CA2080867A1 - Use of substituted pyrrolidines, some of which are known, as medicaments, new active substances and processes for their preparation - Google Patents

Abstract

Use of substituted pyrrrolidines,some of which are known, as medicaments, new active substances and processes for their preparation ABSTRACT OF THE DISCLOSURE

The invention relates to the use of substituted pyrrolidines, some of which are known, as medicaments, in particular as antimycotic agents, to new active substances and to processes for their preparation.

Description

20~0~7 The invention relates to the use of substituted pyrro-lidineR, some of which are known, as medicaments, in particular as antLmycotic agentR, to new active sub-stances and to processes for their preparation.

Pyrrolidinecarboxylic acid derivatives are known from many publications [cf., for example, J. Heterocycl. Chem.
12 ~3), 595-6; Liebiqs Ann. Chem. (6) 1073-88;
Tetrahedron 27 (1971), 4681-6~.

It has now been found that the substituted pyrrolidones of th~ general formula (I) R, A~B
~ (1), R3R2N CO-D-R~
in which A and B are always different and represent a group of the formula -CHX5 or -NR6, in which R5 denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, hydroxyl, phenyl or carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having Le A 28 558 - l -

2~80~67 up to 6 carbon atoms, R6 has the meaning of R2 .indicated below and is identical to or different from this, or denotes methoxycarbonyl.
Rl represents hydrogen or ~traight-chain or branched alkyl having up to 8 carbon atoms, which is option-ally substituted l or 2 tLmes by identical or dif-ferent substituents from the series comprising halogen, hydroxyl, phenyl and carboxyl or by straight-chain or branched alkoxy, acyl or alkoxy-carbonyl each having up to 6 carbon atoms or by a group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl haviny up to 6 carbon atoms, R2 represents hydro~en or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substitut-ed 1 or 2 times by identical or different sub-stituents from the serie~ comprising hydroxyl and formyl or by straiyht-chain or branched acyl having up to 6 carbon atoms or by phenyl or benzoyl, each of which i~ optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, nitro and cyano, or by straight-chain or branched alkyl or alkoxy each having up to Le_A_28 558 - 2 ~

2080~67 6 carbon atoms, or represents straight-chain or branched acyl having up to 8 carbon atoms, or represents tert. butyloxycarbonyl (boc) or benzoyl which is optionally substituted as described above, or repxesents a group of the formula-SO2R9, in which R9 denotes straight-chain or branched alkyl having up to 8 carbon atoms, or benzyl or phenyl, where the latter are optionally substituted up to 3 tLmes by idsntical or different sub-stituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoromethoxy or by straight-chain or branched alkyl, alko~y or alkoxycarbonyl each having up to 6 carbon atoms, carboxyl or by the abovementioned group -NR7R8, in which R7 and R8 have the abovementioned meaning, represents phenyl which is op~ionally substituted up to 3 times by identical or different ~ubstituents from the series comprising halogen, hydroxyl, nitro, Le A 28 558 - 3 -2 ~ 6 7 trifluoromethyl, trifluoromethoxy, straight-chain or br~nched alkyl, acyl, and alkoxy or alkoxycar~onyl each having up to 6 carbon atoms or by a group of the formula -NR7R~ or -SozR9, in which R7, R8 and R9 have the abo~ementioned meaning, ~3 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which i8 option-ally substituted by phenyl, or R2 and R~ together represent the radical of the formula =CHRl, in which R10 has the abovemen~ioned meaning of R5 and is identical to or different from this, D represents an oxygen or sulphur atom or the group, R4 represents hydrogen or straight-chain or branched alkyl ha~ing up to 8 carbon atoms, or phenyl, where the latter are optionally sub~tituted up to 3 times by identical or different substituents from the Le A 28 558 - 4 -2~0gg7 group compri~ing hydroxyl, halogen, nitro, cyano, car~oxyl, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, in the case of phenyl also by alkyl, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7RB or -SO2R9, in which R7, R8 and R9 have the abovementioned meaning, or for the case in which D repre ents the NH group R4 represents the group of the formula -SO2R9, in which R9 has the abovementioned meaning, surprisingly exhibit a potent antimicrobial action, in particular potent antLmycotic action, against dermato-phytes, budding fungi and biphasic fungi and are thus suitable for use in the control of dexmatomycoses and systemic mycoses.

The physiologically acceptable acid addition salts and metal salt complexes of the compound~ of the general formula ~I) and the r~cemic modifications, the antipodes, the diastereomeric mix~ures and the individual isomers are also preferred for this use.

Le A 28 558 5 -20~0~1~7 Preferably used compounds of the general formula (I) are those in which A and B are hlways different and represent a group of the formula -CHRs or -NR6, in which R5 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen or hydroxyl, or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, R6 has the meaning of R7 indicated below and is identical to or different from this, or denotes methoxycarbonyl.
R1 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is option-ally substituted by halogen or hydroxyl, by straight-chain or branched alkoxy, acyl or alkoxy~
carbonyl each having up to 4 carbon atoms or by a group of the formula -~R7Ra, in which R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, Le A 28 558 - 6 -2~0~67 R2 represents hydrogen or represent~ straight-chain or ~ranched alkyl having up ~o 6 carbon atom , which is optionally substituted 1 or 2 tLme~ by identical or different substituents from ~he Reries comprising hydroxyl and formyl or by straight-ch~in or bxanched acyl having up to 4 carbon atoms or by phenyl or benzoyl, each of which is optionally sub~tituted by halogen, nitro or cyano r or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 6 carbon atoms or repre~ents tert . butyl oxycar-bonyl (boc) or benzoyl which is optionally substituted as descri bed above, or represent~ a group of the formula -SO2R9, in which R9 denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, where the latter are optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoro-methoxy or by strai~ht-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by the abovementioned group of the formula -NR'R6 in which Le A 28 558 - 7 -2~80~7 R7 and R3 have the abovementioned meaning, represents phenyl which is optionally ~ubstituted up to 2 times by identical or different groups from the series comprising halogen, hydroxyl, nitro, tri-fluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7R3 or -SO2R9, in which R7, RR and R9 have the abovementioned meaning, R3 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or R2 and R3 together represent the radical of the formula =CHR~, in which R10 has the abovementioned meaning of Rs and is identic~l to or different from this, D repre~ent~ an oxygen or sulphur atom or the NH
group, Le A 28 558 - 8 -2~8~7 R~ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, where the lat~er are optionally substituted up to 2 tLmes by identical or different substituents from ~he S series comprising hydroxyl, halogen, nitro, cyano, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up ~o 4 carbon atoms or by a group of the form~la -NR7Ra or -SO2R9, in which R7, R~ and R9 have the abovementioned meaning, \

or for the case in which D represents the NH group, R~ represents the group of the formula -SO2R9, in which R9 has the abovementioned meaning, if appropriate in an isomexic form and their physiologi-cally acceptable acid addition salts and metal salt complexes in the control of dermato~ycoses and systemic mycoses.

Particularly preferably used compounds of the general formula (I) are those Le A 28 558 - 9 -2~80867 in which A and B are always different and repre ent a group of the formula -CHRs or -NR6, in which S R5 denote~ hydrogen or stxaight-chain or branched alkyl having up to 4 carbon atoms, R6 has the meaning of R2 indica~ed below and i5 identical to or different from this, or denotes methoxycarbonyl.

R1 represents hydrogen or represents ~traight-chain or branched alkyl having up to 4 rarbon atoms, R2 represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atom~, which is optionally substituted 1 or 2 times by identical or dif-'erent phenyl, which can in turn be substituted by methoxy or ethoxy, or represents straight-chain or branched acyl having up to 4 car~on atoms or tert. butyl oxycarbonyl, or represents a group of the formula -SO2R9, in which R9 denote~ straight-chain or branched alkyl having Le A 28 558 - 10 -2 ~ 6 7 up to 4 carbon atoms, phenyl or benzyl, where the latter are optionally substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl or methoxy, R3 repre~ents hydrogen or represents s~raight-chain or branched alkyl having up to 4 carbon atoms or benzyl, or R2 and R3 together repre~ent the radical of the formula =CHR', in which Rl has the abovementioned meaning of R5 and is identical to or different from this, D represents an oxygen or a sulphur atom or the \

NH group, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, where the latter are optionally substituted by fluorine, chlorine, bromine, nitro, cyano, methoxy or ethoxy or by a group of the formula -NR7R8 or -SO2R9, in which Le A 28 5~58 - 11 -2o~67 R7 and R~ are identical or different and denote hydrogen, methyl or ethyl and R9 has the abovementioned meaning, \

or in the case in which D represents the N~ group, R~ represents the group of the formula -SO2R9, in which R9 has the abovementioned meaning, if appropriate in an isomeric formt and their physiologi-cally acceptable acid ad~ition salts and metal salt complexes in ~he control of de.rmatomycoses and ~ystemic mycoses.

Very particularly preferably used compounds of the general formula (I) are those in which both substituents -NR2R3 and -Co-D-R4 are present in the cis-position in the control of dermatomycose6 and systemic mycoses.

The invention additionally relates to new active sub-stances of the general formula (Ia) Le A 28 558 - 12 -~0367 Pl'~ `B' l (Ia), R3R2N CQ D'-R~' in which A' and B' are alway~ different and represent the group of the formula -CHRs or -NR6, in which Rs' denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which i5 optionally subs~ituted by halogen, hydroxyl, phenyl or carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, R6~ has the meaning of R2' indicated below and is identical to or different from this, or denotes metho~ycarbonyl.

15 Rl' represents hydrogen or straight chain or branched alkyl having up ~o 8 carbon atoms, which i5 option-ally substituted 1 or 2 times by identical or different sub~tituents from the series comprising halogen, hydroxyl r phenyl and carboxyl or by traight-chain or branched alkoxy, acyl or alkoxy-carbonyl each having up to 6 carbon atoms or by a Le A 28 558 - 13 -2 ~ 6 7 group of the formula -NR7R~, in which R7 and Ra are identical or different and denote hydro~en, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents hydrogen or repres~nts ~traight-chain or branched alkyl having up to 8 carbon atoms, -which is optionally substltuted 1 or 2 time6 by identical or different groups from the series comprising hydroxyl and formyl or by straight-chain or branchad acyl having up to 6 carbon atoms or by phenyl or benzoyl, each of which i8 optionally substituted up to 2 time~ by identical or different gubstituents from ~he series compri~ing halogenr nitro and cyano, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represents straight-chain or branched acyl having up to 8 carbon atoms, or represents benzoyl which is optionally substi-tuted as described above, or represents a group of the formula -SO2R9', in which R9' denotes straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or Le A 28 558 - 14 -2 ~ 7 phenyl, where the latter are optionally substituted up to 3 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, ~rifluoromethyl and trifluorometh-oxy or by ~traight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, carboxyl or by the abovementioned group -NR7R3, in which R7 and R8 have the abovementioned meaning/

repre ents phenyl which is optionally substituted up to 3 times by identical or different substituents from the serie~ compri~ing halogen, hydroxyl, nitro~
trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atom~ or by a group of the formula -NR7R3 or -So2R3, in which R7, R~ and R~ have the abovementioned meaning, R3 represants hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is option-ally substituted by phenyl, Le A 28 558 - 15 -or R2 and R3 to~ether represent the radical of the formula =CHRl' in which R10' ha the abovementioned meaning of R5' and ic identical to or different from thi~, D' represents an oxygen or ulphur ato~ or the group, R4 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, where ~he latter are optionally sub~tituted up to 3 tLmes by identical or differen~ substituents from the series comprising hydroxyl, halogen, nitro, cy~no, carboxyl, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, in the case of phenyl also by alkyl, acyl or ~lkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7R8 or -SO2R9, in which R7't Ra' and R9' have the abovementione~ meaning, or for the case in which D represents the N~ group, Le A 28 558 - 16 -_ 2~o~67 R4 represents the group of the formula -SO2R9, in which R9 ha~ the abovemen~ioned meaning, with the proviso that if A' represents the -CH2- group, B' represents the -NR6 group, D' represents oxygen and R'/ R2, R3 and R~ represent hydrogen, R6 must not repre~ent hydrogen, and in the case in which R2 repre6ents the tert-butyl group and R3 represents hydrogen, R6' must no~ repre~ent the acetyl group, and if B' represents the -CH2- group, R1, R2 and R3 represent hydrogen, D' represents oxygen, R~ represents ethyl and A~ represent~ the -NR6 group, R6 mus~ not represent hydrogen or benzoyl.

The compounds of the general formulae (I) and (Ia) according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

The acids which can be added preferably include hydro-halic acids, such as, for example, hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, and also phosphoric acid, nitric acid, sulphuric acid, mono-and bifunctional carboxylic acids and hydroxy carboxylic acids, such as, for example, acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, Le A 28 558 - 17 -2~0g67 fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid as well as sulphonic acids, such as, for example, p-toluene ulphonic acid, 1,5-naphthalenedisulphonic acid or camphorsulphonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred are, for example, sodium, pota4sium, magnesium or calcium 8alt3, and smmonium salts which are derived from ammonia, or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine,dicyclohexylamine,dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compoundfi of the general formulae (I) and (Ia~
according to the invention can exist in stereoisomeric forms, for example either as image and mirror Lmage (enantiomers) t or which do not behave as Lmage and mirror image (diasteromers), or are present as a diasteromer mixture or as pure cis- or trans-isomers. The invention relates both to the antipodes, racemic modifications and diasteromer mixtures and to the pure isomers. The racemic modificationP~, like the diasteromers, can also be ~eparated in a known manner into the stereoisomerically uniform constituents [cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962]. Separation into the stereoisomerically uniform compounds is carried out, for example, by means of a chromatographic resolution of diastereomeric esters and amides or on optically active Le A 28 558 - 18 -20~6~

phases. In addition, crystallisation of diastereomeric salts is possible.

The compounds of the general formula (I) according to the invention and the new compounds of the general formula S (Ia) and their acid addition salts and metal Qalt complexes have antimicrobial actions, in particular potent antimycotic actions. They have a very broad spectrum of antimycotic action, in particular against dermatophytes and budding fungi as well as biphasic fungi, for example against Candida specie~ such as Candida albicans, Epidermophyton specieC such as ~pider-mophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus, Trichophyton spe~ies such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Torulopsi species, such as Torulopsis glabrata. The enumeration of these microorganisms in no way represents a restriction of the microorganisms which can be controlled, but is of only illustrative character.

Indica~ion e~amples which may be mentioned in human medicine are, for example:
Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophy~on species, Microsporon species and Epidermophyton floccosum, budding fungi and biphasic fungi as well as mould fungi.

In addition, a process for the preparation of the Le A 28 558 - 19 -2~8~57 compounds of the general formulae (I) and (Ia) ha~ been found characteri4ed in that [A] in the case in which A and A' each correspondingly represent the -NR6 or -NR6 group and ~ or B' correspondingly represent the -CHRs or -CHRs group, compounds of the general formula (II) E
R N

3~ ~ R,I (Il), W ' Co2-R,2 in which W represents a group of the formula ~N- or the N3-group, R1l and R13 correspondingly encompass the particular scope of meaning of R1~R1 and R5/R5, E represent~ a Cl-C6-alkoxycarbonyl radical, G represents an amino-protective group, preferably benzyl, and Rl2 represents Cl-C6-alkyl, are first converted according to customary methods by removal of the protective group G, i n the case in which W
represents the -NH-group, and in the case of the N3-group by reaction with triphenylphosphonoxide/H20 into the compounds of the general formula (III) Le A 28 558 - 20 -20~8fi7 ~ H-R,l (In~, H2N C02-R~2 in which R1l, R12, Rl3 and E have the abovemen~ioned meaning, and then reacted with activated carboxylic acid deriva-tive , in the pre~ence of a base, to give the compound~
of the general formula (IV) ~ (I~, HN C2 R~2 L

in which E, Rll, Rl2 and Rl3 have the abovementioned meaning and L represents a Cl-C6-alkoxycarbonyl radical, and in a last step both the amine and the acid function are libera~ed by reaction with HBr in water, ~imulta-neously with elimination of the radicals ~, L and R~2, or compounds of the general formula (V~

Le A_28 558 - 21 -2~Q~'67 Rl3 CH-R,l (V3, CO2^~l2 ~N
M

in which E, Rl1, Rl2 and Rl3 have the abovementioned meaning and M has the abovementioned meaning of R2 with the exception of hydrogen, but preferably represents a (Cl-C6)-acyl radical, such as acetyl, or the -CH(C6H4-OCH3) 2 radical, are reduced to the corresponding pyrrolidine compounds in inert solvents by hydrogenation with hydrogen in the presence of a catalyst or with hydride~
or rB] in the case in which A and A' correspondingly represent the -CHR5 or -CHR5 group and B and B' corres-pondingly represent the -NR6 or -NR5 yroup, compounds of the general formula (VI) Le A 28 558 - 22 -2 ~ 7 ~11 Rl3 ~ C~N E (Vl), C)~ C2R12 in which E, R1l, R12 and R13 have the abovementioned meaning, are converted with amineC of the formula (VII) NH~-R~4 (V~, in which Rl4 represents (C2-C6)-alkyl or benzyl, preferably benzyl, into the corresponding enaminoesters of the general - formula (VIII) R CH
13 ~ E (YIII), Rl4HN C2R12 in which E, Rlll Rl2, Rl3 and Rl~ have the abovementioned meaning, Le A 28 558 - 23 -2Q~0~7 the double bond i8 reduced wlth hydrogen in the presence of a cataly3t, and in a last step the radical Rl~ i8 likewise removed with hydrogen in the presence of a catalyst S or compounds of the general formula (VI) are directly reductively aminated by reaction with ammonia or ammonium salts and then with the action of hydrogen in the pres-ence of a catalyst, or with cyanoborohydride, in the presence of acids in inert solvents, and if R2/R3 = H, the respective protective groups in each of the abovementioned steps are removed accordinq to custom-ary conditions, and in the case of ~he acids [(I), (Ia) D=O, R4=H] the corresponding esters are optionally hydrolysed, and in the case of the other definition~ mentioned above for D, D', R4 and R4, likewise derivatised by customary methods, such as, for example, amidation, sulphonation or ~ulphoamidation, if appropriate in the presence of auxiliaries such a ca~aly~ts and dehydrating agents, starting from the corresponding carboxylic acids, if appropriate with prior activation.

Le A 28 558 - 24 -2~0867 The proces~es according to the invention can be illustrated by way of example by the following reaction 5C heme:

Le A 28 558 - 25 -c6H5 2 0 g O g 6 7 HN ~, COC2H~ H2Pd H2N ~ COC~H5 COlCH3 HCl COzCH3 C02CHl K2CO3 HN ~ COC2H5 3r I H20 HzN ~ ~ COzH
COlCH3 H

[A~
H2N C02C2H, AcHN CO2C2H5 AcHN CO2C2H5 ~J Ac O ~ H2/Pl ~
COlC2H5 CO2CzH5 ClH50H CO2ClH5 [A]
o CO2C2H5 HO CO2C2Us N3 CO2C2Hs N:~H4 ~n~ Zn(N3)2 \~/
N N P(C6H5~3 N
DEAD

H2N CO2C2Hs NH2 COOH
P(c6Hs)3lH2o \~/HCI or \~/

B]
l.)C6Hs-CHz~~H2 2.)Pt / C
,~ 3.) Pd / C ~H2 N 1 CO2C2H5 ~ CO2H
CO2CH3 1.) NH4 + Cl~ C02CH3 2.) H2 / Pd or cyanoborohyclride Le A 28 558 - 26 -2~0~67 Amino-protective groupq in the contex~ of the invention are the customary amino-protecti~re groups used in peptide chemistry .

These preferably include: benzyloxycarbonyl, 3,4-di-methoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxy-carbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxyca~tionyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxy-carbonyl, cyclohexylcarbonyl, 1, l-dimethyl-ethoxycarbonyl, adamantylcarbonyl, phthaloyl, 2, 2, 2-trichloroethoxycarbonyl, 2, 2, 2-trichloro-tert . -butoxy-carbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromo-acetyl, 2, 2, 2-trif luoroacetyl, 2, 2, 2-trichloroacetyl, 2 0 benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitro-benzyl, 2, 4-dinitrobenzyl or 4-nitrophenyl .

Suitable solvents for all steps of processes [A] a~d ~B]
are in general water and all inert organic solvents which 2 5 do not change under the reaction conditions . These preferably include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides sllch as ~0 dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulphoxide, acetonitrile or pyridine. Suitable Le A 28 558 - 27 -2~0~7 ba~es are organic amines (trialkyl (C1-C5)amines) such as, for example, thiethylamine, or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine.
Triethylamine i8 preferr0d.

The reaction tQmperatures can be varied within a rela-tively wide range. In general, the reaction is carried out between -78~C and +150C, preferably between -lO~C
and +100C, in particular at the boiling point of the respective solvent.

The rsaction~ can be carried out at normal pressure, but also at elevated or reduced pres~ure (for example O.5 to 3 bar). In general, the reactions are carried out at normal pressure.

When carrying out proces variants [A] and [B] according to the invention, any desired ratio of the substances participating in the reaction can bs used. In general, however, the reaction is carried out with molar amounts of the reactants. The substances according ~o the inven-tion are preferably isolated and purified by distilling off the 301vent in vacuo and recrystallising the re~idue, which may only be obtained in crystalline form after ice-cooling, from a suitable solvent. In ~ome cases, it may be necessary to purify the compound~ according to the invention by chromatography.

The amino-protective groups are removed in a manner known per se [cf. Th. Greene, "Protective Group~ in Organic Le A ~8 558 - 28 -2~0~67 Synthesi~", 1. Aufl. J. Wiley & Sons, New York 1981 and Houben Weyl "Methoden der organischen Chemie", Volume XVtl and 1] (~ethod~ of Organic Chemistry).

The hydrogenations (reductions, removal of protective groups) are in general carried out in one of the above-mentioned ~olvent~, ~uch as alcohols, for example meth-anol, ethanol or propanol, in the presence of a noble metal catalyst such as platinum, palladium, palladium on animal carbon or Raney nickel, in the case of the double bond of the compound of the general formula (V) prefer~
ably with H2/platinum, in the case of the reductiYe amination of the compounds of the general formula (VI) and the enaminoesters of the general form~lla (VIII) preferably with H2/palladium.
In the reductive amination or hydrogenation of the compoundq of the general formulae (Y) and (VI) it is also pos~ible to employ hydrides, such as, for example, complex borohydrides or aluminium hydrides. Preferably, in these reactions sodium borohydride or sodium cyano-borohydride are employed. In this case the reaction is ingeneral carried out in a temperature range from -10C to +30C, preferably at room temperature.

The catalyst~ used are in general acids. These preferably include inor~anic acids such as, for example, hydro-chloric acid or sulphuric acid, or organic sulphonic orcarboxylic acids such as, for example, methanesulphonic . acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, acetic acid or propionic acid.

Le A 28 558 - 29 -2~0~67 The hydrogenations can be carried out at normal, elevated or reduced pressure (for example 0.5-5 bar).

The catalysts and base~ are in general employed in an amount from 0 mol to lQ mol, preferably from 1.5 mol to 3.5 mol, in each case relative to 1 mol of the compounds of the general formulae (IV~, (V), (VI) and ~VIII).

The acid is in general employed in an amount from 2 mol to 30 mol, preferably from 5 mol ~o 15 mol, in each case relative to 1 mol of the compound~ of the general for-mulae (IV), (V), (VI) and (VIII).

The hydrolysis of the carboxylic acid esterC is carried out by cu3tomary methods by treating the esters in inert solvents with customary bases, it being possible to convert the salts initially formed into the free car-lS boxylic acids by treatment with acid.

The hydrolysis of the carboxyl~c acid esters can also be carried out with one of the abovementioned acidR.

Suitable bases for the hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium hydrogen carbonate, or alkali metal alkoxides Quch as sodium ethoxide, sodium methoxide, potassium ethoxide, Le A 28 558 - 30 -potafislum methoxide or potas~ium tert-butoxide. Sodium hydroxide or potassium hydroxide are particularly prefer-ably employed.

Suitable solvents for the hydrolysis are water or the 5 organic ~olvents customary for hydrolysis. These prefer-ably include alcohols such a~ methanol, ethanol, propanol, i~opropanol or butanol, or etherc such as tetrahydrofuran or dioxane, or dimethylformamide or dLmethyl sulphoxide. Alcohols such as methanol, ethanol, propanol or i~opxopanol are particularly preferably used.
It is al~o possible to employ mixtures of the solvents mentioned.

The hydrolysis i8 in general ~arried out in a temperature range from 0C to +100C, preferably from +20C to +80C.

In general, the hydroly6i~ i8 carried out at normal pressure. However, it is al~o possible to work at reduced pressure or at elevated pressure ~for example from 0.5 to 5 bar).

When carrying out the hydrolysis~ the base or the acid is in general employed in an amount from 1 to 3 mol, prefer-ably from 1 to 1.5 mol, relative to 1 mol of the ester.
Molar amount~ of the reactant are particularly prefer-ably u~ed.

When carrying out the reaction, in the fir~t step the ~alts of the compounds according to the invention are Le A 28 558 - 31 -20~67 formed as intermediates which can be isolated. The acids according to the invention are obtained by treating the ~alts with customary inorganic acids. rhese preferably include mineral acids ~uch a~, for example, hydrochloric acid, hydrobromic ~cid, sulphuric acid or phosphoric acid. It ha~ proved advantageous in the preparation of the carboxylic acids to acidify the basic reaction mixture from the hydrolysis in a second step without isolation of the 8alt5. The acid~ can then be i~olated in a customary manner.

As an example of the abovementioned derivatisation possibilities, amidation and sulphonation or sulpho-amidation will be illu~trated here.

Amidation is in general carried out in inert solvents in the presence of a base and of a dehydrating agent.

Suitable solvents in this case are ~nert organic solvents which do not change under the reaction conditions. These include halogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloxomathane,1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene r hydrocarbon~ such as ben~ene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, nitromethane, dimethylformamide, acetonitrile or hexamethylpho~phoric triamide. It is also possible to employ mixtures of the 801vent8. Dichloromethane is particularly preferred.

Le A 28 558 - 32 -2 ~ 7 Suitable base~ for the amidation are the customary basic compounds. The e preferably include alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potas~ium hydroxide or barium hydroxide, alkali metal hydrides such a~ sodium hydride, alkali metal or alkaline earth metal carbonates 3uch as sodium carbonate or potassium carbonate, or alkali metal alkoxides such as, for example, ~odium methoxide or ethoxide, potassium methoxide or ethoxide or potassium tert-butoxide, or organic amines such as benzyltrimethylzmmonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine.

The amidation is in general carried out in a temperature range from 0C to 150C, preferably at 25C~ to 40C.

The amidation is in general carried out at normal pressure. However, it i~ al o possible to carry out the proce~s at reduced pressure or at elevated pressure (for example in a range from 0.5 to 5 bar).

Suitable dehydrating reagents are carbodiimides such as, for example, diisopropylcarbodiLmide, dicyclohexyl-carbodiimide or N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propane-pho~phonic anhydride or isobutyl chloroformate or benzo-triazolyloxy-trîs-(dimethylamino)phosphonium hexafluoro-phosphate or diphenyl pho~phoramidate or methanesulfonyl Le A 28 558 - 33 -~0~0~7 chloride, if appropriate in the presence of bases ~uch as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiLmide and N~hydroxysuccinimide [cf.
J.C. Sheehan, S.L. Ledis, J. Am. Chem. Soc. 95, 875 (1973); F.E. Frerman et al., J. Biol. Chem. 225, 507 (1982) and N.B. Benoton, K. Rluroda, Int. Pept. Prot.
Res. I3, 403 (1979), I7, 187 (1981)].

The sulphonation or ~ulphoamidation i8 carried out in the abovementioned inert solvents, if appropriate using the bases and dehydrating agents likewise mentioned above.

The sulphonation and sulphoamidation are in general carried out at normal pressure. However, i~ i8 also possible to carry out the proce~es at reduced presRure or elevated pressure (for example in a range from 0.5 to 5 bar).

The sulphonation and the sulphoamidation are in general carried out in a temperature range from 0C to +150aC, preferably from +25C to ~40C.

For the amidation, the commercially available amine~ ~nd their derivative~ known from the literature are in general suitable [cf. ~ouben-Weyl, ~Methoden der organischen Chemie" (Methods of organic chemistry), Vol.
XI/1 and XI/2].

The sulphonation and zulphoamidation are in general also carried out with the customary sulphonic acid~ and their Le A 28 558 - 34 -2 ~ 7 activated derivatives [cf. Houben~Weyl, "Methoden der organischen Chemie~ (Method~ of organic chemistry), Vol IX, p. 407 et ~eq.; Beilstein 11, 26].

The esterification of the acid~ i8 carried out by a customary method by reacting the acids, if appropriate in one of the abovementioned solvents, with the appropriate alcohols in the presence of a catalyst. Preferably, this alcohol is al~o employed as the 801vent.

Catalysts which can be employed are inorganic acids, such as, for example, sulphuric acid or inorganic acid chlorides, such a~, for example, thionyl chloride.

In general, 0.01 to 1, preferably 0.05 to 0.5, mol of - cataly~t are employed, relative to 1 mol of reactant.

Both the esterification and the amidation can optionally proceed via activated stages of the carboxylic acids, such as, for example, acid halide~, which can be prepared from the corresponding acid by reaction with thionyl chloride, pho~phoru~ trichloride, phosphorus penta-chloride, phosphorus tribromide or oxalyl chloride.

The acid addition 8alt8 of the compounds of the formulae (I) and (Ia) can be obtained in a simple manner by cu~tomary salt formation methods, for example by dissolving a compound of the formula (I) or (Ia) in a suitable solvent and adding the acid, for example hydrochloric acid, and isolated in a known manner, for Le A 28 558 - 35 -2 ~ 6 7 example by filtering off, and if appropriate purified by washing with an inert organic solvent.

The compounds of the general formulae (II), (III), (IVl and (V) are known in ~ome caces [cf. Acta Chemica Scandinavica Vol. 35 (1981), 473-479] or are new and can then be prepared, however, in an analogy to those method~
published in the literature reference cited above.

The compounds of the general formula (VI) are likewi~e known in some cases [cf. J. Am. Chem. Soc. Vol. 86, 1964, 5293-5298] or are new and can then be prepared by the proce6ses mentioned therein.

The amine~ of the general formula (VII) are known ~cf., for example, Beil tein 12, 1013].

The enaminoesters of the general formula (~III) are known in some cases or are new and can then be prepared, for example, by the process described in [B].

The above preparation processes are only giYen for clarification. The preparation of the compounds of the general formulae (I) and (Ia) according to the invention is not restric~ed to the e processes, and any modification of the~e processes can be used in the s~me manner for th~ preparation.

The compound~ of the general fonmulae (I) and (Ia) according to the invention and their acid addition salts Le A 28 558 - 36 -2~0~67 have antLmicrobial actions, in particular potent antimycotic action~. They have a very broad spectrum of antLmycotic action, in particular against dermatophytes and budding fungi as well as biphasic fungi, for example against Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillu~ niger and Aspergillus fumigatus, Trichophyton species such as Trichophyton mentagrophytes, Micro~poron species ~uch a~
Microsporon felineum and Torulop~is ~pecie~, such as Torulops i8 glabrata. The enumeration of these microorganisms in no way represents a restriction of the microorganisms which can bs controlled, but is of only illustrative character.

Indication examples which may be mentioned in human medicine are, for example:
Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophy~on species, Microsporon specie~ and Epidermophyton floccosum, budding fungi and biphasic fungi as well as mould fungi.

Indication axeas in veterinary medicine which may be mentioned are, for example:
All dermatomycoses and systemic mycoses, in particular those which are caused by the abovementioned pathogens.

The new active substance~ can be converted in a known manner into the customary formulations, such as tablets, Le A 28 558 - 37 -coated tablets, pill6, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
In this case the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active substances with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent organic solvents can optionally be used as auxiliary solvents.

Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlin-gually or intravenously.

In the case of parenteral use, solutions of the active substance can be employed using suitable liquid 2Q excipients.

In general, it has proved advantageous on intravenous administration to administer amount~ of about 0.001 to 10 mgtkg, preferably about 0.01 to 5 mg/kg, of body weight to achieve effective results, and on oral ~dminis-tration the dosage is about 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.

Le A 28 558 - 38 -23~8~ ~Q~6 7 In spite of this it may sometimes be nece~sary to deviate from the amounts mentioned, in particular depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other caRes the upper limit mentioned must ~e exceeded. In the case o~ the adminis-tration of relatively large amounts, it may be advisableto divide these into several individual doses over the course of the day.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of general formula (I) or (Ia), together with instructions for its use as an antimicrobial agent.

Le A 28 558 - 39 -2~8~7 Startinq Compounds Example I

Methyl l-methoxycarbonyl-4-(4/4~-dimethoxybenzhydryl) amino-3,4-dehydropyrrolidine-3 carboxylate (~13C~ ~ ; CH - Ntl ~ C02CH3 The preparation is carried out by a standard method (see Act. Chem. Scand. Vol. 35. 1981, 473-479) from methyl 1-methoxycarbonyl-4-oxopyIrolidine-3-carboxylate.
-Example II

Ethyl 4-(4,4'-dimethoxybenzhydryl)amino-1-methoxycarbo-nyl-3,4-dihydropyrrolidine-3-carboxylate CO~Me N ~ .- =

~=<
CO~Et NHCH( ~ OMe)2 Example II is prepared starting from ethyll-methoxycarbo-nyl-4-oxopyrrolidine-3-carboxylate and 4,4'-aimethoxy-benzhydrylamine (see Example I).

Le A 28 558 - 40 -2 ~ 6 7 Example III

Ethyl 1-methylpyrrolidine-3-on-4-carboxy~ate Me O CO2Et The compound is prepared by a Dieckmann cyclisation of N-(~-ethoxycarbonylethyl)-N-(ethoxycarbonylmethyl)methyl-amine following a well known literature procedure.

Ex mple IV

Ethyl 1-methoxycarbonylpyrrolidin-3-one-2-carboxylate ,~NCO2Me O CO2Et The preparation follows a ~ell known literature procedu-re.

Example V

Ethyl 4-~4,4'-dimethoxybenzhydryl)amino-1-methyl-3,4-de-hydropyrrolidine-3-carboxylate Me ~ N ~

CO2Et NHCH( ~ OMe)2 A solution of 21.5 g (0.125 mol) ethyl 1-methylpyrroli-din-3-on-4-carboxylate, 30.3 g (0.125 mol bis(p-methoxy-phenyl)methylamine and 0,4 g p-toluenesulfonic acid in 400 ml benzene is refluxed or. a Dean-Stark trap for 16 h.
Concentration of the reaction mixture yields 49.5 g (100 % of theory~ of an orange oil.
Le A 28 558 - 41 -.. .. . , ..... , .. , . .. ~, _, .. .. .... ..... .. .. .. .... .. .... .. . ... . . .. . . . . .. .. . . .....

2 ~ 5 7 H-NMR (200 MHz, CDCl3):
= 1.24 (t, 3H); 2.38 (s, 3EI); 3.45 - 3.60 (m, 4H);
3.77 (s, 6H); 4.13 (q, 2H); 5.92 (d, MS (Cl, iso-butane):
m/e: 396 [M~]

Example VI

Ethyl 4-hydroxy-1-methoxycarbonylpyrrolidine-3-carboxyla-te CO~Me OH (~O2Et 10 g (46.5 mmol~ ethyl 1-methoxycarbonylpyrrolidin-3-one-

4-carboxylate in 100 ml ethanol were treated with 0.95 g (25 mmol) sodium borohydride at O~C for 20 min. The reaction mixture was acidified with sulfuric acid, diluted with water and extracted with several portions l 5 diethylether. After drying concentration of the combined ether layers yielded 4.7 g (47 % of theory) colorless oil.
MS (Cl, isobutane):
m/e: 217 [M~]

Le A 28 558 - 42 -.. . ... .... , .; ~ ..... . . . . . ... . ..... .. ................ .... . . . . . .. . . . . . . .

2~80~7 Preparation Examples Example 1 Methyl l-methoxycarbonyl-4-(4,4'-dimethoxybenzhydryl)-aminopyrrolidine-3-carboxylate (H3C ~ HC - NH ~ CO2CH3 6 g (14 mmol~ of methyl l-methoxycarbonyl-4-(4,4~-dimethoxybenzhydryl)-amino-3,4-dehydropyrrolidine-3-carboxylate are reduced wi~h 0.7 g (14 mmol) of sodium cyanoborohydride for 12 h in 90 ml of ethanol at room temperature and pH 3-4. The residue obtained after concentration i taken up in ethyl acetate, washed with 1 N ~odium hydrogen carbonate solutio~ and water and dried. After drying and concentration, the oil obtained is chromatographed on Florisil with petroleum ethar/ethyl acetate (l:l). 2.3 g (38 ~ of theory~ of a pale, highly lS viscous oil are obtained.
H-NMR (200 MHz, CDC13):
= 2.95-3.60 (m, 6H); 3.69 ( ,3H~; 3.70 (s,3H); 3.78 (s,3H); 3.80 (s,3H); 4.75 (s,br,lH); 6.78-~.90 and 7.20 7.30 (~,8H)-Le A 28 558 - 43 -2~a867 Example 2 Methyl l-methoxycarbonyl-4-aminopyrrolidine-3-carboxylate N

A solution of 2.3 g (5 mmol) of methyl l-methoxycarbonyl-4-(4,4'-dimethoxybenzhydryl)-aminopyrrolidine-3-carboxylate and 5 ml of glacial acetic acid/water (1:13 i8 stirred at lOOPC for 5 min. After cooling, the mixture is diluted with about 50 ml of water and extracted twice with diethyl ether, and the aqueous phase is then concentrated to about 15-20 ml. At 0C~ the aqueous phase is brought to p~ 10 with conc. an~nonia solu~ion and after saturating with sodium chloride extr2cted several times with diethyl ether. After drying and concentration, O.35 g (35 ~ of theory) of a slightly yellow oil are obtained.
MS (CI, isobutane):
m/e: 202[M~]

Le A 28 558 - 44 -2 ~ 6 7 Example 3 Ethyl 4-(4,4'-dimelhoxybenzhydryl)amino-1-methoxycarbor-ylpytrolidinc-3-carb-oxylate CO2Me CO2Et NHCH~ OMe)2 10 g (22.7 mrnol) ethyl 4-(4,4'-dirnethoxybenzhydryl)amino-1-methoxycarbonyl-3,4-dehydropyrrolidine-3-carboxylate are reduced with 1.43 g (22.7 rnrnol) sodium cyanoborohydride for 24 h in 150 rnl ethanol at room temperature and pH 34. The residue obtained after concentration is taken up in ethyl acetate, washed with sodium hydrogen carbonate solution and water and dried. The oil obtained after concentration is chromatographed on Florisil with petroleum ether/ethyl acetate (1:1). 4.2 g (41.9 % of theory), viscous oil.
MS (CI, isobutane):
mle: 442[M~]

Example 4 Ethyl 4-benzylamino-1-methoxycarbonylpyrrolidine-3-carboxylate CO2Me - CO2Et NH~3 96 g (0.316 mol) of ethyl 4-berl7ylarnino-1-methoxycarbonyl-3,4-dehydropyrrolidine-3-carboxylate are reduced with 22.8 g (0.362 mol) of sodium cyanoboroh-dride for 24 h in 1.6 1 of ethanol at room temperahlre and pH 3-4. After concentration of the reaction 2 0 mixture the residue is taken up in ethyl acetate, washed once with l ,~ sodium hydroge carbonate solution, once with water and dried. After drying and concentration, the oil obtained is chromatographed on Florisil with petroleum ether/ethyl acetate (1:2). 81 g (83.8 % of theory)of a yellowish, viscous oil are obtained.
MS (CI, isobutane):
2 5 rn/e: 306[M~]

Le A 28 558 - 45 -fi 7 Exam~lc S

Ethyl 4-(4,4`-dimetiloxy~enzhydryl)amino-1-mclllylpyrrolidinc-3-carboxylate Me S~
CO2Et NHCEI(~ OMe)2 10 g (25.3 snmol) of ethyl 4-(4,4'-dimethoxybenzhydryl)arnino-1-methyl-3,4-dehydropyrrolidine-3-carboxylate are reduced with 1.76 g ~28 rnrnol) of sodium cyanoborohydride for 24 h in 100 ml of ethanol at room temperature and pH 34. The residue obtau~ed after concentration is taken up in ethyl acetate, washed with 1 N sodium hydrogen carbonate solution and water and dried. After drying and concentration, the oil obtained is chromatographed on Florisil with petroleurn ether/ ethyl acetate (1 Exarnple 6 Ethyl 4-tert-butyloxycarbonylarnino-1-methoxycarbonylpyrrolidine-3-carboxylate CO2Me ~0 CO2Et NH ot~u -13.8 g (50 rnmol) ethyl 4-arr~ino-1-methoxycarbonylpyrrolidine-3-carbo~;ylate in 70 ml of 1,4-dioxane are treated with 14.4 rnl (102 rnmol~ triethylarnine and 13.9 ml (60.5 mrnol~
1 5 di-tert-butyldicarbonate at room temperature for 16 h. The reaction n~ix~lre is poored onto 250 ml cold water and 100 rnl ethyl acetate, acidified with potassium hydrogen sulfate solution and extracted with more ethyl acetate. The orgaruc layers are ~ 2shed with sodium hydrogen carbonate solution, dried and concentrated to yield 6.9 g (45. / % of theory) of a slightly yellow oil.
'H-NMR (200 MHz, CDCI3):
o = 1.26 (t, 3H); 1.53 (s, 9H~; 2.98 - 3.81 (m, 6H~; 3.70 (s, 3H); 4.15 (q, 2H); 4.93 (d, IH).

Le A 28 558 - 46 2~08~

Examplc 7 4-tert-Butyloxycarbonyla~ino-l-mcthoxycarbonylpyrrolidine-3-carboxylic acid CO2Me CO2H NHBoc 6.9 g ~22 mmol) ethyl 4-tert-butyloxycarbonylamino-l-methoxycarbonylpyrrolidine-3-carboxylate in 30 ml methanol, 20 ml tetrahydrofurane and 10 ml water are stirred with 1.5 g (62.5 rnrnol) lithium hydroxide for 16 h at room ternperature. The rni~ture is acidified with potassium hydrogen sulfate solution at 0C and extracted with ethyl acetate. The organic layers are washed with water, dried with magnesium sulfate and concentraled to give 3.6 g (57 % of theory) of a pale yellow oil.
lH-NMR (200 MHz, DMSO-d~):
S = 1.40 (s, 9H); 2.85 - 4.2 (sev. m, 6H); 3.59 (s, 3H); 6.05 (d, lH).
MS (CI, isobutane):
m/e: 288[M~]

Example 8 4-Amino-l-methoxycarbonylpyrrolidine-3-carboxylic acid, hydrochloride CO2Me HCI
A solution of 1.5 g (5 2 mmol) 4-tert-butyloxycarbonylamino-l-methoxycarbonylpyrro1idine-3-Carboxylic acid in 10 ml 1,4-dioxane is treated with lO n71 of a saturated solution of hydrogen chIoride ir~ 1,4-dioxane for 4 h. Concentration yields l.lS g (98.5 % of theory) hygroscopic material.
'H-NMR (200 MHz, D20):
o = 3.32 - 3.99 (m, 6H); 3.71 (s,3H).
MS (Cl, isobutane):
rn/e: 188[M~]

Le A 28 558 - 47 -~o~7 Examelc 9 Ethyl 4-(N-benzyl-N-tert-butoxycarbonylamino)- I -methoxycarbonylpyrrolidine-3-carboxyla~e ~O2~C

CO2Et N
O~O~u 20 g (65.4 mrnol) ethyl 4-benzylamino-l-metho~ycarbonylpyrrolidine-3-carbo~ylatedissolved in 200 ml 1,4-dioxane are treated with 6.6 g (65.5 mmol) triethylamine, 18.5 g (85 mrnol) di-tert-'outyldicarbonate and 2 g dirnethylarninopyridine at room temperature for 30 h. After addition of 1 1 water and 300 ml ethyl acetate the pH is adjusted to 3 - 4 with hydrochloric acid and the aqueous layer is extracted with more ethyl acetate. The combined 1 0 organic layers are washed with sodium hydrogen carbonate solution and brine, dried and concentrated. 25.4 g (95.7 % of theory~ of a pale yello~v oil.
'H-NMR (200 MHz, CDCI3): ~
o = 1.24 (t, 3H); l.S0 (bs, 9H); 3.38 - 4.2 (m, 6H); 3.7û (s,3H~; 4.14 (q, 2H); 4.37 (m 2H); 7.15 - 7.4 (m, SH).

1 5 Example 10 Ethyl 4-amino-1-methoxycarbonylpyrrolidine-3-carboxylate CO2Me NH2 CO2Et A solution of lS.0 g (S0 Irunoi) of Ethyl 4-benzylamino-1-methoxycarborlylpyrrolidine-3-carboxylate in S00 rnl ethanol, S00 ml ~vater and 250 ml 0.1 N h~drochloric acid is hydrogenated at 23C for 20 hours (10 bar H" Pd/C). Filtration and concentration yields 7.6 g (79.2 % of theory) of a highly viscous oil.
'H-NMR (200 MHz, CDCI3):
o = 1.28 (t, 3H); 3.32 - 4.05 (n~, 6H); 3.71 (s, 3H); 4.18 (q, 2H); 6.03 (bs. 2H).

Le A 28 558 - 48 -- -- -- . _ _ . _ . .... . .. ~ . _ , _ Example 11 2 ~ 8 0 ~ 6 7 4-~enzylamino-1-me~lloxycarbonylpyrrolidine-3-carboxylic acid CO2Mc CO2 H N H~--~3 17 g (56 mmol) ethyl 4-benzylamino-1-methoxycarbonylpyrrolidine-3-carboxylate and 4.8 g (200 mmol) li~hiurn hydroxide dissolved in S0 ml tetrahydrofurane, 10 ml methanol and 10 rnl water are stirred at room temperature for 23 h. The reaction mixture is neutralized by adding about 155 ml 1 N potassium hydrogen sulfate solution and thoroughly extracted with ethyl ether. Drying and concentration yields 5.7 g (36.6 ~ of theory) of a viscous oil.
'H-NMR (200 MHz, CDCl3):
10 o = 2.61 (m, lH); 3.30 - 3.85 (m, 6H); 3.72 (s,3H); 4.25 - 4.41 (m, 2H); 7.20 - 7.40 )m, SH).

Example 12 4-Aminopyrrolidine-3-carboxylic acid dihydrobromide 2HBr =
15 1.2 g (4.17 mrrlol) 4-tert-butyloxycarbonylamino-l-methoxycarbonylpyrrolidirle-3-carboxylic acid dissolved in 10 ml acetic acid were treated with 5 ml h~ drogenbrornide in acetic acid at 60 C for 2 h. After cooling to roomtempera~r the precipitate ~as fîltered off. 1.1 g (90 % of theory) of a pinc, highly hygroscopic powder were obla~ned.
IH-NMR (200 MHz, D20):
20 o = 3.47 - 4.03 (m, 5H), 4.29 - 4.50 (rn, lH).
MS (Cl, isobutane):
m/e: 130 [M+]

Le A 28 558 - 49 -Example 13 Ethyl 4-benzylamino- 1-methoxycarbonyl-3,4-dehydropyrrolidine-3-carboxylate CO2Me CO2Et NH~

The synthesis is carried out according to the preparation of example I fiom ethyl 1-metho~ycarbonyl4-oxopyrrolidine-3-carbo~ylate and benzylamine.

Le A 28 558 - 50 -

Claims (15)

1. Patent Claims l. A pharmaceutical composition for controlliny diseases which comprises a substituted pyrrolidine of the general formula (I) (I), in which A and B are always different and represent a group of the formula -CHR5 or -NR6, in which R5 denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, hydroxyl, phenyl or carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, R6 has the meaning of R2 indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 or 2 times by identical Le A 28 558 or different substituents from the series com-prising halogen, hydroxyl, phenyl and carboxyl or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen, phenyl or straiqht-chain or branched alkyl having up to 6 carbon atoms, R2 represents hydrogen or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 or 2 times by identical or different substituents from the series comprising hydroxyl and formyl or by straight-chain or branched acyl having up to 6 carbon atoms or by phenyl or benzoyl, each of which is optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, nitxo and cyano, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represents straight-chain or branched acyl having up to 8 carbon atoms, or represents tert. butyloxy-carbonyl (boc) or benzoyl which is optionally substituted as described above, or Le A 28 558 represents a group of the formula-SO2R9, in which R9 denotes straight chain or branched alkyl having up to 8 carbon atoms, or benzyl or phenyl, where the latter are optionally substituted up to 3 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoromethoxy or by straight chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, carboxyl or by the abovementioned group -NR7R8, in which R7 and R8 have the abovementioned meaning, represents phenyl which is optionally substituted up to 3 times by identical or different sub-stituents from the series comprising halogen, hydroxyl, nitro, trifluoromethyl, trifluorometh-oxy, straight-chain or branched alkyl, acyl, and alkoxy or alkoxycarbonl each having up to 6 carbon atoms or by a group of the formula -NR7R8 or -SO2R9, Le A 28 558 in which R7, R8 and R9 have the abovementioned meaning, R3 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, or R2 and R3 together represent the radical of the formula =CHR10, in which R10 has the abovementioned meaning of R5 and is identical to or different from this, D represents an oxygen or sulphur atom or the group, R4 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or phenyl, where the latter are optionally substituted up to 3 times by identical or different substituents from the group comprising hydroxyl, halogen, nitro, cyano, carboxyl, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, in the case of phenyl also by alkyl, acyl or alkoxycarbonyl each having up to 6 carbon Le A 28 558 - 54 -atoms or by a group of the formula -NR7R8 or -SO2R9, in which R7, R8 and R9 have the abovementioned meaning, or for the case in which D represents the group R4 represents the group of the formula -SO2R9, in which R9 has the abovementioned meaning, a physio-logically acceptable salts thereof, together with a suitable diluent or carrier.
2. 2. A composition according to claim 1, in which in the general formula (I) A and B are always different and represent a group of the formula -CHR5 or -NR6, in which R5 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen or hydroxyl, or by straight-chain or branched alkoxy or alkoxycarbonyl each Le A 28 558 having up to 4 carbon atoms, R6 has the meaning of R2 indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen or hydroxyl, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted 1 or 2 times by identical or different substituents from the series comprising hydroxyl and formyl or by straight-chain or branched acyl having up to 4 carbon atoms or by phenyl or benzoyl, each of which is optionally substituted by halogen, nitro or cyano, or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or Le A 28 558 represents straight-chain or branched acyl having up to 6 carbon atoms or represents tert. butyloxycarbo-nyl (boc) or benzoyl which is optionally substituted as descri-bed above, or represents a group of the formuls -SO2R9, in which R9 denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, where the latter are optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoro-methoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by the abovementioned group of the formula -NR7R8, in which R7 and R8 have the abovementioned meaning, represents phenyl which is optionally substituted up to 2 times by identical or different groups from the series comprising halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms Le A 28 558 or by a group of the formula -NR7R8 or -SO2R9, in which R7, R8 and R9 have the abovementioned meaning, R3 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or R2 and R3 together represent the radical of the formula =CHR10, in which R10 has the abovementioned meaning of R5 and is identical to or different from this, D represents an oxygen or sulphur atom or the group, R4 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, where the latter are optionally substituted up to 2 times by identical or different substituents from the series comprising hydroxyl, halogen, nitro, cyano, trifluoromethyl and trifluoro-methoxy, by straight-chain or branched alkoxy, Le A 28 558 acyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7R8 or -SO2R9, in which R7, R8 and R9 have tho abovementioned meaning, or for the case in which D represents the group, R4 represents the group of the formula SO2R9, in which R9 has the abovementioned meaning.
3. 3. A composition according to claim 1, in which in the general formula (I) A and B are always different and represent a group of the fonmula CHR5 or -NR6, in which R5 denotes hydrogen or straight-chain or branched-alkyl having up to 4 carbon atoms, Le A 28 558 R6 has the meaning of R2 indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1 represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted 1 or 2 times by identical or different phenyl, which can in turn be substituted by methoxy or ethoxy, or represents straight-chain or branched acyl having up to 4 carbon atoms or tert. butyloxycarbonyl (boc) represents a group of the formula -SO2R9, in which R9 denotes straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, where the latter are optionally substituted by hydroxyl, fluorine, chlor-ine, bromine, nitro, cyano, methyl, ethyl or methoxy, R3 represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, Le A 28 558 or R2 and R3 together represent the radical of the formula =CHR10, in which R10 has the abovementioned meaning of R5 and is identical to or different from this, D represents an oxygen or a sulphur atom or the group, R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, where the latter are optionally substituted by fluorine, chlorine, bromine, nitro, cyano, methoxy or ethoxy or by a group of the formula -NR7R8 or -SO2R9, in which R7 and R8 are identical or different and denote hydrogen, methyl or ethyl and R9 has the abovementioned meaning, Le A 28 558 or in the case in which D represents the group.
   
   R4 represents the group of the formula -SO2R9, in which R9 has the abovementioned meaning.
4. 4. A composition according to claim 1 in which in the general formula (I) as claimed in claim 1, the two substituents -NR2R3 and -CO-D-R4, in which R2, R3, D
   and R4 have the meaning indicated in claim 1, are present in the cis-position.
5. 5. A composition according to claim 1 in which the disease is a dermatomycosis or a systemic mycosis.
6. 6. Compounds of the general formula (Ia) (Ia), in which A' and B' are always different and represent the group of the formula -CHR5' or-NR6', in which R5 denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon Le A 28 558 atoms, which is optionally substituted by halogen, hydroxyl, phenyl or carboxyl or by stxaight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, R6 has the meaning of R2 indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 or 2 times by identical or different substituents from the series comprising halogen, hydroxyl, phenyl and carboxyl or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents hydrogen or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 or 2 times by identical or different groups from the series comprising Le A 28 558 hydroxyl and formyl or by straight-chain or branched acyl having up to 6 carbon atoms or by phenyl or benzoyl, each of which is optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, nitro and cyano, or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or represents straight-chain or branched acyl having up to 8 carbon atoms, or represents tert. butyloxycarbonyl (boc) or benzoyl which is optionally substituted as described above, or represents a group of the formula -SO2R9', in which R9' denotes straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or phenyl, where the latter are optionally substituted up to 3 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoro-methoxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, carboxyl or by the abovementioned group -NR7'R8', in which Le A 28 558 R7' and R8' have the abovementioned mean-ing, represents phenyl which is optionally substituted up to 3 times by identical or different substitu-ents from the series comprising halogen, hydroxyl, nitro, trifluoromethyl, trifluoro-methoxy and straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7'R8' or -SO2R9', in which R7, R8 and R9 have the abovementioned meaning, R3' represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, or R2' and R3' together represent the radical of the formula =CHR10', in which R10' has the abovementioned meaning of R5' and is identical to or different from this, Le A 28 558 D' represents an oxygen or sulphur atom or the group, R4' represents hydrogen or straiqht-chain or branched alkyl having up to 8 carbon atoms or phenyl, where the latter are optionally sub-stituted up to 3 times by identical or different substituents from the series compris-ing hydroxyl, halogen, nitro, cyano, carboxyl, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, in the case of phenyl also by alkyl, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR7'R8' or -SO2R9', in which R7', R8' and R9' have the abovementioned meaning, or for the case in which D represents the group, R4' represents the group of the formula -SO2R9, in which R9' has the abovementioned meaning, with the proviso that if A' represents the -CH2-group, B' represents the -NR6'- group, D' represents Le A 28 558 - 65 -oxygen and R1', R2', R3' and R4' represent hydrogen, R6' must not represent hydrogen, and in the case in which R2' represents the tert-butyl group and R3' represents hydrogen, R6' must not represent the acetyl group, and if B' represents the -CH2- group, R1' , R2' and R3' represent hydrogen, D' represents oxygen, R4' represents ethyl and A' represents the -NR6' group, R6' must not represent hydrogen or benzoyl, and the physiologically acceptable salts thereof.
7. 7. Process for the preparation of substituted pyrrolidines of the general formula (I) according to Claim 1, characterised in that [A] in the rase in which A and A' each correspond-ingly represent the -NR6 or -NR6' group and B or B' represent correspondingly, the -CHR5 or -CHR5' group, compounds of the general formula (II) (II), in which W represents a group of the formula or the N3-group, Le A 28 558 - 67 -R11 and R13 correspondingly encompass the particular scope of meaning of R1/R1' and R5/R5', E represents a C1-C6 alkoxycarbonyl radical, G represents an amino-protective group, preferably benzyl, and R12 represents C1-C6-alkyl, are first converted according to customary methods by removal of the protective group G, in the case in which W
   represents the -?H-group, and in the case of the N3-group by reaction with triphenylphosphonoxide/H2O into the compound of the general formula (III) (III), in which R11, R12, R13 and E have the abovementioned meaning, and then reacted with activated carboxylic acid derivatives, in the presence of a base, to give the compounds of the general formula (IV) Le A 28 558 - 68 - (IV), in which E, R11, R12 and R13 have the abovementioned meaning, and L represents a C1-C6-alkoxycarbonyl radical, and in a last step both the amine and the acid function are liberated by reaction with HBr in water, simultaneously with elimination of the radicals E, L and R12, or compounds of the general formula (V) (V), in which Le A 28 558 - 69 -E, R11, R12 and R13 have the abovementioned meaning, and M has the abovementioned meaning of R2 with the exception of hydrogen, but preferably represents a (C1-C6)-acyl radical, such as acetyl, or the -CH(C6H4-OCH3)2 radical, are reduced to the corresponding pyrrolidine compounds in inert solvents by hydrogenation with hydrogen in the presence of a catalyst or with hydrides or [B] in the case in which A and A' correspondingly represent the -CHR5 or -CHR5' group and B and B' correspondingly represent the -NR6 or -NR6' group, compounds of the general formula (VI) (VI), in which E, R11, R12 and R13 have the abovementioned meaning, Le A 28 558 - 70 -are converted with amines of the formula (VII) NH2-R14 (VII), in which R14 represents (C2-C6)-alkyl or benzyl, preferably benzyl, into the corresponding enaminoesters of the general formula (VIII) (VIII), in which E, R11, R12, R13 and R14 have the abovementioned meaning, the double bond is reduced with hydrogen in the presence of a catalyst, and in a last step the radical R14 is likewise removed with hydrogen in the presence of a catalyst or Le A 28 558 - 71 -compounds of the general formula (VI) are directly reductively aminated by reaction with ammonia or ammonium salts and then with the action of hydrogen in the presence of a catalyst, or with cyanoborohydride, in the presence of acids in inert solvents, and if R2/R3 = H, the respective protective groups in each of the abovementioned steps are removed according to customary conditions, and in the case of the acids [(I), (Ia) D=O, R4=H]
   the corresponding esters are optionally hydrolysed, and in the case of the other definitions mentioned above for D, D', R4 and R4', likewise derivatised by customary methods, such as, for example, amidation, sulphonation or sulphoamidation, if appropriate in the presence of auxiliaries such as catalysts and dehydrating agents, starting from the corresponding carboxylic acids, if appropriate with prior activa-tion.
   Le A 28 558 - 72 -
8. 8. A process for preparing a compound of formula (Ia) as defined in claim 6, which process comprises [A'] in the case in which A' represents the NR6' group and B' represents the -CHR5' group, liberating the amine and the acid functions of a compound of general formula in which E represents a C1-C6 alkoxycarbonyl radical, R1' and R5' are as defined in claim 6, R12 represents C1-C6-alkyl and L
   represents a C1-C6-alkoxycarbonyl radical; or [A"] reducing a compound of the general formula in which E, R1', R5' and R12 are as defined above and M has the value other than hydrogen, given for R2' in claim 6;
   [B'] reacting a compound of the general formula in which E, R1', R5' and R12 are as defined above and R14 represents C2-C6-alkyl or benzyl in the presence of a catalyst to reduce the double bond and to eliminate the group R14; or [B"] reductively aminating a compound of general formula in which E, R1', R5' and R12 are as defined above, by reaction with ammonia or an ammonium salt and the action of hydrogen in the presence of a catalyst or a reducing agent; and, if required, hydrolysing an obtained compound containing an esterified carboxy group to obtain a free carboxy group and, if required, subjecting an obtained compound to amidation, sulphonation or sulpho-amidation and, if required, converting an obtained compound into physiologically acceptable salt thereof.
9. 9. A compound according to claim 6, in which in the general formula (Ia) A' and B' are always different and represent a group of the formula -CHR5' or -NR6', in which R5' denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen or hydroxyl, or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, R6' has the meaning of R2' indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1' represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen or hydroxyl, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7'R8', in which R7' and R8' are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 car-bon atoms, R2' represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted 1 or 2 times by identical or different substituents from the series comprising hydroxyl and formyl or by straight-chain or branched acyl having up to 4 carbon atoms or by phenyl or benzoyl, each of which is optionally substituted by halogen, nitro or cyano, or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 6 carbon atoms or represents tert.
   butyloxycarbonyl (boc) or benzoyl which is optionally substituted as described above, or represents a group of the formula -SO2R9', in which R9' denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, where the latter are optionally substituted up to 2 times by identical or different substituents from the series comprising halogen, hydroxyl, nitro, cyano, trifluoromethyl and trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by the abovementioned group of the formula -NR7'R8', in which R7' and R8' have the abovementioned meaning, represents phenyl which is optionally substituted up to 2 times by identical or different groups from the series comprising halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7'R8' or -SO2R9', in which R7', R8' and R9' have the abovementioned meaning, R3' represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or R2' and R3' together represent the radical of the formula =CHR10', in which R10' has the abovementioned meaning of R5' and is identical to or different from this, D' represents an oxygen or sulphur atom or the group, R4' represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, where the latter are optionally substituted up to 2 times by identical or different substituents from the series comprising hydroxyl, halogen, nitro, cyano, trifluoromethyl and trifluoromethoxy, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR7'R8' or -SO2R9', in which R7', R8' and R9' have the abovementioned meaning, or for the case in which D' represents the group, R4' represents the group of the formula -SO2R9', in which R9' has the abovementioned meaning.
10. 10. A compound according to claim 6, in which in the general formula (Ia) A' and B' are always different and represent a group of the formula -CHR5' or -NR6', in which R5' denotes hydrogen or straight-chain or branched-alkyl having up to 4 carbon atoms, R6' has the meaning of R2' indicated below and is identical to or different from this, or denotes methoxycarbonyl, R1' represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, R2' represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted 1 or 2 times by identical or different phenyl, which can in turn be substituted by methoxy or ethoxy, or represents straight-chain or branched acyl having up to 4 carbon atoms or tert. butyloxycarbonyl (boc) represents a group of the formula -SO2R9', in which R9' denotes straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, where the latter are optionally substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl or methoxy, R3' represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, or R2' and R3' together represent the radical of the formula =CHR10', in which R10' has the abovementioned meaning of R5 and is iden-tical to or different from this, D' represents an oxygen or a sulphur atom or the group, R4' represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, where the latter are optionally substituted by fluorine, chlorine, bromine, nitro, cyano, methoxy or ethoxy or by a group of the formula -NR7'R8' or -SO2R9', in which R7' and R8' are identical or different and denote hydrogen, methyl or ethyl and R9' has the abovementioned meaning, or in the case in which D' represents group, R4' represents the group of the formula -SO2R9', in which R9' has the abovementioned meaning.
11. 11. The compound methyl 1-methoxycarbonyl-4-(4,4'-dimethoxy-benzhydryl)-3-carboxylate.
12. 12. A pharmaceutical composition which comprises a com-pound of formula (Ia) or a physiologically acceptable salt thereof as claimed in any one of claims 6, 9, 10 and 11, together with a suitable diluent or carrier.
13. 13. Use of a compound of formula I or a physiologically acceptable salt thereof, as defined in any one of claims 1 to 6, 9, 10 and 11 as an antimycotic agent.
14. 14. A process for preparing an antimycotic agent which comprises admixing a compound of formula I or a physiologically acceptable salt thereof, as defined in any one of claims 1 to 6, 9, 10 and 11 with a suitable diluent or carrier.
15. 15. A commercial package containing, as active pharmaceu-tical ingredient a compound of formula I or a physiologically acceptable salt thereof, as defined in any one of claims 1 to 6, 9, 10 and 11, together with instructions for its use as an antimycotic agent.