CA2235621A1 - Imidazole derivatives and their use as nitrogen monoxide synthase inhibitors - Google Patents

Imidazole derivatives and their use as nitrogen monoxide synthase inhibitors Download PDF

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CA2235621A1
CA2235621A1 CA002235621A CA2235621A CA2235621A1 CA 2235621 A1 CA2235621 A1 CA 2235621A1 CA 002235621 A CA002235621 A CA 002235621A CA 2235621 A CA2235621 A CA 2235621A CA 2235621 A1 CA2235621 A1 CA 2235621A1
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alkyl
phenyl
imidazolyl
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Peter Holscher
Hartmut Rehwinkel
Gerardine Burton
Gary Phillips
John Parkinson
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/68—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Abstract

The invention relates to the compounds of the formula (I), and to the preparation and use thereof in drugs.

Description

CA 0223S62l l998-04-22 ImidasolQ DQrivatives and their Use as Nitrogen Monoxide 8ynthas~
Inhibitors The invention relates to substituted phenylimidazole derivatives and pyridylimidazole derivatives as well as their production and use in pharmaceutical agents, especially their use as nitrogen monoxide synthase inhibitors.
It is known that nitrogen monoxide synthase (NOS) falls into the category of enzymes with hemoglobin groups in the active site, and that phenylimidazole bonds to the latter.
It has now been found that the affinity of imidazole derivatives for NOS can be increased in a way that could not have been predicted, if the latter have suitable substituents.
Compounds that selectively inhibit inducible human nitrogen monoxide synthase (hiNOS) at very small concentrations (IC50) and provide excellent action in vivo are obtained.
Selective nitrogen monoxide synthase inhibitors are suitable as pharmaceutical agents for treating diseases of the central nervous system, such as multiple sclerosis in all forms, dementia such as Alzheimer's disease, HIV dementia, amyotrophic lateral sclerosis and comparable sclerotic diseases, cerebral ischemia and other neurodegenerative diseases. They are also suitable for treating heart and cardiovascular diseases and sepsis or septic shock, hypotension, ARDS (adult respiratory distress syndrome), for treating auto-immune and/or inflammatory diseases such as rheumatoid arthritis, osteoarthritis, insulin-dependent diabetes mellitus (IDDM), inflammatory disease of the pelvis/intestine (bowel disease), meningitis, glomerulonephritis, acute and chronic liver diseases, diseases by rejection (for example, for immunosuppression in the case of transplants such as allogenic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis.
The invention relates to the new compounds of formula I

N
~N~Rl z~A-R2 in which ARZ can be the same or different in one or two places, R1 means hydrogen, halogen, -SH or -S-C14 alkyl, Z means nitrogen or -CH=, A means a bond, straight-chain or branched C14 alkylene, straight-chain or branched C24 alkenylene, straight-chain or branched C24 alkinylene, R2 means hydrogen, halogen, NOz, -C-N, C~3, -CCl3, -S(O) m~
C14 alkyl, -oR5, -S-R6, -Co-R7, -NR8R9, -CH(CN)-COOH, -CH(CN)-COO-C16 alkyl, =C(CN)-COOH, =C(CN)-COOC1 6 alkyl, -NH-SOz-R10, -C(NHz)=NOH, -NH-CO-NH2, -NH-CS-NH2, -NH-CS-NH(C14 alkyl), -C(=NR)-NHR11, -NH-C(=NR)-NR11R1Z, -S-(C=NR)-NR11R1Z, a 5- or 6-membered heteroaryl radical optionally substituted with C14 alkyl or halogen, a phenyl or biphenyl radical optionally substituted in one or more places with halogen, C- N, NO2, NH2, CF3, COOH, CONH2, COOC14 alkyl, -S-C~ 4 alkyl or -O-C14 alkyl;
imidazolosulfonyl, -NH-Co-NR16R17, R3 means hydrogen, halogen, NO2, OH, NH2 or imidazol-l-yl, AR2 and R3 together form -O-(CH2)n-O-, m, n mean 1 or 2, R5 means hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 C atoms, which can contain 1-2 double bonds and/or triple bonds, and in which a -CH2 group can be replaced by oxygen, sulfur, phenyl or C36 cycloalkyl optionally substituted with halogen; C3 7 cycloalkyl optionally substituted with methyl or halogen; -Co-R15, -CS-NH(C14 alkyl), -CH(NH2)-CO016 alkyl, -Si(CH3) 2 tert-butyl, quinolin-yl, Nl -methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-S-C14 alkyl, -CS-CH2-S-C14 alkyl, -C (=NR) NR11R12; phenyl optionally substituted with halogen, NO2, NH2, CF3, C - N, COOC1 4 alkyl, COOH, CONH2, C1 4 alkylthio, C1 4 alkoxy or C1 4 alkyl;
tetrahydropyrimidine, tetrahydropyridine, pyridine, -S~2-C1-4 alkyl, -SO2-C14 perfluoroalk R6 has the meaning of R5, R7 means hydrogen, C18 alkyl, C3 7 cycloalkyl, -CH2-S-C14 alkyl, -(CH2)2-S-C1 4 alkyl, -O-C1-6 alkyl, NH2, NH(C14 alkyl), N(C14 alkyl)2, -S-C14 alkyl, CF3, -C2F5, OH, phenyl, acidic and basic L-amino acid derivatives, [(5-nitro-2-pyridyl)amino]-ethylene amino, (2-anilino)-ethylene amino, R8, R9 are the same or different and mean hydrogen, C14 alkyl, C14 alkanoyl or together with the nitrogen atom form a 5- to 6-membered saturated heterocycle, which can contain another O, N or S atom and can be substituted in one to two places with C~ 4 alkyl, R10, R11, R12 and R mean hydrogen, C16 alkyl, C37 cycloalkyl, phenyl, thienyl, R15 means C1~7 alkyl optionally substituted with halogen, NH2, C--N, C~ 4 alkoxy, C~ 4 alkylthio, C~ 4 alkanoyloxy, thiophene or phenyl; C37 cycloalkyl optionally substituted with CH3 or phenyl; C16 alkoxy, C16 alkylthio, -COOH, -COOC1-6 alkyl, NR13R14, R13, R14 are the same or different and mean hydrogen or C~ 4 alkyl optionally substituted with halogen, R16 R17 are the same or different and mean hydrogen, C~ 4 alkyl, which optionally is substituted with thienyl or phenyl and in which the phenyl radical can be substituted in one or two places with halogen, imidazole, methylenedioxy or C18 alkylene, which is straight-chain or branched, and in which one or two methylene groups can be replaced by oxygen and/or sulfur, or -NR16R17 can form a saturated 5- or 6-membered heterocycle, which can contain another N, O or CA 0223~621 1998-04-22 S atom and can be substituted with phenyl, pyridine, pyridimine, pyridazine or pyrazine, and their isomers and tautomers and physiologically compatible salts, whereby (1) if R1 and * mean hydrogen, and Z = -CH, _AR2 in 2-position cannot be H, OH; Cl, Br, CF3, -CHO, -O-CO-CH3, CH2-Br, -CH20H~ - (CH2) 2-OH, --(CH2) 2-Br, -CH=CH2~ --O-CHZ--CH=CH2, -O-CH2-C-CH, -O-CH2-CN, -SH, -CHOH-CH3, -CH=CH-phenyl, (2) if F, Cl, OH, CH3 or NO2 is in 3-position of the phenyl ring, R1, R3 and -AR2 cannot mean H or imidazole at the same time, (3) if R1 = H, and OCH3, OH, NH2, fluorine or CH2-NH2 is in 4-position of the phenyl ring, H, OCH3 or OH cannot be in 2-position, (4) if R1 = H, and NO2, Br or OH is in 2-position of the phenyl ring, Cl or CH3 cannot be in 5-position, (5) if R1 = H and Z is -CH=, R5 or R6 cannot be optionally substituted benzyl.
The compounds of formula I and formula IA also comprise the possible tautomeric forms, the E or Z iosomers, or, if a chiral center is present, the racemates or enantiomers.
Inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, i.a., are suitable for salt formation.

The inorganic or organic bases that are known for forming physiologically compatible salts, such as, for example, alkali hydroxides such as sodium and potassium hydroxide, alkaline-earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methyl glucamine, tris-(hydroxymethyl)-methylamine, etc., are also suitable for salt formation.
Straight-chain or branched alkylene with 1-4 carbon atoms contains, e.g., methylene, ethylene, propylene, butylene, 1-methylmethylene, 1-ethylmethylene, 1-methylethylene, 1-ethylethylene, l-methylpropylene, 1-propylmethylene, 2-methylpropylene, i.a.
Straight-chain or branched alkenylene and alkinylene with 2-4 carbon atoms are defined as alkenyl or alkinyl groups with 1-2 double bonds and/or triple bonds in all possible positions as well as with all possible methyl or ethyl substitutions.
Alkyl means respectively a straight-chain or branched alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl, sec-hexyl, heptyl, octyl, nonyl, decyl, whereby 1-6 C atoms are preferred.
As hydrocarbon radical R5, alkyls, alkenyls and alkinyls are suitable.
As alkyls, the above-described straight-chain or branched alkyl groups are suitable.
The alkenyl and alkinyl substituents are respectively straight-chain or branched and preferably contain 2-10 C atoms.

CA 0223~621 1998-04-22 For example, the following radicals can be mentioned: vinyl, 2-propenyl, l-propenyl, 2-butenyl, 1-butenyl, l-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl.
If R2 means a heteroaryl radical, a 5- or 6-membered heteroaryl radical, which can contain one to two N, O or S atoms, such as, for example, imidazole, thiophene, furan, thiazole, pyrrole, pyridine, is suitable. The heteroaryl radical can be substituted in one or more places with C14 alkyl or halogen.
C14 alkyl esters, for example, of histidine, arginine, aspartic acid, glutamic acid, as well as histamine, asparagine, glutamine, are defined as L-amino acid derivatives.
In the hydrocarbon radical, a -CH2 group can be replaced by the radical and/or by the cycloalkyl radical ~ X
~<
(CH~p Y

with p = O, 1, 2 or 3, and X, Y = hydrogen or halogen.

Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

CA 0223~621 1998-04-22 Halogen means respectively fluorine, chlorine, bromine or iodine.
Hydrocarbon radicals R5 and R6 can be substituted at any point with up to 3 chlorine, 3 fluorine, bromine or iodine and/or in one to two places with OH, -O-C14 alkyl, -SH, -S-C14 alkyl, -NH(C14 alkyl), -N(C14 alkyl)2, -NH2, -NH-CO-(CH2)2-S-C14 alkyl, --NH-pyridin-2-yl, --C--N,-COOH, -CO-O-C1-6 alkyl, --CO-NH--(C1 4 alkyl), -CO-N-arginine, -CO-CH3, tetrahydrofuranyl, 2,2-dimethyl-1,3-dioxolan, -S(O)m-C14 alkyl, -NH-C(=NR)-NR11R12, -C(=NH)-NH2, -C(=NH)-C14 alkyl, -CH(NH2)-COOH, -CH(NHz)-COOC16 alkyl, C3 7 cycloalkyl, NHSO2R, phenyl, which can be substituted in one to two places with halogen, NO2, -SH, -S-C14 alkyl, -O-C14 alkyl or phenyl, or a 5- or 6-membered heteroaryl radical, which can contain 1-3 nitrogen atoms and/or 1-2 sulfur atoms and can be substituted with C14 alkyl.
Alkyl, alkenyl and alkinyl radicals R1s can be substituted with the same or different radicals in one to two places or else are present in perhalogenated form.
If R8, R9 together with the nitrogen atom form a 5- or 6-membered saturated heterocycle, which can contain another O, N or S atom and can be substituted with 1-2 C14 alkyl in one or two places, e.g., morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, N-methyl-piperazine or 2,6-dimethylmorpholine thus are suitable as heterocycles.
If R16R17 together with the nitrogen atom form a saturated 5-or 6-membered heterocycle, the above-mentioned heterocycles are suitable.

CA 0223~62l l998-04-22 As heteroaryl radicals in R5 or R6, there can be mentioned, for example: pyrazole, imidazole, thiophene, thiazole, thiadiazole, pyridine, pyrimidine and triazine.
Compounds of formula I, which contain the -A-R2 substituents in 2- and/or 4-position of the phenyl or in 3- and/or 5-position of the pyridine, whereby -AR2 can be the same or different, can be viewed as preferred.
Preferred are the following meanings:
R1 = hydrogen, R2 means hydrogen, halogen, NO2, -C--N, CF3, -CCl3, -S(O)~-C1 4 alkyl, -oR5, -S--R6, -Co-R7, -NR8R9 -NH-SOz-R10, -C(NHz)=NOH, -NH-CO-NHz, -NH-CS-NH2, NH-CO-NH(C1 4 alkyl), --NH--CS-NH(C1 4 alkyl), --C(=NR)--NHR11, --NH--C(=NR)-NR11R12 -S-(C=NR)-NR11R12, a 5- or 6-membered heteroaryl radical optionally substituted with C14 alkyl or halogen, a phenyl or biphenyl radical optionally substituted in one or more places with halogen, C-N, NO2, NHz, CF3, COOH, CONHz, COOC14 alkyl, --S--C14 alkyl or --O--C14 alkyl; imidazolosulfonyl, --NH--Co_NR16R17 Especially preferred are combinations in which at least one radical ARZ is present, in which A means a bond and RZ means an optionally substituted heteroaryl radical or an optionally substituted phenyl radical or in which A means a bond or straight-chain or branched C14 alkylene and CA 0223~621 1998-04-22 R2 is ORs or SR6 As preferred meanings for R5 and R6, there can be mentioned:
Hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 C atoms, which can contain 1-2 double bonds and/or triple bonds and in which a -CH2 group can be replaced by oxygen or sulfur, -Si(CH3)2 tert-butyl, quinolin-yl, Nl-methyl-imidazol-2-yl, thiophenyl, -CS-S-C14 alkyl, -CS-CH2-S-C14 alkyl, -C(=NR)NR11R12;
phenyl optionally substituted with halogen, NO2, NH2, CF3, C=N, COOC14 alkyl, COOH, CONH2, C14 alkylthio, C14 alkoxy or C14 alkyl;
tetrahydropyrimidine, tetrahydropyridine, pyridine, --SO2-C14 alkyl, -SO2-C14 perfluoroalkyl.
Straight-chain or branched alkyl with 1-8 C atoms, straight-chain or branched alkenyl with 2-8 C atoms, straight-chain or branched alkinyl with 2-8 C atoms can be viewed as a preferred meaning of -A-R2, whereby one or two of the methylene groups can be replaced by oxygen and/or sulfur in all oxidation stages. If a substituent is present, the latter is preferably in terminal position. Another preferred meaning of AR2 is optionally substituted phenyl.
The invention also relates to the use of substituted phenylimidazole derivatives and substituted pyridylimidazole derivatives, their isomeric and tautomeric forms and their salts for the production of a pharmaceutical agent for treating or preventing diseases in which the inhibition of the nitrogen monoxide synthase is advantageous.

CA 0223~621 1998 - 04 - 22 Used according to the invention as inhibitors of the nitrogen monoxide synthase are the compounds of formula IA

N R
z~A-3R IA

in which AR2 can be the same or different in one or two places, R1 means hydrogen, halogen, -SH or -S-C1 4 alkyl, Z means nitrogen or -CH=, A means a bond, straight-chain or branched C1 4 alkylene, straight-chain or branched C24 alkenylene, straight-chain or branched Cz 4 alkinylene, R2 means hydrogen, halogen, NO2, -C-N, CF3, -CCl3, -S(O) m~
C14 alkyl, -oR5, -S-R6, -Co-R7, -NR8R9, -CH(CN)-COOH, -CH(CN)-COO-C16 alkyl, =C(CN)-COOH, =C(CN)-COOC16 alkyl, -NH-SO2-R1~, -C(NH2)=NOH, -NH-CO-NH2, -NH-CS-NH2, -NH-CS-NH(C1 4 alkyl), -C(=NR)-NHR11, -NH-C(=NR)-NR11R12, -S-(C=NR)-NR11R12, a 5- or 6-membered heteroaryl radical optionally substituted with C1 4 alkyl or halogen, a phenyl or biphenyl radical optionally substituted in one or more places with halogen, C--N, NO2, NH2, CF3, COOH, CONH2, COOC14 alkyl, -S-C14 alkyl or -O-C14 alkyl;
imidazolosulfonyl, -NH-Co-NR16R17, R3 means hydrogen, halogen, NO2, OH, NH2 or imidazol-1-yl, AR2 and R3 together form -O-(CH2)n-O-, m, n mean 1 or 2, R5 means hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 C atoms, which can contain 1-2 double bonds and/or triple bonds, and in which a -CH2 group can be replaced by oxygen, sulfur, phenyl or C36 cycloalkyl optionally substituted with halogen; C37 cycloalkyl optionally substituted with methyl or halogen; -Co-R15, -CS-NH(C14 alkyl), -CH(NH2)-CO016 alkyl, -Si(CH3)2 tert-butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-S-C14 alkyl, -CS-CH2-S-C14 alkyl, -C(=NR)NR11R12, phenyl optionally substituted with halogen, NO2, NH2, CF3, C-N, COOC~ 4 alkyl, COOH, CONH2, C14 alkylthio, C~ 4 alkoxy or C~ 4 alkyl;
tetrahydropyrimidine, tetrahydropyridine, pyridine, -SO2-C14 alkyl, -S02-C~ 4 perfluoroalkyl, R6 has the meaning of R5, R7 means hydrogen, C18 alkyl, C37 cycloalkyl, -CH2-S-C14 alkyl, -(CH2)2-S-C14 alkyl, -O-C16 alkyl, NH2, NH(C1 4 alkyl), -N( C~ 4 alkyl)2, -S - C~ 4 alkyl, CF3, -C2F5, OH, phenyl, acidic and basic L-amino acid derivatives, t(5-nitro-2-pyridyl)amino]-ethylene amino, (2-anilino)-ethylene amino, R8, R9 are the same or different and mean hydrogen, C14 alkyl, C14 alkanoyl or together with the nitrogen atom form a 5- to 6-membered saturated heterocycle, which CA 0 2 2 3 ~ 6 2 l 1 9 9 8 - 0 4 - 2 2 can contain another O, N or S atom and can be substituted in one to two places with C14 alkyl, R10, R11, R12 and R mean hydrogen, C16 alkyl, C37 cycloalkyl, phenyl, thienyl, R15 means C117 alkyl optionally substituted with halogen, NH2, C-N, C14 alkoxy, C14 alkylthio, C~ 4 alkanoyloxy, thiophene or phenyl; C37 cycloalkyl optionally substituted with CH3 or phenyl; C16 alkoxy, C16 alkylthio, -COOH, -COOC1-6 alkyl, NR13R14, R13, R14 are the same or different ~nd mean hydrogen or C14 alkyl optionally substituted with halogen, R16 R17 are the same or different and mean hydrogen, C14 alkyl, which optionally is substituted with thienyl or phenyl and in which the phenyl radical can be substituted in one to two places with halogen, imidazole, methylenedioxy or C18 alkylene, which is straight-chain or branched and in which one or two methylene groups can be replaced by oxygen and/or sulfur or -NR16R17 can form a saturated 5- or 6-membered heterocycle, which can contain another N, O or S atom and can be substituted with phenyl, pyridine, pyridimine, pyridazine or pyrazine, and their isomers and tautomers and physiologically compatible salts, whereby R1, -A-R2 and R3 do not mean hydrogen at the same time, for the production of a pharmaceutical agent for treating diseases CA 0223~62l l998-04-22 that are triggered by the action of nitrogen monoxide at pathological concentrations.
The compounds of formula I as well as their physiologically compatible salts can be used as pharmaceutical agents on the basis of their affinity to and inhibition of the action of the nitrogen monoxide synthases and here especially the inducible nitrogen monoxide synthase. on the basis of their profile of action, the compounds according to the invention are suitable for treating diseases that are caused or intensified or worsened by excess nitrogen monoxide in the body under inducing and pathological conditions.
The above include multiple sclerosis in all forms, dementia such as, e.g., presenile dementia, Alzheimer's disease and HIV
dementia, Parkinson's disease, Huntington's disease, Korsakoff's syndrome, stroke, epilepsy, sleep disturbances, schizophrenia, depression, migraine, hypoglycemia, sepsis or septic shock, amyotrophic lateral sclerosis and comparable sclerotic diseases, cerebral ischemia, hypoxia and other neurodegenerative diseases, which are associated with inflammations. They are also suitable for treating diseases of the cardiovascular system and for treating auto-immune and/or inflammatory diseases such as hypotension, ARDS (adult respiratory distress syndrome), rheumatoid arthritis, osteoarthritis, insulin-dependent diabetes mellitus (IDDM), inflammatory disease of the pelvis/intestine (bowel disease), meningitis, glomerulonephritis, acute and chronic liver diseases, diseases by rejection (for example, CA 0223~621 1998-04-22 1~

allogenic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.
To use the compounds according to the invention as pharmaceutical agents, the latter are put into the form of a pharmaceutical preparation, which, in addition to the active ingredient for enteral or parenteral administration, contains suitable pharmaceutical, organic or inorganic inert vehicles, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, plant oils, polyalkyleneglycols, etc. The pharmaceutical preparations can be present in solid form, for example, as tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. They also optionally contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
For parenteral use, especially injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable.
As vehicle systems, surface-active adjuvants, such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or their components can also be used.
For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as for example, lactose, corn or potato starch, are suitable. The administration can also be carried out in liquid CA 0223~62l l998-04-22 form, such as, for example, as juice, to which optionally a sweetener is added.
The dosage of the active ingredients can vary depending on method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 1-2000 mg, preferably 20-500 mg, whereby the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
The enzyme nitrogen monoxide synthase has at least three different isoforms: the endothelial enzyme, the brain enzyme and the inducible NOS. The NOS-inhibitory action of the compounds of formula IA and their physiologically compatible salts can be determined according to the methods of Bredt and Snyder in Proc.
Natl. Acad. Sci. USA (1990) 87, 682--685.
The production of the compound according to the invention is carried out according to methods known in the art. For example, compounds of formula I are attained, in that a) a compound of formula II

~kAR2 WR

ll in which Z, AR2 and R3 have the above meaning, and Flu represents a leaving group, is reacted with imidazole optionally substituted with R1 in the presence of a base or CA 0223~621 1998 - 04 - 22 b) a compound of formula III

~N ~ R1 ~N ~' R1 Z ~ A-FIu or Z ~ A-FIu III

in which A, Z, R1, AR2 and R3 have the above meaning and Flu represents a leaving group, is substituted in a nucleophilic manner in the presence of a base and/or with an organometallic compound, c) a compound of formula IV

N

Z ~ H

lV

in which Z, R1, R3 have the above meaning, is reacted to compounds of formula I using Aldol reactions or Wittig reactions or by nucleophilic attack with Grignard reagents, and it is then optionally halogenated or selectively reduced, or thioether is CA 0223~62l l998-04-22 formed, or ether is cleaved, or nitriles are saponified, or acids are esterified or amidated, or ethers or esters are synthesized from phenolene, or amino groups are exchanged via Sandmeyer reaction or boiled down, or sulfides are oxidized to sulfones or sulfoxides, or sulfoxides are reduced to sulfides, or amines are reacted or alkylated or decarboxylated to amides or sulfonamides, or isomers or salts are formed.
In this case, Flu can mean, for example, tosylate, mesylate, triflate, nonaflate or halogen. The aromatic compound is reacted in the presence of bases at room temperature or elevated temperature in aprotic solvents. Here and there, the reaction is facilitated or the yield improved, if copper or copper salts are added.
As bases, for example, alkali compounds such as potassium carbonate, sodium hydroxide, alkali alcoholates such as potassium tert-butylate and especially metal hydrides, such as sodium hydride, are suitable. At times, the alkali compounds can also be reacted under phase transfer conditions. If mixtures of compounds with the substituent imidazolyl-, (2'-R1-imidazolyl-), -RZ or -R3 are obtained in various numbers and/or in various positions, the latter are separated in the usual way.
Solvents that are suitable for reaction are aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone or DMSO.
When the reaction is carried out in a suitable manner, both the leaving group and an additionally present halogen atom can be substituted.

CA 0223~621 1998-04-22 If the reaction is performed with organometallic compounds, Grignard compounds optionally under transition metal catalysis, stannyl compounds or palladium-catalyzed coupling with boric acid derivatives are suitable.
Halogen or nitro can be introduced by bromation or nitration, whereby optionally the reactivity of the already present aromatic substituents can be observed. The framework optionally must first be nitrated or halogenated before being reacted with a heterocycle. Then, the nitro group can be reduced, and the amino group that is produced can be exchanged via Sandmeyer reaction or boiled down to phenol or alkylated, and the resulting hydroxy compounds can be etherified or esterified.
By nucleophilic substitution of leaving groups, such as bromides, thio ethers are produced; these sulfides can then be oxidized to sulfones or sulfoxides. Nitriles are saponified and optionally acids are esterified or amidated.
The Aldol reactions are performed according to standard conditions with malonodinitrile, malonic acid derivatives or other CH-acid compounds.
Using Wittig reactions or under modified Wittig-Horner conditions, carbon double bonds are introduced in the ordinary way.
The nucleophilic attack with Grignard reagents is carried out in a known way in aprotic solvents such as ether or THF, for example with alkyl or aryl magnesium bromide.
The optionally subsequent saponification of an ester group can be carried out in a basic or acidic manner by the reaction CA 0223~621 1998-04-22 mixture being hydrolyzed in the presence of alkali hydroxides in ethanol or other alcohols or with the aid of acids, such as, e.g., hydrochloric acid, at room temperature or elevated temperature up to boiling temperature, and optionally imidazolium salts being further processed.
The esterification of the carboxylic acid is carried out in a way known in the art with diazomethane or the corresponding alcohol in acid or in the presence of an activated acid derivative. As activated acid derivatives, for example, acid chloride, acid imidazolide or acid anhydride are suitable.
The amidation is carried out on free acids or on their reactive derivatives, such as, for example, acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature or elevated temperature.
In addition, a nitro group or halogen, especially bromine, can be introduced by electrophilic aromatic substitution. In this case, mixtures are produced that can contain substituted imidazole and can be separated in the usual way. If a nitrile is present, the latter can be saponified according to known processes or can be converted to the corresponding amine, tetrazole or amidoxime.
The reduction of the nitro group or optionally the cyano group to the amino group is carried out catalytically in polar solvents at room temperature or elevated temperature under hydrogen pressure. As catalysts, metals such as Raney nickel or noble metal catalysts, such as palladium or platinum, optionally in the presence of barium sulfate or on vehicles, are suitable.

CA 0223~621 1998 - 04 - 22 Instead of hydrogen, ammonium formate can also be used in a known way. Reducing agents such as tin(II) chloride or titanium(III) chloride can be used just as complex metal hydrides optionally in the presence of heavy metal salts. The ester group can advantageously be introduced before the reduction. Nitro groups can also be reduced selectively in the usual way with Na2S or sodium dithionite. The reduction with zinc in acetic acid or ammonium chloride has proven to be of value.
If an alkylation of an amino group is desired, alkylation can be carried out according to commonly used methods, for example, with alkyl halides.
The introduction of the cyano group can be carried out with the aid of the Sandmeyer reaction; for example, the diazonium salts that are formed intermediately with nitrites from the amino compounds can be reacted with alkali cyanides in the presence of Cu(I) cyanide.
The introduction of the halogens chlorine, bromine or iodine with the amino group can also be carried out, for example, according to Sandmeyer, by the diazonium salts that are intermediately formed with nitrites being reacted with Cu(I) chloride or Cu(I) bromide in the presence of the corresponding acid, such as hydrochloric acid or hydrobromic acid, or being reacted with potassium iodide.
The introduction of an NO2 group is possible by a number of known nitration methods. For example, nitration can be carried out with nitronium tetrafluoroborate in inert solvents, such as halogenated hydrocarbons or in sulfolane or glacial acetic acid.

CA 0223~621 1998-04-22 The introduction is also possible by, e.g., nitrating acid in water or concentrated sulfuric acid as solvent at temperatures of between 0~C and 30~C.
Amidoximes are produced from the corresponding nitrile with hydroxylamine hydrochloride, e.g., in alcohol-water mixtures as solvent.
The activated sulfonic acid derivative, such as, for example, the sulfonic acid chloride, is reacted in the usual way with nucleophilic N-derivatives (such as H2N(Cl4 alkyl) or H2N-CH2coNH2 or H2N-CH2-R)-The isomer mixtures can be separated into enantiomers or E/Zisomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation. As an alternative, optical isomers can also be produced from the corresponding optically active compounds as starting material under reaction conditions which do not cause any racemization.
Intermediate compounds can also be present as enantiomers, diastereomers, racemates or mixtures thereof.
The production of salts is carried out in the usual way, by a solution of the compound of formula I being mixed with the equivalent amount of an acid or excess acid, which is optionally in solution, and the precipitate being separated, or the solution being worked up in the usual way.
In so far as the production of starting compounds is not described, the latter are known or can be produced analogously to known compounds or processes that are described here.

CA 0223~621 1998-04-22 The following examples are intended to show the structures according to the invention and their production.
The compounds according to the invention are not limited to the above-mentioned examples, however.
New compounds were characterized by one or more of the following methods: melting point, mass spectroscopy, infrared spectroscopy, nuclear-magnetic resonance spectroscopy (NMR). NMR
spectra were measured with a Bruker 300 MHz device, the (deuterated) solvents are indicated in each case and abbreviated as follows: CDCl3 ~chloroform), DMSO (dimethyl sulfoxide).
Shifts are indicated in delta and ppm. In addition, THF means tetrahydrofuran, DMF means N,N-dimethylformamide, NMP means N-methylpyrrolidone, and EE means ethyl acetate. All solvents are of analytical quality, unless otherwise indicated. All reactions are performed under protective gas, since these can be aqueous solutions. Mult. means multiplet, several signals; s means singlet; d means doublet; dd means double doublet, etc.; tr means triplet; H means hydrogen protons; J means coupling constant; ml means milliliter; and RT means room temperature. Melting points are indicated in degrees Celsius and are not corrected. Yields in percent refer to the educt, not to the conversion.
Below, the production of a few precursors or intermediate products is described by way of example.

CA 0223~621 1998-04-22 Example 4-Bromo-3-bromomethylbenzonitrile 1.96 g of 4-bromo-3-methylbenzonitrile is dissolved in 15 ml of carbon tetrachloride, mixed with 1.2 equivalents of N-bromosuccinimide and a spatula tip full of AIBN
(azoisobutyronitrile) and refluxed under irradiation with a 500 W
lamp. After the reaction has been completed, it is concentrated by evaporation and chromatographed on a 4 cm thick column with hexane/EE in a gradient. The yield is 35%.
Analogously, different intermediate products are produced from commercially available methyl aromatic compounds.

Example 2 4-Bromo-(3-methylthiomethyl)benzonitrile 1.37 g of 4-bromo-3-bromomethylbenzonitrile in 8 ml of NMP
is dissolved at 5~, and 0.42 g of sodium thiomethylate, dissolved in 5 ml of NMP, is slowly added in drops to it at an internal temperature of 5~. It is stirred for 2 hours at this temperature, then for another 2 hours at room temperature. It is dispersed between EE and water, the organic phases are washed with brine, dried with magnesium sulfate and spun in. Column chromatography with hexane/EE yields 79% product.
Various benzylthioethers are produced in the same way.
Biphenyl-methylthioethers are also produced in the same way;
for example, 2-bromo-5-phenylbenzyl thiomethyl ether is from 2-bromo-S-phenylbenzyl bromide.
Example 3 CA 0223~621 1998-04-22 2-Fluoro-(3-methylthiomethyl)pyridine is produced from 2-~luoro-3-methylpyridine as described above with a yield of 58~.
Various pyridylmethylthioethers are produced in the same way.

Exampl~ 4 2,5-Bis(methylthiomethyl)-bromobenzene 592 mg of 4-(bromomethyl)-2-bromobenzyl bromide is dissolved in 4.81 ml of NMP and slowly mixed at room temperature with 2.2 equivalents, i.e., 267 mg, of sodium thiomethylate while being stirred vigorously. After 12 hours, i~ is diluted with water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. 370 mg, i.e., 77.1%, of a slightly colored oil results.
Various aromatic thioethers and bis-thioethers are thus produced.

Example S
2-Bromobenzyl-ethylthioether 4.62 g of crude product, which is homogeneous in NMR, is obtained from 15 g of ortho-bromobenzyl bromide with 9 g of sodium thioethylate, which was added in portions to the educt in 60 ml of NMP while being cooled in a water bath, after 15 hours of stirring at room temperature and pouring onto water, extraction with EE, drying and concentration by evaporation. The yield is 45%.

CA 0223~621 1998-04-22 Analogously, various substituted benzylethylthioethers are obtained from commercially available precursors or precursors that can be produced in the described way.

Example 6 (2-Chloro-6-fluoro-benzyl)-methylthioether After 1.2 equivalents of sodium thiomethylate is added after 1 hour at room temperature in 20 ml of dry NMP, 2.6 ml (20 mmol) of 2-chloro-6-fluoro-benzyl chloride yields 2 new products. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. 59% of (2-chloro-6-fluoro-benzyl)-methylthioether and 9.8% of (2-chloro-6-methylthio-benzyl)-methylthioether result.

Example 7 Benzoic acids are suitably esterified as precursors. Thus, 3-bromo-4-methylbenzoic acid methyl ester is added to 24.94 g of 3-bromo-4-methylbenzoic acid with 19.35 g of potassium carbonate, 12.5 ml of iodomethane in 200 ml of acetone after 3 hours of reflux, cooled, suctioned off, concentrated by evaporation and column chromatography with hexane/EE with a yield of 96~.

Example 8 S-(Ortho-bromo-benzyl)-L-cysteic acid ethyl ester 2.5 g of bromobenzyl bromide is dissolved with 1 equivalent of L--cysteic acid ethyl ester hydrochloride and 2.2 equivalents of potassium carbonate in 10 ml of DMF. After 3 hours at 80~, it is suctioned off, rewashed with EE, concentrated by evaporation and column-chromatographed with hexane/EE. 358 mg of product is obtained.

Bxample 9 2-(2-Bromophenyl)ethanol 15 mmol of 2-bromophenylacetic acid in 15 ml of THF is added in drops to 15 ml of THF with 2 equivalents of lithium aluminum hydride. Hydrogen is produced. After the end of the reaction, it is acidified with dilute sulfuric acid, extracted with EE, the organic phase is washed with sulfuric acid, then with water, then with soda solution. It is dried and spun in. The yield is 81%.
In an analogous implementation, 2-(2-chlorophenyl)propanol (the yield is 96%) and similar reduction products are produced.

~xample 10 3-(2-Chlorophenyl)propanol-tert-butyldimethylsilyl ether At an internal temperature of 5~, 2.23 g of 3-(2-chlorophenyl)propanol in 15 ml of NMP with 3.54 g of imidazole and 2 equivalents of tert-butyldimethylsilyl chloride are mixed and stirred for 1 hour. Then, stirring is continued for 12 hours at room temperature. It is shaken out between EE and water, washed with dilute acid, the organic phase is washed with brine, dried with magnesium sulfate and spun in. Column chromatography with hexane provides a 100% yield.
Other precursors are etherified analogously.

CA 0223~621 1998-04-22 Below are a few selected examples of the compounds according to the invention.
Example 11 [2-(1-Imidazolyl)-phenyl]-isobutylthioether 162 mg of 2-(1-imidazolyl)-fluorobenzene in 3 ml of NMP is stirred with 1.5 equivalents of 2-methyl-1-mercaptopropane and 1.5 equivalents of 80% sodium hydride for 4 hours at 120~. It is diluted with water, extracted with EE, the organic phase is washed with brine, it is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with hexane/EE 1:1 provides a 76% yield. lH NMR (CDCl3): 7.7(1H), 7.17 to 7.5 (mult. 6H), 2.13(d 2H), 1.8(heptet lH), 0.97(d 6H).

Analogously, there are produced from the substituted fluorobenzene, i.a.:
Example 12 [2-(1-Imidazolyl)-phenyl]-cyclohexyl ether. The yield is 93%.
[lH]-NMR (acetone d6): 7.81(1H), 7.05 to 7.37 (mult. 6H), 4.44 (mult. lH), 1.2 to 2.0 (mult. lOH).

Example 13 [2-(1-Imidazolyl)-phenyl]-(3-methylbut-1-yl)ether, yield 73%, oil.

Example 14 [2-(1-Imidazolyl)-phenyl]-tert-butyl ether, yield: 73%. [lH]-NMR (CDCl3): 7.82(1H), 7.15 to 7.4 (mult. 6H), l.ll(s 9H).

CA 0223~621 1998-04-22 Example 15 [2-(1-Imidazolyl)-phenyl]-cyclopentyl ether, yield: 49%. [lH]-NMR (CDCl3): 7.8(1H), 6.98 to 7.33 (mult. 6H), 4.8 (mult. lH), 1.5 to 0.9 (mult. 8H).

Example 6 [2-(1-Imidazolyl)-phenyl]-(tetrahydrofuran-2-ylmethyl)ether. The yield is 10%.
Melting point: oil.

Bxample 17 3-Chloro-2-(1-imidazolyl)-pyridine 1.48 g of 2,3-dichloropyridine is dissolved in NMP, and 0.68 g of imidazole as well as 1.66 g of dry potassium carbonate are added to it. Then, the mixture is heated for 6 hours to 150~.
The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After column chromatography with EE, 39% product results. [lH]-NMR (CDCl3): 7.2 to 8.5 (mult.
6H).

Bxample 18 2-Nitro-4-methyl-phenyl-1-(1-imidazole) 300 mg of 3-nitro-4-fluoro-toluene is heated in 2 ml of NMP
with 132 mg of imidazole as well as 280 mg of potassium carbonate (ground) to 100~. After the reaction has been completed, the mixture is poured onto water, extracted with ethyl acetate, the CA 0223~621 1998 - 04 - 22 organic phase is dried with magnesium sulfate and concentrated by evaporation. 98.2% product results. [lH]-NMR (CDC13):
7.61(1H), 7.21(1H), 7.05(1H), 7.80(d lH), 7.52(dd J=8/1.5 Hz, lH), 7.33(d J=8Hz lH), 2.52(s 3H).

Example 18a [5-Chloro-2-(1-imidazolyl)-phenylmethyl]-methylthioether consisting of [2-bromo-5-chloro-phenylmethyl]-methylthioether.
The yield is 15%.

Example 19 [3-Trifluoromethyl-2-(1-imidazolyl)-phenylmethyl]-methylthioether 448 mg of (2-fluoro-3-trifluoromethyl-benzyl)methylthioether is heated with 1 equivalent of imidazole and 1 equivalent of powdered potassium carbonate as well as 30 mg of copper powder for 2 hours to 200~. It is diluted with EE, suctioned off, and the mother liquor is concentrated by evaporation. After column chromatography with hexane with increasing addition of EE, 240 mg of product is obtained. The yield is 44%. [lH]-NMR (CDC13):
7.7 (mult. 2H), 7.54 (mult. 2H), 7.21 (singlet lH), 7.05(1H), 3.24(s 2H), 2.0(s 3H).

Under the above-described conditions of the reactions with imidazole are obtained the compounds claimed from fluorine, chlorine or bromine aromatic compounds, a few examples of which are mentioned below.

-CA 0223~621 1998-04-22 Example 20 1-[5-Chloro-2-(1-imidazolyl)-phenyl]-ethanol, yield: 25%, oil.

Example 21 2-Bromo-3-fluoro-phenyl-(1-imidazole), yield: 8%, melting point:
52~.

Example 22 2-Hydroxymethyl-3-fluoro-phenyl-(1-imidazole), yield: 11~, lH-NMR (DMS0 d6): 7.96(1H), 7.5(1H), 7.1(1H), 7.25 to 7.5 (in addition to 3H), 4.3(s 2H).

Example 23 [4-(1-Imidazolyl)-phenyl]-3-chlorophenol, yield: 80%, lH-NMR
(CDCl3): 7.7(1H), 7.22(1H), 7.09(1H), 7.30(d lH), 6.86(dd lH), 7.01(d lH).

Example 24 1-[2-(1-Imidazolyl)-4-chloro-phenyl]-ethanol, yield: 22%, lH-NMR

(DMS0 d6): 7.82(1H), 7.4(1H), 7.1(1H), 7.7 (mult. 3H), 4.5 (mult. lH), 5.3(s broad lH), 1.2(d 3H).

Example 25 2-Cyano-5-fluoro-phenyl-1-(1-imidazole), yield: 28%, lH-NMR
(CDCl3): 7.9(1H), 7.85(1H), 7.38(1H), 7.22 (mult. 3H).

Example 26 2-Cyano-5-(1-imidazolyl)-phenyl-1-(1-imidazole), yield: 7%, lH-NMR (CDCl3): 7.97(1H), 7.79(1H), 7.31(1H), 7.23(1H), 6.98(1H), 6.91(1H), 7.68(d lH), 7.58(d lH), 7.40(dd lH).

Ex mple 27 2-Hydroxy-3-(1-imidazolyl)-4-methoxy-phenyl-1-(1-imidazole), yield: 17%, melting point 253~.

Example 28 2-(1-Imidazolyl)-5-nitrophenol, yield: 12%, lH-NMR (DMS0 d6):
8.14(1H), 7.1(1H), 7.6(1H), 7.88(d lH), 7.80(dd lH), 7.69(d lH).

Ex~mple 29 2-(1-Imidazolyl)-6-methyl-phenyl]-methyl ether, yield: 99%, lH-NMR (CDCl3): 7.2 (mult. 5H), 7.82(1H), 3.38(s 3H), 2.36(s 3H).

Example 30 2-Methoxy-4-methoxy-phenyl-1-(1-imidazole), yield: 51%, lH-NMR
(CDCl3): 6.5 to 7.8 (mult. 6H), 3.80(s 3H), 3.83(s 3H).

Example 31 2-Methyl-4-methoxy-phenyl-1-(1-imidazole), yield: 60%, melting point: 47~.

_ :

Example 32 2-Methoxy-5-methoxy-phenyl-1-(1-imidazole), yield: 50%, lH-NMR
(DMS0 d6): 7.0 to 8.0 (mult. 6H), 3.78(s 3H), 3.80(s 3H).

Example 33 2-Methoxy-4-nitro-phenyl-1-(l-imidazole), yield: 7%, melting point: 136~.

Example 34 2~Methoxy-5-(imidazol-1-yl)-phenyl-1-(1-imidazole), yield: 10%, melting point: 116~.

Example 35 2-Methoxy-5-tert-butyl-phenyl-1-(1-imidazole), yield: 21%, melting point: 79~.

Example 36 2-Trichloromethyl-3-fluoro-phenyl-1-(1-imidazole), yield: 7%, melting point: oil.

Exampl~ 37 2-Nitro-5-cyano-phenyl-1-(1-imidazole), yield: 78~, melting point: 161~, lH-NMR (CDCl3): 7.6(lH), 7.12(lH), 7.0(lH), 8.22(d lH), 7.96(dd lH), 7.59(1H).

CA 0223~621 1998-04-22 Example 38 2-Nitro-5-chloro-phenyl-1-(1-imidazole), yield: 51%, lH-NMR
(CDC13): 7.05(1H), 7.22(1H), 7.63(1H), 8.0(d lH), 7.6(dd lH), 7.49(d lH,J=1.5Hz).

Example 39 2-Nitro-4-methoxy-phenyl-1-(1-imidazole), yield: 35%, melting point: 98~.

Example 40 2-Thiomethyl-5-nitro-phenyl-1-(1-imidazole), yield: 37%, melting point: 225~.

Bxample 41 (2-t2-(1-Imidazolyl)-phenyl]ethyl)-methylthioether, yield: 29%, melting point: 79~.

Example 42 6-Chloro-2-(1-imidazolyl)-acetophenone, yield: 11%, lH-NMR

(CDC13): 7.74(1H), 7.13(1H), 6.1(1H), 7.2 (mult. 2H), 7.27(1H), 1.55(s 3H).

Exampl~ 43 (rac)-[2-(1-Imidazolyl)-phenylmethyl]-(l-phenyl-ethyl)-thioether, yield: 38%, lH-NMR (CDC13): 7.1 to 7.62 (mult. 12H), 3.3 (mult.
2H), 3.89 (~uartet lH), 1.51(d 3H).

CA 0223~621 1998-04-22 Example 44 [2~ Imidazolyl)-phenylmethyl]-ethylthioether, yield: 82%, lH-NMR (CDCl3): 7.72(1H), 7.22(1H), 7.2(1H), 7.23 to 7.5 (mult.
4H), 3.52(s 2H), 2.47 (quartet 2H), 1.2(tr3H).

Example 45 [2-(1-Imidazolyl)-phenylmethyl]-isopropylthioether, yield: 58%, lH-NMR (CDCl3): 7.72(1H), 7.2 to 7.5 (mult. 6H), 3.53(s 2H), 2.8 (mult. lH), 1.2(lH), 1.22 each (d 3H).

Example 46 [2-(1-Imidazolyl)-phenyl]-methylthioether, yield: 65%, melting point: 208~.

Example 47 [2-(1-Imidazolyl)-phenylmethyl]-methylthioether, yield: 59%, lH-NMR (CDCl3): 7.72(1H), 7.22 2H(lH), 7.38 (mult. 2H), 7.45 (mult.
2H), 3.50(s 2H), 2.01(s 3H).

Example 48 2-Fluoro-4-nitro-phenyl-1-(1-imidazole), yield: 84%, lH-NMR
(CDCl3): 7.95(1H), 7.36(1H), 7.29(1H), 7.63d(dd lH), 8.2 (mult.
2H).

Ex~mple 49 2-Fluoro-phenyl-1-(1-imidazole), yield: 59%, oil.
Example 50 CA 0223~621 1998-04-22 J~

3-Chloro-4-methoxy-phenyl-1-(1-imidazole), yield: 12%, lH-NMR
(CDC13): 7.75(1H), 7.18(1H), 7.18(1H), 7.0 to 7.42 (in addition to 3H), 3.95(s 3H).

Example 51 2-Nitro-4-chloro-phenyl-1-(1-imidazole), yield: 53%, lH-NMR
(CDC13): 7.62(1H), 7.07(1H), 7.23(1H), 8.02(d lH), 7.75(dd lH), 7.44(d lH)-Example 52 2-Nitro-4-(1-imidazolosulfonyl)-phenyl-1-(1-imidazole), yield 65%, oil.

Example 53 2-(1-Imidazolyl)-4-bromobiphenyl, yield: 23%, lH-NMR (CDC13):
7.34 (mult. 5H), 7.08 (mult. 3H), 7.63(dd lH), 7.56(d lH), 6.8(lH) Example 54 [4-(1-Imidazolyl)-phenyl)]-methylthioether, yield: 65%, melting point: 93~.

Example 55 [3-(1-Imidazolyl)-phenyl)]-methylthioether, yield: 69%, lH-NMR
(CDC13): 7.85(1H), 7.1-7.4 (mult. 6H), 2.52(s 3H).

Example 56 CA 0223~621 1998-04-22 3-Chloro-4-nitro-phenyl-1-(1-imidazole), yield: 17%, lH-NMR
(CDCl3): 7.29(1H), 7.35(1H), 7.95(1H), 8.47(dd lH), 8.11d8(1H), 7.62(d lH J=1.5Hz).

Example 57 2-Bromo-phenyl-l-(l-imidazole), yield: 29%, melting point: 55~.

Example 58 3-Fluoro-4-cyano-phenyl-1-(1-imidazole), yield: 16~, lH-NMR
(CDCl3): 7.95(lH), 7.78(lH), 7.3 (mult. 4H).

Example 59 2-Fluoro-4-(1-imidazolyl)-biphenyl, yield: 11%, lH-NMR (CDCl3):
7.5 (mult. 6H), 7.27 (mult. 4H), 7.92(s lH).

Example 60 3-Methoxy-4-methoxy-phenyl-1-(1-imidazole), yield: 44%. lH-NMR
(DMSO d6): 8.12(1H), 7.64 to 7.1(5H), 3.82(s 3H), 3.87(s 3H).

Example 61 [3-(1-Imidazolyl)-benzyl)]-methylthioether, yield: 54%. lH-NMR (CDCl3): 7.9(1H), 7.3 to 7.5 (mult. 6H), 3.72(s 2H), 2.03(s 3H).

-Example 623,4 Methylenedioxyphenyl-1-(1-imidazole), yield: 42%, melting point: 84~.

Example 63 t(2-(1-Imidazolyl)-phenyl)-1-ethyl)]-methylthioether, yield:
58%. lH-NMR (CDCl3): 7.1 to 7.62 (mult. 12H), 3.3 (mult. 2H), 3.89 (quartet lH), 1.51(d 3H).

Example 64 2-(1-Imidazolyl)-3-trifluoromethyl-pyridine, yield: 18%, lH-NMR
(CDCl3): 7.2 to 8.8 (mult. 6H).

For example, the following compounds are obtained in the same way preferably from the corresponding substituted chlorine aromatic compounds:
Example 65 2-(1-Imidazolyl)-3-bromopyridine. Yield: 37%. Melting point:
87.8~.

Ex~mple 66 [6-Methylthio-2-(1-imidazolyl)-phenylmethyl]-methylthioether, yield: 72%, lH-NMR (CDCl3): 7.74(1H), 7.05 to 7.33 (mult. 5H), 3.74(s 2H), 2.57(s 3H), 2.09(s 3H).

CA 0223~621 1998-04-22 Exampl~ 67 [4-Chloro-2-(1-imidazolyl)-phenylmethyl]-methylthioether, yield:
9.1%. Oil.

Example 68 [5-Phenyl-2-(1-imidazolyl)-phenylmethyl]-methylthioether, yield:
16%. Melting point: 123.8~.

Example 69 [4--Methoxy-2-(1-imidazolyl)-phenylmethyl]-methylthioether, yield:
19%. lH--NMR (CDC13): 7.71(1H), 7.38(1H), 7.20(s 2H), 6.96(dd lH), 6.78(d lH), 3.82(s 3H), 3.44(s 2H), 2.01(s 3H).

Example 70 2,6 Dichloro-4-nitro-phenyl-1-(1-imidazole), yield: 71%.
Melting point: 173.6~.

Example 71 3-[2-(1-Imidazolyl)-phen-l-yl]propyl-methylthioether, yield:
12%, lH--NMR (CDC13): 7.60(1H), 7.21(1H), 7.06(1H), 7.2 to 7.47 (mult. 4H), 2.6 (mult. 2H), 2.4 (mult. 2H), 2.02(s 3H), 1.71 (mult. 2H).

Example 72 [2-Chloro-4-(1-imidazolyl)-phenylmethyl]-methylthioether, yield:
5.1%. Oil.

CA 0223~621 1998-04-22 For example, the following compounds are obtained in the same way preferably from the corresponding substituted fluorine aromatic compounds:
Example 73 5-Nitro-2-(1-imidazolyl)-benzaldehyde. Yield: 39%. lH-NMR
(CDCl3): 9.93(s broad lH), 8.91(1H), 8.59(dd lH), 7.81s(1H), 7.68(1H), 7.37(1H), 7.30(1H).

Example 74 [4-Trifluoromethyl-2-(1-imidazolyl)-phenylmethyl]-methylthioether, yield: 8%. lH-NMR (CDCl3): 7.20 to 7.72 (mult. 6H), 3.51(s 2H), 2.03(s 3H).

Example 75 5-Methyl-2-nitro-phenyl-1-(1-imidazole). Yield: 99%. lH-NMR
(CDCl3): 7.62(lH), 7.21(lH), 7.06(lH), 7.95(d 8Hz, lH), 7.40(dd lH), 7.25(d lH), 2.50(s 3H).

Example 76 4-Methyl-2-nitro-phenyl-1-(1-imidazole). Yield: 98.2%8751H-NMR
(CDCl3): 7.61(1H), 7.21(1H), 7.05(1H), 7.80(d lH), 7.52(dd lH), 7.33(d 8H), 2.52(s 3H).

Example 77 t3-(Methylthiomethyl)-2-(1-imidazolyl)-phenylmethyl]-methylthioether. Yield: 7.5%. lH-NMR (CDCl3): 7.62(1H), 7.4 (mult. 3H), 7.25(1H), 7.07(1H), 3.30(s 4H), 2.01(s 6H).

Example 78 [3-Trifluoromethyl-2-(1-imidazolyl)-phenylmethyl]-methylthioether. Yield: 44%. lH-NMR (CDCl3): 7.7 (mult. 2H), 7.54m2(lH), 7.21 (singlet lH), 7.05(lH), 3.24(s 2H), 2.0(s 3H).

Example 79 2-Cyano-6-trifluoromethyl-phenyl-1-(1-imidazole). Yield: 43%.
H-NMR (CDCl3): 8.10(lH), 8.03(lH), 7.80(lH), 7.64(lH), 7.32(lH), 7.13(lH).

Example 80 [2-(1-Imidazolyl)-pyridine-3-methyl]-methylthioether, yield:
45%, lH-NMR (CDCl3): 8.06(lH), 7.5(lH), 7.20(lH), 8.47 ml(lH), 7.87 (mult. lH), 7.35 (mult. lH), 3.63(s 2H), 2.09(s 3H).

Example 81 5-Nitro-2-(1-imidazolyl)-phenylmethyl]-methylthioether. Yield:
20%, lH-NMR (DMS0 d6): 8.4(1H), 8.24(1H), 7.79(1H), 7.47(1H), 7.27(dd 2H).

Example 82 2-(1-Imidazolyl)-3-trifluoromethyl-phenol. Yield 69%, melting point: oil.

Example 83 5-Fluoro-2-nitro-phenyl-1-(1-imidazole), melting point 78-84~.

CA 0223~621 1998-04-22 Also, the following compounds are obtained in the same way preferably from the corresponding substituted bromine aromatic compounds:
Examplc 84 [4-(Methylthiomethyl)-2-(1- imidazolyl)--phenylmethyl]-methylthioether, yield: 48%. Melting point: oil.

Example 85 [5-(Methylthiomethyl) -2- (l-imidazolyl)-phenylmethyl~--methylthioether, yield: 38%. Melting point: oil.

Example 86 [5-Cyano-2-(1-imidazolyl)-phenylmethyl]-methythioether. Yield:
34%, lH-NMR (CDCl3): 7.22 to 7.82 (mult. 6H), 3.53(s 2H), 2.09(s 3H).

Example 87 2-E-[2-(1-Imidazolyl)-phenyl]-acrylic acid ethyl ester. Yield:
33%. lH-NMR (CDCl3): 7.1 to 7.8 (mult. 8H), 6.39 (d lH, J=16Hz), 4.22 (quartet 2H), 1.29(tr 3H).

Example 88 2-(1-Imidazolyl)-styrene. Yield: 11%. lH-NMR (CDCl3): 7.7 to 7.20 (mult. 6H), 7.10(s lH), 6.44(dd lH olef.), 5.75(d lH), 5.32(d lH).

CA 0223~621 1998-04-22 Example 89 [4,5--Dimethoxy--2-(1--imidazolyl)-phenylmethyl]--methylthioether.
Yield: 22%. Melting point: oil.

Example 90 6-Methyl-2-nitro-phenyl-1-(1-imidazole). Yield 31%. Melting point: oil.

Example 91 [5-Methoxy-2-(1-imidazolyl)-phenylmethyl]-methylthioether.
Yield: 61%. lH--NMR (CDCl3): 7.63(1H), 6.84 to 7.70 (mult. 5H), 3.86(s 3H), 3.41(s 2H), 2.02(s 3H).

Example 92 [5-Bromo-2-(1-imidazolyl)-benzoic acid methyl ester. Yield:
61%. Melting point: 68~.

Example 93 S-Ethyl-thiocarboxylic acid-0-[2-(1-imidazolyl)-phenyl]--ester 400 mg of 2-(1-imidazolyl)-phenol is dissolved in 5 ml of NMP, mixed with 1.1 equivalents of 80% sodium hydride (in oil) and then stirred for 30 minutes at 30~. While being cooled, 1.1 equivalents of chlorothioformic acid-S-ethyl ester is introduced and stirred for another 2 hours at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried on magnesium sulfate and concentrated by evaporation. After column chromatography, 84% (520 mg) of product results. lH-NMR (CDCl3): 7.68(1H), 7.18(1H), 7.10(1H), 7.3 to 7.5 (mult. 4H), 2.84 (quartet 2H), 1.28(tr 3H).

Bxample 94 Cyclobutanecarboxylic acid-[2-(1-imidazolyl)-phenyl]-ester 1.1 equivalents of 80% sodium hydride (in oil) is added to 0.25 g of 2-(1-imidazolyl)-phenol in 3 ml of DMF, and the mixture is then stirred for 30 minutes at 30~. 1 equivalent of cyclobutanecarboxylic acid chloride is slowly added and stirred overnight at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with EE/ethanol 9:1 yields 46~ product. lH-NMR
(CDCl3): 7.1 to 7.65 (mult. 7H), 3.24 (pentet lH), 1.8 to 2.3 (mult. 6H).

Quite analogously, the esters and ethers that are mentioned below are obtained:
Example 94a 1-t2-(1-Imidazolyl)-phenyl]-(2-methoxy-ethyl)ether, yield: 40%.
lH-NMR (DMS0 d6): 7.1 to 7.96 (mult. 7H), 3.3(s 3H), 3.65 (mult.
2H), 4.20 (mult. 2H).

Example 94b [2-(1-Imidazolyl)-phenyl]-(methylthiomethyl)-ether, yield: 13%.

oil .

CA 0223~621 1998-04-22 Example 95 [2-(1-Imidazolyl)-phenyl]-~3-methyl-but-2-enyl)ether, yield:
62%, lH-NMR (CDC13): 7.02 to 7.8 (mult. 7H), 4.52(d 2H), 5.37 (mult. lH), 16.8(s 3H), 1.75(s 3H).

Example 96 t2-(1-Imidazolyl)-phenyl]-(2-chloro-prop-2-enyl)ether, yield:
51%. lH-NMR (CDC13): 7.92(1H), 7.4(1H), 7.05(1H), 7.1 to 7.4 (mult. 4H), 4.8(s 2H), 5.5(1H), 5.65(1H).

Bxample 97 [2-(1-Imidazolyl)-phenyl]-(E-but-2-enyl)ether, yield: 40%.
Melting point: oil.

Example 98 [2-(1-Imidazolyl)-phenyl]-allyl ether, yield: 55%, melting point: oil.

Example 99 [2-(1-Imidazolyl)-phenyl]-(3-chloro-but-2-enyl)ether, yield:
73%.

Example 100 [2-(1-Imidazolyl)-phenyl]-([cyclopropyl]methyl)ether, yield:
25%. Melting point: oil.

CA 0223~621 1998-04-22 ~o Example 101 [2~ Imidazolyl)-phenyl]-(2,2-dichloro-2,1,1-trifluoroeth-1-yl)ether, yield: 52%. Melting point: oil.

Example 102 [2-(1-Imidazolyl)-phenyl]-(2-neopentyl)ether, yield: 44%. lH-NMR (acetone d6): 7.8(1H), 7.33(1H), 7.05(1H), 7.2 (mult. 3H), 3.75(s 2H), O.95(s 9H).

Example 103 t2-(1-Imidazolyl)-phenyl]-(2-methylthioeth-1-yl)ether, yield:
42~. lH-NMR (CDCl3): 7.81(1H), 7.16(1H), 7.3(1H), 7.3 (mult lH), 7.05 (mult. 2H), 4.2 (mult. 2H), 2.82 (mult. 2H); 2.10 (mult. 3H).

Example 104 [2-(1-Imidazolyl)-phenyl]-(2-bromo-prop-2-enyl)ether, yield: 44%
melting point: oil.

Example 105 [4-Chloro-2-(1-imidazolyl)-phenyl]-(2-chloro-prop-2-enyl)ether, yield: 47%, lH-NMR (CDCl3): 7.8(1H), 7.2 to 7.3 (mult. 4H), 6.98(1H), 4.6(s 2H), 5.45(s 2H).

Example 106 [3-Methyl-4-(1-imidazolyl)-phenyl]-(2-chloro-prop-2-enyl)ether, yield: 49%, melting point: oil.

CA 0223~621 1998-04-22 Bxample 107 [2~ Imidazolyl)-phenyl]-(2,2-spirot2',2'-dichlorocyclopropyl]-prop-1-yl)ether, yield: 51%, melting point: oil.

Ex~mple 108 [2-(1-Imidazolyl)-phenyl]-[(2,2-dichloro-3-methyl)cycloprop-1-yl]meth-1-yl)ether, yield: 34%, oil.

Example 109 [2-(1-Imidazolyl)-phenyl]-4-[lH]quinolinyl)ether, yield: 17%, oil.

Example 110 [2-(1-Imidazolyl)-phenyl]-(1,1-dimethyl-1-acetoxyacetic acid)ester, yield: 69%. Melting point: oil.

Example llOa [4-(Imidazol-1-yl)-3-methylthiomethyl-phenol]-heptanecarboxylic acid ester, 92%.

Example 111 [2-(1-Imidazolyl)-phenyl]-cyclohexanecarboxylic acid ester, yield: 84%, melting point: 68~.

CA 0223~621 1998-04-22 Example 112 [2-(1-Imidazolyl)-phenyl]-n-hexanecarboxylic acid ester, yield:
78%, lH-NMR (acetone d6): 7.7(1H), 7.07 to 7.55 (mult. 6H), 0.9 to 2.50 (mult. 13H).

Example 113 t2-(1-Imidazolyl)-phenyl]-n-heptadecanecarboxylic acid ester, yield: 52%, melting point: 101~.

Example 114 [2-(1-Imidazolyl)-phenyl]-perfluoropropanecarboxylic acid ester, yield: 23%, lH-NMR (CDCl3): 8.5(1H), 8(1H), 7.77(1H), 7.3 (mult. 4H).

Example 115 [2-(1-Imidazolyl)-phenyl]-N,N-dimethylcarbamic acid ester, yield:
27%, lH-NMR (CDCl3): 7.73(lH), 7.09 to 7.51 (mult. 6H), 2.85(s 3H), 3.0(s 3H).

Example 116 [2-(1-Imidazolyl)-phenyl]-N-(2-chloroethyl)-N-methylcarbamate, yield: 55%, lH-NMR (CDCl3): 7.64(lH), 7.1 to 7.4 (mult. 6H), 3.5 (mult. 4H), 3.01(s 3H).

CA 0223~621 1998-04-22 Example 117 [2-(1-Imidazolyl)-phenyl]-decanoic acid ester, yield: 98%, lH-NMR (CDCl3): 7.68(1H), 7.18(1H), 7.10(1H), 7.24 to 7.44 (mult.
4H), 2.42(dd 2H), 1.28 (mult. 14H), 0.89(tr 3H).

Example 118 t2-(1-Imidazolyl)-phenyl]-cyclopropanecarboxylic acid ester, yield: 44%, lH-NMR (CDCl3): 7.68(1H), 7.18(lH), 7.10(1H), 7.28 to 7.48 (mult. 4H), 1.7 (mult. lH), 1.0 (mult. 4H).

Example 119 [2-(1-Imidazolyl)-phenyl]-isobutyric acid ester, yield: 97%, lH-NMR (CDCl3): 7.68(1H), 7.18(1H), 7.10(1H), 7.20 to 7.50 (mult.
4H), 2.67 (heptet lH), l.ll(d 6H).

Example 120 [2-(1-Imidazolyl)-phenyl]-3-methylbutyric acid ester, yield:
72%, lH-NMR (CDCl3): 7.68(1H), 7.18(1H), 7.10(1H), 7.24 to 7.44 (mult. 4H), 2.31(d 2H), 2.07 (heptet lH), O.91(d 6H).

Example 121 [2-(1-Imidazolyl)-phenyl]-omega-chloro-pentanoic acid ester, yield: 97%, melting point: 218.6~.

-CA 0223~621 1998-04-22 Example 122 [2-(1-Imidazolyl)-phenyl]-3-phenylpropionic acid ester, yield:
96%, lH-NMR (CDCl3): 7.05 to 7.69 (mult. 6H), 2.95 (mult. 2H), 2.7 (mult. 2H).

Example 123 [2-(1-Imidazolyl)-phenyl]-(tert-butylacetic acid)ester, yield:
80%, melting point: 111~.

Example 124 [2-(1-Imidazolyl)-phenyl]-(trans-phenylcyclopropanecarboxylic acid)ester, yield: 70%, melting point: oil.

Example 125 [2-(1-Imidazolyl)-phenyl]-([1-methylthio]acetic acid)ester, yield: 17%, lH-NMR (CDCl3): 7.72(1H), 7.2(1H), 7.14(1H), 7.22 to 7.52 (mult. 4H), 3.3(s 2H), 2.1(s 3H).

Example 126 [2-(l~Imidazolyl)-phenyl]-oxalic acid semi-ester, yield: 42%, melting point: oil.

Example 127 [2-(1-Imidazolyl)-phenoxy]-acetonitrile 500 mg (3.086 mmol) of 2-[2-(1-imidazolyl)-phenol is dissolved in 15 ml of anhydrous DMF and mixed with 185.2 mg (26.172 mmol) of an 80% NaH suspension. After 1 and 1/2 hours of CA 0223~62l l998-04-22 stirring at room temperature, 404.7 mg (3.373 mmol) of bromoacetonitrile is added, and the batch is stirred overnight at room temperature. The mixture is added to 100 ml of H20 and extracted 3 times with 70 ml of ethyl acetate each. The combined organic extracts are washed twice with 50 ml of saturated NaCl solution each, dried on NaS04, and the organic solvent is spun off. After chromatography of the crude product on SiO2 (EE/hexane ~ EE as mobile solvent), 365.4 mg (58.8%) of the desired product is obtained.

Example 128 4-[2-(1-Imidazolyl)-phenoxy]-butyric acid nitrile 500 mg (3.086 mmol) of 2-(1-imidazolyl)-phenol is reacted with 499.2 mg (3.373 mmol) of 4-bromobutyric acid nitrile analogously to Example 127. After the above-described working-up and chromatography, 445 mg (62.7%) of product is obtained.

Example 129 5-[2-(1-Imidazolyl)-phenoxy]-pentanoic acid nitrile 500 mg (3.086 mmol) of 2-(1-imidazolyl)-phenol is reacted with 546.4 mg (3.373 mmol) of 5-bromophentanoic acid nitrile as described in Example 127. After working-up and chromatography, 752.9 mg (99.9%) of product is obtained.

CA 0223~621 1998-04-22 :~G

Example 130 6-[2-(1-Imidazolyl)-phenoxy]-hexanoic acid nitrile 500 mg (3.086 mmol) of 2-(1-imidazolyl)-phenol is reacted as usual with 593.6 mg (3.373 mmol) of 6-bromohexanoic acid nitrile.
After working-up and chromatography, 750.8 mg (94.2%) of product is obtained.

Bxample 131 7-[2-(1-Imidazolyl)-phenoxy]-heptanoic acid nitrile 500 mg (3.086 mmol) of 2-(1-imidazolyl)-phenol is reacted as usual with 640.9 g (3.373 mmol) of 7-bromoheptanoic acid nitrile.
After working-up and chromatography, 810 mg (96.4%) of product is obtained.

Example 132 6-[2-(1-Imidazolyl)-phenoxy]-2,2-dimethylhexanoic acid nitrile 100 mg (0.617 mmol) of 2-(1-imidazolyl)-phenol is reacted as usual with 138.5 mg (0.679 mmol) of 2,2-dimethyl-6-bromohexanoic acid nitrile. After working-up and chromatography, 103 mg (58.2%) of product is obtained.

Example 133 2-t2-(1-Imidazolyl)-phenoxy]-acetic acid-tert-butyl ester 100 mg (0.617 mmol) of 2-(1-imidazolyl)-phenol is reacted with NaH and bromoacetic acid-tert-butyl ester in DMF analogously to Example 127. After working-up and chromatography, 84.9 mg (49.6%) of product is obtained.

CA 0223~621 1998-04-22 Example 134 4-[2-(1-Imidazolyl)-phenoxy]-butyric acid ethyl ester 2 g (12.344 mmol) of 2-(1-imidazolyl)-phenol is reacted with NaH and 4-bromobutyric acid ethyl ester in DMF analogously to Example 127. After working-up and chromatography, 1.23 g (36%) of product is obtained.

Example 135 5-[2-(1-Imidazolyl)-phenoxy]-pentanoic acid methyl ester 2 g (12.344 mmol) of 2-(1-imidazolyl)-phenol is reacted with NaH and 5-bromopentanoic acid methyl ester in DMF analogously to Example 127. After the usual working-up, 2.7 g (75.1%) of product is isolated.

Example 136 6-[2-(1-Imidazolyl)-phenoxy]-hexanoic acid ethyl ester 2 g (12.344 mmol) of 2-(1-imidazolyl)-phenol is reacted with 6-bromohexanoic acid ethyl ester and NaH in DMF as already described (Example 127). The product is isolated with a yield of 59.2% (2.32 g).

Example 137 7-[2-(1-Imidazolyl)-phenoxy]-heptanoic acid ethyl ester 1 g (6.172 mmol) of 2-(1-imidazolyl)-phenol is reacted with 7-bromoheptanoic acid-ethyl ester and NaH in DMF according to Example 127. After working-up, the yield is 0.416 g (31.3%).

Example 138 2-[4-(1-Imidazolyl)-phenoxy]-acetic acid methyl ester 4 g of 4-(imidazol-1-yl)phenol, 4.8 ml of bromoacetic acid methyl ester and 6.5 g of cesium carbonate are added to 50 ml of DMSO. After 1 day of stirring, the reaction mixture is added to water and extracted with methylene chloride. The organic phase is separated, washed with water, dried, and the solvent is drawn off in a vacuum. After recrystallization from petroleum ether, the title compound with a melting point of 116-117~C is obtained.

Example 139 3-[4-(1-Imidazolyl)-3--(methylthiomethyl)-phenoxy]-butyricacid nitrile 2 equivalents of 80% sodium hydride (in oil) is added to 0.15 g of 4-(1-imidazolyl)-3-(methylthiomethyl)-phenol in 3.5 ml of DMF, and, after being stirred briefly at room temperature, 1.08 equivalents of 4--bromobutyronitrileis slowly added.
Overnight, it is stirred at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with EE yields 81% product.
lH--NMR (CDCl3): 7.62(1H), 6.82 to 7.2 (mult. 5H), 4.14(tr 2H), (lH), 2.62(tr 2H), 3.41(s 2H), 2.2m2(lH), 2.05(s 3H).

Analogously, there are obtained:
Example 140 1-[4-(1-Imidazolyl)-3-(methylthiomethyl)-phenyl]-prop-2-in-ether, yield: 85%, melting point: oil.

Example 141 1-t4-(1-Imidazolyl)-3-(methylthiomethyl)-phenyl]-2-chloroprop-2-ene ether, yield: 56% as well as 32% of the product of Example 140, melting point: oil.

Example 142 t4-(1-Imidazolyl)-3-(methylthiomethyl)-pheny]-benzyl ether, yield: 81.6%, melting point: oil.

Bxample 143 1-[2-(1-Imidazolyl)-phenyl]-(3-methylthio)propyl ether 240 mg of 2-(1-imidazolyl)-phenol, 1 equivalent of 3-methylthiopropan-1-ol and 1 equivalent of triphenylphosphine are dissolved in succession in 10 ml of THF. 0.23 ml of azodicarboxylic acid diethyl ester is slowly added in drops at an internal temperature of 4~. After a few hours at room temperature, it is worked up. The mixture is concentrated by evaporation and chromatographed on a column with silica gel.
Mobile solvent: hexane/EE. The yield is 60%. lH-NMR (CDCl3):
7.79(lH), 7.4 to 7.0 (mult. 6H), 4.12m2(lH), 2.57 (mult. 2H), 2.02 (mult. 2H), 2.07(s 3H).

In the same way, there are obtained:
Example 144 [2-(1--Imidazolyl)-phenylmethyl]-(ortho-methylthio)phenolether, yield: 72%, melting point: 83~.

Example 145 L-[2-(1-Imidazolyl)-benzyl alcohol]-(S-methylcysteic acid)ester, yield: 41%, melting point: 78~.

Example 146 [2-(1-Imidazolyl)-benzyl alcohol]-(2-S-methylthioacetic acid)ester, yield: 75%. lH-NMR (CDCl3): 7.7(lH), 7.2 (mult.
7H), 5.0(s 2H), 3.2(s 2H), 2.18(s 3H).

Example 147 [2-(1-Imidazolyl)-phenyl]-[(2,2-dimethyl-1,3-dioxolan)--4-methyl]ether, yield: 62%, melting point: oil.

Example 148 [2-(1-Imidazolyl)-phenyl]-(3-thiacyclohex-1-yl)-ether, yield:

75%, melting point: oil.

Example 149 [2-(1-Imidazolyl)-phenyl]-(2--thiophenyl)methylether, yield:
17%, lH--NMR (CDCl3): 7.81(1H), 6.95 to 7.4 (mult. 9H), 5.25(s 2H).

CA 0223~621 1998-04-22 Example 150 [2-(1-Imidazolyl)-phenyl]-but-1-in-3-yl ether, yield: 26%, lH-NMR (CDCl3): 7.81(1H), 7.07 to 7.4 (mult. 6H), 4.82 (mult. lH), 2.48 (mult. lH), 1.60(d 3H).

Example 151 l-[2-(l-Imidazolyl)-phenoxyethyl]-(2-chloroethyl)-ether, yield:
19%, lH-NMR (acetone d6): 7.92(1H), 7.05 to 7.7 (mult. 6H), 4.41 (dd 2H), 3.95(dd 2H).

Example 152 [2-(1-Imidazolyl)-phenoxy-2-eth-1-yl]-(2-hydroxyethyl)-thioether, yield: 33%, lH-NMR (CDCl3): 7.87(1H), 7.40 to 7.00 (mult. 6H), 4.21, 3.69, 2.88, 2.61 each (tr 2H).

Exampl~ 153 [2-(1-Imidazolyl)-phenyl]-(1,3-bis-methylthiopropan-2-yl)ether, yield: 44%, lH-NMR (CDCl3): 7.8 (mult. lH), 7.0 to 7.4 (mult.
6H), 4.25 (mult. lH), 2.8 (mult. lH), 2.1 (mult. lH).

Example 154 [4-(l-Imidazolyl)-3-methylthiomethyl-phenyl]-(2-methylthioeth-l-yl)ether, yield: 45%, melting point: oil.

Example 155 [2-(l-Imidazolyl)-phenylmethyl]-(2-thiomethylethyl)ether, yield:
33%, lH-NMR (CDCl3): 7.72(1H), 7.20 (mult. 2H), 7.3(1H), 7.6 CA 0223~621 1998-04-22 (mult. 4H), 4.30(s 2H), (lH), 3.62(tr 2H), (lH), 2.70(tr 2H), 2.12(s 3H).

Example 155a 2-(1-Imidazolyl)-benzylnitrile is obtained analogously with acetone cyanohydrin in 66% yield from 2-(1-imidazolyl)-benzyl alcohol.

Example 156 2-Chlora-4-methoxy-phenyl-1-(1-imidazole) 378 mg of 2-amino-4-methoxy-phenyl-1-(1-imidazole) is dissolved with 5 ml of semiconcentrated hydrochloric acid at about 50~; sodium nitrite solution is added in portions at ice bath temperature and stirred for 15 minutes at this temperature.
The diazonium salt solution is added in portions to 440 mg of copper(I) chloride, which is dissolved in 4 mol of concentrated hydrochloric acid. After a few hours, it is poured onto soda solution, extracted with EE, suctioned off on Celite and dried with magnesium sulfate. Concentration by evaporation and column chromatography yield 61% of the above-mentioned compound. lH-NMR
(CDC13): 7.05 to 7.61 (mult. 5H), 6.87(1H), 3.83(s 3H).

Example 157 4-Bromo-2-fluoro-phenyl-1-(1-imidazole), yield: 32%, lH-NMR
(CDC13): 7.85(lH), 7.47(lH), 7.4(lH), 7.27 (mult. 3H).

CA 0223~621 1998-04-22 Example 158 3,4-Dichloro-phenyl-1-(1-imidazole), yield: 59%, lH-NMR (CDCl3):
7.85 ~mult. lH), 7.25 (mult. 3H), 7.55 (mult. 2H).

Example 159 2,5-Dichloro-phenyl-1-(1-imidazole), yield: 33%, melting point:
100~.

Example 160 2,4-Dichloro-phe~yl-1-(1-imidazole), yield: 42%, lH-NMR (DMS0 d6): 7.82 (mult. 2H), 7.55 (mult. 2H), 7.41(1H), 7.11(1H).

Example 161 4-Chloro-2-fluoro-phenyl-1-(1-imidazole), yield: 64%, lH-NMR
(CDCl3): 7.795(s lH), 7.3 (mult. 5H).

Example 162 2-(1-Imidazolyl)-3-methylthiopyridine 180 mg (1 mmol) of 2-(1-imidazolyl)-3-chloropyridine is heated to 110~ in 2 ml of NMP with 1.5 equivalents of sodium thiomethanolate for 4 hours. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After column chromatography with EE, 190 mg of title compound results. Yield:
99%, lH-NMR (CDCl3): 7.19 to 8.3 (mult. 6H), 2.42(s 3H).

CA 0223~621 1998 - 04 - 22 Example 163 [2-(1-Imidazolyl)-phenyl]-ethylthioether In 3 ml of NMP, a total of 3 equivalents of sodium thioethylate in NMP is added successively to 223 mg of 2-bromo-phenyl-1-(1-imidazole). After 8 hours at 120~, thin-layer chromatography shows many products. Working-up as in Example 162 provides a yield of 51%. lH-NMR (CDCl3): 7.64(lH), 7.22(lH), 7.13(1H), 7.22 (mult. 2H), 7.4 (mult. 2H), 2.8 (quartet 2H), 1.23(tr 3H).

EXample 164 3-[3-(1-Imidazolyl)-phenyl]-prop-1-yl-methylthioether 3-[3-(1-Imidazolyl)-phenyl]-prop-1-yl-bromide (300 mg) is dissolved in 3 ml of NMP. After 1.1 equivalents of sodium thiomethanolate is added, it is stirred for 24 hours at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After chromatography (EE/hex 2:3), 27% product results. lH-NMR (CDCl3): 7.83(1H), 7.4 to 7.2 (mult. 6H), 2.8(1H), 2.54(1H), 1.95 each (mult. 2H), 2.12(s 3H).

Analogously, there is synthesized:
Example 16S
[2-(1-Imidazolyl)-phenyl]-iso-propylthioether with thioisopropylate, yield: 79%, lH-NMR (CDCl3): 7.67(1H), 7.19(lH), 7.15(lH), 7.3 to 7.5 (mult. 4H), 3.12 (heptet lH), 1.2(d 6H).

CA 0223~621 1998 - 04 - 22 Example 16 6 ~2-(1-Imidazolyl)-phenyl]-tert-butylthioether with tert-butyl mercaptan, yield: 69%, 91H-NMR (CDCl3): 7.77(lH), 7.75(lH), 7.14 to 7.5 (mult. 5H), 1.07(s 9H).

Example 167 [2-(1-Imidazolyl)-phenyl]-(3-furanylmeth-1-yl)-thioether with furfuryl mercaptan, yield: 27%.

Example 168 2,3-Bismethylthio-phenyl-1-(1-imidazole) with thiomethylate, yield: 45%, lH-NMR (CDCl3): 7.7(1H), 7.2 (mult. 3H), 7.4(dd lH), 7.08(d lH), 2.50(s 3H), 2.09(s 3H).

Example 169 [5-Nitro-2-(1-imidazolyl)-phenyl]-methylthioether with thiomethylate, yield: 18%, lH-NMR (CDCl3): 7.7(1H), 7.28(1H), 7.18(1H), 8.1 (mult. 2H), 7.4(1H), 2.53(s 3H).

Example 17 O
[5-Chloro-2-(1-imidazolyl)-phenyl]-methylthioether with thiomethylate, yield: 50%, lH-NMR (CDCl3): 7.1 to 7.62 (mult.
6H), 2.40(s 3H).

Example 17 oa [5-Bromo-2-(1-imidazolyl)-benzyl]-methylthioether, yield: 75~, oil. In addition, a few percent of [5-methylthiomethyl-2-(1-CA 0223~621 1998-04-22 imidazolyl)-benzyl]-methylthioether is obtained. The compound is also produced in 77% yield from [5-bromo-2-(1-imidazolyl)-benzyl]-methylthioether with thiomethylate.

Example 17Ob t4-Bromo-2-(1-imidazolyl)-benzyl]-methylthioether, yield: 91%, oil.

Example 170c [6-Nitro-2-(1-imidazolyl)-benzyl]-methylthioether, yield: 65%, oil.

Example 17Od [6-Chloro-2-(1-imidazolyl)-benzyl]-methylthioether, yield: 50%, oil.

Example 170e [3-Nitro-2-(1-imidazolyl)-benzyl]-methylthioether, yield: 15%, oil.

Example 171 ~5-Nitro-2-(1-imidazolyl)-phenyl]-ethylthioether with thioethylate, yield: 25%, lH-NMR (CDC13): 7.7(1H), 7.25(1H), 7.18(1H), 8.21(1H), 8.09(1H), 7.4(1H), 2.99 (quartet 2H), 1.34 (tr 3H).

CA 0223~621 1998-04-22 Example 172 [5-Chloro-2-(1-imidazolyl)-phenyl]-ethylthioether with thioethylate, yield: 82%, lH-NMR (CDCl3): 7.62(lH), 7.09(lH), 7.20(1H), 7.15 to 7.33 (mult. 3H), 2.83 (quartet 2H), 1.28(tr 3H).

Example 173 (1-t2-(1-Imidazolyl)-phenyl]-eth-1-yl)methylthioether with thiomethylate, yield: 34~, lH-NMR (CDCl3): 7.1 to 7.7 (mult.
7H), 3.62 (quartet lH), 1.52(d 3H).

Example 174 (1-[2-(1-Imidazolyl)-phenyl]-eth-1-yl)-ethylthioether with thioethylate, yield: 28%, melting point: oil.

Example 175 [2-(1-Imidazolyl)-phenyl]-(l-phenyleth-1-yl)thioether with 1-phenylethanethiol, yield: 75%, lH-NMR (CDCl3): 7.05 to 7.55 (mult. 12H), 4.05(1H), 1.50(d 3H).

Example 176 [2-(1-Imidazolyl)-phenyl]-but-2-ylthioether with 1-methyl propyl mercaptan, yield: 74%, lH-NMR (CDCl3): 7.66(1H), 7.20(1H), 7.15(1H), 7.54(dd lH), 7.3 (mult. 3H), 2.9 (mult. lH), 1.50(m 2H), 1.15(m 3H), O.9(tr 3H).

CA 0223~621 1998-04-22 Example 177 [2-(1-Imidazolyl)-phenyl]-(2-phenyleth-1-yl)thioether with 2-phenylethanethiol, yield: 60%, lH-NMR (CDCl3): 7.69(1H), 7.1 to 7.5 (mult. llH), 3.0 (mult. 2H), 2.83 (mult. 2H).

Example 178 [2-(1-Imidazolyl)-phenyl]-cyclohexylthioether with cyclohexyl mercaptan, yield: 80%, melting point: oil.

Bxample 179 [2-(1-Imidazolyl)-phenyl]-decylthioether with decyl mercaptan, yield: 58%, lH-NMR (CDCl3): 7.65(1H), 7.13 to 7.45 (mult. 6H), 2.75 (mult. 2H), 0.9 to 1.6 (mult. l9H).

Example 180 [2-(1-Imidazolyl)-phenyl]-(2-N,N-dimethylaminoeth-l-yl)thioether with N,N-dimethylaminoethanethiol, yield: 40%, melting point:
oil.

Example 181 [2-(1-Imidazolyl)-phenyl]-benzylthioether with thiomethylbenzene, yield: 75%, melting point: 87~.

Example 182 [2-(1-Imidazolyl)-phenyl]-(2-thiophenyl)thioether with 2-mercaptothiophene, yield: 28~. Melting point: oil.

CA 0223~621 1998-04-22 Example 183 2-[2-(1-Imidazolyl)-benzylthio]-N-methylacetamide with methylmercaptoacetamide, yield: 44%, lH-NMR (CDCl3): 7.68(1H), 7.22(1H), 7.17(1H), 7.25 to 7.5 (mult. 4H), 3.53(s 2H), 3.14(s 2H), 2.77(d 3H).

Example 184 [2-(1-Imidazolyl)-phenylmethyl]-[lN-methyl-imidazol-2-yl~thioether with 2-mercapto-1-methylimidazole, yield: 14%, melting point: 226~.

Ex~lmple 185 3-[2-(1-Imidazolyl)-benzylthio]-propionic acid methyl ester with mercaptopropionic acid methyl ester, yield: 49%, lH-NMR (CDCl3):
7.7(1H), 7.2 to 7.5 (mult. 6H), 3.55(s 2H), 3.7(s 3H), 2.7(dd 2H), 2.5(dd 2H)-Example 1862-[2-(1-Imidazolyl)-benzylthio]-3,4,5,6-tetrahydropyrimidine hydrobromide with 2-mercapto-tetrahydropyrimidine 1,3, yield:
35%, melting point: 269~.

Example 187 [3-(1--Imidazolyl)--4--phenyl-phenyl]methylthioetherwith sodium thiomethylate, yield: 81%, melting point: oil.

CA 0223~621 1998-04-22 Example 188 [3-(1-Imidazolyl)-4-phenyl-phenyl]methylthioether with sodium thioethylate, yield: 77%, melting point: oil.

Example 189 2-[2-(1-Imidazolyl)-benzylmercapto]-acetic acid ethyl ester with ethyl-2-mercaptoacetate, yield: 62%, lH-NM (CDCl3): 7.7(1H), 7.2 to 7.55 (mult. 6H), 4.15 (quartet 2H), 3.69(s 2H), (lH), 3.12(s 2H), 1.28(tr 3H).

Example 190 [2-(1-Imidazolyl)-benzyl]-benzylthioether with benzyl mercaptan, yield: 71%, lH-NMR (CDC13): 7.68(1H), 7.1 to 7.45 (mult. 12H), 3.68(s 2H), 3.42(s 2H).

Example 191 S-[2-(1-Imidazolyl)-benzyl]isothiourea hydrobromide 318 mg of 2-(1-imidazolyl)-benzylbromide hydrobromide is refluxed with 153 mg of thiourea in 5 ml of ethanol for 5 hours.
After the crystals are cooled, suctioned off and washed, 250 mg of S-~2-(1-imidazolyl)-benzyl]isothiourea hydrobromide is obtained. Melting point: 247~. The crude product is dissolved in saturated sodium bicarbonate solution; after a short time, the free base S-[2-(1-imidazolyl)-benzyl]isothiourea again precipitates. It is suctioned off and washed with water.

CA 0223~621 1998-04-22 A few examples illustrate the process:
Example 192 S-[2-(2-(1-Imidazolyl))-phenyleth-1-yl]isothiourea hydrobromide.
Yield: 97%, melting point: 229~.

Example 193 S-[3-(2-(1-Imidazolyl))-phenylpropyl]isothiourea hydrobromide.
Yield: 69%, lH-NMR (DMS0 d6): 9.45(lH), 9.0(lH), 8.02(lH), 7.92(lH), 7.4 to 7.7 (mult. 4H), 3.13m2(lH), 2.6 (mult. 2H), 1.8 (mult. 2H).

Example 194 N-Phenyl-S-[2-(1-imidazolyl)-benzyl]isothiourea hydrobromide.
Yield: 60%, melting point: 217~.

Example 195 S-[1-(2-(1-Imidazolyl))-phenyleth-1-yl]isothiourea hydrobromide.
Yield: 81~, melting point: 164~.

Example 196 N,N-Dimethyl-S-[2-(1-imidazolyl)-benzyl]isothiourea hydrobromide.
Yield: 87%, melting point: 183~.

Example 197 [2-(1-Imidazolyl)-benzyl]-propargylthioether A solution of S-[2-(1-imidazolyl)-benzyl]isothiourea hydrobromide (Example 191) is boiled in a solution of 1.5 g of potassium hydroxide pellets and 3 g of water. Dichloromethane is carefully added to 2 ml of the reaction solution, so that 2 phases are formed. 80 mg of propargyl bromide as well as 10 mg of triethylbenzylammonium bromide are added to it and stirred for 3 hours at room temperature. It is diluted with water, extracted with dichloromethane, the organic phase is washed with brine, dried with magnesium sulfate and spun in.
Column chromatography with hexane/EE at a 1:1 ratio yields 50% product. lH-NMR (CDCl3): 7.7~(1H), 7.21(1H), 7.20(1H), 7.24 to 7.55 (mult. 4H), 3.71(s 2H), 3.17(d 2H), 2.27 (mult. lH).

In the same way, there are obtained:
Example 198 [2-(1-Imidazolyl)-benzyl]-(2-bromo-prop-2-enyl)thioether, yield:
68%, lH-NMR (CDCl3): 7.71(1H), 7.2 to 7.54 (mult. 6H), 5.23 ml(lH), 5.03 (mult. lH), 3.56(s 2H), 3.39(s 2H).

Example 199 S-~2-(1-Imidazolyl)-benzyl]-thiocarboxylic acid-0-ethyl ester, yield: 45%, lH-NMR (CDCl3): 7.63(1H), 7.1(1H), 7.2(1H), 7.2 to 7.6 (mult. 4H), 3.9(s 2H), 4.29 (quartet 2H), (lH), 1.29(tr 3H).

Example l99a (2-(1-Imidazolyl)-benzylthio)-acetone, yield: 55%, lH-NMR
(CDCl3): 7.7(1H), 7.2 to 7.5 (mult.), 3.51(s 2H), 3.16(s 2H), 2.22(s 3H).

CA 0223~621 1998-04-22 Example 199b S-[2-(1-Imidazolyl)-benzyl]-N,N-dimethyl-thio-carbamate, yield:
69~, melting point: 60~.

Example 200 [2-(1-Imidazolyl)-benzyl]-(l-propen-2-yl)thioether, yield: 58%, lH-NMR (CDCl3): 7.71(1H), 7.21(1H), 7.20(1H), 7.22 to 7.52 (mult. 4H), 5.7 (mult. lH), 5.1 (mult. 2H), 3.49(s 2H), (lH), 3.09(d 2H).

Example 201 2-(1-Imidazolyl)-benzylbromide hydrobromide 2.61 g of 2-(1-imidazolyl)-benzyl alcohol is heated for 4 hours at 140~ in 47~ HBr. It is concentrated by evaporation, and the crude product is carefully dried. The yield is 98~. lH-NMR
(DMS0 d6): 9.51(1H), 8.10(1H), 7.98(1H), 7.79(1H), 7.6 to 7.7 (mult. 3H), 4.68(s 2H).

Phenols are obtained from methoxy aromatic compounds, according to this example, under corresponding conditions, for example:

Example 202 2-Hydroxy-3-methyl-phenyl-1-(1-imidazole), yield: 88~, melting point: oil.

-CA 0223~621 1998-04-22 Example 203 2-Hydroxy-3-(imidazol-1-yl)-4-hydroxy-phenyl-1-(1-imidazole), yield: 77%, melting point: > 300~.

Example 204 2-Hydroxy-5-tert-butyl-phenyl-1-(1-imidazole), yield: 90%, melting point: 198~.

Example 205 2-Hydroxy-4-(imidazol-1-yl)-phenyl-1-(1-imidazole), yield: 70%, melting point: > 300~.

Example 206 2-Methyl-4-hydroxy-phenyl-1-(1-imidazole), yield: 85~, lH-NMR
tDMS0 d6): 9.52(1H), 6.7 to 7.7 (mult. 6H), 2.02(s 3H), ethyl-l-bromide hydrobromide, yield: 100%, lH-NMR (CDC13): 9.55(1H), 7.5 to 8.1 (mult. 6H), 5.19 (quartet lH), 2.01(d 3H).

Example 207 2-Nitro-4-hydroxy-phenyl-1-(1-imidazole), yield: 54%, melting point: 228-230~.

Example 208 2-Hydroxy-5-hydroxy-phenyl-1-(1-imidazole), yield: 65%, lH-NMR
(DMS0 d6): 7.9(1H), 7.03(1H), 7.4(1H), 9.2(1H), 9.33(1H), 6.65 to 6.9 (mult. 3H).

CA 0223~621 1998-04-22 Example 209 2-[2-(1-Imidazolyl)-phenyl]-ethylbromide hydrobromide, yield 100%, lH-NMR (DMS0 d6): 9.5(1H), 8.1(1H), 7.95(1H), 7.5(1H), 7.7 (mult. 4H), 3.70(tr 2H), 3.02(tr 2H).

Example 210 2,4-Dihydroxy-phenyl-1-(1-imidazole), yield: 65%, melting point:
195~.

Examplo 211 3-[2-(1-Imidazolyl)-phenyl]-propyl-1-bromide hydrobromide, yield:
99%, lH-NMR (DMS0 d6): 9.5(1H), 8.1(1H), 7.95(1H), 7.7 to 7.4 (mult. 4H), 3.49m2(lH), 2.64 (mult. 2H), 1.99 (mult. 2H).

Example 212 [2-(1-Imidazolyl)-phenyl]-methylthioether hydrobromide 95 mg of [2-(1-imidazolyl)-phenyl]-methylthioether is stirred into 2 ml of 47% HBr and concentrated by evaporation. It is dried on a bulb tube. The hydrobromide is obtained in quantitative yield. Melting point: 176~.

Example 213 2-Hydroxyphenyl-l-(1-imidazole). Yield 96%.

Example 214 3-Chloro-4-hydroxy-phenyl-1-(1-imidazole), yield: 87%, melting point: 216~.

CA 0223~621 1998 - 04 - 22 Example 215 3,4-Dihydroxy-phenyl-1-(1-imidazole), yield: 88%, lH-NMR (DMS0 d6): 8.0(1H), 7.5(1H), 7.1(1H), 9.2(s broad 2H), 6.92(1H), 6.8 (mult. 2H).

Example 216 4-Nitro-2-(1-imidazolyl)-benzylbromide hydrobromide, yield: 90%, lH-NMR (DMS0 d6): 9.63(lH), 8.71(lH), 7.95 to 8.5 (mult.
4H)(lH), 4.81(s 2H).

Example 217 3-t3-(1-Imidazolyl)-phenyl]-propyl-l-bromide hydrobromide, yield:
92.6% melting point: oil.

Example 218 2-Amino-4-cyano-phenyl-1-(1-imidazole) 214 mg of 2-nitro-4-cyano-phenyl-1-(1-imidazole) with 110 mg of ammonium chloride in 1 ml of water is mixed in a mixture of 2 ml of THF and 3 ml of ethanol. After 630 mg of zinc powder is added, it is stirred for 3 hours at room temperature. It is diluted with EE, suctioned off on Celite, the filtrate is washed once with ammonium chloride solution and with brine until neutrality is reached. Drying and concentration by evaporation yield 93% product. Melting point: 214~.

Example 218a t5--Amino-2-(imidazolyl)-benzyl]-methylthioether, yield 99%.

CA 0223~621 1998 - 04 - 22 Example 218b [6-Amino-2-(1-imidazolyl)-benzyl]-methylthioether, yield 51%.

Analogously, there are produced:
Example 219 2-Amino-5-chloro-phenyl-1-(1-imidazole), yield: 95%, melting point: 136~.

Example 220 2-Amino-4-amino-phenyl-1-(1-imidazole), yield: 54%, lH-NMR
(CDC13): 7.6(1H), 7.20(1H), 7.05(1H), 6.9 (mult. lH), 6.1 (mult.
2H).

Example 221 4-Amino-2-hydroxy-phenyl-1-(1-imidazole), yield: 69%, melting point: 232~.

Example 222 4-Amino-[2-(1-imidazolyl)-thiophenol]-methyl ether, yield: 100%, lH-NMR (CDCl3): 7.7(1H), 7.15(1H), 7.16(1H), 6.6(1H), 6.72(1H), 7.30(1H), 2.20(s 3H).

Example 223 4-Amino-2-fluoro-phenyl-1-(1-imidazole), yield: 95%, melting point: 69-72~.

CA 0223~621 1998-04-22 Example 224 2-Amino-4-chloro-phenyl-1-(1-imidazole), yield: 100%, melting point: 144~.

Example 225 4-Amino-3-chloro-phenyl-1-(1-imidazole~, yield: 100%, melting point: 114~.

Example 226 2-Amino-4-methoxy-phenyl-1-(1-imidazole), yield: 100%, lH-NMR
(CDCl3): 7.8(1H), 7.30(1H), 7.1(1H), 6.99(dd lH), 6.33 (singlet lH), 6.31 (mult. lH), 3.80(s 3H).

Example 227 3-t2-(1-Imidazolyl)-phenyl]-propionic acid ethyl ester 1.44 g of E-3-[2-(1-imidazolyl)-phenyl]-acrylic acid ethyl ester is hydrogenated in 50 ml of ethanol at low pressure with 144 mg of 10% palladium/carbon catalyst. The reaction requires 2 hours at room temperature. It is suctioned off, concentrated by evaporation, and 89% product is obtained. lH-NMR (CDCl3):
7.61(1H), 7.22(lH), 7.09(lH), 7.2 to 7.4 (mult. 4H), 4.09 (~uartet lH), 2.43(tr 2H), (lH), 2.83(tr 2H), 1.21(tr 3H).

A selection of other catalytic hydrogenations:
Example 228 2-Cyano-3-[2-(1-imidazolyl)-phenyl]-propionic acid ethyl ester, yield: 48%, oil.

Example 229 3-t3-(1-Imidazolyl)-phenyl]-propionic acid ethyl ester, yield:
95.4~, lH-NMR (CDCl3): 7.87(lH), 7.4 to 7.2 (mult. 6H), 4.12 (quartet 2H), 3.03(tr 2H), (lH), 2.68(tr 2H), 1.22(tr 3H).

Example 230 4-(1-Imidazolyl)-3-(methylthiomethyl)-benzylamine, yield: 33%, melting point: oil.

Example 231 2-~2-(1-Imidazolyl)-phenoxy]-ethylamine 528.4 mg (2.65 mmol) of 2-[2-(1-imidazole)-phenoxy]-acetonitrile is mixed in 25 ml of methanol with a catalytic amount of Raney nickel. Ammonia is now applied and hydrogenated with hydrogen at 50~C for four hours (80 bar, autoclave). After the reaction has been completed, the catalyst is suctioned off, and the solvent is spun off. The residue is chromatographed on silica gel with dichloromethane/isopropanol/ammonia as mobile solvent. 147.1 mg (27.3%) is isolated.

Example 232 4-[2-(1-Imidazolyl)-phenoxy]-butylamine 415 mg (1.82 mmol) of the compound that is produced according to Example 128 is reacted as described in Example 231.

After working-up and chromatography, 349.3 mg (83.8%) of amine is obtained.

Example 233 5-[2-(1-Imidazolyl)-phenoxy]-pentylamine 723 mg (3 mmol) of the compound produced according to Example 129 is reacted as described in Example 231. After working-up and chromatography, 389.2 mg (52.9%) of amine is obtained.

Example 234 6-[2-(1-Imidazolyl)-phenoxy]-hexylamine 720.8 mg (2.82 mmol) of the nitrile that is produced according to Example 130 is reacted as described in Example 231.
After working-up and chromatography, 575 mg (78.7%) of amine is obtained.

Example 235 7-[2-(1-Imidazolyl)-phenoxy]-heptylamine 780 mg (2.9 mmol) of the compound that is produced according to Example 131 is reacted analogously to Example 231. Working-up and chromatography yield 529.5 mg (66.8%) of amine.

Example 236 2-Cyano-E-3-[2-(1-Imidazolyl)-phenyl]-acrylic acid ethyl ester 5 mmol of cyanoacetic acid ethyl ester is boiled in toluene with 5 mmol of 2-(1-imidazolyl)-benzaldehyde with the addition of a small amount of acid in a water separator. After cooling, needles precipitate, which are washed with toluene and dried at 60~. The yield is 79%, melting point: 129.5. The aldehyde can CA 0223~621 1998-04-22 be obtained according to standard methods from glycolacetal by cleavage with semiconcentrated hydrochloric acid/THF/water 1~
with a yield of 98%. The acetal is produced by aldehyde being stirred with glycol and para-toluenesulfonic acid with a yield of 69~ or by reaction of 2-bromobenzaldehyde acetal with imidazole.

Example 237 Ortho-bromoci ~n~m; c acid ethyl ester Ortho-bromoc; nn~m; c acid (5.22 g) is esterified with 3.05 g of ethyl bromide, 3.86 g of potassium carbonate and 25 ml of DMF
after 2 hours at 60~. The mixture is poured onto water, extracted with ethyl acetate; the organic phase is dried with magnesium sulfate and concentrated by evaporation. 99% of crude product, which is further reacted, results (Example 87).

Analogously, there are obtained Example 238 Meta-bromocinnamic acid ethyl ester, yield 99%, oil.

Example 239 E-3-[2-(1-Imidazolyl)-phenyl]-allyl alcohol and E-3-[2-(1-imidazolyl)-phenyl]-acrolein In the case of the reduction of E-3-[2-(1-imidazolyl)-phenyl]-acrylic acid ethyl ester (242 mg) with DiBAH in 5 ml of toluene at --78~ and then for 1 hour at 0~C, a mixture of aldehyde and allyl alcohol, which is separated chromatographically with EE
with the addition of ethanol as eluant, is obtained after CA 0223~621 1998-04-22 working-up. Yield of aldehyde: 13%, lH-NMR (CDCl3): 9.57(d lH), 7.1 to 7. 8 (mult. 8H), 6.69(dd lH).
Yield of alcohol: 48%, lH-NMR (CDCl3): 7.7 to 7.07 (mult.
7H), 6.37 (mult. 2H), 4.28(dd 2H).

Analogously, there are obtained Examp le 2 4 0 E-3-[3-(1-Imidazolyl)-phenyl~-allyl alcohol, yield: 88%, oil.

Example 241 3-[2-(1-Imidazolyl)-phenyl]-propanol and 3-[2-(1-imidazolyl)-phenyl]-propanal consisting of 3-[2-(1-imidazolyl)-phenyl]-propionic acid ethyl ester, yield of aldehyde: 13%, lH-NMR
~DCl3): 9=68(1H); 7=61(1H); 7=09(1H); 7=2 to 7=45 (mUlt= 5H) 2.83m2(1H), 2.57 (mult. 2H).
Alcohol: lH-NMR (CDCl3): 7.59(1H), 7.07(1H), 7.18(1H), 7.2 to 7.47 (mult. 4H), 3.55 (mult. 2H), 2.57 (mult. 2H), 1.7 (mult.
2H).

Example 2 42 3-[3-(1-Imidazolyl)-phenyl]-propanol After extraction, the crude product is obtained with T.; Al ~4 (1.1 equivalents in THF) and 3-[3-(1-imidazolyl)-phenyl]-propionic acid ethyl ester after reaction and pouring on sodium tartrate in water.
Yield: 99.7~, lH-NMR (CDCl3): 7.84(1H), 7.4 to 7.2 (mult.
6H), 3.7m2(1H), 2.8m2(1H), 1.95 (mult. 2H).

CA 0223~621 1 998 - 04 - 22 Example 243 2-Fluoro-4-(1-pyrrolo)-phenyl-1-(1-imidazole) 133 mg of 4-amino-2-fluoro-phenyl-1-(1-imidazole) is refluxed in acetic acid (1 ml) with 1 equivalent of 2,5-dimethoxytetrahydrofuran for 2 hours. It is poured onto saturated potassium bicarbonate solution, extracted twice with EE, and the organic phase is washed. It is dried with magnesium sulfate, spun in, and column chromatography is carried out with EE. Yield: 69%, lH-NMR (CDCl3): 6.4 to 7.43 (mult. 9H), 7.8(s broad lH).

In the same way, there are produced:
Example 243b 4-Chloro-2-pyrrolo-phenyl-1-(1-imidazole), yield 100%, melting point: 84~.

Example 244 5-Chloro-2-pyrrolo-phenyl-1-(1-imidazole), yield: 94%, melting point: 115~.

Example 245 3-Chloro-4-pyrrolo-phenyl-1-(1-imidazole), yield: 61%, lH-NMR
(CDCl3): 6.38 (mult. 2H), 6.92 (mult. 2H), 7.23 to 7.9 (mult.
6H).

CA 0223~621 1998-04-22 Example 246 1-[2-(1-Imidazolyl)-phenyl]-ethanol 1.72 g of 2-(1-imidazolyl)-benzaldehyde is reacted with 3.7 ml of methylmagnesium bromide (3M solution) in 12 ml of THF.
After 2 hours, ammonium chloride solution is added, extracted with EE, washed with brine, dried and concentrated by evaporation. After column chromatography with EE, the yield is 51%. lH-NMR (CDC13): 7.07 to 7.79 (mult. 7H), 4.74 (quartet lH), 1.41(d 3H).

Example 247 2-[2-(1-Imidazolyl)-phenoxy]-acetic acid 1.3 g (4.74 mmol) of the ester that is produced according to Example 133 is mixed with 10 ml of a mixture of KOH/CH30H/H20 (3.6 g, 24 ml, 120 ml), and it is stirred at room temperature until saponification is completed. It is acidified with 10%
sulfuric acid and then poured over Extrelut with CH2Cl2. The filtrate is spun in, and the residue is chromatographed on sio2 with a mobile solvent mixture that consists of CH2Cl2/isopropanol/water. The yield is 759.2 mg (73.7%).

Example 248 4-[2-(1-Imidazolyl)-phenoxy]-butyric acid 0.600 g (2.19 mmol) of the ester that is produced according to Example 134 is saponified analogously to Example 247. 412.1 mg (76.5%) of product is isolated.

CA 0223~621 1998-04-22 Example 249 5-[2-(1-Imidazolyl)-phenoxy]-pentanoic acid 1.35 g (4.92 mmol) of the ester that is produced according to Example 135 is saponified analogously to Example 247. The yield of product is 604.3 mg (49.1%).

Example 250 6-[2-(1-Imidazolyl)-phenoxy]-hexanoic acid 1.1 g (4.64 mmol) of the ester that is produced according to Example 136 is saponified as described in ~xample 247 and worked up. 784.2 mg (78.6~) is isolated.

Example 251 7-[2-(1-Imidazolyl)-phenoxy]-heptanoic acid 0.148 g (0.464 mmol) of the that is produced according to Example 137 is saponified analogously to Example 247 and worked up. 132.8 mg (98.5%) of product is isolated.

Example 25lb 2-[2-(1-Imidazolyl)-benzylthio]-acetic acid, yield: 81%, melting point: 140~.

Example 252 4-(1-Imidazolyl)-3-(methylthiomethyl)phenol 1.5 mmol of 4-(1-imidazolyl)-3-(methylthiomethyl)phenolmethylether with 5 mmol of sodium thiomethylate is refluxed for 2 hours in DMF. It is poured onto CA 0223~621 1998-04-22 saturated potassium bicarbonate solution, extracted twice with EE, and the organic phase is washed with brine. It is dried with magnesium sulfate, spun in and, after column chromatography with EE/ethanol, a 64% yield is obtained. Melting point: 129~.

Analogously, there are obtained:
Example 253 3-(1-Imidazolyl)-4-(methylthiomethyl)phenol, yield: 43%, lH-NMR
(CDCl3): 7.77(1H), 7.24(1H), 7.18(1H), 7.3(1H), 7.0(1H), 6.8(1H), 3.40(s 2H), 2.02(s 3H).

Bxnmple 254 2-(lH-Imidazol-l-yl)-3-pyridinol 2-Chloro-3-phenylmethoxy-pyridine (1.4 g) and imidazole (4.3 g) are heated for 4 days in an oil bath to 120~C. The mixture is cooled to room temperature and mixed with 5N NaOH and chloroform.
The organic phase is separated, dried and concentrated by evaporation. The residue is purified chromatographically, and 2-(l-imidazolyl)-3-phenylmethoxy-pyridine is obtained. 2-(1-Imidazolyl)-3-phenylmethoxy-pyridine and 0.01 g of Pd/C are added to 2 ml of methanol, stirred for 1 hour under hydrogen, filtered off, and the solvent is drawn off. The title compound with a melting point of 162-164~C is obtained.

Example 255 [2--(1-Imidazolyl)-benzyl]-methylsulfone 3.05 g of [2-(1--imidazolyl)-benzyl]-methylthioetheris mixed at 5~ in 75 ml of dichloromethane with 7.08 g of meta-chloroperbenzoic acid. It is stirred overnight and then diluted with dichloromethane, extracted twice with lN sodium hydroxide solution, twice with water, and the organic phase is dried with magnesium sulfate. After spinning--in and column chromatography with EE/ethanol, the sulfone is obtained, in addition to a little sulfoxide, in 78% yield. Melting point: 156~. lH-NMR (CDC13):
7.71(1H), 7.70(1H), 7.52 (mult. 2H), 7.34 (mult. lH), 7.22(s 2H), 4.13(s 2H), (lH), 2.83(s 3H).

Analogously, there are obtained:
Example 256 [2--(1-Imidazolyl)-phenylmethyl]-methylsulfoxide, yield: 67%, melting point: 94~, lH-NMR (CDCl3): 7.67(1H), 7.22(1H), 7.15(1H), 7.33 to 7.57 (mult. 4H), 3.75 (AB quartet 2H), 2.50(s 3H).

Example 257 [2--(2--(1-Imidazolyl)--phenyl)eth-1-yl]-methylsulfone, yield: 71%, lH-NMR (CDCl3): 7.72 to 7.12 (mult. 7H), 3.02 (mult. 4H), 2.72(s 3H).

Example 258 [2-(1-Imidazolyl)-phenyl]-methylsulfone, yield: 67%, melting point: 139-141~.

Example 259 [2-(1-Imidazolyl)-5-phenyl-benz-1-yl]-methylsulfone, yield: 34%, lH-NMR (CDC13): 7.29 to 7.77 (mult. lOH), 7.91(d lH), 4.20(s 2H), 2.89(s 3H).

Example 260 [2-(1-Imidazolyl)-5-methoxy-benzyl]-methylsulfone, yield: 25%, melting point: 115.9~.

Ex~mple 261 [2-(1-Imidazolyl)-5-cyano-benzyl]-methylsulfoxide, yield: 26%, lH-NMR (CDC13): 7.20 to 7.9 (mult. 6H), 3.79 (mult. 2H), 2.60(s 3H).

Example 262 [2-(1-Imidazolyl)-5-phenyl-benzyl]-methylsulfoxide, yield: 77%, lH-NMR (CDC13): 7.20 to 7.80 (mult. llH), 3.82(dd 2H), 2.56(s 3H).

Example 263 [2-(1-Imidazolyl)-5-methoxy-benzyl]-methylsulfoxide, yield:
68.8%, melting point: 103.1~.

CA 0223~621 1998-04-22 Example 264 [2-(1-Imidazolyl)-5-amido-benzyl]-methylsulfoxide, yield: 22%, melting point: 226~.

Example 265 [2-(1-Imidazolyl)-5-cyano-benzyl]-methylsulfone, yield: 25%, lH-NMR (CDCl3): 7.27 to 8.05 (mult. 6H), 4.20(s 2H), 2.99(s 3H).

Example 266 [2-(1-Imidazolyl)-5-amido-benzyl]-methylsulfone, yield: 36%, melting point: 189.5~.

Example 267 [2-(2-(1-Imidazolyl)-phenyl)-et-1-yl]-methylsulfoxide, yield:
61%, lH-NMR (CDCl3): 7.72 to 7.12 (mult. 7H), 3.0(tr 2H), 2.7 (mult. 2H), 2.46(s 3H).

Example 268 [2-(1-Imidazolyl)-benzyl]-ethylsulfone, yield: 76%, lH-NMR
(CDCl3): 7.72 to 7.2 (mult. 7H), 4.03(s 2H), 2.95 (quartet 2H), 1.82(tr 3H).

Example 269 [2-(1-Imidazolyl)-benzyl]-isopropylsulfone, yield: 75%, lH-NMR
(CDCl3): 7.72 to 7.2 (mult. 7H), 4.00(s 2H), 3.07 (heptet lH), 1.45(d 6H).

Example 270 [2~ Imidazolyl)-benzyl]-ethylsulfoxide, yield: 77%, lH-NMR
(CDC13): 7.67 to 7.17 (mult. 7H), 3.7 (quartet 2H), 2.7 (mult.
2H), 1.28(tr 3H).

Example 271 [2-(l-Imidazolyl)-benzyl]-isopropylsulfoxide, yield: 82%, lH-NMR
(CDC13): 7.72 to 7.2 (mult. 7H), 3.6(s 2H), 2.74 (heptet lH), 1.2(dd 6H).

Example 272 [2-(2-(1-Imidazolyl)-phenoxy)-eth-l-ylmethylsulfone, yield: 31%, lH-NMR (CDC13): 7.7(1H), 7.45 to 7.04 (mult. 6H), 4.47(dd 2H), 3.39 (mult. 2H), 2.61(s 3H).

Example 273 [2-(2-(1-Imidazolyl)-phenoxy)-eth-1-ylmethylsulfoxide, yield:
32%, lH-NMR (CDC13): 7.74(1H), 7.45 to 7.04 (mult. 6H), 4.47 (mult. 2H), 3.2(1H), 3.1(1H), 2.54(s 3H).

Example 274 t(2-(1-Imidazolyl)-pyridyl-3-meth)yl]methylsulfone, yield: 35%, lH-NMR (CDC13): 8.62(dd lH), 8.12(dd lH), (lH), 8.00(s lH), 7.5m2(1H), 7.24(s lH), 4.29(s 2H), 2.92(s 3H).

CA 0223~621 1998-04-22 Example 275 [2-(2-(1-Imidazolyl)-phenyl]-isopropylsulfoxide, yield: 34%, melting point: 91.5~.

Examplo 276 [2-(2-(l-Imidazolyl)-phenyl]-isopropylsulfone~ yield: 57%, melting point: 80.8~.

Example 277 [2-(1-Imidazolyl)-5-hydroxy-benzyl]-methylsulfone, yield: 62.6%, melting point: > 300~.

Example 278 [2-(1-Imidazolyl)-5-hydroxy-benzyl]-methylsulfoxide, yield: 9096, melting point: oil.

Example 279 [3-(1-Imidazolyl)-benzyl]-methylsulfone, yield: 82%, melting point: 144.5~.

Example 280 [3-(1-Imidazolyl)-benzyl]-methylsulfoxide, yield: 65%, lH-NMR
(CDCl3): 7.87(lH), 7.2 to 7.52 (mult. 6H), 3.99(d 2H), 2.52(s 3H).

-CA 0223~621 1998-04-22 Bxample 281 [3-(1-Imidazolyl)-phenyl]-methylsulfone, yield: 56%, lH-NMR
(CDCl3): 8.01(1H), 7.94 (mult. 2H), 7.7 (mult. 2H), 7.37(lH), 7.27(1H), 3.12(s 3H).

Exampls 282 [3-(1-Imidazolyl)-benzyl]-methylsulfoxide, yield 22%, melting point: oil.

Example 283 [2-(1-Imidazolyl)-5-(meta-pyridyl)-benzyl]-methylsulfone, yield 25%, melting point: oil.

Example 284 [2-(1-Imidazolyl)-5-(meta-pyridyl)-benzyl]-methylsulfoxide, yield 11~, melting point: oil.

Example 285 [2-(1-Imidazolyl)-phenyl]-methylsulfoxide, yield: 26%, melting point: 147~.

Example 286 [4-(1-Imidazolyl)-phenyl]-methylsulfone, yield: 25~, lH-NMR
(acetone d6): 8.3(1H), 7.76(1H), 7.18(1H), 7.94 (mult. 2H), 8.10 (mult. 2H), 3.2(s 3H).

Example 287 [4-(1-Imidazolyl)-phenyl]-methylsulfoxide, yield: 60%, lH-NMR
(CDCl3): 7.23(lH), 7.32(lH), 7.92(lH), 7.58 (mult. 2H), 7.80 (mult. 2H), 2.26(s 3H).

Example 287a t3-(Dimethylsulfon-1-yl)-4-(1-imidazolyl)-phenyl]-methylsulfone, yield 34%, melting point: decomposition.

Exampl~ 288 [2-(1-Imidazolyl)-5-(meta-pyridyl)-benzyl]-methylthioether ~ 5-Bromo-2-(1-imidazolyl)-benzyl]-methylthioether (142 mg) is refluxed together with 1 equivalent of diethyl-3-pyridylborane, 10 mol% of tetrabutylammonium bromide, 57 mg of KOH powder and 58 mg of tetrakistriphenylphosphine-palladium(~) for 3 hours. The mixture is poured onto water, extracted with ethyl acetate; the organic phase is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with EE
and ethanol follows. The yield is 84%. Melting point: 105~.

Bxample 289 a) [5-(Thien-2-yl)-2-(1-imidazolyl)-phenylmethyl]-thiomethylether and [5-(thien-2-yl)-2-(1-imidazolyl)-phenylmethyl]-methyl sulfoxide 5-Bromo-2-(1-imidazolyl)-phenylmethyl]-thiomethylether (141 mg) is mixed under protective gas in 2 ml of DME with 58 mg of tetrakis-triphenylphosphine-palladium(O); 1.2 equivalents of 2-CA 0223~621 1998-04-22 thiopheneboric acid (77 mg) as well as 126 mg of sodium bicarbonate in 2 ml of water are added, and the mixture is stirred for 4 hours at 100~. It is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Column chromatography with toluene/EE 1:1 follows. The yield totals 64%. [lH]-NMR
(CDCl3): 7.9(s broad lH), 7.6 to 7.2(m 8H), 3.48(s 2H), 2.01 (s 3H)- tlH]-NMR (CDCl3) sulfoxide: 7.78 to 7.16(m 9H), 3.78, (q, 2H), 2.53 (s 3H).

CA 0223~621 1998-04-22 Yl Analogously, there are obtained:
b) [5-(Thien-3-yl)-2-(1-imidazolyl)-phenylmethyl]-thiomethylether in 87% from 3-thiopheneboric acid.
Educt Product Yield c) 2-Bromo-phenyl-l-(l- 2-Thien-2-yl-phenyl-1-(l- 71%
imidazole) imidazole) d) 2-bromo-phenyl-l-(1- 2-thien-3-yl-phenyl-1-(1- 77%
imidazole) imidazole) e) 3-bromo-pyridyl-2-(1- 3-thien-2-yl-pyridyl-2-(l- 97%
imidazole) imidazole) f) 3-bromo-pyridyl-2-(1- 3-thien-3-yl-pyridyl-2-(1- 98%
imidazole) imidazole) g) 2-bromo-3-chloro- 3-chloro-2-(thien-2-yl)- 55%
phenyl-1-(1-imidazole) phenyl-1-(1-imidazole) h) 2-bromo-5-chloro- 5-chloro-2-(thien-2-yl)- 61%
phenyl-1-(1-imidazole) phenyl-l-(l-imidazole) i) 2-bromo-5-chloro- 5-chloro-2-(thien-3-yl)- 94%
phenyl-l-(1-imidazole) phenyl-1-(1-imidazole) k) 2-bromo-4-nitro- 4-nitro-2-(thien-2-yl)- 84%
phenyl-l-(l-imidazole) phenyl-1-(1-imidazole) l) 2-bromo-4-nitro- 4-nitro-2-(thien-3-yl)- 70%
phenyl-1-(1-imidazole) phenyl-l-(1-imidazole) m) 2-bromo-4-methyl- 4-methyl-2-(thien-2-yl)- 64 phenyl-l-(1-imidazole) phenyl-1-(1-imidazole) n) 2-bromo-4-methoxy- 4-methoxy-2-(thien-2-yl)- 80 phenyl-1-(1-imidazole) phenyl-l-(l-imidazole) o) 4-methoxy-2-(thien-2- 4-hydroxy-2-(thien-2-yl)- 99%
yl)-phenyl-l-(l- phenyl-l-(1-imidazole) by imidazole) ether cleavage p) 4-nitro-2-(thien-2- 4-amino-2-(thien-2-yl)- 79%
yl)-phenyl-1-(1- phenyl-1-(1-imidazole) by imidazole) reduction q) 4-nitro-2-(thien-3- 4-amino-2-(thien-3-yl)- 51%
yl)-phenyl-1-(1- phenyl-1-(1-imidazole) by imidazole) reduction r) 4-amino-2-(thien-2- 4-bromo-2-(thien-2-yl)- 33 yl)-phenyl-1-(1- phenyl-1-(1-imidazole) imidazole) according to Sandmeyer Example 290 3-(1-Imidazolyl)-benzamidine-hydrochloride Hydrochloric acid is directed into a cooled solution of 0.47 g of 3-(1-imidazolyl)-benzonitrile in 5 ml of ethanol, and the reaction mixture is stirred overnight in a sealed flask. After the solvent is removed, the residue is dissolved in 10 ml of ethanol, and ammonia is directed into the cooled solution. The sealed flask is heated to 75~C in an oil bath for 2 hours. After cooling, the title compound is filtered off.

Example 291 N-{2-t2-(1-Imidazolyl)-phenoxy]-ethyl}-quanidine-hydrochloride 100 mg (10.5 mmol) of the amine that is produced according to Example 231 is added to 1.5 ml of DMF, mixed with equivalent amounts of 1-H-pyrazole-carboxamidine-hydrochloride and diisopropylethylamine and stirred until the reaction is completed at room temperature. Since it was spun in until the dry state was achieved, it is chromatographed on silica gel with CHzCl2, ethanol, H20 as mobile solvent. 62.2 mg (40%) is obtained.

Example 2 9 la Analogously, N-{2-[4-(1-imidazolyl)-3-methylthiomethyl-phenoxy]-ethyl}-quanidine hydrochloride follows from the amine in 18% yield.

- . -CA 0223~621 1998-04-22 Example 29lb N-{4-[2-(1-Imidazolyl)-phenoxy]-butyl}-guanidine-hydrochloride 100 mg (0.43 mmol) of the amine that is produced according to Example 232 is reacted as described in Example 290. 48.6 mg (88.6%) of the desired compound is isolated.

Example 292 N-{5-[2-(1-Imidazolyl)-phenoxy]-pentyl}-guanidine-hydrochloride 100 mg (0.41 mmol) of the compound that is produced according to Example 233 is reacted as described in Example 290.
57 mg (45.4%) of the desired guanidine hydrochloride is obtained.

Example 293 N-~6-[2-(1-Imidazolyl)-phenoxy]-hexyl}-guanidine-hydrochloride 100 mg (0.38 mmol) of the compound that is produced according to Example 234 is reacted as described in Example 290.
112.7 mg (86.5%) of the desired compound is obtained.

Ex~mpl~ 294 N-~7-[2-(1-Imidazolyl)-phenoxy]-heptyl}-guanidine-hydrochloride 100 mg (0.37 mmol) of the compound that is produced according to Example 235 is reacted as described in Example 290.
115.7 mg (89.6%) of the desired guanidine-hydrochloride is isolated.

CA 0223~621 1998-04-22 Bxample 2 95 N-{6-t4-(1-Imidazolyl)-phenoxy]-hexyl}-guanidine-hydrochloride 100 mg (0.386 mmol) of 6-[4-(1-imidazolyl)-phenoxy]--hexylamine is reacted as described in Example 290. After the working-up, 115.2 mg (88%) of the desired compound is isolated.

Example 296 N-[2-(1-Imidazolyl)--phenyl]-N'-methyl-thiourea 0.2 g of 2-amino-phenyl-1-(1-imidazole) is dissolved in 4 ml of THF and mixed with 86 ,~Ll of methyl isothiocyanate in 1 ml of THF. After slight heating, the reaction is terminated. The THF
is spun off, and the residue is recrystallized from isopropanol.
First, some educt precipitates; in addition, product is obtained with a melting point of 287~C dec. and with a yield of 27%.

Analogously, there are obtained:
Examp 1~ 2 9 7 N-[2-(1-Imidazolyl)-benzyl]-N'-methyl-thiourea, yield: 31%, melting point: 128~.

Example 2 9 8 [2-(1-Imidazolyl)-benzyl]-methylsulfone hydrochloride [2-(1--Imidazolyl)--benzyl]--methylsulfone(0.75 mmol) is stirred in 6 ml of lN HCl in ether and 10 ml of ethanol for 6 hours at room temperature. Some ether is added, and it is put into the refrigerator. Crystals are suctioned off, washed and dried. Yield: 89%, melting point: 201~.

- ~ = -CA 0223~62l l998-04-22 Example 299 [5-Cyano-2-(1-imidazolyl)-benzyl]-methylthioether hydrochloride, yield: 88%, melting point: 211~ dec., lH-NMR (DMSO d6):
9.32d(s lH), 8.16(1H), 8.1 (mult. 2H), 7.8 (mult. 2H), 3.77(s 2H), 1.93(s 3H).

Analogously, hydrochlorides and hydrobromides are produced, such as Example 300 t2-(1-Imidazolyl)-benzyl]-methylthioether hydrobromide 150 mg of [2-(1-imidazolyl)-benzyl]-methylthioether in 3 ml of 47% HBr is dissolved, concentrated by evaporation after 3 hours at room temperature and dried on a bulb tube in a vacuum.
Yield: 100%, lH-NMR (DMSO d6): 9.51s broad(lH), 8.1(s lH), (lH), 7.97(s lH), 7.7 to 7.50 (mult. 4H), 3.71(s 2H), 1.92(s 3H).

Other salts are also produced analogously, such as Example 301 [2-(1-Imidazolyl)-benzyl]-methylthioether oxalate [2-(1-Imidazolyl)-benzyl]-methylthioether (110 mg) is stirred in 2 ml of ethanol with 1 equivalent of oxalic acid for a total of 12 hours at room temperature; after 24 hours in a refrigerator, it is suctioned off and dried. Yield: 85%, melting point: 102~.

CA 0223~621 1998 - 04 - 22 Example 302 [2-(1--Imidazolyl)-benzyl]-methylsulfoneoxalate, yield: 88%, melting point: 175~.

Example 303 [2-(2'-Bromo-imidazol--1-yl)-benzyl]-methylthioether 204 mg of t2-(imidazol-1-yl)-benzyl]-methylthioether is stirred with 1 equivalent each of triphenylphosphine and tetrabromomethane in 6 ml of dichloromethane. After 12 hours at room temperature, the reaction is completed. The mixture is concentrated by evaporation, and it is all added on a column.
After column chromatography, the title compound is obtained with a yield of 59%. lH-NMR (CDCl3): 7.58 to 7.2 (mult. 6H), 3.35(d lH), 3.53(d lH), l.99(s 3H).

Example 304 2--[4--(1--Imidazolyl)--phenoxy]-aceticacid--hydrochloride 100 ml of 6N HCl is mixed with 1.2 g of 2-[4-(1-imidazolyl)-phenoxy]-acetic acid methyl ester, stirred for 4 hours and concentrated by evaporation. The residue is treated with ethanol, and the title compound with a melting point of 116--117~C
is obtained.

Example 305 2--[3--(1--Imidazolyl)-phenoxy]--aceticacid--hydrochloride 4 g of 3-(1-imidazolyl)--phenol, 1.8 ml of bromoacetic acid methyl ester and 6.5 g of cesium carbonate are added to 50 ml of DMS0. The mixture is stirred for 1 day, added in water and extracted with methylene chloride. The organic phase is separated, washed with water, dried, and the solvent is drawn off. The residue is taken up in 100 ml of 6N HCl. After 4 hours of stirring, it is concentrated by evaporation, and the residue i5 treated with ethanol. The title compound with a melting point of 206-208~C is obtained.

Example 306 2-t2-(1-Imidazolyl)-phenylmethyl]-methanesulfonamide 20 ml of methylene chloride is mixed with 1.0 g of 2-(1-imidazolyl)-benzenemethanamine, 0.43 ml of methanesulfonyl chloride and 1.3 ml of triethylamine. After stirring overnight, water is added, the organic phase is separated, dried, and the solvent is drawn off in a vacuum. After recrystallization in alcohol, the title compound is obtained.

Example 307 [4-(1-Imidazolyl)-3methylthiomethyl-phenol]-4'-cyanophenylether 2 g of 4-(1-imidazolyl)-3-methylthiomethyl-phenol is stirred in DMF with 1.1 g of p-fluorobenzonitrile and 1.506 g of potassium carbonate for 7 hours at 120~. The mixture is poured onto waterj extraeted wit~. et~yl acetate, the organiG phasQ is dried with magnesium sulfate and concentrated by evaporation.
77.4% product results. [lH]-NMR (CDCl3): 7.7(m 3H), 7.32 to 7.0(m 7H), 3.46(s 2H), 2.03(s 3H).

CA 0223~62l l998-04-22 4-[4-(1-Imidazolyl)-3-methylthiomethyl-phenoxy]-benzoic acid amide is obtained from the above in 33% yield with potassium hydroxide in ethylene glycol.
Analogously, there are obtained:
a) from fluorobenzene, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-phenylether in 26% yield b) from 2-bromopyridine, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-2-pyridylether in 7% yield c) from 3-bromopyridine, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-3-pyridylether in 18% yield d) from 4-fluoronitrobenzene, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-4'-nitrophenylether in 91% yield e) from 2-fluorobenzonitrile, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]--2'-cyanophenylether in 81% yield f) from 4-fluoroanisole, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-4'-methoxyphenylether in 30% yield g) from 4-bromobenzotrifluoride, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]--4'-trifluoromethylphenylether in 58%
yield h) from 4-fluorobenzoic acid ethyl ester, 4-[4-(1-imidazolyl)-3-methylthiomethyl-phenoxy]-ethylbenzoate in 17%
yield i) 3-iodobenzotrifluoride, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-3'-trifluoromethylphenylether in 62%
yield CA 0223~621 1998-04-22 k) 4-hydroxymethylpyridine, [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-4-pyridylmethylether in 17% yield under Mitsunobu conditions l) from e) in 22% yield with potassium hydroxide in ethylene glycol, 2-[4-(1-imidazolyl)-3-methylthiomethylphenoxy]-benzoic acid amide m) by reduction, t4-(1-imidazolyl)-3-methylthiomethyl-phenol]-4'-aminophenylether from [4-(1-imidazolyl)-3-methylthiomethyl-phenol]-4'-nitrophenylether in 59% yield.
Melting point: 203~.

Example 308 N-{[4-(1-Imidazolyl)]-(3-methylthiomethyl)-phenyl}-N'-{[4-(2-pyridiminyl)]-(4-azapentamethylene)]-urea 110.2 mg (0.371 mmol) of triphosgene is dissolved in 2 ml of absolute dichloromethane. 219.9 mg (1 mmol) of {[4-(1-imidazolyl)]-(3-methylthiomethyl)}-aniline (amine 1) and 142.6 mg (1.103 mmol) of diisopropylethylamine, dissolved in 4 ml of dichloromethane, are added in drops to this solution under protective gas within 30 minutes at room temperature. Then, 237.8 mg (1.003 mmol) of N-(2-pyrimidinyl)-piperazine-dihydrochloride (amine 2) and 427.8 mg (3.309 mmol) of diisopropylethylamine, dissolved in a mixture of 4 ml of dimethylformamide and 4 ml of dichloromethane, are added. After being stirred overnight, it is evaporated to the dry state, and the residue that remains is chromatographed on silica gel (mobile solvent dichloromethane/isopropanol or ethyl CA 0223~621 1998-04-22 acetate/isopropanol). 186.6 mg (45.4%) of the desired urea remains. Melting point 175-180~C.
IR (KBr) 3115, 1670, 1586, 1508, 1410, 1254, 1214 cm~

Example 309 N-{[4-(1-Imidazolyl)]-(3-methylthiomethyl)-phenyl}-N'-{2-[(3,4-methylenedioxy)-phenyl]-ethyl}-urea Production is carried out as described in Example 1 with use of 439.9 mg (2.006 mmol) of {[4-(1-imidazolyl)]-(3-methylthiomethyl]}-aniline (amine 1) and 404.5 g (2.006 mmol) of {2-[(3,4-methylenedioxy)-phenyl]-ethylamine (amine 2). The base amounts are adapted accordingly. After chromatography on silica gel (dichloromethane/methanol or ethyl acetate as mobile solvent), 144.8 mg (17.5%) of the desired urea is obtained, melting point 55-60~C.
IR (KBr) 1701, 1685, 1654, 1560, 1508 cm~

Examplo 310 N,N'-Bis-[4-(1-imidazolyl)]-3-methylthiomethyl)-phenyl]-urea 219.9 mg (1.003 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)]-aniline (amine 1) is reacted as described. As amine 2, [4-(1-imidazolyl)]-(3-methylthiomethyl)]-aniline is also used. After chromatography on silica gel (mobile solvent ethyl acetate/methanol), the product is isolated in 41.7~ (194.5 mg) yield, melting point 204-210~C.
IR (KBr) 3066, 2914, 2814, 1709, 1593, 1575, 1412, 1207 cm~

.
CA 0223~621 1998-04-22 Example 311 N-{t4-(1-Imidazolyl)]-(3-methylthiomethyl)-phenyl}-N'-(2-thienylmethyl)-urea 219.9 mg (1.003 mmol) of {[4-(1-imidazolyl)]-(3-methylthiomethyl)}-aniline (amine 1) is reacted as described. As amine component 2, 2-thienylmethylamine is used. After chromatography on silica gel (mobile solvent: ethyl acetate), 172.9 mg (52.8%) of the desired urea is obtained.
IR (KBr) 3320, 2920, 1700, 1660, 1550, 1500, 1410, 1220, 1050 cm~1 Example 312 [4-(1-Imidazolyl)]-(3-methylthiomethyl)-phenol-nonaflate 5 g (22.67 mmol) of {[4-(1-imidazolyl)]-(3-methylthiomethyl)}-phenol is dissolved in 75 ml of dimethylformamide and mixed at room temperature with 755.7 mg of an 80% NaH suspension (25.19 mmol). After 30 minutes of stirring at 60~C, 8.47 g (28.05 mmol) of perfluorobutanesulfonic acid fluoride is added, and it is stirred for another 90 minutes at 60~C. After cooling, the reaction mixture is mixed with about 50 ml of saturated NaHC03 solution and stirred for 30 minutes at room temperature, and the mixture is diluted with water. After shaking three times with ethyl acetate, the combined organic extracts are washed twice with saturated NaCl solution and dried on sodium sulfate. After the dessicant is filtered off, the solvent is spun in, and the remaining residue is chromatographed CA 0223~621 1998-04-22 lU~

on silica gel (mobile solvent ethyl acetate). 11.2 g (28.2%
product) is isolated.

Bxampl~ 313 t4-(1-Imidazolyl)]-(3-methylthiomethyl)-benzoic acid methyl ester 11.2 g (22.3 mmol) of 4-(1-imidazolyl)]-(3-methylthiomethyl)-phenol-nonaflate is dissolved in a mixture of 22.2 ml of methanol and 44.6 ml of dimethylformamide. After 4.5 g (44.6 mmol) of triethylamine, û.145 (0.646 mmol) of palladium(II) acetate and 0.275 g (0.666 mmol) of 1,3-bis-diphenylphosphonopropane are added, O-gas is allowed to bubble through for 30 minutes. Under CO atmosphere, the reaction is stirred overnight at 80~C.
The reaction mixture is added to NaCl solution. After extraction with ethyl acetate three times, the combined organic phases are washed twice with saturated NaCl solution. After drying on Na2SO4 and after the dessicant is filtered off, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate; then dichloromethane/methanol). The yield is 5.30 g (1.4%).

Example 314 [4-(1-Imidazolyl)]-(3-methylthiomethyl)-benzoic acid 4.3 g (16.4 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)-benzoic acid methyl ester in 10 ml of methanol is stirred with 10 ml of a 5% aqueous lithium hydroxide solution overnight at room temperature.

CA 0223~621 1998-04-22 The reaction mixture is brought to pH 4-5 with 10% sulfuric acid and then poured onto Extrelut. After elution with about 300 ml of dichloromethane and about 300 ml of methanol, the organic extracts are concentrated by evaporation, and the residue is chromatographed on silica gel (mobile solvent dichloromethane/methanol). 3.36 g (82.6%) of product is isolated, melting point 130-135~C.

Example 315 [4-(1-Imidazolyl)]-(3-methylthiomethyl)-benzoic acid-L-histidine methyl ester amide 0.400 g (1.611 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)-benzoic acid is added together with 30 ml of dimethylformamide, 0.320 g (1.611 mmol) of L-histidine methyl ester, 2 HCl, 0.570 g (5.639 mmol) of triethylamine and 0.569 (1.772 mmol) of TBTU and stirred overnight at room temperature.
The reaction mixture is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent dichloromethane/methanol). 0.376 g (58.4~) of product remains, melting point 55-65~C.

Exampl~ 316 [4-(1-Imidazolyl)]-(3-methylthiomethyl)-benzoic acid-histamine-amide 0.200 g (0.806 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)-benzoic acid is mixed in 15 ml of dimethylformamide with 0.0869 g (0.806 mmol) of histamine, CA 0223~621 1998-04-22 0.0815 g (0.806 mmol) of triethylamine and 0.2763 g (0.861 mmol) of TBTU and stirred overnight at room temperature. After spinning-in and chromatography on silica gel (mobile solvent dichloromethane/mçthanol), 0.2445 g (88.9%) of product is obtained.

Exampl~ 317 [4-(1-Imidazolyl)]-(3-methylthiomethyl)-benzoic acid]-[(5-nitro-2-pyridyl)-amino]-ethylenamide 0.150 g (0.604 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)-benzoic acid is reacted under the usual conditions with 2-(2-aminoethylamino)-5-nitropyridine. After working-up and chromatography on silica gel (mobile solvent ethyl acetate/ethanol or dichloromethane/isopropanol), 86 mg (34.5~) of product remains, melting point 201-203~C.

Example 318 t4-(1-Imidazolyl)]-(3-methythiomethyl)-benzoic acid-(2-anilino)-ethylenamide 0.150 g (0.604 mmol) of [4-(1-imidazolyl)]-(3-methylthiomethyl)-benzoic acid is reacted as usual with (2-anilino)-ethyl~n~;ne. After working-up and chromatography on silica gel (mobile solvent ethyl acetate or dichloromethane/isopropanol), 149.6 mg (67.6%) of product is obtained, melting point 114-170~C.

Claims (9)

Claims
1. Compounds of formula I

in which AR2 can be the same or different in one or two places, R1 means hydrogen, Z means nitrogen or -CH=, A means a bond, straight-chain or branched C1-4 alkylene, straight-chain or branched C2-4 alkenylene, straight-chain or branched C2-4 alkinylene, R2 means hydrogen, halogen, NO2, -C=N, CF3, -CCl3, -S(O)m-C1-4 alkyl, -OR5, -S-R6, -CO-R7, -NR8R9, -CH(CN)-COOH, -CH(CN)-COO-C1-6 alkyl, =C(CN)-COOH, =C(CN)-COOC1-6 alkyl, -NH-SO2-R10, -C(NH2)=NOH, -NH-CO-NH2, -NH-CS-NH2, -NH-CS-NH(C1-4 alkyl), -C(=NR)-NHR11, -NH-C(=NR)-NR11R12, -S-(C=NR)-NR11R12, a 5- or 6-membered heteroaryl radical optionally substituted with C1-4 alkyl or halogen, a phenyl or biphenyl radical optionally substituted in one or more places with halogen, C=N, NO2, NH2, CF3, COOH, CONH2, COOC1-4 alkyl, -S-C1-4 alkyl or -O-C1-4 alkyl;
imidazolosulfonyl, -NH-CO-NR16R17, R3 means hydrogen, halogen, NO2, OH, NH2 or imidazol-1-yl, AR2 and R3 together form -O-(CH2)n-O-, m, n mean 1 or 2, R5 means hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 C atoms, which can contain 1-2 double bonds and/or triple bonds, and in which a -CH2 group ... by can be substituted with phenyl, pyridine, pyridimine, pyridazine or pyrazine, and their isomers and tautomers and physiologically compatible salts, whereby (1) if Z = CH- and AR2 means H, halogen, NO2, NH2, CN, CH3, C2H5, CF3, OH, OCH3, O-phenyl, O-CH2-C~CH, O-CH2-CH=CH2, CHO, CONH2, CH2NH2, CH2OH, CO2C2H5, COOH, NH-C1-4 alkyl, NH-CO-CH3 or -O- optionally substituted benzyl, and R3 is hydrogen or NH2, a radical AR2 has a meaning other than that mentioned under 1), (2) if Z = CH- and AR2 is in two places and means OH, NH2 or NO2, R3 is not imidazol-1-yl, (3) if Z is nitrogen, R3 is hydrogen and AR2 is hydrogen, NH2, CH3 or NHCOCH3, a radical AR2 has a meaning other than H, NH2, CH3 or NHCOCH3.
2. Compounds of formula I according to claim 1, in which R1 = hydrogen.
3. Compounds of formula I according to claim 1, in which A means a bond and R2 means an optionally substituted heteroaryl radical or an optionally substituted phenyl radical.
4. Compounds of formula I according to claim 1, in which A means a bond or straight-chain or branched C1-4 alkylene and R2 is OR5 or SR6.
5. Use of the compounds of formula I according to claim 1 for the production of pharmaceutical agents.
6. Use of the compounds of formula IA

in which AR2 can be the same or different in one or two places, R1 means hydrogen, halogen, -SH or -S-C1-4 alkyl, Z means nitrogen or -CH=, A means a bond, straight-chain or branched C1-4 alkylene, straight-chain or branched C2-4 alkenylene, straight-chain or branched C2-4 alkinylene, R2 means hydrogen, halogen, NO2, -C~N, CF3, -CCl3, -S(O)m-C1-4 alkyl, -OR5, -S-R6, -CO-R7, -NR8R9, -CH(CN)-COOH, -CH(CN)-COO-C1-6 alkyl, =C(CN)-COOH, =C(CN)-COOC1-6 alkyl, -NH-SO2-R10, -C(NH2)=NOH, -NH-CO-NH2, -NH-CS-NH2, -NH-CS-NH(C1-4 alkyl), -C(=NR)-NHR11, -NH-C(=NR)-NR11R12, -S-(C=NR)-NR11R12, a 5- or 6-membered heteroaryl radical optionally substituted with C1-4 alkyl or halogen, a phenyl or biphenyl radical optionally substituted in one or more places with halogen, C=N, NO2, NH2, CF3, COOH, CONH2, COOC1-4 alkyl, -S-C1-4 alkyl or -O-C1-4 alkyl;
imidazolosulfonyl, -NH-CO-NR16R17, R3 means hydrogen, halogen, NO2, OH, NH2 or imidazol-1-yl, AR2 and R3 together form -O-(CH2) n-O-, m, n mean 1 or 2, R5 means hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 C atoms, which can contain 1-2 double bonds and/or triple bonds, and in which a -CH2 group can be replaced by oxygen, sulfur, phenyl or C3-6 cycloalkyl optionally substituted with halogen; C3-7 cycloalkyl optionally substituted with methyl or halogen; -CO-R15, -CS-NH(C1-4 alkyl), -CH(NH2)-COO1-6 alkyl, -Si(CH3)2 tert-butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-S-C1-4 alkyl, -CS-CH2-S-C1-4 alkyl, -C(=NR)NR11R12; phenyl optionally substituted with halogen, NO2, NH2, CF3, C=N, COOC1-4 alkyl, COOH, CONH2, C1-4 alkylthio, C1-4 alkoxy or C1-4 alkyl;
tetrahydropyrimidine, tetrahydropyridine, pyridine, -SO2-C1-4 alkyl, -SO2-C1-4 perfluoroalkyl, R6 has the meaning of R5, R7 means hydrogen, C1-8 alkyl, C3-7 cycloalkyl, -CH2-S-C1-4 alkyl, -(CH2)2-S-C1-4 alkyl, -O-C1-6 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, -S-C1-4 alkyl, CF3, -C2F5, OH, phenyl, acidic and basic L-amino acid derivatives, [(5-nitro-2-pyridyl)amino]-ethylene amino, (2-anilino)-ethylene amino, R8, R9 are the same or different and mean hydrogen, C1-4 alkyl, C1-4 alkanoyl or together with the nitrogen atom form a 5- to 6-membered saturated heterocycle, which can contain another O, N or S atom and can be substituted in one to two places with C1-4 alkyl, R10, R11, R12 and R mean hydrogen, C1-6 alkyl, C3-7 cycloalkyl, phenyl, thienyl, R15 means C1-17 alkyl optionally substituted with halogen, NH2 C~N, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkanoyloxy, thiophene or phenyl; C3-7 cycloalkyl optionally substituted with CH3 or phenyl; C1-6 alkoxy, C1-6 alkylthio, -COOH, -COOC1-6 alkyl, NR13R14, R13, R14 are the same or different and mean hydrogen or C1-4 alkyl optionally substituted with halogen, R16 R17 are the same or different and mean hydrogen, C1-4 alkyl, which optionally is substituted with thienyl or phenyl and in which the phenyl radical can be substituted in one or two places with halogen, imidazole, methylenedioxy or C1-8 alkylene, which is straight-chain or branched, and in which one or two methylene groups can be replaced by oxygen and/or sulfur, or -NR16R17 can form a saturated 5- or 6- membered heterocycle, which can contain another N, O or S atom and can be substituted with phenyl, pyridine, pyridimine, pyridazine or pyrazine, and their isomers and tautomers and physiologically compatible salts, for the production of a pharmaceutical agent for inhibiting nitrogen monoxide synthase, whereby R1, AR2 and R3 do not mean hydrogen at the same time.
7. Use of the compounds according to claims 1-4 for the production of a pharmaceutical agent for treating neurodegenerative, auto-immune and/or inflammatory diseases as well as for treating diseases of the cardiovascular system and inflammatory skin diseases and for immunosuppression.
8. Use according to claim 5 for treating multiple sclerosis, Alzheimer's disease, HIV dementia, amyotrophic lateral sclerosis or cerebral ischemia.
9. Process for the production of the compounds of formula I
according to claim 1, in that a) a compound of formula II

in which Z, AR2 and R3 have the above meaning, and Flu represents a leaving group, is reacted with imidazole optionally substituted with R1 in the presence of a base or b) a compound of formula III

or in which A, Z, R1, AR2 and R3 have the above meaning and Flu represents a leaving group, is substituted in a nucleophilic manner in the presence of a base and/or with an organometallic compound, c) a compound of formula IV

in which Z, R1, R3 have the above meaning, is reacted to compounds of formula I using Aldol reactions or Wittig reactions or by nucleophilic attack with Grignard reagents, and is then optionally halogenated or selectively reduced, or thioether is formed, or ether is cleaved, or nitriles are saponified, or acids are esterified or amidated, or ethers or esters are synthesized from phenolene, or amino groups are exchanged via Sandmeyer reaction or boiled down, or sulfides are oxidized to sulfones or sulfoxides, or sulfoxides are reduced to sulfides, or amines are reacted or alkylated or decarboxylated to amides or sulfonamides, or isomers or salts are formed.
CA002235621A 1995-10-25 1996-10-24 Imidazole derivatives and their use as nitrogen monoxide synthase inhibitors Abandoned CA2235621A1 (en)

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