-C6)-alkyl, phenyl-(Cl-C4)-alkoxy, biphenylyl, F, Cl, CF3, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C,-C4)-alkyl, (Cl-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) i 6 defined as R(4), R(4) and R(5) being identical or different, or R(6) is ~ ( Cl-C4 ) -alkyl, Y-( Cl-c4 ) -alkyl, F, Cl, X is oxygen or sulfur, R(7) is (Cl-C~O)-alkyl, (C3-C~2)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-yl, phenyl-methyl-phenyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, (Cl-C4)-alkyl, (Cl-C4)-alkoxy, CF3, ( C~-C4 ) -alkylthio.
Very particularly preferred compounds of the formula I
are those in which 25 R(l) is H, R(2) is H, (C,-C,5)-alkyl, (C,-C6)-alkyl-oxy-(C,-C6)-alkyl, (C,-C6)-alkyl-thio-phenyl, (Cl-C6)-alkyl-oxy-phenyl, (C3-Cl2)-alkenyl, (c3-clo)-cycloalk (mono-, bi- or multicyclic, such as norbornyl, adamantyl, decahydronaphthyl), phenyl-(Cl-C4)-2078a~7 alkyl, diphenyl-(Cl-C6)-alkyl, the phenyl systems being unsubstituted or monosubstituted or disub-stituted by substituents selected from the group comprising F, Cl, (C,-C6)-alkyl, (C3-C6)-cycloal-kyl, (C1-C1O)-alkoxy, (C1-Cz)-alkylenedioxy~
phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thien-ylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is a group R ~ 4 ) ,~, R(5) R ( 6 ) in which the radicals R(4), R(5) and R(6) have the following meaning:
2 ~ 7 ~ 7 R(4) is H~ (Cl-Cl2)-alkyl~ (C3-C12)-alkenyl, ~C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(Cl-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-~C3-cl2) cycloalkyl (mono-, bi- or multicycliC), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-~Cl-C4)-alkoxy, F, Cl, the phenyl systems being unsubsti-tuted or monosubstitutecl or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y ecluals oxygen or sulfur, 0 R(5) is defined as R(4), R(4) and R(5) being identical or different, R(6) is H, (C1-C4)-alkyl, Y-( C~-C4 ) -alkyl, X is oxygen, R(7) is (C,-C4)-alkyl, (C3-Cl2)-cycloalkyl (mono-, bi-or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenyl-yl, phenyl, the aromatic ring 6ystems mentioned being unsubstituted or monosubstituted or disub-stituted by F, Cl, (Cl-C4)-alkyl, (Cl-C4)-alkoxy, CF3, ( C~-C4 ) -alkylthio.
Racemates can be resolved into the enantiomers by custom-ary 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. Moreover, the enantiomers can also be resolved by means of chromatography on chiral phases or enzymatically.
The invention furthermore relates to a process for the preparation of compounds of the formula (I), which comprises reacting a compound of the formula (II) 2078~7 // (II) A - X - CH2 -'~
R ( 7 ) in which R(7), A and x have the meanings mentioned, with a sulfur ylide of the formula III
(H3C)2S = CHi~
ll (III) (O)p in which p is zero or 1, to give a compound of the formula IV
A - X - CH2 V R ( 7 ) (IV), and subsequently reacting the compound IV with a nucleophile of the formula M~R(2)R(3) in which R(2) and R(3) have the meanings mentioned and M i8 hydrogen or a metal equivalent, giving a compound I where R(1) = H, which is isolated in the form of the free base, of an acid addition salt or of a physiologically hydrolyzable derivative.
2a78~
To prepare the compounds of the formula (I), a ketone of the formula (II) in which R(7), .A and X have the above-mentioned meanings is reacted, in a first reaction step for the preparation of the compou,nds of the formula (IV), with a sulfur ylide of the formula (III) in an inert solvent, preferably dimethyl sulfoxide or tetrahydrofur-an, or in mixtures of dimethyl sulfoxide with other inert solvents, for example tetrahydrofuran. A temperature range of from -10 to 50C, preferably from 0 to 30C, is expedient if a sulfur ylide of the formula (III) is used where p = zero; if a sulfur ylide of the form-ula (III) is used where p = 1, then a temperature range of from 0 to 80C, preferably from 20 to 60C, is expedient.
The intermediates of the formula IV are converted into the end products of the formula I where R(1) = H in a second reaction step by reaction with a compound of the formula MNR(2)R(3) in which R(2), R(3) and M have the abovementioned meanings.
This reaction is effected in a temperature range of from 20 - 160C, if appropriate in an inert solvent.
Examples of suitable solvents are N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetoni-trile, 4-methyl-2-pentanone, methanol, ethanol, isopropyl alcohol, propanol, butanol, pentanol, tert-butyl alcohol, methyl glycol, methylene chloride or an aromatic hydro-carbon such as benzene, chlorobenzene, nitrobenzene, toluene or xylene, or water. Mixtures of the solvents which have been mentioned by way of example can also be used.
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 their reaction with compounds of the 2078~.57 formula MNR(2)R(3) to give compounds of the formula I
where R(l) = H can also be carried out in the form of a one-pot process.
To this end, a solution of a compound of the formula IV
in one of the abovementioned inert solvents is first prepared as indicated above by reacting a compound of the formula II with a compound of the formula III. At least an equivalent amount of a compound of the formula HNR(2)R(3) is subsequently added to this solution.
Compounds of the formula I in which R(l) has the meanings mentioned and is not hydrogen, are prepared by reacting a compound of the formula where R(l) = H with a corresponding alkyl halide, alkenyl halide or henzyl halide, preferably a chloride, bromide or a tosylate or mesylate, in the presence of a base, in an inert solvent, in a temperature range of from 0 - 100C. The solvents used are preferably those which are indicated for the reaction of compounds of the formula IV with M-NR(2)R(3), and bases which are suitable are, for example, inorganic bases such as carbonates, hydrogen carbonates, hydrox-ides, alcoholates or hydrides of alkali metals or alkal-ine earth metals, for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydrox-ide, sodium methylate or sodium hydride, or organic bases such as tert-amines, such as triethylamine, ethylmor-pholine or, for example, DBU, imidazole or pyridine.
Compounds of the formula I in which R(l) has the meaning of C(0)-(Cl-C8)-alkyl or -C(0)-phenyl are prepared by reacting a compound of the formula I where R(l) equals H
with a compound of the formula Va or Vb R(l)-Q R(l)-0-R(l) Va Vb 2078~)~7 where Q equals hydroxyl, halogen, such as chlorine or bromine, or an imidazolide. To do so, a procedure is best followed in which equimolar amountg or an up to 50-fold excess of a compound of the formula I where R(l) equals H, if appropriate in an inert, aprotic solvent such as chloroform, dichloromethane, tetrahydrofuran (THF) or dioxane, are reacted with a compound of the formula Va until the reaction is complete, if appropriate in the presence of a base, preferably pyridine or triethylamine. If a compound of the formula Va where Q equals OH is employed, then it is recommended that dicyclohexylcarbodiimide (DCC), if appropriate in the presence of a catalyst such as N,N-dimethylaminopyridine (DMAP) is added. If Vb tan acid anhydride) is used, R(l)-O-R(1) Vb then the process can be carried out without or with a catalyst such as DMAP or 4-pyrrolidinopyridine (PPY). The reaction temperatures here are between -70C and +120C, preferably, if a solvent is used, between the melting point and the boiling point of the solvent, in particular between -30 and +60C. The reaction times are 1 to 180 hours, preferably 1 to 48 hours, particularly prefer-ably 1 to 8 hours.
Compounds of the formula I which contain a thioether group can be oxidized on the sulfur to give a sulfoxide or sulfone. To this end, such compounds of the formula I
are reacted in an inert solvent and in a temperature range of from -10 to 80C with an oxidant, for example hydrogen peroxide or m-chloroperbenzoic acid. To prepare sulfoxides, one mole equivalent of oxidant is employed for this purpose, and for the preparation of sulfones two mole equivalents, or, if appropriate, an excess.
2378a~7 Solvents which are preferably uied are tho~e indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
The invention furthermore relates to a process for the preparation of the compounds of the formula I, in which a compound of the formula II
ll (II) A-X-CH2-C-R(7) in which R(7), X and A have the meanings mentioned, is reacted with a phosphorus ylide to give a compound of the formula VI
A - X - CH2 - ~ (VI) R ( 7 ) and the compound VI is subsequently reacted with a peroxide to give a compound of the formula IV
A - X - CH2 V R ( 7 ) (IV) and IV is reacted further as already mentioned above with a nucleophile of the formula M-NR(2)R(3) in which R(2) and R(3) have the meanings mentioned and M is hydrogen or a metal equivalent, giving a compound I where R(1) equals 207~57 hydrogen, and, if desired, this compound I is alkylated, alkenylated, benzylated or esterified and, if appropriate, oxidized on the sulfur of a thioether group to give the sulfoxide or sulfone, and, if appropriate, the product iB converted into the salt with a physiologically acceptable acid, or into a physiologically hydrolyzable derivative.
To prepare the compound~ of the formula I, a ketone of the formula II in which A, X and R(7) have the abovementioned meanings i8 reacted, in a first reaction step to prepare compounds of the formula V, with a phosphorus ylide in an inert solvent at a temperature of from -60 to +80C.
The phosphorus ylide used here is prepared by reacting a methyltriarylphosphonium salt, preferably methyltriphenylphosphonium chloride, methyltriphenyl-phosphonium bromide or methyltriphenylphosphonium iodide, with a strong base in an inert solvent. Examples of suitable bases are alkali metal hydrides, alkali metal amides, alkali metal alcoholates, alkaline earth metal hydrides, alkaline earth metal amides or alkaline earth metal alcoholates, sodium bistrimethylsilylamide or lithium organyls such as n-butyllithium or phenyllithium.
The solvents used are those indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
In a second reaction step for the preparation of com-pounds of the formula IV, a compound of the formula VI is reacted with an oxidant in an inert solvent at a tempera-ture of from -10 to +80C, if appropriate in the presence of a base and of a nitrile, for example benzonitrile, or thionylbisimidazole or -triazole.
Examples of suitable oxidants are HzO2 or percarboxylic acids such as, for example, peracetic acid, trifluoroper-2~78a~r~
acetic acid, perbenzoic acid or m-chloroperbenzoiC acid.
The solvents used are those indicated for the reaction of compounds of the formula IV with M-NR(2)R(3).
In a third reaction step for the preparation of compounds of the formula I where R(1) c ~I from compounds of the formula IV, the procedure is as indicated in the process above.
These compounds of the formula I where R(1) ~ H can, if desired, be alkylated, alkenylated, benzylated or esteri-fied and oxidized to give compounds where R(1) isnot equal to H, and, if appropriate, converted with a physiologically acceptable acid into the salt as indicated in the process above.
Preparation of the starting substances The preparation of compounds of the formula II i8 known from the literature. For example, an ~-haloketone of the formula VII:
,1~
¦ R(7) (VII) Hsl is reacted with a phenol or thiophenol in an inert solvent such as acetone, using a base (for example X2CO3).
Examples of suitable bases are carbonates, hydrogen carbonates, hydroxides or hydrides of alkali metals or alkaline earth metals such as, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbon-ate, sodium hydroxide or sodium hydride.
2078~7 The compounds of the formula VII are either commercially available or can be synthesized by halogenating the corresponding aryl methyl ketones by processes known from the literature.
The compounds of the formula I, their acid addition salts and their physiologically hydrolyzable derivatives are valuable pharmaceuticals. They have, in particular, an antimicrobial action and are suitable for preventing and treating fungal infections in humans and in various mammalian specie6.
The invention also relates to the preparation and the use of the compounds of the type I in the form of the free bases or of an acid addition salt as potent inhibitors of the exoenzymes of fungi, or as antimycotics.
Examples of pharmaceutically acceptable salt-forming acids are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, ~ulfuric acid, phos-phoric acid or nitric acid, or organic acids such as malonic acid, oxalic acid, gluconic acid, camphorsulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, p-toluenesulfonic acid or salicylic acid.
The compounds I have at least one asymmetrical C atom and can therefore exist in the form of enantiomers and diastereomers. The invention embraces the preparation and the use of the pure isomers as well as their mixtures.
Mixtures of diastereomers can be resolved into the components by customary methods, for example by selective crystallization from suitable solvents or by chromato-graphy on silica gel or aluminum oxide.
The compounds of the formula I, their acid addition salts and their physiologically hydrolyzable derivatives are valuable pharmaceuticals. They have, in particular, an antimicrobial action and are suitable for preventing and 2~781~
treating fungal infections in humans and in various mammallan specles.
The compounds have a very good in vitro activity against dermatomycetes such as, for example, Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum; against molds such as, for example, Aspergillus niger, or against yeasts such as, for example, Candida albicans, C. tropicalis, Torulopsis glabrata and Trichosporon cutanuem or against Protozoa such as Trichomonas vaginalis or T. fetus, or else against Gram-positive and Gram-negative bacteria.
After oral or parenteral administration, the compounds also have a very good systemic effect in vitro, for example against Candida albicans, for example in experi-mental renal candidosis in mice. In this case, in parti-cular the exoenzyme system of the yeast Candida albicans is affected in such a way that the pathogenicity of the pathogens is markedly reduced. There is also a very good effect against various pathogens of dermatomycoses (for example Trichophyton mentagrophytes) in guinea-pigs after oral, parenteral or local administration.
- Examples of indication areas in human medicine which may be mentioned are: dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporon species, Epidermophyton floccosum, and biphasic fungi, as well as molds.
In particular, deep mycoses caused by Candida albicans are affected favorably since penetration of the fungi into the host cell is prevented or hindered.
Examples of indication areas in veterinary medicine which - may be mentioned are:
2~78~7 All dermatomycoses and systemic mycoses, in particular those caused by the abovementioned pathogens.
The present invention includes pharmaceutical prepara-tions which contain one or more active ~ubstances in addition to non-toxic, inert pharmaceutically suitable carriers, or which are composed of one or more active substances used according to the invention, and processe~
for manufacturing these preparations.
Non-toxic, ~nert pharmaceutically suitable carriers are to be understood as meaning solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any type.
An inhibitor for the various phospholipases of Candida albicans must be present in adequate concentrations in the patient in all regions where the fungus can colonize the parenchyma. A precondition for this is the fact that the appropriate substances must be administered in a concentration which has previously proven effective in animal experiments.
When patients show severe symptoms of deep candidosis, they are frequently in a very poor general state. ~igh temperature and other diseases can frequently be found.
When deciding on the dosage rate, a difference must be made between prophylactic administration and therapy in the case where an infection has been established. In prophylaxis, it can be assumed that the general state of the patients is better, which allows oral administration.
Tablets, solutions, gels or inspissated juice can be used. In forms where deep candidoses have been estab-lished, it must frequently be assumed that controlledoral resorption of the active substances is not always guaranteed. In this case, parenteral administration forms are suitable. In exceptional cases, subcutaneous administration may also be considered.
207~a57 Candidates for prophylaxis are mainly immunocompressed patients who are in this situation due to strain caused by medicaments or due to endogenous immunity problems.
These are, in particular, transplant patients, diabetics and/or patients suffering from adiposis, AIDS patients, patients under chemotherapy, long-term ventilation patients, and others.
Some of the compounds inhibit the phospholipase of Candida albicans to an extent which is far below the minimum inhibitory concentrations of the active substanc-es to Candida albicans which have been determined in vitro. The dosage rate can therefore in many cases be below the rate which would be necessary for a purely antimycotic therapy.
The action within the patient is based on the fact that the active substances have two different effects on the Candida cells in the vicinity of the parenchyms. On the one hand, adhesion of the yeast cells to the somatic cells is prevented and, on the other hand, Candida albicans is prevented from penetrating the somatic cells with germination tubes.
This dual concept of action prevents the yeast from fully exploiting its pathogenicity. However, it must be men-tioned that in addition to the phospholipases Candida albicans also has other pathogenicity mechanisms such as, for example, the protease. Adhesion to endogenous cells is, however, the first step towards penetration. Since this adhesion is prevented by phospholipase inhibitors, the other pathogenicity mechanisms cannot be utilized fully.
Suitable formulations are, for example, tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile solutions for injec-tion, non-aqueous emulsions, suspensions and solutions, 2~7~.57 ointments, creams, pastes, lotions, gprays etc.
The abovementioned pharmaceutical preparations should contain the prophylactically ancl therapeutiCallY active compounds preferably in a concentration of about 0.1 to 99.5, preferably approximately 0.5 to 95, % by weight of the total mixture.
The abovementioned pharmaceutical preparations can also contain other pharmaceutical active substances in addi-tion to the active substances used according to the lQ invention.
The abovementioned pharmaceutical preparations are prepared in the customary manner by known methods, for example by mixing the active substance, or active sub-stances, with the carrier, or carriers.
The present invention includes the use of the active substances according to the invention and the pharmaceut-ical preparations which contain one or more active substances according to the invention in human and veterinary medicine for preventing, alleviating and/or curing the abovementioned diseases.
The active substances or the pharmaceutical preparations can be aclministered locally, orally, parenterally, intraparenterally and/or rectally.
In general, it has proved advantageous in both human and veterinary medicine to administer the active substance, or active substances, used according to the invention in total amounts of from at least about 0.05, preferably 0.1, in particular 0.5, mg/kg of body weight up to not more than about 200, preferably up to 100, in particular up to 10, mg/kg of body weight per 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. The total amount is 2~78~.~7 administered in 1 to 8, preferabLy in 1 to 3, individual doses, but over considerably longer period~ (up to 6 weeks) in the case of deep mycoses.
However, it may be necessary to deviate from the dosage rates mentioned, namely as a function of the species and the body weight of the subject to be treated, the nature and severity of the disea~e, the nature of the prepara-tion and administration of the pharmaceutical, and the period or interval within which the administration is effected. Thus, in some cases it may suffice to make do with less than the abovementioned amount of active -- substance, while in other cases the abovementioned amount of active substance must be exceeded. The decision with regard to optimum dosage rate and type of application of the active substances which are necessary in each case can be made easily by anyone skilled in the art due to his expert knowledge.
Example 1 Synthesisof2-t-butyl-1-(2,4-dichlorophenoxy)-3-isoprop-yl-amino-2-propanol (I.7) C i o Cl ~~ V~ (CH~)~5 (O) I, NaH ~~
/~ ! DVSO, 25 'C ~J
I . 7 IV.7 ClOH
isopropylamine o ~ NH
ethanol, H20 Cl l 7 (2 steps) 2~78i~.57 a) Preparation of the oxirane :rv. 7 1.5 g of trimethylsulfoxonium iodide (6.8 mmol) are dissolved in 30 ml of ab~olute ~MSO, 0.195 g (6.5 mmol) of sodium hydride ~80 % suspens:ion in mineral oil) are added, and the mixture iB stirred until the evolution of gas has ceased (approx. 30 minutes). 1.51 g (5.8 mmol) of 1-(2,4-dichlorophenoxy)-~,3-dimethyl-2-butanone~ di~-solved in 5 mi of absolute DMSO, are subsequently added at 25C, and the reaction mixture is stirred for 1 hour at 25C and for 2 hours at 40C.
For work-up, the reaction mixture is poured into water (400 ml), and the aqueous phase i9 extracted four times using 100 ml portions of dichloromethane. The combined organic phases are washed four times with 100 ml portions of water and dried over Na2SO4, the drying agent is filtered off, and the mixture is concentrated on a rotary evaporator under reduced pressure.
Yield: 1.24 g (78 %, 4.5 mmol, colorless oil).
The crude product is reacted directly, without further purification steps.
b) Reaction with isopropylamine 1 g of the oxirane prepared under a) t3.63 mmol) are dissolved in 30 ml of ethanol, and 6.38 ml (4.43 g, 75 mmol) of isopropylamine and l ml of water are added.
The reaction mixture is refluxed for 12 hours. The course of the reaction is monitored by thin-layer chromatography (silica gel plates, mobile phase: dichloromethane/ethyl acetate = 1/1).
For work-up, the solvent is removed on a rotary evaporat-or under reduced pressure, and the crude product obtained is chromatographed over silica gel (Silica Gel 60, manufactured by Merck 0.043 - 0.060 mm, mobile phase:
CH2Cl2/methanol z 19/1).
2~78~7 Yield: 0.972 g (2.9 mmol, 80 % of theory), colorless oil.
RF (CHzCl2/ethyl acetate = 1:1 silica gel glass plates) = 0.18.
Example 2 Synthesis of 3-N-benzylamino-2-t-butyl-l-(4-hept phenyloxy)-2-propanol (I.l9) (2 steps) C H 3 - ( C H 2 ) 6 - ~ ~( C H ~ S ( O ) I
I I .19 7 benzylamine CH~-(CH2)6-0 ~ ~ l20C
IV.l9 O H
CH3- ( CH~ ) 6- ~ O ~NH,J3 I . 19 2~78~57 a) Preparation of the oxirane IV.l9 7.37 g (33.5 mmol) of trimethylsulfoxonium iodide are introduced into 150 ml of absolute tetrahydrofuran, and 0.88 g (29 mmol) of sodium hydride (80 % ~uspension in paraffin oil) i8 added in portion6 under an N2 protective gas atmosphere. To deprotonate the mixture completely, it is refluxed for 2 hours, with stirring. 7.67 g (25 mol) of 3~3-dimethyl-l-(4-heptyloxy-phenyloxy)-2-butanone~
dissolved in 40 ml of absolute THF, are subseguently added, and the reaction solution i~ heated for 6 hours at 40C.
For work-up, the reaction mixture is poured into 400 ml of ice-water, and, after phase separation, the aqueous phase is extracted using 4 x 100 ml of ethyl acetate. The combined organic phases are washed with 4 x 100 ml of water and dried over Na2S04. After the drying agent has been removed by filtration, the solvent is removed under reduced pressure.
According to lH NMR spectra, the yellow solid residue has the structure indicated and a purity of approx. 96 %.
Yield 6.9 g (87 ~), yellow solid RF (silica gel glass plates, mobile phase CH2Cl2): 0.42 b) Reaction of the oxirane IV.19 with benzylamine 1 g (3.14 mmol) of the oxirane from a) is dissolved in 6 ml of benzylamine and heated for 2 hours at 120C.
After most of the benzylamine has been removed by means of bulb tube distillation under an oil pump vacuum (0.1 mbar), the product is chromatographed over a silica gel column (mobile phase: CH2Cl2/MeOH = 40:1).
The reaction product is subsequently recrystallized from heptane.
2 0 7 ~
Yield: 1.002 g (2.3 mmol, 75 ~) Melting point: 52C
Other compounds of the formula I where R(l) - H which were prepared analogously to Examples 1 and 2, but using corresponding compounds of the formula IV and MNR(2)R(3), are those listed in Table 1. ExampleQ 1 and 2 are con-tained in ~able 1 under I.7 and I.l9.
2~78~7 M.p.: oil OH CH, EA: calc . f ound:
Cl--~3 ~`'~ CH3 C 66.06% C 6 5 0 H 8.99% H8 9 J Cl 11.30%
N 4.46% N4 . 5 O 10.19%
H C
M . p .: oil OH CH3 EA: calc .: f ound :
--CH3 C 684 79% 8 8 HN Cl 11.82%
N 4 67% 4 . 8 O 1067%
H3C\ CH3 M.p.: oil OH CH, EA: calc .: f ound :
3 ~ CH3 Cl= o HN CH3 C66.06% 6 5 . 2 H8.99% 9.1 H3C ~ Cl11 30/O 4 . 6 \~ O 10.19%
H,C
2~7~7 M.p, oil OH CH~ calc .: f ound :
1 . 4 ~ ~ CH~
C74.77%74 7 H9.15% 9 3 \~CH, N3i63-/;3 . 7 M . p . resin 1 - OH CH~ calc .: f ound :
~ '/~ C74 77%7 4 . 82 H9.15% 9-H3C C~3 N3.63%3 . 8 ~=9 ,H3 012.45%
M.p.: oil OH CH3 EA: calc .: f ound :
1 . 6 ~ /~CH~
HN C 74.36% 7 4 5 H3C 1 CH3 N3.77% 3 7 2~78~
M.p-: oil 1 . 7Cl OH CH~ EA: calc.: found:
Cl= ~/ T CH~
CH~ C 57.49%5 7 . 4 \=/ HN Cl 21 210;o 7 . 6 N 4.19%4 3 O 9.57%
H~C ~ CH~
M.p.: oil Cl OH CH~ EA: calc. found-= CH~
HN C 58.62%58 . 6 Cl 2~086O/;D 79 H~C I--CH~ N 4.02% 4 1 CH~
M.p.: oil 1 9 Cl OH CH~ EA: calc.: found:
Cl ~ O~ CH~
C 58.62%58. 6 \ Cl 27 86o/; 7 . 9 . N 4.02%4 . 2 O 9.19%
CH~
- 32 - 207~7 M.p.: oil EA: calc.: found:
1.10 OH CH~
H~C ~ O ~ CH3 C 75.19% 74.2 HN N 4.38-/ 40 64 CH~ ¦ O 10.02%
,~ /\
M.p.: oil EA:calc.: found:
OH CH~
1.,, 1 1 ~ CH3 H~r \ ~ O ~ CH~C 75.17% 7;.2 j ~ HN H 11.12% 11 3 CH~ ~ N 417% 4 3 CH~
M.p.: oil EA: calc.: found:
1.12 OH CH~
H~C ~ O ~ CH~ C 74.72% 74.8 HN H 10.97% 10.8 CH~ l N 4360/; 4.4 H~C CH~
2~78~
M.p.: oil OH CH, EA:calc.: found:
H,C ~)_ /~ CH, CH HN C 78.00% 78 . 2 3 H9.55% 9 6 \~ 03 660/3 8 M.p.: oil 1 ~ OH CH, EA: calc.: found:
H,~o ~CH, C76.34%76.4 3 H1 1 .48% 11 6 H3C~ ~,CH3 N3 71% 3 9 CH, CH, M.p.: oil 1 .1; HO EA: calc .: found:
CH
C80.70%8 0 . 8 \~ H8.64% 8 . 6 ~ / N3.25%
H C~CH, O741%
CH, - 34 - 2~78~7 M.p.: oil 1.16 ~ EA: calc.: found:
~0 C81 .~2%8 1 . 7 ~ ~ CH H9.82/~9: 9 $ O 5.88-/
H~C + CH~
A M.p.: oil 17 ~ EA:calc.: found:
~N J
C 76.58% 7 6.6 H 9.38Yo 9 5 I CH3Cl 6 11%
H Cl~ N 241% 2.7 O 551%
H3C - ~ CH~
CH~
M.p. oil EA: calc.: found:
1 . 18 OH CH~
o ~ o/;~, _/ I C73.24% 7 3 3 ~ N3.56-Jo 3 5 8 H3C H~C
2~78a~
M.p-: oil EA: calc .: f ound :
OH CH, ~ /~' C 75.84% 7 5 . 9 H,C ~ N 3 28/; 3 3 M . p .: re6in EA: calc .: f ound:
' OH CH, /--/ ~ H~
~ ~H~C--LCH C 75.55% 7; . 3 H~C ~ N 5 51% 5 6 M.p.: oil 1 . 21 ~o OH CH, EA: calc.: found:
/--/ \~ CH, -- H,C CH, H,C O ~J H 9 300/o 9 3 o~J O 1268470/~ 3 . o CH, 2~78~57 M.p.: oil 1 . 2 2 EA calc .: f ound :
~ O OH CH, H~C ~ H 9.29 / 9 1 ~3 0 9.03% . 6 M.p.: oil <~ \~CH, EA: calc .: f ound :
~_~ HN
/--/ J C75.99%7 5 7 H~C ~/ N2 77 ~o 1 2 8 O 9.49%
H~C
M . p .: oil EA: calc .: found :
O ~ O OH CH~
/--/ \~ CH~
-- CH~ C72.78%7 3 . O
~ HN N3.69% 3 6 H,C H,C CH, O12.64%
207~57 M. p : oil 1 . 2 5 EA: calc .: f ound :
--J~ N 2.51.Y 2.6 H,C
M.p.: oil EA: calc .: f ound :
1.25 O ,HN J~3 11 H3C T CH3 C 78.94% 7 8 . 9 CH3 N 3 54% 3 O 8.09% ' M . p .: oil 1 . 27 OH EA: calc.: found:
[~ ~3 CH, H 190.. 2713% 10 9 - 38 - 2~78a5~
M.p.: oil 1.28 EA:calc.: found:
OH
CH ~ C 78.S9%78.7 H 11.70%11.6 ~_~,H,C~ ~_~_~ N 296%3 0 M.p.: resin 1.29 ~ EA: calc.: found:
OH ~
O~HNJ C79.17~o 79 . 2 H~C ~ CH3 H9.60% 9 8 CH, O7 81C~o 3 4 ~f M.p.: oil EA:calc.: found:
1.30 OH
,- ~ CH, CH, H :037% 0 9 8.85% 3. 9 - 39 - 2~7~7 H,C CHl 28 42 2 3 >~ N found: -alc.:
~H CH, H9'4 769'967 ~-t C CH, O 10,56 CH, 1.32 C23H33N3 ~ found: calc:
H C74,1 74,36 ~O ~, CH, H3 8 3,77 Oh ~ found calc.:
~O~N~J~ C76 ~3 77 01 '',~ . c~, N3,4 3,45 -CH, O11,84 . C31H49~03 Oh H found: calc.:
C77,1 76,97 ~,c 1.3, C38H65N3 found: calc.:
~=a C78,4 78,16 ~,, ~ o~o/~ ~ N2 6 t82,222 ~,c ,~r 2 ~ 7 1.36 C27H40CLN2 c~ found: calc.
~,c~ ~,c ,_~ C72,5 72,70 r~ \~ OH H 9,0 9,04 - N3,2 3,14 Cl~ H l7 17 C26H38ClN2 c~ found: calc r - / ~ r C72~4 72,28 , Cl3 8 3.24 f ound: calc o o~ c~ C73 3 73 4, c~, N3,0 6 75 Cl ~C CH, Cl 7,48 32H4 9ClN22 f ound: calc O O H C759'3 72,63 Cl6,70 CH, 2~7~7 found: calc.:
c~ C75,8 75,61 H,C ~ OH N 2 5 2 67 u,c ~c ~ O 6,10 ~ ~ ~N H Cl 6,76 found: calc.:
C67,4 67,26 ~ ~ O 7,17 I Cl 15,88 NH ~ ~Cl C~ gH23C12N02 found: calc - C61,8 61,96 H 6,4 6.29 ~ Cl 3,80 r, Cl CH, C~ 8H21C12N02 found: calc c ~ C60.8 61,03 o O 3 9 3,95 N H ~CI C1 20.01 H,C--~
2~78~7 1 44 C21H27Cl2N2 found: calc.:
~' C 6'.5 6:i,64 H 6 8 638,,85077 Cl 17,89 ~7C
c27~37Cl2No2 found: calc.:
C 67,9 67,78 H 7,8 7,79 Cl 124~682 '~ 'r, Cl ~ C30H39N5 found calc.
O~ H C72,9 72,99 ~,o ~ N ~ ~ H7,8 7,96 1.47 C31H51 2 found: calc.:
OH ~ C 80,0 7~26 H ~ H 10,9 10,94 ~3C~H C~ ~CH, - ~ N3,12 98 Cli, ~,, 2~7~7 Oh H ~cl found: calc.:
~-~ C68 48 68 306 ~ ,C ~ CH Cl ~ 2,8 2,83 h~ I CH, C, 6,47 H,C ~
Ch, ,~ ~ found: calc :
-3-~ ~,C CH, ~ H2 9 12 728 A~ X ~ O6,35 ~A,C
~ C30H47 4 Ch H ~5~CH, found: calc.:
H,C~CH, H,C N2,8 2,88 h~ Ch~ H,C 13,18 CH, 1._ C33H47N3 OH ~ found: calc.:
o~30/~ 99,2 9 37 ~q 2~78~7 1.5~ C30H49N3 O~ ~ found: calc.:
C76,6~6,39 o ~ ~Y H10,610,47 o ~ `NH '--' N3,1 2,97 O 10,17 CH, found: calc.:
C!~ C77,477,66 h H ~ H 10 4 12 646 J
~/ ~ ~
rl~C
2~780~7 To determine the enzyme inhibition, a suspension of Candida albicans blastoconidia (~itrain 200/175), in which the cell density had been adjusted photometriCallY to an absorption of 0.5 (500 nm), was mixed with solution of preparations, or with solvent ~olution as a control, namely a) 100 ~l solution of preparation (suspension) +900 ~1 cell suspension b) 100 ~1 solvent +900 ~l cell suspension 5 ~l aliquots of the blastoconidia suspension which had been incubated for 30 minutes at 21C were added dropwise onto an agar plate (Sabouraud agar with an addition of 8 ~ egg yolk, 1 mM NaCl, 5 mM CaCl2).
The plate which had been inoculated in this manner was incubated for 3 days at 37C.
The evaluation was carried out in such a way that 1. the diameter (mm) of the Candida albicans colony (treated and untreated) and 0 2. the total diameter of colony and zone of turbidity caused by exoenzymes (treated and untreated) was determined.
Determination of the quotient of treated group and control group gave a value which was to be regarded as a measure for enzyme activity.
As can be seen from Table 2, the compound5 used according to the invention inhibit the exoenzymes freed to a considerably greater extent than propranolol.
Propranolol is described in the literature (Pappu A.S. et al. in Biochem. Pharmacol. 34, 521-24, 1985) as the most 2~7~7 effective substance which showed an inhibitory action to phospholipase from liver cells in a suitable in vitro test.
The compounds I used according to the invention clearly outperform the prior art.
Table 2 Percentage inhibition of the freed exoenzymes of Candida albicans in vitro PreparationConcentration% Inhibition of (~m/ml) the phospholipase 1 . 5 100 100 1.7 100 100 lS 10 20 1. 11 100 100 1. 15 100 100 1.17 100 100 1.18 100 100 2078~7 1 . 19 100 100 1.21 100 100 1 . 22 100 100 1.23 100 100 1 . 24 100 100 20 1.31 100 100 7.7 1 . 34 100 100 33.3 6 .3 1.48 100 100 2~78~5~
1 14.3 1.53 100 100 Propranolol 100 30 The fungus-destroying, antimycotic activity of the compounds was verified with the aid of a few examples (see Table 3) with reference to the percentage destruc-tion of Trichophyton mentagrophytes in vitro (~tandard preparation Rilopirox as comparison 6ubstance).
Table 3 15 Compound ~g/ml 1.17 100 97.8 Rilopirox 100 100 (Values in ~ destruction of Trichophyton mentagrophytes after 14 hours in distilled water)~
H,C
2~7~7 M.p, oil OH CH~ calc .: f ound :
1 . 4 ~ ~ CH~
C74.77%74 7 H9.15% 9 3 \~CH, N3i63-/;3 . 7 M . p . resin 1 - OH CH~ calc .: f ound :
~ '/~ C74 77%7 4 . 82 H9.15% 9-H3C C~3 N3.63%3 . 8 ~=9 ,H3 012.45%
M.p.: oil OH CH3 EA: calc .: f ound :
1 . 6 ~ /~CH~
HN C 74.36% 7 4 5 H3C 1 CH3 N3.77% 3 7 2~78~
M.p-: oil 1 . 7Cl OH CH~ EA: calc.: found:
Cl= ~/ T CH~
CH~ C 57.49%5 7 . 4 \=/ HN Cl 21 210;o 7 . 6 N 4.19%4 3 O 9.57%
H~C ~ CH~
M.p.: oil Cl OH CH~ EA: calc. found-= CH~
HN C 58.62%58 . 6 Cl 2~086O/;D 79 H~C I--CH~ N 4.02% 4 1 CH~
M.p.: oil 1 9 Cl OH CH~ EA: calc.: found:
Cl ~ O~ CH~
C 58.62%58. 6 \ Cl 27 86o/; 7 . 9 . N 4.02%4 . 2 O 9.19%
CH~
- 32 - 207~7 M.p.: oil EA: calc.: found:
1.10 OH CH~
H~C ~ O ~ CH3 C 75.19% 74.2 HN N 4.38-/ 40 64 CH~ ¦ O 10.02%
,~ /\
M.p.: oil EA:calc.: found:
OH CH~
1.,, 1 1 ~ CH3 H~r \ ~ O ~ CH~C 75.17% 7;.2 j ~ HN H 11.12% 11 3 CH~ ~ N 417% 4 3 CH~
M.p.: oil EA: calc.: found:
1.12 OH CH~
H~C ~ O ~ CH~ C 74.72% 74.8 HN H 10.97% 10.8 CH~ l N 4360/; 4.4 H~C CH~
2~78~
M.p.: oil OH CH, EA:calc.: found:
H,C ~)_ /~ CH, CH HN C 78.00% 78 . 2 3 H9.55% 9 6 \~ 03 660/3 8 M.p.: oil 1 ~ OH CH, EA: calc.: found:
H,~o ~CH, C76.34%76.4 3 H1 1 .48% 11 6 H3C~ ~,CH3 N3 71% 3 9 CH, CH, M.p.: oil 1 .1; HO EA: calc .: found:
CH
C80.70%8 0 . 8 \~ H8.64% 8 . 6 ~ / N3.25%
H C~CH, O741%
CH, - 34 - 2~78~7 M.p.: oil 1.16 ~ EA: calc.: found:
~0 C81 .~2%8 1 . 7 ~ ~ CH H9.82/~9: 9 $ O 5.88-/
H~C + CH~
A M.p.: oil 17 ~ EA:calc.: found:
~N J
C 76.58% 7 6.6 H 9.38Yo 9 5 I CH3Cl 6 11%
H Cl~ N 241% 2.7 O 551%
H3C - ~ CH~
CH~
M.p. oil EA: calc.: found:
1 . 18 OH CH~
o ~ o/;~, _/ I C73.24% 7 3 3 ~ N3.56-Jo 3 5 8 H3C H~C
2~78a~
M.p-: oil EA: calc .: f ound :
OH CH, ~ /~' C 75.84% 7 5 . 9 H,C ~ N 3 28/; 3 3 M . p .: re6in EA: calc .: f ound:
' OH CH, /--/ ~ H~
~ ~H~C--LCH C 75.55% 7; . 3 H~C ~ N 5 51% 5 6 M.p.: oil 1 . 21 ~o OH CH, EA: calc.: found:
/--/ \~ CH, -- H,C CH, H,C O ~J H 9 300/o 9 3 o~J O 1268470/~ 3 . o CH, 2~78~57 M.p.: oil 1 . 2 2 EA calc .: f ound :
~ O OH CH, H~C ~ H 9.29 / 9 1 ~3 0 9.03% . 6 M.p.: oil <~ \~CH, EA: calc .: f ound :
~_~ HN
/--/ J C75.99%7 5 7 H~C ~/ N2 77 ~o 1 2 8 O 9.49%
H~C
M . p .: oil EA: calc .: found :
O ~ O OH CH~
/--/ \~ CH~
-- CH~ C72.78%7 3 . O
~ HN N3.69% 3 6 H,C H,C CH, O12.64%
207~57 M. p : oil 1 . 2 5 EA: calc .: f ound :
--J~ N 2.51.Y 2.6 H,C
M.p.: oil EA: calc .: f ound :
1.25 O ,HN J~3 11 H3C T CH3 C 78.94% 7 8 . 9 CH3 N 3 54% 3 O 8.09% ' M . p .: oil 1 . 27 OH EA: calc.: found:
[~ ~3 CH, H 190.. 2713% 10 9 - 38 - 2~78a5~
M.p.: oil 1.28 EA:calc.: found:
OH
CH ~ C 78.S9%78.7 H 11.70%11.6 ~_~,H,C~ ~_~_~ N 296%3 0 M.p.: resin 1.29 ~ EA: calc.: found:
OH ~
O~HNJ C79.17~o 79 . 2 H~C ~ CH3 H9.60% 9 8 CH, O7 81C~o 3 4 ~f M.p.: oil EA:calc.: found:
1.30 OH
,- ~ CH, CH, H :037% 0 9 8.85% 3. 9 - 39 - 2~7~7 H,C CHl 28 42 2 3 >~ N found: -alc.:
~H CH, H9'4 769'967 ~-t C CH, O 10,56 CH, 1.32 C23H33N3 ~ found: calc:
H C74,1 74,36 ~O ~, CH, H3 8 3,77 Oh ~ found calc.:
~O~N~J~ C76 ~3 77 01 '',~ . c~, N3,4 3,45 -CH, O11,84 . C31H49~03 Oh H found: calc.:
C77,1 76,97 ~,c 1.3, C38H65N3 found: calc.:
~=a C78,4 78,16 ~,, ~ o~o/~ ~ N2 6 t82,222 ~,c ,~r 2 ~ 7 1.36 C27H40CLN2 c~ found: calc.
~,c~ ~,c ,_~ C72,5 72,70 r~ \~ OH H 9,0 9,04 - N3,2 3,14 Cl~ H l7 17 C26H38ClN2 c~ found: calc r - / ~ r C72~4 72,28 , Cl3 8 3.24 f ound: calc o o~ c~ C73 3 73 4, c~, N3,0 6 75 Cl ~C CH, Cl 7,48 32H4 9ClN22 f ound: calc O O H C759'3 72,63 Cl6,70 CH, 2~7~7 found: calc.:
c~ C75,8 75,61 H,C ~ OH N 2 5 2 67 u,c ~c ~ O 6,10 ~ ~ ~N H Cl 6,76 found: calc.:
C67,4 67,26 ~ ~ O 7,17 I Cl 15,88 NH ~ ~Cl C~ gH23C12N02 found: calc - C61,8 61,96 H 6,4 6.29 ~ Cl 3,80 r, Cl CH, C~ 8H21C12N02 found: calc c ~ C60.8 61,03 o O 3 9 3,95 N H ~CI C1 20.01 H,C--~
2~78~7 1 44 C21H27Cl2N2 found: calc.:
~' C 6'.5 6:i,64 H 6 8 638,,85077 Cl 17,89 ~7C
c27~37Cl2No2 found: calc.:
C 67,9 67,78 H 7,8 7,79 Cl 124~682 '~ 'r, Cl ~ C30H39N5 found calc.
O~ H C72,9 72,99 ~,o ~ N ~ ~ H7,8 7,96 1.47 C31H51 2 found: calc.:
OH ~ C 80,0 7~26 H ~ H 10,9 10,94 ~3C~H C~ ~CH, - ~ N3,12 98 Cli, ~,, 2~7~7 Oh H ~cl found: calc.:
~-~ C68 48 68 306 ~ ,C ~ CH Cl ~ 2,8 2,83 h~ I CH, C, 6,47 H,C ~
Ch, ,~ ~ found: calc :
-3-~ ~,C CH, ~ H2 9 12 728 A~ X ~ O6,35 ~A,C
~ C30H47 4 Ch H ~5~CH, found: calc.:
H,C~CH, H,C N2,8 2,88 h~ Ch~ H,C 13,18 CH, 1._ C33H47N3 OH ~ found: calc.:
o~30/~ 99,2 9 37 ~q 2~78~7 1.5~ C30H49N3 O~ ~ found: calc.:
C76,6~6,39 o ~ ~Y H10,610,47 o ~ `NH '--' N3,1 2,97 O 10,17 CH, found: calc.:
C!~ C77,477,66 h H ~ H 10 4 12 646 J
~/ ~ ~
rl~C
2~780~7 To determine the enzyme inhibition, a suspension of Candida albicans blastoconidia (~itrain 200/175), in which the cell density had been adjusted photometriCallY to an absorption of 0.5 (500 nm), was mixed with solution of preparations, or with solvent ~olution as a control, namely a) 100 ~l solution of preparation (suspension) +900 ~1 cell suspension b) 100 ~1 solvent +900 ~l cell suspension 5 ~l aliquots of the blastoconidia suspension which had been incubated for 30 minutes at 21C were added dropwise onto an agar plate (Sabouraud agar with an addition of 8 ~ egg yolk, 1 mM NaCl, 5 mM CaCl2).
The plate which had been inoculated in this manner was incubated for 3 days at 37C.
The evaluation was carried out in such a way that 1. the diameter (mm) of the Candida albicans colony (treated and untreated) and 0 2. the total diameter of colony and zone of turbidity caused by exoenzymes (treated and untreated) was determined.
Determination of the quotient of treated group and control group gave a value which was to be regarded as a measure for enzyme activity.
As can be seen from Table 2, the compound5 used according to the invention inhibit the exoenzymes freed to a considerably greater extent than propranolol.
Propranolol is described in the literature (Pappu A.S. et al. in Biochem. Pharmacol. 34, 521-24, 1985) as the most 2~7~7 effective substance which showed an inhibitory action to phospholipase from liver cells in a suitable in vitro test.
The compounds I used according to the invention clearly outperform the prior art.
Table 2 Percentage inhibition of the freed exoenzymes of Candida albicans in vitro PreparationConcentration% Inhibition of (~m/ml) the phospholipase 1 . 5 100 100 1.7 100 100 lS 10 20 1. 11 100 100 1. 15 100 100 1.17 100 100 1.18 100 100 2078~7 1 . 19 100 100 1.21 100 100 1 . 22 100 100 1.23 100 100 1 . 24 100 100 20 1.31 100 100 7.7 1 . 34 100 100 33.3 6 .3 1.48 100 100 2~78~5~
1 14.3 1.53 100 100 Propranolol 100 30 The fungus-destroying, antimycotic activity of the compounds was verified with the aid of a few examples (see Table 3) with reference to the percentage destruc-tion of Trichophyton mentagrophytes in vitro (~tandard preparation Rilopirox as comparison 6ubstance).
Table 3 15 Compound ~g/ml 1.17 100 97.8 Rilopirox 100 100 (Values in ~ destruction of Trichophyton mentagrophytes after 14 hours in distilled water)~
Claims (7)
1. Substituted aminopropanes of the formula I
I
in which R(1) is H, (C1-C10)-alkyl, (C2-C10)-alkenyl, benzyl, [unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl or phenyl], C(O)-( C1-C8)-alkyl, C(O)-phenyl R(2) is H, (C1-C18)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C2-C18)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or disubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubstituted by substituents selected from the group comprising F, Cl, Br, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, OH, SH, (C1-C10)-alkoxy, (C1-C4)-alkylenedioxy, (C1-C10)-alkylthio, dimethylaminoethoxy, (C1-C4)-alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CaF2a+1 (where a equals 1 - 6), or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by F, Cl, (C1-C4)-alkyl, O(C1-C4)-alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N
atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or R(2) together with R(3) forms a chain -(CH2)m-where m equals 4 - 6 and in which a CH2 group can be replaced by oxygen or sulfur, A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C18)-alkyl, (C2-C18)-alkenyl, (C3-C20)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C20)-alkyl, Y-(C2-C18)-alkenyl, Y-(C3-C20)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, Br, CaF2a+1 (where a equals 1 to 8), CCl3, YH, naphthyl, CN, NO2, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, CN, -O-(CH2)1-2-O-, where Y equals oxygen or sulfur, SO, SO2, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded to the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, or an O(CH2)1-2-O-chain, R(6) is H, (C1-C15)-alkyl, (C2-C15)-alkenyl, Y-(C1-C15)-alkyl, Y-(C2-C15)-alkenyl, phenyl, Y-phenyl, benzyl, biphenylyl, F, Cl, Br, I, CaF2a+1 (where a equals 1 - 8), CCl3, naphthyl, YH, X is oxygen or sulfur, R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, naph-thyl, phenyl, thienyl, pyridyl, the aromatic and heteroaromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, CN, (C1-C18)-alkylthio.
I
in which R(1) is H, (C1-C10)-alkyl, (C2-C10)-alkenyl, benzyl, [unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl or phenyl], C(O)-( C1-C8)-alkyl, C(O)-phenyl R(2) is H, (C1-C18)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C2-C18)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or disubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubstituted by substituents selected from the group comprising F, Cl, Br, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, OH, SH, (C1-C10)-alkoxy, (C1-C4)-alkylenedioxy, (C1-C10)-alkylthio, dimethylaminoethoxy, (C1-C4)-alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CaF2a+1 (where a equals 1 - 6), or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by F, Cl, (C1-C4)-alkyl, O(C1-C4)-alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N
atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or R(2) together with R(3) forms a chain -(CH2)m-where m equals 4 - 6 and in which a CH2 group can be replaced by oxygen or sulfur, A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C18)-alkyl, (C2-C18)-alkenyl, (C3-C20)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C20)-alkyl, Y-(C2-C18)-alkenyl, Y-(C3-C20)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, Br, CaF2a+1 (where a equals 1 to 8), CCl3, YH, naphthyl, CN, NO2, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, CN, -O-(CH2)1-2-O-, where Y equals oxygen or sulfur, SO, SO2, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded to the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, or an O(CH2)1-2-O-chain, R(6) is H, (C1-C15)-alkyl, (C2-C15)-alkenyl, Y-(C1-C15)-alkyl, Y-(C2-C15)-alkenyl, phenyl, Y-phenyl, benzyl, biphenylyl, F, Cl, Br, I, CaF2a+1 (where a equals 1 - 8), CCl3, naphthyl, YH, X is oxygen or sulfur, R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, naph-thyl, phenyl, thienyl, pyridyl, the aromatic and heteroaromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, CN, (C1-C18)-alkylthio.
2. A compound of the formula I as claimed in claim 1, in which R(1) is H, (C1-C6)-alkyl, benzyl, [unsubstituted or monosubstituted or disubstituted by F, Cl, Br, CF3, (C1-C4)-alkyl, OCH3, O-phenyl orphenyl],C(O)-(C1-C8)-alkyl,C(O)-phenyl R(2) is H, (C1-C18)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C2-C18)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C6)-alkyl, the alkyl chain being unsubstituted or monosubstituted or disubstituted by OH, or is phenyl-(C2-C6)-alkenyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or polysubstituted by substituents selected from the group comprising F, Cl, Br, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C1-C10)-alkoxy, (C1-C4)-alkylenedioxy, (C1-C4)-alkoxycarbonylmethoxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted or substituted by Cl, (C1-C4)-alkyl, O(C1-C4)-alkyl, or R(2) is piperidin-4-yl, unsubstituted or substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or 21 benzyl group on the N
atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C16)-alkyl, (C3-C16)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C16)-alkyl, Y-(C3-C16)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, CF3, naphthyl, CN, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, -O-(CH2)1-2-O-, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded on the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl, CF3, X is oxygen or sulfur, R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, phenyl, thienyl, the aromatic ring systems mentioned and the heteroaromatic ring system mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, (C1-C18)-alkylthio.
atom of the piperidine, R(3) is defined as R(2), the meanings of R(2) and R(3) in each case being identical or different, or A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C16)-alkyl, (C3-C16)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C16)-alkyl, Y-(C3-C16)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, CF3, naphthyl, CN, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, -O-(CH2)1-2-O-, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or if the substituents are bonded on the phenyl ring in adjacent positions, R(4) together with R(5) forms a (CH2)r chain where r equals 3 or 4, R(6) is H, (C1-C6)-alkyl, Y-(C1-C6)-alkyl, F, Cl, CF3, X is oxygen or sulfur, R(7) is (C1-C12)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), (C3-C12)-alkenyl, phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, phenyl, thienyl, the aromatic ring systems mentioned and the heteroaromatic ring system mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, Br, (C1-C18)-alkyl, (C1-C18)-alkoxy, (C2-C18)-alkenyloxy, CF3, C2F5, (C1-C18)-alkylthio.
3. A compound of the formula I as claimed in claim 1, in which R(1) is H, C(O)-(C1-C4)-alkyl, C(O)-phenyl R(2) is H, (Cl-C15)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C2-C15)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C5)-alkyl, diphenyl-(C1-C6)-alkyl, phenyl, the phenyl systems being unsubstituted or monosubstituted or disubstituted by substituents selected from the group comprising F, Cl, (C1-C8) -alkyl, (C3-C6)-cycloalkyl, (C1-C10)-alkoxy, (C1-C4)-alkylenedioxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to
4 methyl groups and having a hydrogen, an acetyl group, a phenyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is (C1-C18)-alkyl, (C2-C18)-alkenyl or a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, CF3, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl, F, Cl, X is oxygen or sulfur, R(7) is (C1-C10)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, (C1-C4)-alkyl, (C1-C4)-alkoxy, CF3, (C1-C4)-alkylthio.
4. A compound of the formula I as claimed in claim 1, in which R(1) is H, R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C3-C12)-alkenyl, (C3-C10)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C4)-alkyl, diphenyl-(C1-C6)-alkyl, the phenyl systems being unsubstituted or monosubstituted or disubstituted by substituents selected from the group comprising F, Cl, (C1-C8)-alkyl, (C3-C6)-cycloalkyl, (C1-C10)-alkoxy, (C1-C2)-alkylenedioxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl,phenyl-(C1-C4)-alkoxy,F,Cl, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl, X is oxygen, R(7) is (C1-C4)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or disubstituted by F, Cl, (C1-C4)-alkyl, (C1-C4)-alkoxy, CF3, (C1-C4)-alkylthio.
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C1-C4)-alkoxy, biphenylyl, F, Cl, CF3, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, or R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl, F, Cl, X is oxygen or sulfur, R(7) is (C1-C10)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl-methyl-phenyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or polysubstituted by F, Cl, (C1-C4)-alkyl, (C1-C4)-alkoxy, CF3, (C1-C4)-alkylthio.
4. A compound of the formula I as claimed in claim 1, in which R(1) is H, R(2) is H, (C1-C15)-alkyl, (C1-C6)-alkyl-oxy-(C1-C6)-alkyl, (C1-C6)-alkyl-thio-phenyl, (C1-C6)-alkyl-oxy-phenyl, (C3-C12)-alkenyl, (C3-C10)-cycloalkyl (mono-, bi- or multicyclic), phenyl-(C1-C4)-alkyl, diphenyl-(C1-C6)-alkyl, the phenyl systems being unsubstituted or monosubstituted or disubstituted by substituents selected from the group comprising F, Cl, (C1-C8)-alkyl, (C3-C6)-cycloalkyl, (C1-C10)-alkoxy, (C1-C2)-alkylenedioxy, phenoxy, phenyl, benzyl, phenethyl, thiophenyl, CF3, or R(2) is an indol-3-yl-(C1-C4)-alkyl, thienyl or thienylmethyl radical, the thienyl ring being unsubstituted, or R(2) is piperidin-4-yl, substituted by 1 to 4 methyl groups and having a hydrogen, an acetyl group or a benzyl group on the N atom of the piperidine, R(3) is hydrogen, A is a group , in which the radicals R(4), R(5) and R(6) have the following meaning:
R(4) is H, (C1-C12)-alkyl, (C3-C12)-alkenyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic), Y-(C1-C12)-alkyl, Y-(C3-C12)-alkenyl, Y-(C3-C12)-cycloalkyl (mono-, bi-or multicyclic), phenyl, Y-phenyl, phenyl-(C1-C6)-alkyl,phenyl-(C1-C4)-alkoxy,F,Cl, the phenyl systems being unsubstituted or monosubstituted or disubstituted by F, Cl, CF3, (C1-C4)-alkyl, (C1-C4)-alkoxy, where Y equals oxygen or sulfur, R(5) is defined as R(4), R(4) and R(5) being identical or different, R(6) is H, (C1-C4)-alkyl, Y-(C1-C4)-alkyl, X is oxygen, R(7) is (C1-C4)-alkyl, (C3-C12)-cycloalkyl (mono-, bi- or multicyclic, such as norbornyl or adamantyl), phenyl-thio-phenyl, phenyl-oxy-phenyl, biphenylyl, phenyl, the aromatic ring systems mentioned being unsubstituted or monosubstituted or disubstituted by F, Cl, (C1-C4)-alkyl, (C1-C4)-alkoxy, CF3, (C1-C4)-alkylthio.
5. A process for the preparation of a compound of the formula (I) as claimed in claim 1, which comprises reacting a compound of the formula (II) (II) in which R(7), A and X have the meanings mentioned in claim 1, with a sulfur ylide of the formula III
(III) in which p is zero or 1, to give a compound of the formula IV
(IV), and subsequently reacting the compound IV with a nucleophile of the formula M-NR(2)R(3) in which R(2) and R(3) have the meanings mentioned and M is hydrogen or a metal equivalent, giving a compound I
where R(1) = H, which is isolated in the form of the free base, of an acid addition salt or of a physiologically hydrolyzable derivative.
(III) in which p is zero or 1, to give a compound of the formula IV
(IV), and subsequently reacting the compound IV with a nucleophile of the formula M-NR(2)R(3) in which R(2) and R(3) have the meanings mentioned and M is hydrogen or a metal equivalent, giving a compound I
where R(1) = H, which is isolated in the form of the free base, of an acid addition salt or of a physiologically hydrolyzable derivative.
6. A compound I as claimed in claim 1 for use in the treatment and prophylaxis of fungal diseases.
7. The use of a compound I as claimed in claim 1 for the preparation of a pharmaceutical for the treatment and for the prophylaxis of fungal diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4130708 | 1991-09-14 | ||
| DEP4130708.9 | 1991-09-14 |
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| Publication Number | Publication Date |
|---|---|
| CA2078057A1 true CA2078057A1 (en) | 1993-03-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078057A Abandoned CA2078057A1 (en) | 1991-09-14 | 1992-09-11 | Substituted aminopropanes, processes for their preparation, and their use |
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| Country | Link |
|---|---|
| EP (1) | EP0533056A3 (en) |
| JP (1) | JPH05221938A (en) |
| KR (1) | KR930005966A (en) |
| CN (1) | CN1070906A (en) |
| AU (1) | AU2353092A (en) |
| BR (1) | BR9203540A (en) |
| CA (1) | CA2078057A1 (en) |
| CZ (1) | CZ280892A3 (en) |
| FI (1) | FI924053A (en) |
| HU (1) | HU9202929D0 (en) |
| IL (1) | IL103142A0 (en) |
| MX (1) | MX9205236A (en) |
| NO (1) | NO923536L (en) |
| TW (1) | TW210283B (en) |
| ZA (1) | ZA926937B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11040935B2 (en) | 2016-10-05 | 2021-06-22 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule AMPK activators |
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| WO1998002151A2 (en) | 1996-07-12 | 1998-01-22 | Leukosite, Inc. | Chemokine receptor antagonists and methods of use therefor |
| MX2020003242A (en) | 2017-09-22 | 2020-09-18 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors. |
| BR112020007607A2 (en) | 2017-10-18 | 2020-09-29 | Jubilant Epipad LLC | compounds of formulas (i), (ii) and (iii); processes for preparing compounds of formulas (i), (ii) and (iii); pharmaceutical composition; compounds; method for inhibiting one or more pad families in a cell; method of treating a condition mediated by one or more pads; compound of formula (i), formula (ii) and formula (iii); use of the compound; method for treating and / or preventing a condition; method for the treatment of rheumatoid arthritis; and cancer treatment method |
| CN111386265A (en) | 2017-11-06 | 2020-07-07 | 朱比连特普罗德尔有限责任公司 | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
| MX2020005363A (en) | 2017-11-24 | 2020-10-01 | Jubilant Episcribe Llc | Heterocyclic compounds as prmt5 inhibitors. |
| WO2019175897A1 (en) | 2018-03-13 | 2019-09-19 | Jubilant Biosys Limited | Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation |
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| IL89997A0 (en) * | 1988-04-25 | 1989-12-15 | Lilly Co Eli | Propanamine derivatives |
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1992
- 1992-09-10 FI FI924053A patent/FI924053A/en unknown
- 1992-09-10 EP EP19920115497 patent/EP0533056A3/en not_active Withdrawn
- 1992-09-11 AU AU23530/92A patent/AU2353092A/en not_active Abandoned
- 1992-09-11 BR BR929203540A patent/BR9203540A/en not_active Application Discontinuation
- 1992-09-11 NO NO92923536A patent/NO923536L/en unknown
- 1992-09-11 JP JP4267931A patent/JPH05221938A/en active Pending
- 1992-09-11 IL IL103142A patent/IL103142A0/en unknown
- 1992-09-11 CZ CS922808A patent/CZ280892A3/en unknown
- 1992-09-11 CA CA002078057A patent/CA2078057A1/en not_active Abandoned
- 1992-09-11 ZA ZA926937A patent/ZA926937B/en unknown
- 1992-09-12 CN CN92110563A patent/CN1070906A/en active Pending
- 1992-09-14 KR KR1019920016635A patent/KR930005966A/en not_active Application Discontinuation
- 1992-09-14 MX MX9205236A patent/MX9205236A/en unknown
- 1992-09-14 HU HU9202929A patent/HU9202929D0/en unknown
- 1992-09-15 TW TW081107228A patent/TW210283B/zh active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11040935B2 (en) | 2016-10-05 | 2021-06-22 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule AMPK activators |
| US11673853B2 (en) | 2016-10-05 | 2023-06-13 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule AMPK activators |
Also Published As
| Publication number | Publication date |
|---|---|
| FI924053A0 (en) | 1992-09-10 |
| BR9203540A (en) | 1993-04-13 |
| JPH05221938A (en) | 1993-08-31 |
| EP0533056A2 (en) | 1993-03-24 |
| IL103142A0 (en) | 1993-02-21 |
| ZA926937B (en) | 1993-04-28 |
| NO923536L (en) | 1993-03-15 |
| HU9202929D0 (en) | 1992-11-30 |
| FI924053A (en) | 1993-03-15 |
| MX9205236A (en) | 1993-12-01 |
| AU2353092A (en) | 1993-03-18 |
| CN1070906A (en) | 1993-04-14 |
| EP0533056A3 (en) | 1993-06-16 |
| TW210283B (en) | 1993-08-01 |
| KR930005966A (en) | 1993-04-20 |
| NO923536D0 (en) | 1992-09-11 |
| CZ280892A3 (en) | 1993-03-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |