CA2109975A1

CA2109975A1 - Diaminobenzoic acid derivatives

Info

Publication number: CA2109975A1
Application number: CA002109975A
Authority: CA
Inventors: Wilhelm Kump; Uwe Trinks; Peter Traxler
Original assignee: Wilhelm Kump; Uwe Trinks; Peter Traxler; Ciba-Geigy Ag
Current assignee: Novartis AG
Priority date: 1992-11-27
Filing date: 1993-11-25
Publication date: 1994-05-28
Also published as: JPH0776562A; AU5184193A; EP0600832A1; CN1094030A

Abstract

Abstract Diaminobenzoic acid derivatives The invention relates to compounds of the formula I

(I) in which A1 and A2 are hydrogen, unsubstituted or substituted lower alkyl, lower alkenyl or lower alkynyl, heterocyclyl-lower-alkyl, acyl, lower alkylsulfonyl or arylsulfonyl, or together are unsubstituted or substituted lower alkylene; Ar1 and Ar2 are aryl, heteroaryl or unsubstituted or substituted cycloalkyl, X is O or S, Y is amino, substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio; or, if X is O and Z
is substituted methyl, Y is hydroxyl; and Z is substituted methyl, carboxyl or esterified or amidated carboxyl or thiocarboxyl; or Y and Z together are 1-oxamethylene; to salts thereof, tautomers thereof, processes for their preparation, pharmaceutical compositions, and/or to these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions. The compounds inhibit protein kinases.

Description

-21 0997~

~19368/A
.

Diaminobenzoic acid derivatives The invention relates tO compounds of the formula I
Arl X
Al- N ~ C--Y

A2~ N ~ Z
Ar in which A1 and A2 independendy of one another are hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, heterocyclyl-lower-al~yl, acyl, lower allylsulfonyl oq :~
arylsulfonyl, or in which Arl and Ar2 together are unsubstituted or substituted lower aL~cylene; Arl and Ar2 independendy of one another are aryl, heteroaryl or unsubsdtuted or substituted cycloaL~cyl, X is O or S, Y is amino, substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio; or fuTthermore, if X is O and Z is substituted methyl, Y is hydroxyl; and Z is substituted me~hyl, carboxyl, esterified :
carboxyl or an analogous radical in which the oxo of dhe carbonyl radical is replaced by dlio, or amidated carboxyl or an analogous radical in which the oxo of the carbonyl radical is replaced by dlio; o¢ Y and Z together are l-oxamethylene which is bonded via the oxygen in dhe position of Y and via the methylene carbon atom in ~e position of Z; and, if ` ::
salt-forming groups are present, to salts thereof, and/or, if tautomerizable radicals are present, to tautomers thereo~, to processes for the preparation of these compounds, to pharmaceudcal compositions comprising these compounds, to these substances for use in : : -`
a therapeutic method for the treatment of the human or animal body andlor to the use of these compounds for the therapeutic treatment of the human or animal body or for the :
preparation of pharmaceutical compositions.

Within the scope of the present application, the general terms used hereinabove and hereinafter are preferably as defined below:

, .. .. , . . . .. . . ~ ., 210997~

- 2 -If the text hereinabove or hereinafter mentions methods for the treatment of the human or animal body, then this term also embraces methods for ~he treatment of wann-blo~ded species and methods for inhibiting protein kinases in warm-blooded species.

Unless otherwise indicated, the prefix "lower" specifies a radical up to and including 7, in particular up to and including 4, and especially 1 to 3, carbon atoms.

Lower alkyl is preferably n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl or n-propyl.

Lower aL~enyl has 2 to 7, preferably 3 to 7, in particular 3 or 4, carbon atoms, and is, for example, allyl or crotyl.

Lower aL~cynyl has 2 to 7, preferably 3 to 7, in particular 3 or 4, carbon atoms, and is, for example,propyn-l-ylorpropyn-2-ylor2-butyn-1-yl.

Substituted lower alkyl is preferably lower a1kyl as defined above, which is substituted by up to 4, preferably up to 2, radicals selected from the series consis~ng of amino, such as in aminomethyl, aminoethyl, aminopropyl or aminobutyl, mono- or di-lower-alkylamino, in which the lower allcyl radical is monosubstituted or disubstituted by hydroxyl, low.er alkoxy, phcnyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-allcylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or, preferably, unsubstituted, such as aminomethyl, aminoethyl, aminopropyl or aminobutyl, cycloalkylamino, phenyl-lower-alkylamino or phenylamino, acylamino, for example, lower alkanoylamino, phenyl-lower-alkanoylamino or phenylcarbonylamino ( - beylan~ino), hydroxyl, such as in hydroxymethyl, hydroxyethyl or hydroxypropyl, lower alkoxy, in which the lower alkyl radical is mono- or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, N,N-di-lower-aLIcylcarbamoyl and/or cyano, or preferably unsubstituted, phenyl-lower-alkoxy, acyloxy, in particular lower alkanoyloxy, mercapto, lower alkylthio, in which the lower alkyl radical is mono- or disubstituted by hydroxyl, lower aL~oxy, phenyl-lower-alkoxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-allylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower , : .

.... , . ~ . , -.: . . ~ ~ . .

21 0997~

- 3 -alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, or preferably unsubstituted, phenyl-lower-alkylthio, acylthioj in particular lower aLkanoylthio, carboxyl, such as in carboxymethyl, carboxyethyl or carboxypropyl, esterified carboxyl, for exarnple lower aLlcoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, especially in methoxy-or ethoxycarbonylmethyl, -ethyl or -propyl, or phenyl-lower-alkoxycarbonyl, such as ~:
benzyloxycarbonyl, cyano, carbamoyl, such as in carbamoylmethyl, carbamoylethyl or carbamoylpropyl, N-lower-alkylcarbamoyl, N,N-di-lower-aL~ylcarbarnoyl, N-hydroxy-carbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower-alkylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl, ureido, ureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-aL~cyl, in particular 1- or 3-mono-, 1,3- or 3,3-di-or 1,3,3-tri-lower-alkylureido, 1- or 3-phenylureido, 1- or 3-mon~, 1,3- or 3,3-di- or - ~:
1 ,3,3-triphenyl-lower-alkylureido, for example 3-lower-alkylureido, such as 3-methyl- or 3-ethylureido, especially in 3-methyl- or 3-ethylureidomethyl, -ethyl or -propyl, thioureido, thioureido which is substituted on one or both nitrogen atoms by lower aL~yl, aryl or aryl-lower-aL~cyl, in particular 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower-alkylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-aLkylthioureido, for example 3-lower-alkylthioureido, such as : ~ ~ :
3-methyl- or 3-ethylthioureido, especially in 3-methyl- or 3-ethylthioureidomethyl, -ethyl ; h or -propyl, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aL~yl, aryl or aryl-lower-aL~cyl, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower-alkylhydrazinoj 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower-alkylhydrazino, for example 2,2-di-lower-aL~ylhydrazino, such as 2,2 dimethyl- or 2,2-diethylhydrazino, an~idino, such as in amidinomethyl, arnidinoethyl ~ : :
or amidinopropyl, amidino which is substituted on one or both nitrogen atoms by lower aLIcyl, aryl or aryl-lower-aL~cyl, in particular Nl- or N2-mon~, Nl,N2-di- or Nl,Nl-di- or Nl,Nl,N2-tri-lower-aLtcylamidino, Nl- or N2-phenylamidino, Nl- or N2-mono-, Nl,N2-, Nl,Nl-di- or Nl,Nl,N2-triphenyl-lower-aL~cylamidino, for example Nl,Nl-di-lower-alkylamidino, such as Nl,Nl-dirnethyl- or Nl,Nl-diethylamidino, guanidino, such as in guanidinomethyl, guanidinoethyl or guanidinopropyl, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-aL~cyl, in particular 1-, 2- or 3-mono-, 1,1-, 3,3-, 1,2-, 1,3- or 2,3-di-, 1,1,2-, 1,1,3-, 1,2,3-, 1,3,3- or 2,3,3-tri-, 1,1,2,3-, 1,2,3,3- or 1,1,3,3-tetra- or 1,1,2,3,3-pentalower-alkylguanidino or -phenyl-lower-alkylguanidino, in particular 3,3-di-lower-aL~ylguanidino, such as3,3-diethylguanidino or 3,3-diethylguanidino, oxo which is not bonded to the carbon which is bonded to the nitrogen car ying Al or A2, such as in 2-oxopropyl or 3-oxo-: . . ; ....... .; - . . . . ~ . ......... .
:. . . : ::: :.: I ~, . .. : - .

4 21~337a n-butyl, thioxo, imino, lower-alkylimino, acylimino, in particular lower-alkanoylimino, such as acetylimino, hydroxyimino (HO-N=), such as in hydroxyiminomethyl (HO-N=CH-), hy~roxyiminoethyl or hydToxyiminopropyl, lower-aLtcoxyimino, such asmethoxyimino, hydrazono, such as in hydrazonomethyl, -ethyl or -propyl, N-mono- or N,N-di-lower-aLkylhydrazono, N-acylhydrazono, in par~cular N-lower-alkanoylhy-drazono, such as acetylhydrazono or lower-alkoxycarbonylhydrazono, such as tert-butoxy-carbonylhydrazono, and lower-alkylthioimino, such as methylthioimino or ethylthioimino, especially in methylthioimino- or ethylthioiminomethyl, -ethyl or -propyl. Lower aLkyl is preferably linear and terminally substituted by one of the abovementioned substituents.

Aryl-lower-aL~cyl preferably contains aryl, as defined below, and is, in particular, phenyl-lower-aLl~yl, such as benzyl.

Substituted lower alkenyl is preferably lower alkenyl as defined above, in particular having 3 to 7, especially 3 or 4, carbon atoms which is substituted by up to 4 radicals, preferably a radical selected fmm amongst ~e substituents which have been mentioned in the definition of substituted lower alkyL In certain substituents, tautomers are possible because of the interaction of the doublc bond. Thus, hydroxyl, mercapto or N-bonded substituents which have a free hydrogen on the bonding nitrogen, can tautomerize when bonded to a carbon atom of a triple bond to give oxo, thioxo, or imino compounds;
substituents which are bonded via nitrogen by means of a double bond, such as hydroxyimino or hydrazono, can also tautomerize when conjugated to a doubb bond in the lower allcenyl radical; such compounds can also exist in tautomeric equilibria I?referred as substituted lower alkenyl are those radicals in which there is no tautomerism, i.e. in which for example hydroxyl, mercapto or N-bonded substituents, which have a free hydrogen on the bonding nitrogen, are not bonded to a carbon atom in the lower alkenyl radical from which a doublebond originates and/or where substituents bonded via nitrogen by means of a double bond, such as hydroxyimino or hydrazono, are not conjugated with a double bond in the lower alkenyl radical. However, unsubsdtuted lower alkenyl Al and/or A2 is prefe~ed to subsdtuted lower alkenyl.

Substdtuted lower alkynyl is preferably lower alkynyl as defined above, in pardcular having 3 to 7, especially 3 or 4, carbon atoms which is subsdtuted by up to 4 radicals, preferably by a radical selected from the substdtuents mentioned in the definition of substdtuted lower alkyl. In analogy with the definidon of tautomers and tautomeric equilibria for substituted lower alkenyl, co~responding tautomers and tautomeric equilibria 210937~

can also exist for substituted lower aLkynyl. In this case too, radicals which are preferred are the corresponding radicals in which there is no tautomerism, these radicals being defined analogously to substituted lower aLkenyl. However, unsubstituted lower alkynyl Al and/or A2 is preferred to substituted lower aL~cynyl.

Heterocyclyl-lower-alkyl is one of the abovementioned lower alkyl radicals, preferably methyl, ethyl or n-propyl, which is substituted, preferably on the terrninal carbon atom, by heterocyclyl, which is, in particular, a saturated, partially saturated or unsaturated single ring which is bonded via a ring nitrogen atom and has 3 to 7, mainly 5-7, ring atoms, it being possible for up to two further heteroatoms selected from the series consisting of nitrogen, sulfur and/or oxygen to be present in addition to the bonding nitrogen atom;
which is a single ring or can be fused to one or two, ~referably one, benzene, cyclopentane, cyclohexane or cycloheptane Iings; and which can be unsubstituted or, in particular, substituted by lower alk~l, lower alkanoyl, hydroxyl, lower aLlcoxy, halogen, cyano and/or trifluoromethyl, for example pyrrolyl, 2,5-dihydropyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolinyL pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,~ or 1,3,~triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro thiazolyl, tetrahydr~isothiazolyl, indolyl, isoindolyl, benzimidazolyL piperidinyl, piperazin-l-yl, morpholino, thiomorpholino, S,S-dioxothiomorpholino, 1,2-dihydro- or 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydr~ or 1,2,3,~tetrahydroisoquinolyl, the abovementionedradicals being unsubstituted or substituted as above, in particular by lower alkyl, for example in 4-lower-allcylpiperazin-1-yl, such as 4-methyl- or 4ethylpiperazin-1-yl, or by lower alkanoyl, for example in 4 lower-aL~anoylpiperazin-l-yl, such as 4acetylpiperazin-1-yl.

Acyl is preferably lower aL~canoyl, halo-lower-alkanoyl, such æ ~ifluoro- or trichloroacetyl, aryl-lower-alkanoyl, for example phenyl-lo ver-alkanoyl, such æphenylacetyl, arylcarbonyl, such æ phenylcarbonyl, where aryl in the two læt-mentioned cases is as defined above, with the exception that acyl substituents in the læt-mentioned aryl radicals are preferably selected from amongst lower alkanoyl, phenyl-lower-aL~canoyl and phenylcarbonyl, or is lower alkoxycarbonyl, such as tert-butoxycarbonyl, or phenyl-lower-alkoxycarbonyl, such as benzyloxycarbonyl. Acyl is mainly lower alkanoyl.

Lower aL~canoyl is preferably formyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, in particular formyl, aoetyl or propionyl.

2109~7~

Halogen is, in particular, fluorine, chlorine, bromine andJor iodine, mainly fluorine or iodine.

Lower aLkylsulfonyl (= lower aL~cyl-SO2-~ is preferably methane- or ethanesulfonyl.

Arylsulfonyl (= aryl-SO2-) is preferably benzene- or toluenesulfonyl, such as 4-toluenesulfonyl.

Lower aL~cylene, which is formed by Al and A2 together, is unbranched, has in particular 1 to 4, preferably 2 to 3, carbon atoms and is unsubstituted or substituted by one or more, preferably up to 3, in particular one, substituent selected from amongst lower alkyl, such as methyl or ethyl, amino-lower-alkyl, such as aminomethyl, aminoethyl or aminopropyl, mono- or di-lower-aLkylamino or mono- or di-lower-alkylan~ino-lower-aL~cyl in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower aLttoxy, phenyl-lower-alkoxy, lower-aLIcanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lower aL~ylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N di-lower-aLIcylcarbamoyl and/or cyano or is preferably urlsubstituted, cycloalkylamino, cycloalkylamino-lower-aL~cyl, phenyl-lower-alkylamino, phenyl-lower-aL~ylamino-lower-alkyl, phenyl-amino, phenylamino-lower-aL~yL acylamino, for example lower al~anoylamino, phenyl-lower-alkanoylamino or phenylcarbonylamino ( - benzoylamino), acylamino-lower-aLlcyl, for example lower-alkanoylamino-lower-aLtcyl, phenyl-lower-alkanoylamino-lower-aLkyl or phenylcarbonylamino-lower-alkyl ( - benzoylamino-lower-alkyl), hydroxyl, hydroxy-lower-aLIcyl, for example hydroxymethyl, hydroxyethyl or hydroxypropyl, lower alkoxy or lower-alkoxy-lower-alkyl in which the terminal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-aL~coxy, lower-aLIcanoyloxy, halogenj amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aL~cylthio, lower aLkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aLkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-aLkylcarbamoyl and/or cyano or is preferably unsubstituted, for exa nple 2-methoxy- or 2-ethoxyethoxy-lower-alkyl,phenyl-lower-alkoxy, such as benzyloxy, phenyl-lower-alkoxy-lower-aLkyl, such as2-benzyloxyethyl, acyloxy, in parlicular lower alkanoyloxy, acyloxy-lower-alkyl, in particular lower-aL~canoyloxy-lower-aL~yl, such as 2-acetoxyethyl, mercapto, mercapto-lower-alkyl, for example mercaptomethyl or mercaptoethyl, lower alkylthio or lower-alkylthio-lower-alkyl in which the tern~inal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, 2~997~

halogen, amino, lower aLcylamino, di-lower-aLtcylamino, mercapto, lower aLIcylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, ~,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, for exarnple 2-methylthi~ or 2-ethylthioethylthio-lower-alkyl, phenyl-lower-alkylthio, such as benzylthio, phenyl-lower-aLkylthio-lower-aL~cyl, such as 2-benzylthioethyl, acylthio, in particular lower-aLIcanoylthio, acylthio-lower-alkyl, in particularlower-alkanoylthiolower-allcyl, such as 2-acetylthioethyl, carboxyl, carboxy-lower-aLt~yl, such as carboxymethyl, esterified carboxyl, for example lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, esterified carboxy-lower-alkyl, for example lower-alkoxycarbonyl-lower-allyl, such as methoxycarbonylmethyl, ethoxycarbonylmethyl or tert-butoxycarbonylmethyl, or phenyl-lower-alkoxycarbonyl- :
lower-aLkyl, such as benzyloxycarbonylmethyl, cyano, cyano-lower-aLkyl, carbamoyl, carbarnoyl-lower-alkyl, such as carbamoylmethyl, carbamoylethyl or carbamoylpropyl, N-lower-aLkylcarbamoyl, such as N-methyl- or N-ethylcarbarnoylmethyl, -ethyl or -propyl, N,N-di-lower-alkylcarbamoyl, N-lower- aL~cylcarbamoyl-lower-alkyl, N,N-di-lower-alkylcarbamoyl-lower-alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower-aLkyl, N-phenylcarbamoyl, N-phenyl- carbamoyl-lower-aL~cyl, thiocarbamoyl,thiocarbamoyl-lower-aL~cyl, N-lower-alkylthiocarbamoyl, N-lower-alkylthiocarbamoyl-lower-alkyl, N,N-di-lower-alkylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl-lower-alkyl, ureido, ureido-lower-alkyl, or ureido or ureido-lower-alkyl, each of which is subsdtuted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-allyl, in particular 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower-alkylureido, 1- or 3-phenylureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-alkylureido, for example 3-lower-alkylureido, such as 3-methyl- or 3-ethylureido, 1- or 3-mono-, 1,3~i- or 3,3~i- or 1,3,3-tri-lower-alkylureido-lower-aL~cyl, 1- or 3-phenylureido-lower-alkyl, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-alkylureido-lower-aLIcyl, for example 3-lower-alkylureido-lower-alkyl, such as 3-methyl- or 3-ethylureido-lower-alkyl,especially 3-methyl- or 3-ethylureidomethyl, -ethyl or -propyl, thioureiido, thioureido-lower-alkyl, or thioureido or thioureido-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower aLlcyl, aryl or aryl-lower-alkyl, in particular 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower-alkylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-alkylthioureido, for example 3-lower-alkylthioureido, such as 3-methylthioureido or 3-ethylthioureido, 1- or 3-mono-, 1,3-di- or 3,3-di- or 1,3,3-tri-lower-alkylthioureido-lower-alkyl, 1- or 3-phenylthioureido-lower-alkyl, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-alkylthioureido-lower-alkyl, for example 3-lower-alkylthioureido-lower-aLlcyl, such as 3-methyl- or 3-ethyl- .

.. ~ . : - . ,.. ' ' ' ' " '.,. ' . .... . . ., , ` : .' ",:, ' ! ' ' ~ , ' i `.. , -8- 210~97~

thioureido-lower-alkyl, mainly 3-methyl- or 3-ethylthioureidomethyl, -ethyl or -propyl, hydrazino, hydrazinolower-aL~cyl, such as hydrazinomethyl, -ethyl or -propyl, or hydrazino or hydrazinolower-alkyl, each of which is substituted on one or both nitrogen atoms by lower aL~cyl, aryl or aryl-lower-aLlcyl, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower- alkylhydrazino, 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyllower-alkylhydrazino, for example 2,2-di-lower-alkylhydrazino, such as 2,2-dimethyl- or 2,2-diethylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower-aLkylhydrazino-lower- aLIcyl, 1- or 2-phenylhydrazino-lower-aL~cyl, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl- lower-alkylhydrazino-lower-alkyl, for example 2,2-di-lower-aL~ylhydrazino-lower-alkyl, such as 2,2-dimethyl- or 2,2-diethyl-hydrazino-lower-alkyl, amidino, amidino-lower-alkyl, such as amidinomethyl, amidinoethyl or amidinopropyl, or amidino or amidino-lower-aL~yl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-aL~cyl, in particular Nl- or N2-mono-, Nl,N2- or Nl,NI-di- or Nl,NI,N2-tri-lower- aLIcylamidino, Nl-or N2-phenylamidino, Nl- or N2-mono-, Nl,N2-, Nl,NI-di- or Nl,Nl,N2-triphenyl-lower-alkylamidino, for exarnple N1,NI-di-lower-aL~cylamidino, such as Nl,Nl~imethyl-or N1,NI-diethylarnidino, Nl- or N2-mono-, Nl,N2- or Nl,NI-di- or Nl,N1,N2-tri-lower-alkylamidino-lower-alkyl, Nl- or N2-phenylamidino-lower-alkyl, N1- or N2-mono-, Nl,N2-, N1,NI-di- or Nl,NI,N2-triphenyl-lower-alkyl-amidino-lower-alkyl, for example Nl,NI-di-lower-aLtcyla nidino-lower-allcyl, such as Nl,Nl dirnethyl- or N1,N1 diethyl-amidino-lower-alkyl, guanidino, guanidino-lower-alkyl, such as guanidinomethyl, guanidinoethyl or guanidinopropyl, or guanidino or guanidino-lower-alkyl, each of which is substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, in particular 1-, 2- or 3-mono-, 1,1-, 3,3-, 1,2-, 1,3- or 2,3~i-, 1,1,2-, 1,1,3-, 1,2,3-, 1,3,3- or 2,3,3-tri-, 1,1,2,3-, 1,2,3,3- or 1,1,3,3-tetra- or 1,1,2,3,3-penta-lower-alkyl- or -phenyl-lower-alkylguanidino, in particular 3,3-di-lower-alkylguanidino, such as 3,3-di-methylguanidino or 3,3-diethylguanidino, 1-, 2- or 3-mono-, 1,1-, 3,3-, 1,2-, 1,3- or 2,3~i-, 1,1,2-, 1,1,3-, 1,2,3-, 1,3,3- or 2,3,3-tri-, 1,1,2,3-, 1,2,3,3- or 1,1,3,3-tetra- or 1,1,2,3,3-penta-lower-alkyl or -phenyl-lower-aLIcylguanidino-lower-alkyl, in particular 3,3-di-lower-alkylguanidino-lower-aLkyl, such as 3,3~imethylguanidino-lower-aL~cyl or 3,3~iethylguanidino-lower-alkyl, oxo, oxo-lower-alkyl, in particular lower alkanoyl, such as formyl, acetyl or propionyl, thioxo, thioxo-lower-alkyl, imino, imino-lower-slkyl, lower alkylimino, lower aL~ylimino-lower-alkyl, acylimino, in particular lower aL~cMoylimino, such as acetylimino, acylimino-lower-alkyl, in particular lower aL~canoylimino-lower-aL~yl, such as acetylimino-lower-alkyl, hydroxyimino, hydroxyimino-lower-aL~cyl, such as hydroxyiminomethyl, hydroxyiminoethyl or hydroxyiminopropyl, lower aLkoxyimino or . ~ . . ................ .. .
,: : ., . : ., . : . . , :
: :. . - . : .
., ~ , . -. ~

.; : , . :

2109~7;) g lower aL~coxyimino-lower-alkyl, such as methoxyimino or methoxyimino-lower-alkyl, hy-drazono, hydrazono-lower-aLkyl, such as hydrazonomethyl, hydrazonoethyl or hydrazono-propyl, N-mon~ or N,N-di-lower-alkylhydrazono, N-mono- or N,N-di-loweraL~cyl-hydrazono-lower-aLkyl, N-acylhydrazono, in particular N-lower-alLcanoylhydrazono, such as acetylhydrazono, or lower aL~coxycarbonylhydrazono, such as tert-butoxycarbonylhy-drazono, N-acylhydrazono-lower-alkyl, in particular N-lower-aLkanoylhydrazono-lower-alkyl, such as acetylhydrazono-lower-alkyl, or lower alkoxycarbonylhydrazono-lower-alkyl, such as tert-butoxycarbonylhydrazono-lower-alkyl, lower aLIcylthioimino, such as methylthioimino or ethylthioimino, and lower-alkylthoimino-lower-aL~yl, such as methyl-or ethylthioimino-lower-alkyl, mainly methyl- or ethylthioiminomethyl, -ethyl or -propyl.

If the text hereinabove and hereinafter mentions thioxo, this substituent is not bonded to a terminal methyl since thioaldehydes are, as a rule, unstable.

Aryl is preferably phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl and naphthyl radicals can be unsubstituted or substituted, in particular as indicated below for phenyl.
Aryl is preferably phenyl which is unsubstituted or substituted by one or more, preferably up to 5, in particular one or two, especially one, substituent(s) in particular in the p-position, or, in the case of halogen, mainly fluorine, up to S substituents, selected from the group consisting of hydrocarbyl, for example lower aL~cyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent C atoms), cycloaLlcyl, phenyl-lower-aLlcyl or phenyl; substituted hydrocarbyl, for example lower alkyl which is substituted, for example, by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-alkylaminojmercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl andlor cyano; hydroxyl; etherified hydroxyl, for example lower aL~oxy, halo-lower-aL~oxy, phenyl-lower-aLIcoxy, phenyloxy, lower aL~enyloxy, halo-lower-aLlcenyloxy or lower alkynyloxy; lower aL~cylenedioxy (linked to two adjacent C atoms); esterified hydroxyl, for example lower aLlcanoyloxy, phenyl-lower-aL~canoyloxy or phenylcarbonyloxy ( - benzoyloxy); mercapto; etherified mercapto which is free or oxidiæd, for example lower alkylthio, phenyl-lower-aLIcylthio, phenylthio, lower alkylsulfinyl [-S(=O)-lower-alkyl], phenyl-lower-aLIcylsulfinyl, phenylsulfinyl, lower alkylsulfonyl l-S(O~)-lower-alkyl], phenyl-lower-aL~cylsulfonyl or benzenesulfonyl (=phenylsulfonyl); halogen, nitro, amino; monohydrocarbylamino, for example lower aL~cylamino, cycloalkylamino, phenyl-lower-alkylamino or phenylamino;
dihydrocarbylamino, for example di-lower-alkylamino, N-lower-alkyl-N-phenylamino, .,. "

210937~

N-lower-alkyl-N-phenyl-loweralkylamino, lower aLkyleneamino, or lower alkylenearnino which is interrupted by -O-, -S- or -NR" (in which R" is hydrogen, lower alkyl or acyl, for example lower aL~canoyl); acylamino, for example lower aL~canoylamino, phenyl-lower-aL~canoylamino or phenylcarbonylamino ( - benzoylamino); acyl, for example loweraLIcanoyl, phenyl-lower-aL~canoyl or phenylcarbonyl (= benzoyl); carboxyl; esterified carboxyl, for example lower alkoxycarbonyl; amidated carboxyl, for example carbamoyl, N-lower-a~ylcarbamoyl, N,N-di-lower-allylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl; cyano, phosphoryloxy which is substituted on the phosphorus by two radicals selected independently of one another from the series consisting of hydroxyl, lower alkoxy or phenyl-lower-aL~oxy, such as benzyloxy, or phosphoryloxy which is substituted on the phosphorus by phenylene-1,2~ioxy (i.e. a radical of dhe formula o O--P--O
Q1 b ~ in which Ql and Q2 independendy of one another are hydrogen, lower alkyl and phenyl-lower-alkyl, or in which Ql and Q2 togedher are ortho-phenylene), sulfo (SO3H); esterified sulfo, for example lower alkoxysulfonyl; and amidated sulfo, for example sulfamoyl (-SO2NH2), N-lower-alkylsulfamoyl, N,N-di-lower-alkylsulfamoyl or N-phenylsulfamoyl, where phenyl groups in the substituents are in each case unsubstituted or subsdtuted by lower aLIcyl, lower alkoxy, hydroxyl, halogen and/or trifluoromethyl; aryl `
is mainly unsubsdtuted phenyl or phenyl which is o-, m- or p-subsdtuted by a radical selected from the series consisdng of lower alkyl, such as methyl or ethyl, hydroxyl, lower alkoxy, such as methoxy, halogen, such as fluorine or iodine, carboxyl, lower alkoxy-carbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano, or is pentafluorophenyl.

Lower alkylene, linlced to two adjacent C atoms of a benzene ring, is preferably C3-C4alkylene, for example 1,3-propylene or l,~butylene.

Lower alkylenedioxy, linked to two adjacent C atoms, is preferably Cl-C2alkylenedioxy, - `
for example methylene- or 1,2-ethylenedioxy.

Lower aL~cyleneamino is preferably C4-C7alkyleneamino, in particular C4-C5alkylene-amino, for example piperidino. Lower alkyleneamino which is interrupted by -O-, -S- or -NR'- is preferably such a C4-C7alkyleneamino, in particular C4-Csallyleneamino, in which a ring carbon atom is replaced by the corresponding hetero group, and is, in particular, morpholino, thiom~pholino, piperazino, or ~lower-alkyl- or ~lower-t .- : .

2~997~

aLkanoylpiperazino.

Heteroaryl is an unsaturated heterocyclic radical and is preferably linked via a ring carbon atom. It is, in particular, a 5- or ~membered ring having up to three heteroatoms selected from amongst N, O and S, mainly N, for example imidazolyl, triazolyl, pyridyl, pyrimidin-yl or tIiazinyl and, above all, pyridyl. These radicals can be unsubstituted or substituted, for example by lower aLIcyl, hydroxyl, lower alkoxy, halogen, cyano andlor trifluoro-methyl.

Pyridyl is, for example, 2-, 3- or 4-pyridyl.

Imidazolyl is, for example, 2- or 4(5~imidazolyl.

Triazolyl is, for example, 1,2,4triazol-3- or ~yl or 1,2,3-triazol-4-yl.

Pyrimidinyl is, for example, 2-, ~ or 5-pyrimidinyl.

Triazinyl is, for example, 1,3,5-triazin-2-yl.

Heteroaryl is, in particular, 2-, 3- or 4-pyr,idyl, 2-, 4- or 5-pyrimidinyl or 1,3,5-triazin-2-yl.

Cycloalkyl is preferably C3j-C8cycloalkyl and, in particular, Cs-C7cycloalkyl, which means that it has 3 to 8, or 5 to 7, ring carbon atoms, for example cyclopentyl, cyclohexyl or cycloheptyl. The abovementioned cycloalkyl radicals can also be substituted, for example by lower alkyl, halogen, such as fluorine, chlorine or bromine, or hydroxyl.

When the group -(C=X) is defined as -((~0)- and -(C=S)-, then -(C=O)- is preferred.
~ .
Substituted amino is, preferably mono- or di-lower-alkylamino, in which lower alkyl is unsubstituted or further substituted by hydroxyl, lower aL~coxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aLIcylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarba noyl, N,N-di-lower-alkylcarbamoyl and/or cyano, such as methylamino, cycloaLIcylamino, for example Cs-C7cycloalkylamino, phenyl-lower-aL~cyl-amino, such as benzylamino, phenylamino or acylamino, in particular lower alkanoyl-amino, halo-lower-aL~anoylamino, such as trifluo~ or trichloroacetylamino, alyl-., ~ . .,. - - ; . , , . . , - . .
,,, . . ,.,, ... , ,.. ", ~ ..... ~. .
~. . . . ~ .. .
,: - . , ~ .

,............ .... ; : . . . :

: , ~ :. ~ .. . . .
- ,, .: ~ ,,, : . ~ . , ..

21~9~7~

lower-aL~canoylamino, for example, phenyl-lower-alkanoyl-amino, such as phenylacetyl-amino, or arylcarbonylamino (aroylamino), in which aryl is preferably unsubstituted phenyl or phenyl which is substituted as defined above, such as phenylcarbonylamino, ( -benzoylamino), hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aL~cyl which is unsubstituted or further subsdtuted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower aL~ylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower aLkylsulfonyl, carboxyl, lower aLI~oxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-aLkylcarbarnoyl and/or cyano, or hydrazino which is substituted by aryl or aryl-lower-alkyl, aryl being, in particular, unsubstituted phenyl or phenyl which is substituted as above, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower-alkyLhydrazino, 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower-aL~ylhydrazino, for example 2,2-di-lower-alkylhydrazino, such as 2,2-dimethylhydrazino or 2,2-diethylhydrazino, hydroxy-amino, lower alkoxyamino, in which the lower alkyl radical is unsubstituted or further substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower aLlcanoyloxy, halogen, amino, lower alkylarnino, di-lower-alkylamino, mercapto, lower alkylthio, lower aL~yl-sulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N,N-di-lower-a1kylcarbamoyl andlor cyano, or lower aLkyleneamino, preferab-ly C4-C7alkyleneamino, in particular C4-Csalkyleneamino, such as piperidino, or lower al-kylenearmino (as defined above) which is inteIrupted by ~, -S- or -NR'-, preferably C4-C7alkyleneamino, in particular C4-Csalkyleneamino, in which a ring carbon atom is replaced by the corresponding hetero group, such as morpholino, thiomorpholino, piper-azino or 4-lower-alkylpiperazino or ~lower-aLIcanoylpiperazino, mainly lower alkylamino, such as methylamino, phenylamino or hydrazino.

Substituted lower aLkoxy is preferably lower alkoxy in which the lower alkyl radical is substituted, in particular mono- or disubstituted, by hydroxyl, lower alkoxy, phenyl-lower-aLlcoxy, lower aL~canoyloxy, halogen, amino, lower alkylamino, di-lower-alkyl-amino, mercapto, lower alkylthio, lower alkylsulfinyl, lower aL~ylsulfonyl, carboxyl, lower aLIcoxycarbonyl, cyano, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-aLIcyl-carbamoyl and/or cyano, mainly hydroxy-lower-aL~coxy, such as 2-hydroxyethoxy.

Unsubstituted or substituted lower aLlcylthio is preferably lower aL~cylthio which is unsubstituted or substituted, in particular mono- or disubstituted, in the lower alkylthio radical by hydroxyl, lower aLkoxy, phenyl-lower-aL~coxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkyl-.. ~ . - . .

210997a sulfinyl, lower aLkylsulfonyl, carboxyl, lower aL~coxycarbonyl, cyano, carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl and/or cyano, in particularhydroxy-lower~aLIcylthio, such as 2-hydroxyethylthio.

Substituted methyl is, in particular, methyl which is subsdtuted by a radical selected from the series consisdng of amino, mono- or di-lower-aL~cylamino in which the lower alkyl radical is mono- or di-subsdtuted by hydroxyl, lower alkoxy, phenyl-lower-aLkoxyt lower aLkanoyloxy, halogen, amino, lower aL~cylamino, di-lower-aLkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl andlor cyano or, preferably, unsubsdtuted, or lower-aLlcanoylamino, hydroxyl, lower aL~oxy in which the lower allcyl radical is monosubsdtuted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-aLIcoxy, lower aL~anoyloxy, amino, lower aLkylamino and/or di-}ower-aLIcyl-amino or, preferably, unsubsdtuted, or lower aL~anoyloxy, lower alkylthio in which the lower aLlcyl radical is monosubstdtuted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-aL~coxy, lower alkanoyloxy, halogen, amino, lower a1kylamino, di-lower-aL~ylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, ..
lower aLIcoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or, preferably, unsubstituted, cyano, ureido, 1- or 3-mono-lower-aLtcylureido, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aL~yl, guanidino, guanidino which is subsdtuted on one, two or all three nitrogen atoms by lower alkyl; oxo, imino, lower aL~cylimino, acylimino, in pardcular lower aLlcanoylimino, such as : :
acetylimino, hydroxyimino, lower aLlcoxyimino, hydrazono, N-mono- or . :
N,N-di-lower-alkylhydrazono, N-acylhydrazono, in particular N-lower-alkanoyl- : ~:
hydrazono, such as acetylhydrazono, or lower aL~coxycarbonylhydrazono, such as tert-butoxycarbonylhydrazono, and lower alkylthioimino, mainly hydroxymethyl, lower aL~canoyloxymethyl, such as acetoxymethyl, fonnyl or furthermore hydroxyiminomethyl.

In the definition of Z, esterified carboxyl or an analogous radical in which the oxo of the carbonyl radical is replaced by thio is preferably lower alkoxycarbonyl or lower aLlcylthio-carbonyl (lower alkyl-S-(C=O)-) in which the lower aL~yl radical is unsubstituted or sub-stituted, in particular mono- or disubstituted, by hydroxyl (particularly preferred), lower aL~coxy, phenyl-lower-alkoxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aL~cylthio, lower aL~cylsulf~nyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lo-wer-aL~cylcarbamoyl and/or cyano; aIyloxycarbonyl, arylthiocarbonyl (aryl-S-(C=O)-), ; . . , : . - -.. -: . . ................... .
,.. :.:. ,:. . ..

-14- 210997a aryl-lower-aLlcoxycarbonyl or aryl-lower-alkylthiocarbonyl (aryl-lower-aL~cyl-S-(C=O)-), in which aryl is as defined above, mainly phenyl- or phenyl-lower-aL~coxycarbonyl, in which the phenyl radical is substituted as defined above for aryl, such as phenyloxy-carbonyl or benzyloxycarbonyl, or (with the exception of unsubstituted lower allcylthio-carbonyl or lower aLlcylthiocarbonyl which is subsdtuted as above, arylthiocarbonyl or aryl-lower-aL~cylthiocarbonyl) a corresponding thiocarbonyl analogue, and is mainly lower alkoxycarbonyl, such as methoxycarbonyl, or hydroxy-lower-alkoxycarbonyl, such as 2-hydroxyethoxycarbonyl.
., .
Amidated carboxyl or an analogous radical in which the oxo of the carbonyl radical is . .
replaced by thio is preferably carbamoyl, N-mono- or N,N-di-lower-aLlcylcarbamoyl in which lower alkyl is unsubsdtuted or substituted by hydroxyl, lower aLIcoxy, phenyl- ;~
lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-aLIcyl-amino, mercapto, lower alkylthio, lower aLtcylsulfmyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl an~/or cyano, such as N-methylaminocarbonyl, N-cycloallylcarbamoyl, for example .~ -C5-C7cycloalkylaminocarbonyl, N-phenyl-lower-alkylcarbamoyl, such as N-benzyl-carbamoyl, phenylcarbamoyl, hydrazinocarbonyl, hydrazinocarbonyl.which is subsdtuted : . .
on one or both nitrogen atoms by lower alkyl which is unsubsdtuted or subsdtuted by.
hydroxyl, lower aL~oxy, phenyl-lower-aLlcoxy~ lower aL~anoyloxy~ halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower aLt~ylsulfinyl, lower alkylsulfonyl, carboxyl, lower aLlcoxycarbonyl, carbamoyl, N-lower-aL~ylcarbamoyl, N,N-di~lower-alkylcarbamoyl and/or cyano, or by aryl or aryl-lower-aL~yl, ir~ which aryl is, in particular, unsubsdtuted phenyl or phenyl which is subsdtuted as above, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower-alkylhydrazinocarbonyl, 1- or 2-phenyl-hydrazinocarbonyl, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower-aLlcylhydrazino-carbonyl, for example 2,2-di-lower-allcylhydrazinocarbonyl, such as 2,2 dimethyl- or 2,2~iethylhydrazinocarbonyl, hydroxyaminocarbonyl, lower alkoxyaminocarbonyl in which the lower aL~cyl radical is unsubsdtuted or subsdtuted by hydroxyl, lower alkoxy, phenyl-lower-allcoxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-aLkylamino, mercapto, lower alkylthio, lower alkylsulfmyl, lower aL1cylsulfonyl, carboxyl, lower aL~oxycarbonyl, carbamoyl, N-lower-aL~ylcarbamoyl, N,N-di-lower-alkylcarbamoyl andlor cyano, or lower aL~cyleneaminocarbonyl, preferably C4-C7aL~cyleneaminocarbonyl, in pardcular C4-CsaL~cyleneaminocarbonyl, such as piperidinocarbonyl, or lower aL~cylene-aminocarbonyl which is interrupted by -~, -S- or -NR'- (as defined above), preferably C4-C7aL~cyleneaminocarbonyl, in particular C4-C5aL~cyleneaminocarbonyl, in which a ring ,.,,. ,~ , ,- : :, . ..
,:
: ~- - :, ~ : , 21G937~

carbon atom is replaced by the corresponding hetero group, such as morpholino-, thio-morpholino-, piperazino-, ~lower-aL~cylpiperazino- or ~lower-aL~canoylpiperazino-carbonyl; or a coIresponding thio analogue of the abovementioned radicals; mainly carbamoyl, lower aL~cylaminocarbonyl, such as methylaminocarbonyl, phenylamino-carbonyl or hydrazinocarbonyl.

Salts of compounds of the formula I which have salt-forming groups are mainly pharma-ceutically utilizable, non-toxic salts. For example, compounds of the formula I which have basic groups, for example primary, secondary or tertiary amino groups (also in hydrazino or hydrazono), car~ form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example acetic acid, fumaric acid or methanesulfonic acid, or with amino acids, such as argilune or Iysine. Compounds of the fonnula I which have an acidic group, for example carboxyl, sulfo or phospho, form, for example, metal salts orammonium salts, such as alkali metal salts and alkaline earth metal salts, for example -~
sodium salts, potassium salts, magnesium salts or calcium salts, and also ammonium salts ~ -with ammonia or suitable organic amines, such as lower aLkylamines, for example triethylamine, hydroxy-lower-aLIcylamines, for example 2-hydroxyethylamine, bis(2-hydroxyethyl)amine or tris(2-hydroxyethyVamine, basic aliphatic esters of carboxylic acids, for example 2-diethyla ninoethyl ~aminobenzoate, lower alkyleneamines, for ~ ~ -example l-ethylpiperidine, cycloaLIcylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, dibenzylamine or benzyl-,~phenethylamine. Compc)unds of the formula I which have an acidic and a basic group can also exist in the form of internal salts, i.e. in the forrn of zwitter ions.
The salts of compounds of the formula I also embrace complexes of compounds of the formula I with transition metal ions, for example copper, cobalt, platinum or manganese.

For the purpose of isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. Only the pharmaceutically utilizable, non-toxic salts are used for therapy, which is why these salts are preferred.

If a plurality of isomers are possible, then the compounds of the formula I can exist as individual isomers or mixtures of isomers. If unsymmetrically substituted double bonds or rings are present, for exarnple in the case of substituted lower alkenyl Al or A2, the cis and/or trans forms can exist, if double-bonded nitrogen is present on the ring systems, : ....:. : ~

-16- 2~0~7~

such as in hydroxyimino, the syn or anti form can, for example, exist. Asymmetrically substituted carbon atoms can exist in the (S), (R) or (R,S) form. If suitable structural prerequisites exist, mixtures of isomers (such as racemates or mixtures of diastereomers), pure diastereomers or pure enantiomers may exist.

If tautomers of the compounds of the formula I can exist, be it in pure form or in an equilibrium with other tautomers, then the definitions hereinabove and hereinafter also embrace these tautomers. For example, tautomerizaMe groups are present when hydrogen is bonded to O, S or N, which are bonded to a carbon atom with a double bond, which allows (thio)keto/enol, or imine/enamine, tautomerism. This is the case, for example, in those compounds of the formula I which have thioureido or guanidino radicals or their ~ ~
derivatives which are substituted as defined above which have at least one hydrogen atom ~ -on a nitrogen atom. Other possibilities are, in particular, ring/chain tautomers of those compounds of the formula I in which Y is amino or substitu~ed amino with a fIee hydrogen atom on the nitrogen and Z is formyl. These compounds are preferably in the ring form of the formula Ia below Arl X
Al--N ~,~ C~
ll N--Gl (IA) A2 ,N ~H
Ar2 HO

in which Gl is hydrogen or one of the substituents of substituted amino, as defined above (with the exception of substituents which are bonded via carbonyl, such as acyl), in particular hydrogen or unsubsdtuted lower alkyl or furthermore lower aLkyl which is substituted as defined above in the definidon of substituted amino, or cycloalkyl or phenyl-lower-aL~cyl, and the remaining radicals are as defined for compounds of the formula I (X preferably being oxygen).

It is also possible for the tautomeric forms to exist in an equilibrium, for example in solutions. All such tautomers, whose occurrence is known to the person skilled in the art, are equally part of the invention. Preferred from amongst the tautomerizable compounds of the formula I are those which exist in only one tautomeric form or in which one tautomeric form predominates to a large extent.

-17- 21~9~7~

The compounds of the formula I have valuable, in particular phannacologically utilizable, properties. In particular, they have specific innibitory activities which are interesting from the pharmacological point of view. They mainly act as protein tyrosine kinase inhibitors and show, for example, a potent inhibidon of tyrosine kinase activity of the receptor for `
the epider nal growth factor (EGF) and of c-erbB2 kinase. These receptor-speci~lc enzyme activities play a key role in the transmission of signals in a large number of mammalian cells including human cells, in particular epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. In a range of cell types, EGF-induced activation of the receptor-æsociated protein tyrosine kinase (EGF-R-PIK) is a prerequi-site for cell division and hence for proliferation of a cell population. An addition of EGF-receptor-specific tyrosine kinase inhibitors will therefore inhibit the multiplication of these cells.

The inhibition of the EGF-receptor-specific protein tyrosine kinase (EGF-R-PIK) can be detected, for example, by the method of E. McGlynn et al. (see Europ. J. Biochem. 207, 265-275 (1992)). The compounds of the formula I inhibit the enzyme activity to an extent f 50% aC50), preferably in concentrations from approximately O.Q01 llM or above, in particular 10-9 to 10-3 M~ for example approximately 10-7 M to approximately 104 M. In the micromolar range, preferably in the range of 10-7 to 10-3 M, in particular between 7 x 10-6 and 104 M, they furthermore also show inhiSition of the cell growth of an EGF-dependent cell line, such as the epidermoid murine keratinocyte cell line. The EGP-stimulated cell proliferation of epidermal BALB~MK keratinocytes is used to measure the inhibition of the cell growth (description of the method in Meyer, T., et al., Int. J. Cancer ~, 851 (1989)). To proliferate, these cells a~e largely dependent on the presence of EGF (Weissmann, B. E., Aaronson, S. A, Cell ~, 599 (1983). To carry out the test, BALB/MK cells (10,000/well) are transfer ed to 9~well microtiter plates and incubated overnight. The test substances (dissolved in DMSO) are added at various concentrations (in dilution series), so that the end concentration of DMSO is not greater than 1%. After the addition, the plates are incubated for three days, during which the control cultures without test substance can undergo at least three mitotic cycles. The growth of the MK cells is measured by means of methylene blue staining. ICso values are defined as the concentration of the test substance in question which results in a 50%
decrease in comparison with the control cultures without inhibitor.

Besides, or instead of, EGF-R-PIK, the compounds of the formula I also inhibit other .. ,:,` ......... : " . ' - ' i . ~ . : . . . ~ ` , , 210997a tyrosine kinases which are involved in the trophically mediated transmission of signals, for example abl kinase (preferably in the range of above 10-6 M), kinases from the family of the src kinases (preferably in the range of above 10-6 M) and c-erbB2 kinase (HER-2), and also serine/threonine kinases, for example protein kinase C (preferably in the range -above 10-5 M), all of which play a role in the growth regulation and transformadon of mammalian cells including human cells.

The inhibition of c-erbB2 tyrosine kinase (HER-2) can be detected, for example, analogously to the method of E. McGlynn et al. (see Europ. J. Biochem. 207, 265-275 (1992)) used for EGF-R-PIK. The c-erbB2 kinase can be isolated by known protocols and its activity can be determined, for example by the method of T. Akiyama et al., Science ~, 1644 (1986), or preferably P.M. Guy et al. (see J. Biol. Chem. ~Z, 13851-13856 (1992)).

This means that the compounds of the fo~mula I are also suitable for inhibiting the processes mediated by this tyrosine kinase and by related tyrosine kinases.

The in-vivo antitumour activity is tested for example using human epithelial cell carcinoma A431 (ATCC No. CRL 1555), which is transplanted into female BAL13/c naked mice ~Bomholtgard, Denmaric). For the experiments, tumours found in vivo which have a size of approx. 1 cm3 are excized from the animals under sterile condidons; These tumours are homogeni~cd, suspended in 10 volumes (w/v) o~phosphate-buffered saline and injected subcutaneously (0.2 mVmouse, for example 106 cells/mouse) into the left side of the anima1s. The treatment with a test substance is st~d 5 to 8 days after the transplant, when the diameter of the tumours is 4 to 5 mm. The test substance in question (for example dissolved in ~9Lauroglycol (1,2-propylenglycol monolaurate, mixture of both constitutional isomers, Gattefoss6 S.A., Saint Priest, France), ~9Gelucire (glyceides and partial polyglycerides of fatty acids, GAttefossé S.A., Saint Priest, France) oq sesame seed oil) is administered peroraUy daily over 15 consecutive days. The tumour growth is determined by monitoring the vertical tumour diameter, and tumour volume is calculated using the formula ~ x L x D2/6 (L = length, D = diameter of the tumour at right angles to the tumour axis). The results are expressed as treatment/control (T/C) in percent.

The compounds of the formula I are therefore useful for example in the treatment of benign or malignant tumours. They are capable of causing tumour regression and of pre-venting metastatic spread and the gr~wth of micrometastases. In panicular, they can be 210997a used in epidermal hyperproliferation ~psoriasis), in the tleatment of neoplasias of epithe-lial nature, for example breast cancer, and in leukaemias. Furthermore, the compounds can be used in the treatrnent of disorders of the immune system and of inflammations as long as these disorders involve protein kinases. The compounds can also be used in the treat-ment of disorders of the central or peripheral nervous system as long as protein kinases are involved in the transmission of signals. Finally, the compounds of the formula I also have antimicrobial properties which make them suitable for example for the treatment of disea-ses caused by bacteria, such as Salmonella typhimurium, viruses, such as vaccinia virus, and other microbes which interact with protein kinases which respond to growth factors.

The compounds of the formula I can be used on their own and in combination with other pharmacologically active substances, for example with (a) inhibitors of the enzyrnes of polyamine synthesis, (b) inhiWtors of protein kinase C, (c) inhibitors of other tyrosine kinases, (d) cytokines, (e) negative growth regulators, for example TGF-,B or IFN4, (f) aromatase inhibitors, (g) antioestrogens or (h) cytostates.

In dhe groups of compounds of the formula I which are mentioned below, general definitions, for example of substituents, can be replaced independently of each other by more specific definitions which have been mentioned above in the case of the general definitions.

Preferred compounds of thc formula I are those in which A1 and A2 indepedendy of one anodher represent hydrogen, lower alkyl, substituted lower alkyl which is substituted by up to 2 radicals selected from dhe series consisting of amino, mono- or di-lower-alkylamino, in which the lower alkyl radical is monosubsdtuted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower aL~anoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkyldlio, lower alkylsulfinyl, lower aL~cylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbarnoyl and/or cyano or is preferably unsubstituted, C3-C8cycloalkylamino, phenyl-lower-a~ylamino, phenylamino, lower aL1canoylamino, phenyl-lower-alkanoyl-amino, phenylcarbonylamino, hydroxyl, lower alkoxy in which the lower alkoxy radical is monosubstituted or disubstituted by hydroxyl, lower aL~oxy, phenyl-lower-alkoxy, lower aLkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkyldlio, lower alkylsulfinyl, lower aL~ylsulfonyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, phenyl-lower-alkoxy, lower alkanoyloxy, mercapto, lower alkyl-210~7~

thio in which the lower aLkyl radical is monosubstituted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-aL~oxy, lower aL~anoyloxy, halogen, amino, lower aL~cyl-amino, di-lower-aL~cylamino, mercapto, lower aLkylthio, lower alkylsulfinyl, lower aLkyl-sulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-aLIcylcarbamoyl and/or cyano or is preferably unsubstituted, phenyl-lower-alkylthio, lower aLIcanoylthio, carboxyl, lower aL~coxycarbonyl, phenyl-lower-aL~oxycarbonyl, cyano, carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-alkylcarbamoyl, N-hydroxycarb-arnoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower-aLkylthiocarbamoyl, N,N-di-lower-aLkylthiocarbamoyl, ureido, ureido which is substituted on one or both nitrogen atoms by lower aLl~yl, aryl or aryl-lower-aL~yl, thioureido, thioureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-aLIcyl, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, arnidino, arnidino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, guanidino, guanidino which is substituted on one, two or all dlree nitrogen atoms by lower aL~cyl, aryl or aryl-lower-alkyl, oxo which is not bonded on the carbon which is bonded to the nitrogen carrying Al or A2, thioxo, imino, lower aL~cylimino, lower aLlcanoylimino, hydroxyirnino, lower aLkoxyimino, hydrazono, N-mono- or N,N-di-lower-aL~ylhydrazono, N-lower-aL~anoylhydrazono, lower aLkoxy-carbonylhydrazono, lower alkylthioimino, lower alkenyl or lower alkynyl, each of which is substituted by one of the radicals mentioned fo~ substituted lower alkyl or is preferably unsubstituted, heterocyclyl-lower-alkyl in which heterocyclyl is a radical selected from the series consisting of pyrrolyl, 2,5-dihydropyrrolyl, pyrrolinyl, irnidazolyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,~ or 1,3,~triazolyl, tetrazolyl, such as l- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro isoxazolyl, tetrahydro thiazolyl, tetrabydr~isothiazolyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin-1-yl, morpholino, tbiomorpholino, S,S-dioxothioma~pholino,1,2-dibydro or1,2,3,~tetrabydroquinolylandl,2-dihydro or1,2,3,~tetrahydroisoquinolyl, each of which is bonded terminally to lower aL~yl and bonded via a ring nitrogen atom and each of which is unsubstituted or substituted, in particular, by lower alkyl, lower alkanoyl, hydroxyl, lower aL~coxy, halogen, cyano and~or tnfluoromethyl, lower alkylsulfonyl, benzenesulfonyl or toluenesulfonyl; or in which A
and A2 togetber form lower aL~cylene which is unsubstituted or substituted by up to 3 substituents selected from the series consisting of lower aLkyl, amino-lower-alkyl, mono- ~ `
or di-lower-alkylamino or mono- or di-lower-alkylamino-lower-aL~cyl in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl- :
lower-alkoxy, lower alkanoyloxy, halogen, amino, lower aLlcylamino, di-lower-aL~cyl-., . . ~ . .. .

210997~

amino, mercapto, lower alkylthio, lower a1~cyIsulfimyl, lower alkylsulfonyl, carboxyl, lower aLkoxycarbonyl, carbamoyl, N-lower-allcylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, cycloalkylamino, cycloalkylamino-lower-aL~cyl, phenyl-lower-alkylamino, phenyl-lower-alkylamino-lower-alkyl, phenyl-amino, phenylamin~lower-aL~cyl, lower alkanoylamino, phenyl-lower-aL~canoylamino, phenylcarbonylamino, lower alkanoylarnino-lower-aLIcyl, phenyl-lower-aLkanoyl-amino-lower-alkyl, phenylcarbonylamino-lower-aL~yl, hydroxyl, hydroxy-lower-aL~yl, lower alkoxy or lower alkoxy-lower-alkyl in which the terminal lower aL~cyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylarnino, di-lower-alkylarnino, mercapto, lower aLkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aL~ylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl and/or cyano or is preferably unsubstituted, phenyl-lower-alkoxy, phenyl-lower-aL~oxy-lower-aL~yl, lower alkanoyloxy, lower alkanoyloxy-lower-aL~cyl, mercapto, mercapto-lower-alkyl, lower alkylthio or lower alkylthio-lower-alkyl in which the terminal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower~ coxy, lower alkanoyloxy, halogen, amino. Iower alkylamino, di-lower-alkylarnino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carba noyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, phenyl-lower-alkylthio, phenyl-lower-alkylthio-lower-alkyl, lower aL~canoylthio, lower aL~anoylthio-lower-alkyl, carboxyl, carboxy-lower-alkyl, lower alkoxycarbonyl, lower alkoxy-carbonyl-lower-alkyl, phenyl-lower-al~oxycarbonyl-lower-alkyl, cyano, cyano-lower-alkyl, carbamoyl, carbamoyl-lower-alkyl, N-lower-alkyl-carbamoyl, N,N-di-lower-alkylcarbamoyl, N-lower-a~cylcarbamoyl-lower-alkyl, N,N~i-lower-alkylcarbamoyl-lower-alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower-alkyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower-alkyl, thiocarbamoyl, thiocarb-amoyl-lower-alkyl, N-lower-alkylthiocarbamoyl, N-lower-alkylthiocarbamoyl-lower-alkyl, N,N-di-lower-aL~ylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl-lower-aL~cyl, ureido, ureido-lower-aL~cyl, or ureido or ureido-lower-aL~yl, each of which is subsdtuted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, thioureido or thio- :
ureido-lower-aLkyl, or thioureido or thioureido-lower-aLIcyl, each of which is subsdtuted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-aL~cyl, hydrazino or hydrazino-lower-aL~yl, or hydrazino or hydrazino-lower-aLlcyl, each of which is subsdtuted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, arnidino or amidino-lower-alkyl, or amidino or amidino-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-aLkyl, guanidino or : : - . : ~

" '~ ` " ' ' , :
' ' ' : ' ' , 2109~7a guanidino-lower-aLIcyl, or guanidino or guanidino-lower-aLkyl, each of which is substituted on one, two or all three nitrogen atoms by lower aL~cyl, aryl or aryl-lower-aLlcyl, oxo, oxo-lower-alkyl, thioxo, thioxo-lower-aL~yl, imino, imino-lower-alkyl, lower alkylimino, lower-aL~cylimino-lower-alkyl, lower aL~anoylimino, lower-alkanoylimin~lower-aLIcyl, hydroxyimino, hydroxyimino-lower-aLkyl, lower aL~coxyimino, lower~ coxy-imino-lower-aLIcyl, hydrazono, hydræono-lower-aL~cyl, N-mono- or N,N-di-lower-aLIcyl-hydrazono, N-mono- or N,N-di-lower-aLIcylhydrazono-lower-aLlcyl, N-lower-alkanoyl-hydrazono, lower aL~coxycarbonylhydrazono, N-lower-aL~canoylhydrazono-lower-aL~cyl, lower-alkoxycarbonylhydrazono-lower-alkyl, lower alkylthioimino and lower-alkylthio-irnino-lower-aLIcyl; Arl and Ar2 independently of one another are aryl, heteroaryl selected from the series consisting of imidazolyl, triazolyl, pyridyl, pynmidinyl and ~iazinyl, each of which is unsubstituted or substituted by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, or C3-C8cycloalkyl which is unsubstituted or substituted by lower aL~coxy or hydroxyl; X is O or S; Y is amino, mono- or di- lower-alkylamino in which lower aL~yl is unsubstituted or substituted by hydroxyl, lower aLkoxy, phenyl-lower-aL~oxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-aL~cylamino, mercapto, lower aLlcylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aLlcylcarbamoyl~ N,N-di-lower-alkylcarbarnoyl and/or cyano, or is Cs-(~7cycloaLkylamino, phenyl-lower-alkyl-arnino, phenylamino, lower alkanoylarnino, halo-lower-alkanoylarnino, phenyl-lower-aL~anoylarnino, phenylcarbonyla nino, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl which is substituted by hydroxyl, lower aL~coxy, phenyl-lower-aL~coxy, lower aL~canoyloxy, halogen, arnino, lower aL~cylamino, di-lower-alkylamino, mercapto, lower alkyl~hio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, or by alyl or aryl-lower-a~yl, or is : :
hydroxyamino, lower alkoxyamino in which the lower alkyl radical is substituted by hydroxyl, lower aL~oxy, phenyl-lower-aL~coxy, lower aLtcanoyloxy, halogen, amino, lower ~ -aLIcylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower aL~cylsulfinyl, lower : ~:
aL~cylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, ~ :
N,N-di-lower-alkylcarbamoyl and/or cyano or is preferably unsubstituted, lower alkyleneamino or lower alkyleneamino which is interrupted by -O-, -S- or -NR'- in which R' is lower aL~cyl or lower alkanoyl, lower aL~coxy in which the lower alkyl radical is substituted, in particular mono- or disubsdtuted, by hydroxyl, lower aLlcoxy, phenyl-lower-aLkoxy, lower alkanoyloxy, halogen, amino, lower aLkylamino, di-lower-aLIcyl-amino, mercapto, lower alkylthio, lower aLkylsulfinyl, lower aLIcylsulfonyl, carboxyl, -210997a lower aL~coxycarbonyl, carbamoyl, N-lower-aLlcylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl and/or cyano, or lower aL~ylthio which is unsubstituted or substituted, in particular mono-or disubstitutedr i~ the lower aL~ylthio radical by hydToxyl, lower aL~coxy, phenyl-lower-aL~coxy, lower aL~canoyloxy, halogen, amino, lower alkylamino, di-lower-aLtcyl-amino, mercapto, lower alkylthio, lower alkylsul~nyl, lower alkylsulfonyl, carboxyl, lower aLkoxycarbonyl, carbamoyl, N-lower-aLI~ylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, or furthermore, if X is oxygen and Z is substituted methyl, Y is hydroxyl; Z
is substituted methyl in which the substituent is selected from the series consisting of amino, mono- or di-lower-aLkylamino in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, : ~:
N-lower-aLtcylcarbamoyl, N,N-di-lower-alkylcarbamoyl andlor cyano or is preferably unsubstituted, lower aLIcanoylamino, hydroxyl, lower aL~coxy in which the lower aL~cyl radical is monosubstituted or disubstituted by hydroxyl, lower aLl~oxy, phenyl-lower-alkoxy, lower aL~anoyloxy, amino, lower aL~ylamino and/or di-lower-alkylamino or is preferably unsubstituted, lower alkanoyloxy, lower alkylthio in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower aL~canoyloxy, halogen, amino, lower aL~cylamino, di-lower-aL~ylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, N,N-di-lower-aLkylcarbarnoyl and/or cyano or is preferably unsubstituted, cyano, ureido, .. ;
1- or 3-mono-lower-aL~cylureido, hydra~no, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl or guanidino, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl; oxo, imino, lower alkylimino, hydroxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono and lower aL~cylthioimino, mainly hydroxymethyl, lower aLlcanoyloxymethyl~ such as acetoxymethyl, formyl or fur~ermore hydroxyiminomethyl; carboxyl, lower aL~oxycarbonyl or lower aLkylthiocarbonyl ~ .
(lower-alkyl-S-(~O in which the lower aL~cyl radical is substituted, in particular mono- or disubstituted, by hydroxyl, lower aL~oxy, phenyl-lower-aL~coxy, lower alkanoyloxy, halogen, arnino, lower alkylamino, di-lower-alkylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lowa alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or preferably unsubstituted; aryloxycarbonyl or aryl-lower-alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl in which lower alkyl is substituted by hydroxyl, lower aLcoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower : ~ . - . ~ . - . .
. . .
,~ .. :~ - :.
: .: - -, ; ,. .
.- ... . :

2109~7a aL~cylamino, di-lower-alkylamino, mercapto, lower allcylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-allcylcarbamoyl, N,N-di-lower-aL~ylcarbamoyl and/or cyano or is preferably unsubstituted, Cs-C7cycloallcylaminocarbonyl, N-phenyl-lower-allcylcarbamoyl, phenylcarbamoyl, hydrazinocarbonyl, hydrazinocarbonyl which is substituted on one or both nitrogen atoms by lower allcyl which is substituted by hydroxyl, lower aL~coxy, phenyl-lower-allcoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower aDcylthio, lower aDcylsulfinyl, lower aDcylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aLlcyl-carbamoyl, N,N-di-lower-allcylcarbamoyl and/or cyano or is preferably unsubstituted, by aryl or by aryl-lower-aDcyl; hydroxyarninocarbonyl, lower alkoxyaminocarbonyl in which the lower allcyl radical is substituted by hydroxyl, lower alkoxy, phenyl-lower-allcoxy, lower aUcanoyloxy, halogen, arnino, lower allcylamino, di-lower-allcylamino, mercapto, lower alkylthio, lower allcylsulfinyl, lower aUcylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aDylcarbarnoyl, N,N-di-lower-aDcylcarbarnoyl and/or cyano or is preferably unsubstituted, lower alkylene-aminocarbonyl or lower alkyleneaminocarbonyl which is interrupted by -O-, -S- or -NR'-in which R' is lower aDkyl or lower aDcanoyl, or a corresponding thio analogue of the abovementioned radica1s in which the bonding carbonyl group is replaced by thio-carbonyl; or in which Y and Z together form a bivalent radical of the formula -O-CH2-, the oxygen being bonded in the place of Y and the methylene carbon instead of Z, . ~:

where, in the abovementioned radicals, aryl is, in particular, phenyl which is unsubstituted :
or subsdtuted by one or more substituents, preferably up to 5, in particular 1 or 2, especiaUy one substituent which is mainly in the p-position or, in the case of halogen, especiaUy fluorine, up to S substituents, selected from the group comprising lower allcyl, lower aDcenyl, lower allcynyl, lower aDkylene (linked to two adjacent C atoms), ~- .
Cs-C7cycloaDcyl, phenyl-lower-aDcyl or phenyl; lower aUcyl which is substituted by -~
hydroxyl, lower aDkoxy, phenyl-lower-aDcoxy, lower aDcanoyloxy, halogen, amino, lower allcylamino, di-lower-aDcylamino, mercapto, lower aDcylthio, lower aUcylsulfinyl, lower - -alkylsulfonyl, carboxyl, l~wer alkoxycarbonyl, carbamoyl, N-lower-allcylcarbamoyl, N,N-di-lower-aDcylcarbamoyl andlor eyano; hydroxyl; lower alkoxy, halo-lower-alkoxy, phenyl-lower-aDcoxy, phenyloxy, lower aD~enyloxy, halo-lower-alkenyloxy or loweraDcynyloxy; lower alkylenedioxy (linked to two adjacent C atoms); lower alkanoyloxy, phenyl-lower-alkanoyloxy or phenylcarbonyloxy ( ^ benzoyloxy); mercapto; lower allcyl-thio, phenyl-lower-a'~kylthio, phenylthio, lower a11cylsulfinyl [-S-(=O)-lower-allcyl], phenyl-lower-aDkylsulfinyl, benzenesulfinyl, lower allcylsulfonyl [-S(02)-lower-allcyl], ., - .. ~ . . ..

:' ~"`- ' -' ' -... ~ - ,. ~ .
, ,: , , -.
. ~ -. .

21~997~

phenyl-lower-aLl~ylsulfonyl or benzenesulfonyl; halc gen, nitro, amino; lower alkylamino, C5-C7cycloalkylamino, phenyl-lower-alkylamino or phenylamino; di-lower-aL~ylamino, N-lower-aLkyl-~-phenylamino, N-lower-aLkyl-N-phenyl-lower-aLIcylamino, lower alkyleneamino; lower alkanoylamino, phenyl-lower-alkanoylamino or phenylcarbonyl-amino ( ^ benzoylamino); lower aL~anoyl, phenyl-lower-alkanoyl or phenylcarbonyl(= benzoyl); carboxyl; lower aLkoxycarbonyl; carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-alkylcarbamoyl, N-hydroxycarbarnoyl or N-phenylcarbamoyl; syano, phosphoryloxy which is substituted on the phosphorus by two radicals which, independently of one another, are selected from the series consisdng of hydroxyl, lower alkoxy and phenyl-lower-alkoxy, such as benzyloxy, or phosphoryloxy which is substituted on the phosphorus by phenylene-1,2-dioxy, sulfo (SO3H); lower aLIcoxy-sulfonyl; sulfamoyl (SO2NH2), N-lower-aL~cylsulfamoyl, N,N di-lower-aLkylsulfamoyl and N-phenylsulfamoyl; where phenyl groups in the substituents are in each case unsubstituted or substituted by lower alkyl, lower aL~coxy, hydroxyl, halogen and/or trifluoromethyl;
pharmaceutically acceptable salts thereof if salt-forming groups are present, and tautomers thereof if tautomerizable groups are present, in particular pharmaceutical compositions with these compounds as active ingredient, these compounds for use in a therapeutic method for the treatment of the human or. animal body and/or the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions for the treatment of the abovementioned diseases.

Compounds of the formula I which are very preferred are those in which Al and A2independendy of one another are hydrogen, amino-lower-alkyl, such as 2-aminoethyl or 3-aminopropyl, carbamoyl-lower-alkyl, such as 3-carbamoylpropyl, (3-lower-alkylureido)-lower-alkyl, for example (3-methylureido)-lower-alkyl, such as 3-(3-methylureido)p.ropyl, or furthermore lower aL~enyl, such as allyl, or in which Al and A2 together form 1,2-ethylene, which is unsubstituted or substituted by a substituent selected from the series consisting of amino-lower-aLkyl, such as aminomethyl, hydroxy-lower-aLkyl, such as hydroxymethyl, and hydroxyimino-lower-aLIcyl, such as hydroxyiminomethyl, in particular 1,2-ethylene, 1-hydroxymethyl-1,2-ethylene, l-aminomethyl-1,2-ethylene or 1-hydroxyiminomethyl-1,2-ethylene; Arl and Ar2 independently of one another are unsubstituted phenyl or phenyl which is substituted in the o-, m- or p-position by a radical selected from the series consisting of lower aL~cyl, such as methyl or ethyl, hydroxyl, lower aLImxy, such as methoxy, halogen, such as fluorine or iodine, carboxyl, lower aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano, or are pentafluorophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl or . I ' .:

.; . . . . . .

2~997~

1,3,5-triazin-2-yl, preferably both are the same radical, in particular phenyl or 4-fluorophenyl; X is oxygen; Y is amino, lower aLkylamino, such as methylamino, phenylamino, hydroxy-lower-aL~coxy, such as 2-hydroxyethoxy, or hydrazino, or furthermore, if Z is hydroxymethyl, lower aL~canoyloxymethyl, formyl or hydroxyiminomethyl, Y is hydroxyl; Z is hydroxymethyl, lower aL~canoyloxymethyl, such as acetoxymethyl, carboxyl, lower aL~coxycarbonyl, such as methoxycarbonyl, hydroxy-lower-aL~coxycarbonyl, such as 2-hydroxyethoxycarbonyl, carbamoyl, formyl or furthermore hydroxyiminomethyl; or in which Y and Z together form a bivalent radical of the forrnula -O-C~I2-, where the oxygen is bonded in the place of Y and the methylene carbon in the place of Z, salts thereof, if salt-forming groups exist, or tautomers thereof, in particular ring chain tautomers of those compounds of the formula I in which Y is amino or lower aLIcylamino and Z is formyl; in particular pharmaceutical compositions with these compounds as active ingredient, these compounds for use in a therapeutic method for the treatment of the human or anirnal body and/or the use of these compounds for the :
therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions for the treatment of the abovementioned diseases. :

More preferred compounds of the formula I are those in which Al and A2 in each case are ~ :
a hydrogen atom; Arl and Ar2 independendy of one anodler are unsubstituted phenyl or phenyl which is substituted in the o-, m- or p-position by a radical selected from the series consisting of lower aL~cyl, such as methyl or ethyl, hydroxyl, lower aLt~oxy, such as : ~ :
methoxy, halogen, such as fluorine or iodine, carboxyl, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano, or are pentafluorophenyl, preferably both are the same radical, in pardcular phenyl or ~fluorophenyl; X is oxygen; Y is amino; and Z is carbamoyl; salts thereof, if salt-faq~ning groups exist; or pharmaceudcal composidons with these compounds as active ingledient, these compounds for use in a therapeutic ::
method for dhe treatment of the human or animal body andlor the use of these compounds ~ .
for the therapeudc t~eatment of the human or animal body or for the preparation of .
pharmaceutical compositions for the tteatment of the abovementioned diseases.

Other compounds of the fonnula I which are more preferred are those in which Al and A2 together are unsubstituted 1,2-ethylene or 1,2-ethy1ene which is substituted by a radical selected from the series consisting of hydroxy-lower-allyl, such as hydroxymethyl, amino-lower-alkyl, such as aminomethyl, and hydroxyimino-lower-alkyl, such as hy-droxyiminomethyl, Arl and Ar2 independendy of one another are phenyl which is unsub-stdtuted or substituted in the o-, m- or p-posidon by a radical selected from the series con-.:~,.' . ' -- : 1: ' ' '' ,:~ - . . . . ~ -.; ~ : , , , . .. - . .

- 27 ~ 9 7 ~

sisting of lower aLkyl, such as methyl or ethyl, hyd~oxyl, lower aL~coxy, such as methoxy, halogen, such as fluorine or iodine, carboxyl, lower aL~coxycarbonyl, such as methoxy-carbonyl or ethoxycarbonyl, and cyano, or are pentafluorophenyl, preferably both are the same radical, in particular phenyl or 4-fluorophenyl; X is oxygen; Y is arnino or hydro-xy-lower-aL~coxy, such as 2-hydroxyethoxy; and Z is carboxyl, lower aLIcoxycarbonyl, such as methoxycarbonyl, hydroxy-lower-alkoxycarbonyl, such as 2-hydroxyethoxycarbonyl or carbamoyl; or salts thereof if salt-forming groups exist; or pharmaceutical compositions with these compounds as active ingredient, these compounds for use in a therapeutic method for the treatment of the human or animal body andlor the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of -pharmaceutical compositions for the treatment of the abovementioned diseases.

Particularly preferred cornpounds of the formula I are those in which Al and A2 indepen-dently of one another are hydrogen or subsdtuted lower aLkyl, preferably hydnogen or lower alkyl which is substituted by up to 2 radicals selected from the series consisting of amino, as in aminomethyl, -ethyl, -propyl or -butyl, mono- or di-lower-alkylamino, in which the lower aLIcyl radical is monosubsdtuted or disubstituted by hydroxyl, lower :
aL~coxy, phenyl-lower-alkoxy, lower al~anoyloxy, halogen, amino, lower aL~cylarnino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, N,N~i-lower-alkylcarbamoyl and/or cyano or, in particular, unsubstituted, such as aminomethyl, aminoethyl, aminop~opyl or aminobutyl, Cs-C7cycloalkylamino, phenyl-lower-aLIcylamino or phenylamino; lower aLIcanoylamino,.phenyl-lower-a~kanoylamino or phenylcarbonyl-amino ( - ber zoylamino); hydroxyL such as in hydroxyrnethyl, hydroxyethyl or hydroxypropyl, lower alkoxy in which the a1kyl radical is monosubstituted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-aLlcoxy, lower alkanoyloxy, halogen, arnino, lower aLtcylamino, di-lower-allcylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower aLlcylsulfonyl, carboxyl, lower aL~oxycarbonyl, carbamoyl, N-lower-aLtcylcarbamoyl, N,N-di-lower-a1kylcarbamoyl and/or cyano or is preferably unsubstituted, phenyl-lower-aL~coxy, lower alkanoyloxy, mercapto, lower alkylthio in which the lower aL~yl radical is monosubsdtuted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-aL~oxy, lower aL~canoyloxy, halogen, amino, lower aLIcylarnino, di-lower-alkylamino, mercapto, lower alkylthio, lower aL~ylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, N,N~i-lower-alkylcarbamoyl and/or cyano or is preferably unsubs~tuted, phenyl-lower-aL~ylthio, lower aL~canoylthio, carboxyl, such as in carboxyrnethyl, -ethyl or -propyl, lower aLlcoxycarbonyl, .

.. . . .
- - , ... . :
. , .
.. . ~ ~ .

2109~7~

such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, especially in methoxy-or ethoxycarbonyl-methyl, -ethyl or -propyl, or phenyl-lower-aLlcoxycarbonyl, such as benzyloxycarbonyl, cyano, carbamoyl, such as in carbamoylmethyl, carbamoylethyl or carbamoylpropyl, N-lower-aL~cylcarbamoyl, N,N-di-lower-aLlcylcarbamoyl, N-hydroxy-carbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower-aLIcylthiocarbamoyl, N,N-di-lower-aL~cylthiocarbamoyl, ureido, ureido which is substituted on one or both nitrogen atoms by lower aLlcyl, aryl or aryl-lower-aL~yl, in particular 1- or 3-mono-, 1,3- or 3,3-di-or 1,3,3-tri-lower-aLIcylureido, 1- or 3-phenylureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-aLkylureido, for example 3-lower-aLIcylureido, such as 3-methyl- or 3-ethylureido, especially in 3-methyl- or 3-ethyl-ureido-methyl, -ethyl or -propyl, thioureido, thioureido which is substituted on one or both nitrogen atoms by lower aLtcyl, - i aryl or aryl-lower-alkyl, in particular 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower-aL~cylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower-aLkylthioureido,forexample3-lower-aL~ylthioureido,suchas 1 ~:~
3-methyl- or 3-ethylthioureido, especially in 3-methyl- or 3-ethyl-thioureido-methyl, -ethyl or -propyl, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, in particular 1- or 2-mono-, 1,2- or 2,2-di- or ~ .
1 ,2,2-tri-lower-aLtcylhydrazino, 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower-a~ylhydrazino, for example 2,2~i-lower-alkylhydrazino, such as 2,2-dimethyl- or 2,2-diethylhydrazino, amidino, such as in amidinomethyl, -ethyl or -propyl, amidino which is substituted on one or both nitrogen atoms by }ower alkyl, aryl or aryl-lower-aL~yl, in particular Nl- or N2-mono-, Nl,N2- or Nl,Nl-di- or Nl,Nl,N2-tri-lower-aLtcylamidino, Nl- or N2-phenylamidino, Nl- or N2-mono-, Nl,N2-, Nl,Nl-di- or Nl,Nl,N2-triphenyl-lower-alkylamidino, for example Nl,Nl-di-lower-aL~cylamidino, such as Nl,Nl-dimethyl- or Nl,Nl-diethylamidino, guanidino, such as in guanidinomethyl, -ethyl or -propyl, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, in particular 1-, 2- or 3-mono-, 1,1-, 3,3-, 1,2-, 1,3- or :
2,3-di-, 1,1,2-, 1,1,3-, 1,2,3-, 1,3,3- or 2,3,3-tri-, 1,1,2,3-, 1,2,3,3- or 1,1,3,3-tetra- or :
1,1 ,2,3,3-penta-lower-aLIcyl- or -phenyl-lower-alkylguanidino, in particular 3,3-di-lower-aLlcylguanidino, such as 3,3-dimethylguanidino or 3,3 diethylguanidino, oxo which is not bonded to the on the carbon which is bonded to the nitrogen carrying Al or A2, such as in 2-oxopropyl or 3-oxo-n-butyl, thioxo, irnino, lower alkylimino, lower aL~anoylimino, such as acetylimino, hydroxyimino (H~N=), such as in hydroxyiminomethyl (H~N=CH-), hydroxyiminoethyl or -propyl, lower alkoxyimino, such as methoxyimino, hydrazono, such as in hydrazonomethyl, -ethyl or -propyl, N-mono- or N,N-di-lower-alkylhydrazono, N-lower-alkanoylhydrazono, such as acetylhydrazono or lower alkoxycarbonylhydrazono, .. .. . . ~ ~ . :
.. .. . ................ . . .

, ; , .. . -;,. :: , . . :

210~97~

such as tert-butoxycarbonylhydrazono, and lower aL~cylthioimino, such as methyl- or ethyl-thioimino, especially in methylthioimino- or ethyl~ioiminomethyl, -ethyl or -propyl, in particular hydrogen or linear lower aL~cyl which is terminally substituted by one of the abovementioned radicals, mainly hydrogen or amino-lower-aLkyl, such as 2-aminoethyl or 3-aminopropyl, carbamoyl-lower-alkyl, such as 3-carbamoylpropyl, or (3-lower-alkyl-ureido)-lower-alkyl, for example (3-methylureido)-lower-alkyl, such as 3-(3-methyl-ureido)-propyl; Arl and Ar2 independently of one another are aryl or heteroaryl; X is O; Y
is amino, lower alkylamino, such as methylamino, phenylamino or hydrazino, or substi-tuted lower aLkoxy, in particular hydroxy-lower-aL~coxy, such as 2-hydroxyethoxy, or else, if Z is substituted methyl, Y is hydroxyl; and Z is substituted methyl, in particular hydroxymethyl, lower alkanoyloxymethyl, such as acetoxymethyl, or formyl, carboxyl, ~ :~
esterified carboxyl, in particular lower alkoxycarbonyl, such as methoxycarbonyl, or hydroxy-lower-alkoxycarbonyl, such as 2-hydroxyethoxycarbonyl, or (furthermore) hydroxyiminomethyl; or in which Y and Z together form a bivalent radical of the formula -O-CH2- where the oxygen is bonded in the place of Y and the methylene car~on in the place of Z, where, in the abovementioned definitions, aryl is, in particular, phenyl which is unsubstituted or substituted by one or more, preferably up to 5, in particular one or two, especially one, substituent which is mainly in the p-position or, in the case of halogen, especially fluorine, up to S substituents, selected from the group consisting of lower aLt~yl, lower alkenyl, lower aL~cynyl, lower alkylene (linked to two adjacent C atoms), Cs-C7cycloaL~cyl, phenyl-lower-alkyl or phenyl; lower alkyl which is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, loweralkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl andlor cyano;
hydroxyl; lower alkoxy, halo-lower-aLkoxy, phenyl-lower-alkoxy, phenyloxy, loweralkenyloxy, halo-lower-alkenyloxy or lower alkynyloxy; lower alkylenedioxy (linked tO
two adjacent C atoms); lower alkanoyloxy, phenyl-lower-alkanoyloxy or phenylcarbonyl-oxy ( ^ benzoyloxy); mercapto; lower alkylthio, phenyl-lower-alkylthio, phenylthio, lower aLIcylsulfinyl ~-S(=O)-lower-alkyl], phenyl-lower-alkylsulfinyl, benzonesulfinyl~
lower alkylsulfonyl [-S(02) lower-alkyl~, phenyl-lower-allcylsulfonyl or benzenesulfonyl;
halogen, nitro, amino; lower alkylamino, Cs-C7cycloalkylamino, phenyl-lower-alkylamino or phenylamino; di-lower-alkylamino, N-lower-aL~yl-N-phenylamino, N-lower-alkyl-N-phenyl-lower-aLkylamino, lower alkyleneamino, lower alkanoylamino, phenyl-lower-alkanoylamino or phenylcarbonylamino ( - benzoylamino); lower aLkanoyl, ,. . . ............ . ~ ~ . . ~
, . .,.. -.. -.......... ........

, . ~ :. - ,. - , 2~ ~997~

phenyl-lower-aL~canoyl or phenylcarbonyl (= benzoyl); carboxyl; lower aLIcoxycarbonyl;
carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl; cyano, phosphoryloxy which is substituted on the phosphorus by two radicals selected independently of one another from amongst hydroxyl, lower alkoxy and phenyl-lower-aLlcoxy, such as benzyloxy, or phosphoryloxy which is substituted on the phosphorus by phenylene-1,2-dioxy, or sulfo ((SO3H); lower aL~oxysulfonyl; sulfamoyl (SO2NH2), N-lower-aLkylsulfamoyl, N,N-di-lower-allylsulfamoyl and N-phenylsulfamo-yl; where phenyl groups in the substituents are in each case unsubstituted or substituted by lower alkyl, lower aL~coxy, hydroxyl, halogen and/or trifluoromethyl; preferably unsubsti-tuted phenyl or phenyl which is substituted in the o-, m- o~ p-position by a radical selected from the series comprising lower alkyl, such as methyl or ethyl, hydroxyl, lower aLtcoxy, such as methoxy, halogen, such as fluorine or iodine, carboxyl, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano, or is pentafluorophenyl, : ::
and heteroaryl is preferably a 5- or ~membered ring which has up to 3 ring nitrogen atoms, for example imidazolyl, triazolyl, pyridyl, pyrimidinyl or triazinyl, and which is linlced via a ring carbon atom, it being possible for the ring to be unsubstituted or substituted by, for example, lower alkyl, hydroxyl, lower aL~coxy, halogen, cyano and/or :
trifluoromethyl; mainly 2-, 3- or 4^pyridyl, 2-, ~ or 5-pyrimidinyl or 1 ,3,5-triazin-2-yl; : :
and salts thereof, if salt-forming groups are present, and/or tautomers thereof, if tautomerizable radicals are present.

Very particularly preferred compounds of the formula I are those in which Al and A2 independently of one another are hydrogen or lower aL~yl which is substituted by up to 2 radicals selected from the series consisting of amino, mono- or di-lower-alkylamino in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower aLkoxy, phenyl-lower-alkoxy, lower aL~tanoyloxy, halogen, amino, lower alkylamino, - `:
di-lower-aL~ylamino, mercapto, lower aLIcylthio, lower alkylsulfinyl, lower aLkylsulfonyl, carboxyl, lower aL~oxycarbonyl, carbamoyl, N-lower-aLkylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl andlor cyano or is preferably unsubstituted, phenyl-lower-a~cylamino, phenylamino, lower aL~anoylamino, phenyl-lower-alkanoylamino, phenylcarbonylamino, hydroxyl, lower a~oxy in which the lower aLtcyl radical is monosubstituted or disubstituted by hydroxyl, lower aL~oxy, phenyl-lower-aL~coxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower allylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and~or cyano or preferably 21~9~7~

unsubstituted, phenyl-lower-alkoxy, lower aL~canoyloxy, carboxyl, lower aL~coxycarbonyl, phenyl-lower-aLkoxycarbonyl, carbarnoyl, N-lower-alkylcarbamoyl, N,N-di-lower-aL~cyl-carbamoyl, ureidoi 1- or 3-mono- or 1,3- or 3,3-di-lower-alkylureido, oxo which is not bonded on the carbon which is bonded to the nitrogen canying Al or A2, imino andhydroxyimino alO-N=), in particular hydrogen or linear lower alkyl which is substituted terminally by one of the abovementioned radicals, mainly hydrogen or amino-lower-aLkyl, such as 2-aminoethyl or 3-aminopropyl, carbamoyl-lower-aL~cyl, such as 3-carbamoyl-propyl, or (3-lower-aL~cylureido)-lower-aL~cyl, for example (3-methylureido)-lower-alkyl, such as 3-(3-methylureido)-propyl; Arl and Ar2 independently of one another are phenyl which is unsubstituted or substituted by one or two substituents, especially one substituent which is mainly in the p-position, or, in the case of halogen, especially fluorine, up to S
substituents, selected from the group consisting of lower aL~cyl, trifluoromethyl, hydroxyl, lower alkoxy, halogen, carboxyl, lower aL~oxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N,N-di-lower-aLkylcarbamoyl and cyano, or are heteroaryl selected from amongst 2-, 3- or 4pyridyl, 2-, ~ or 5-pyrimidinyl and 1,3,5-triazin-2-yl, each of which is unsubstituted or substituted by lower aL~cyI, hydroxyl, lower aL~coxy, halogen, cyano and/or trifluoromethyl; X is O; Y is amino, lower alkylamino, phenylamino, hydrazino orhydroxy-lower-alkoxy, or furthermore, if Z is hydroxymethyl, lower aL~canoyloxymethyl, formyl or hydroxyiminomethyl, Y is hydroxyl; and Z is hydroxymethyl, lower aL~canoyl-oxymethyl, formyl, carboxyl, lower aLkoxycarbonyl or hydroxy-lower-aLkoxycarbonyl, or (furthermore) is hydroxyiminomethyl; or in which Y and Z together form a bivalent radical of the formula -~CHr, where oxygen is bonded in place of Y and the methylene carbon in place of Z; and salts thereof if salt-forming groups are present, and/or tautomers thereof if tautomerizable radicals are present.

Compounds of the formula I which are most preferred from amongst all those which have previously been mentioned are those in which A1 and A2 are hydrogen; or in which one of the two radicals Al and A2 are hydrogen and the other is lower alkyl which is unsubsti-tuted or substituted by one of the subsdtuents mentioned in each case; or in which Al and A2 together are lower alkylene which is unsubstituted or substituted by one of the substi-tuents which have been mentioned in each case; while the remaining radicals are as de-fined above; pharmaceudcally acceptable salts thereof if salt-forming groups are present, and tautomers thereof if tautomerizable groups are present; or, in pardcular, pharmaceu-tical composidons with these compounds as acdve ingIedient, these compounds for use in a therapeutic method for the treatment of the human or animal body and/or the use of these compounds for the therapeutic treatment of the human or animal body or for the prepara--32- 2~937~
~ion of pharmaceutical compositions for the treatment of the abovementioned diseases.

Very important a~e also the following compounds of the formula I:
4,5-bis(4-fluoroanilino)phthalic diamide, bis(2-hydroxyethyl)-5,8-diphenyl-5,8-diaza-

-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate, 4,5-dianilinophtha1ic diamide,4,5-bis(2-iodoanilino)phthalic diamide, 4,5-bis(3-iodoanilino)phthalic diamide, 4,5-bis(4-iodoanilino)phthalic diamide, 4,5-bis(2-methoxyanilino)phthalic diamide, 4,5-bis(3-methoxyanilino)phthalic diamide, 4,5-bis(4-methoxyanilino)phthalic diamide, 4,5-bis(2-cyanoanilino)phthalic diamide, 4,5-bis(3-cyanoanilino)phthalic diamide, 4,5-bis(4-cyanoanilino)phthalic diamide, 4,5-bis(2^fluoroanilinokhthalic dia nide, 4,5-bis(3-fluoroanilino)phthalic diamide, 4,5-bis(pentafluoroanilino)phthalic diamide, 4,5-bis(4-hydroxyanilino)phthalic diarnide, 4,5?-bis(3-hydroxyanilino)phthalic diamide, 4,5-bis(2-hydroxyanilino)phthalic diamide, 4,5-bis(4ethylanilino)phthalic diamide, 4,5-bis(3-ethylanilino)phthalic diamide, 4,5-bis(2-ethylanilino)phthalic diamide, 4,5-bis(4-methylanilino)phthalic diamide, 4,5-bis(3-methylanilino)phthalic diamide, 4,5-bis(2-methylanilino)phthalic diamide, 5,8-diphenyl-5,8-diaza-~hydroxymethyl--5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide, 6-aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide, methyl 5,8-diphenyl-5,8-diaza-

-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, methyl ~amino-methyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, 5,8-bis(4-fluorophenyl)-5,8-diaza-6-hydro?xymethyl-5,6,7,8-tetrahydronaphtha-lene-2,3-dicarboxamide, ~aminomethyl-5,8-bis(4-fluorophenyl~5,8 diaza-5,6,7,8-tetra hydronaphthalene-2,3-dicarboxamide, methyl 5,8-bis(4-fluorophenyl)-5,8-diaza--6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, methyl ~amino-methyl-5,8-bis(~fluorophenyl~5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-di-carboxamidate, methyl 5,8-bis(~fluorophenyl)-5,8-diaza-~hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, methyl 5,8-bis(~fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, 5,8-bis(~fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphtha-lene-2,3-dicarboxamide, methyl 5,8-diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,798-tetrahydronaphthalene-2,3-dicarboxamidate or 5,8-diphenyl-5,8-diaza-~hydroximino-methyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide; or salts thereof if salt-forming groups are present.

Most preferred are the individual compounds of the formula I which are mentioned in the examples, the salts thereof if salt-forming groups are present, and the tautomers thereof if 2~0997~

tautomerizable groups are present, and the processes for the preparation thereof mentioned in the examples; or pharmaceutical compositions with these compounds as active ingredient, these compounds for use in a therapeutic method for the treatment of the human or anima1 body and/or the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutica1 compositions for the treatment of the abovementioned diseases.
The compounds of the formula I can be obtained by processes known per se, for example a) to prepare compounds of the formula I, in which X is O, Y is amino, substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio and Z is carboxyl, esterified carboxyl or amidated carboxyl, and in which the remaining radicals are as defined for the compounds of the formula I, or a sa1t thereof, by reacting a reactive acid derivative of a dicarboxylic acid of the formula II

Arl O
Al-N~,~C--OH

A2- N ~--C--OH
Ar2 in which Al, A2, Arl and Ar2 are as defined above, with a compound of the formula m Wl-H ~III) in which Wl is unsubstituted or substituted amino, substituted lower alkoxy or unsubsdtuted or substituted lower alkylthio, so as to introduce the radical Y, and/or with water or a compound of the formula IV
.

W2-H . (IV) in which W2 is a complementary radical suitable for the preparation of esterified carboxy1 or amidated carboxyl Z, so as to prepare the radical Z, where functiona1 groups in the star~ng materials of the formulae II, m and IV, which are not to participate in the reaction, exist, if necessary, in protec~ed form, and by detaching protecting groups which :..

210997~

are present before and/or after one of d~e additional operational measures mendoned below, or b) to prepare compounds of the fo~mula I, in which Z is hydroxymethyl or formyl and in which the remaining radicals are as defined for the compounds of the formula I, or a salt andJor tautomer thereof, by reducing a carboxylic acid o~ the fonnula V

Arl X
Al- N ~ C--Y' 2 , C--OH
Ar2 in which Y' is hydroxyl or one of the radicals Y as defined for compounds of the formula I, with the proviso that X is oxygen if Y' is hydroxyl, and in which the remaining radicals are as defined for compounds of the formula I, or a reacdve derivative of such acarboxylic acid, where funcdonal groups in the starting material of the foImula V, which are not to participate in the reacdon, exist, if necessary, in protected form, and detaching protecdng groups which are present before and/or after one of the additional operational measures mendoned, and, if desired as an additional operadonal measure, converting a compoùnd of the fo~mula I which can be obtained into a differeint compound of the formula I, and/or converting a salt which can be obtained into the free compound or into a different salt, and/or converting a free compound of the for nula I which can be obtained into a sal~
andlor separating a mixture of isomeric compounds of the formula I which can be obtained into the individual isomers.

Unless otheIwise indicated, the symbols Al, A2, Arl, Ar2, X, Y and Z given in the more detailed description of the process which follows, are in each case as defined for the compounds of the formula I.
Re a) Preparation of dicarboxvlic acid derivatives The dicarboxylic acids of dle formula II exist as reactive derivatives, it being possible for 2ln~s7~

one or both carboxyl groups to be derivasized, preferably both, for example as an activated acid derivative, as an ester derived from the free carboxyl compound, for example as a lower aL~cyl ester, as a reactive anhydride or as a reactive cyclic imide. Furthermore, the reactive derivatives can also be formed in situ. Both carboxyl groups can be reacted simultaneously (compound of the formula m equals compound of the formula IV; gives compounds of the formula I in which -(C=X)-Y equals Z) or in succession (the compound of the formula m and the compound of the formula IV are identical or different; also gives compounds in which -(C=X)-Y is defined as other than Z).

A suitable activated acid derivative is, for example, a compound of the formula IIa Arl Al- N ~ C--Z, a) A2- Nf~ ICI - Z2 Ar2 in which Zl andJor Z2 is hydroxyl or, in particular, reactively activated hydroxyl, where not more than one of the two radicals Zl and Z2 iS hydroxyl.

The free carboxylic acid ~f the foqmula I~ can be activated, for example by strong acids, such as hydrohatic acid, sulfuric acid, sulfonic acid or carboxylic acid, or acidic ion exchangers, for example by hydrochtoric acid, hydrobromic acid or hydriodic acid, sutfuric acid, an atkanecarboxylic acid which is unsubstituted or substituted for example by halogen, or by an acid of the formula II, preferably an excess of the acid of the formula IL if required white binding the water of reaction which is formed by water-binding agents, white removing the water of reaction by azeotropic distillation or with extractive esterification by acid anhydrides, in particular inorganic acid anhydrides, for example carboxytic anhydrides, such as lower-alkanecarboxytic anhydrides (with the exception of fonnic anhydride), such as acetic anhydride, or by suitable activation or coupling reagents of the type listed below, in particular also in situ. Zl andlor Z2 can atso be an azido (which can be obtained, for example, by reacting a suitable acid ester via the corresponding hydrazide and treating the latter with nitrous acid); hatogen, in particular chlorine or bromine (which can be obtained, for example, by reaction with organic acid halides, in particular oxalyl dihalides, such as oxatyl dichtoride, or, especiatly, with inorganic acid :.

:~ ' ' ' ' ' ' ' ' , : ~
.. . , : .
'' :'.' , ,. ' .. ' ' . .
. ' ~ , .

2~37~

halides, for example with acid halides of phosphorus or sulfur, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride or thionyl bromide);
cyanomethoxy, nitrophenoxy, such as 4-nitrophenoxy or 2,~dinitrophenoxy, or polyhalophenoxy, such as pentachlorophenoxy (which can be prepared, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base, or by reacting the acid with the corresponding nitrophenol or polyhalophenol in the presence of a condensing agent, such as N,N'-dicyclohexylcarbodiimide or, in particular, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline); or an asymmetric acid anhydride, which can be obtained, for example, by allowing a salt, for example an aLkali metal salt, such as the sodium or potassium salt, of an acid of the formula II or of its reactant, preferably a lower aL~canecarboxylic acid, such as acetic acid, to act on an acid halide, which is in each case complementary, in particular in the case of the reaction with a salt of a carboxylic acid of the formula II, a carboxylic halide, for example carboxylic chloIide, or in the case of the reaction of a carboxylic halide of the formula IIa, in which Zl and Z2 are halogen, for example chlorine or bromine, with a salt of a lower aLkanecarboxylic acid, in particular sodium acetate or potassium acetate. Zl and Z2 are preferably halogen, such as chlorine or bromine, and acyloxy, for example lower aL~anoyloxy, such as acetyloxy.

Compounds of the formula II can be prepared from the compounds of the formula Ilb which are mentioned below by hyd~olysis and detachment of Rl and R2, for example by hydroxy bases, such as alkali metal hydroxides or aL~caline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, in anhydrous or aqueous solvents or solvent mixtures, such as aqueous alcoholic solutions, for example methanoVwater, at elevated temperatures. for example from 40C to reflux temperature, in particular from 10C below reflux temperature up to reflux temperature. If the lower aL~cyl radicals Rl and/or R2 are branched on the bonding carbon atom, then acid hydrolysis is also possible, for exa nple using sulfuric acid or hydrohalic acids, such as hydrochloric acid. The preparation of analogues of the compounds of the formula IIb, in which carboxyl protecting groups, for example those mentioned below, are present instead of Rl and/or R2, is also possible by detachment of protecting groups. The analogues of the compounds of the formula IIb, in which carboxyl protecting groups are present instead of Rl and/or R2, are obtained for example by using hereinbelow, instead of the compounds of the formula V, analogous compounds in which a carboxyl protecting group is present instead of Rl and/or R2 (can be prepared analogously to the compounds of the fo~mula V), which are used for preparing the compounds which are analogous to the compounds of the ,' ' ' " ': ~ . - . ~ ;, ' :
$' - ' ~ : ~ ' ' . :
- :: ~ ................... .. . .
: ~: ' :

37 21a997~

fonnula IIb but have carboxyl protecting groups instead of Rl and/or R2, by means of analogous reactions, as described hereinbelow for compounds of the formula IIb themselves. By detachment of protecting groups under suitable conditions, preferably the conditions mentioned below for the detachment of protecting groups, can be used to obtain the compounds of the formula II from analogues of the compounds of the for nula IIb which have been obtained. As described above, these can be used for preparing the free compounds of the formula IIa.

Esters of compounds of the formula II are preferably those of the formula IIb, Arl Al--N ~ COORl ~IIb) Ar2 in which Arl, Ar2, Al and A2 are as defined for fo~rnula I, Rl is lower alkyl, such as methyl, and R2 is hydrogen or lower alkyl, such as methyl. The reaction of compour ds of the formula IIb, in particular the coIresponding mono- or di-lower-alkyl esters, with a compound of the formula m and/or IV to give the abovementioned compounds of the formula I is carried out in suitable solvents, in parlicular polar solvents, for example alcohols, such as methanol or ethanol, or in ethers, such as tetrahydrofuran, nitriles, such as acetonitriles or mixtures of these (preferably when amidation of the esters is carried out using amino compounds of the for nula m and/or IV), or (preferably when the transesterification is carried out using alcohols of the formula m and/or alcohols of the formula IV, it also being possible for ammonia to be present) with or, preferably, without inert solvents in a solution or melt which is liquid at the reaction temperature, with a suitable compound of the formula m andlor IV, if required under protective gas or in an autoclave, at temperatures between 30C and 240C, for example between 50C and the melting temperature of the reaction mixtuIe in question, or between 50C and the boiling point of the reaction mixture in question, for example at approximately 50 to 130C, preferably at approximately 120C, in an autoclave, in the case of amidation with amino compounds of the formula m and/or IV in the absence or, preferably, presence of a condensing agent, as mentioned above in the reaction of a compound of the formula IIa, in particular 2-ethoxy-1-ethoxycarbonyl-1,2~ihydroquinoline, in the presence or absence of bases, such as hydrogen carbonate or carbonate (can be present as the carbonate or - ~ , .

. ~

21~97~

hydrogen carbonate of an amino compound of the formula m and/or IV) at temperatures between 0 and 50C, in particular at room temperature; if the compounds of the formulae III and IV are not.identical, it is carried out for example in two consecutive reaction steps, first with one and then with the other of the compounds of the formulae m and IV (it being possible for the desired compound of the fo~mula I to be separated from any secondary products which may be present); or, in particular, by simultaneously replacing Rl and R2, if each of these is lower aL~yl and the compounds of the formulae m and IV
are identical.

The starting materials of the formula lIb are prepared, for example, by reacting a cyclohexadiene of the formula V

Me3SiO ~ ~OR
Il 11 (V) Me3SiO~~ COOR2 in which Me is methyl (alternadvely, other lower alkyl radicals might also be present) and in which Rl and R2 are as defined for compounds of the formula lIb, with an aniline of the fo~mula VI
AHN-Ar (VI) in which A is, in particular, hydrogen, unsubstituted or subsdtuted lower aL~yl,unsubsdtuted o~ subsdtuted lower alkenyl, unsubsdtuted or substituted lower alkynyl, heterocyclyl-lower-alkyl, aryl, acyl, lower alkylsulfonyl OI' a~ylsulfonyl, as.defined above -for Al or A2, and in which Ar is aryl, heteroaryl or unsubsdtuted or subsdtuted cycloaL~cyl, as defined above for Arl or Ar2, or with a dianilino-lower-alkylene compound of the -: ~:
formula VI' Arl-NH-K-NH-Ar2 (VI') in which Arl and Ar2 are as defined for compounds of the formula I, for example are phenyl, and K is substituted or, preferably, unsubstituted lower aL~cylene, as defined above for unsubstituted or substituted lower alkylene formed by Al and A2 together, with acid catalysis, for example in a lower a1kanecarboxylic acid, such as acetic acid, at ,. .. ~"~.~ . " , :

., . - , .: -, . . . .

2109~7~

temperatures between 80C and the reflux temperature, for example between 100 and approximately 140C [see Matlin, Stephen A. and Barron, Kenneth, J. Chem. Res. Synop.
8, 246-247 (199û~]. Functional groups in the stalting materials, which are not to participate in the reaction are, if necessary, protected. Protecting groups which are present can be removed in a suitable reaction step. Protecting groups, their introduction and their detachment are described below. Substituents on the radicals Ar can also be introduced after the condensation reaction by methods of conventional aromatics or heterocycle chemistry, or by enzymatic methods (for example ~hydroxylations).

The compounds of the formula V are prepared, for example, via a Diels-Alder reaction from a 2,3-bis(tri-lower-alkylsilyloxy)butadiene and a di-lower-alkyl acetylenedicarboxylate, which is also described in the abovementioned literature (Matlin et al.) and can be carried out analogously to the method described therein.

To prepare asymmetric compounds of the formula Ilb, in which Al and A2 and/or Arl and Ar2 are different, it is possible, for example, to react compounds of the formula V with two different compounds of the formula VI, for example stepwise, and to isolate the desired compounds of the formula IIb by chromatographic separation, for example over silica gel.
. ~
Furthermore, to prepare compounds of the formula IIb in which the radicals are as defined above with the exception of unsubstituted or substituted lower alkylene formed by Al and A2 together, it is possible to react for example compounds of the formula IIb which have hydrogen instead of A1 and A2, 1) with a reagent of the formula V~

W3-L (VII) in which W3 is unsubstituted or substituted lower altcyl~ unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower aL~cynyl or heterocyclyl-lower-a1~cyl, as mentioned above in the definition of A1 and/or A2, where, in the case of substituted lower alkenyl or substituted lower alkynyl, L is preferably bonded to a carbon atom from which no multiple originates, and is chosen in such a way that the reaction by substitution proceeds more rapidly than the addition to the multiple bond; and L is a nucleofugic group, preferably toluenesulfonyloxy or halogen, such as chlorine, bromine or iodine, or, ... . .. .... . . , , . . ;. . . .. - . . . .

-: . . .....
, :- - : :- . . .

.. - . . . ... . ,. ... .. -.- ~ . - .:
- ~

' ?

2~09~7~

if the radical W3 has 2 or more carbon atoms, oxa(-O-) or thia(-S-), which is bonded to two vicinal carbon atoms (forming an oxirane or thiirane, which reacts during alkylation, which is carried out, in particular, in the presence of a strong base, such as lithium diisopropylamide, sodium amide or, especially, sodium hydride, at temperatures between 50C and the boiling point of the reaction mixture, for example at 80 to 100C, in an acid amide, such as dimethylformamide, or a urea derivative, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and during subsequent hydrolysis giving a 2-hydroxy- or 2-mercapt~lower-alkyl group), or aza(-NH-), which is bonded to twovicinal carbon atoms (forming an azirane which reacts during reaction, which is carried out, in particular, in the presence of a strong base, such as lithium diisopropylamide, sodium amide or, especially, sodium hydride, at temperatures between 50C and the boiling point of the reaction mixture, for example at 80 to 100C, in an acid amide, such as dimethylformamide, or a urea derivative, such as 1,3-dimethyl-3,4,5,~tetrahydro 2(1H)-pyrimidinone (DMPU), and during subsequent hydrolysis for ning a 2-amino- ...
Iower-alkyl group), where functional groups in starting materials, which are not to participate in the reaction, are in free or protected fo¢m, and protecting groups which are present are, if necessary, detached in suitable reaction steps. The reaction is preferably carried out in the presence of a strong base, such as an alkali metal hydride, for example sodium hydride, an alkali metal amide, such æ sodium amide, or an aL~cali metal : :
di-lower-aL~ylamide, such æ lithiurn diisopropylamide, in particular sodiurn hydride or -~:
sodium amide, which can be added, for example, æ a dispersion in oil, using, relative to the molar amount of the compound of the formula IIb which has in each case a hydrogen atom in the place of Al and A2, an equirnolar amount, or an excess, of the bæe, for example once to S times the molar amount, especially once to twice the molar amount, at temperatures between room temperature and the reflux temperature of the reaction mix-ture, in particular between approximately 80 and approximately 100C, in aprotic, in parti-cular polar, solvents, such as acid amides, for example dimethylformamide, 1,3-dirnethyl-3,4,5,~tetrahydro-2(1H)-pyrimidiTIone (DMPU) or hexamethylphosphoric triamide, or mixtures of such solvents, in the presence or absence of protective gæ, such æ argon or nitrogen, where, if the aLIcali metal amides are used as bæes, ammonia which forms is removed by applying a vacuum, forexample 0. 1 to 100, in particular 0.5 to 10 torr, and/or 2) with an acid of the forrnula VII' W3~-L~ (VII') : ~. . ..................... . .
, , .

21 ~9~7~

in which W3' iS acyl, lower aL~cylsulfonyl or arylsulfonyl, as mentioned above in the definition of Al and/or A2, or with a reactive derivative thereof, where ~' is hydrogen or a radical as defined above for Zl in compounds of the forrnula IIa, in particular halogen, under conditions which are analogous to those described for the reaction of compounds of the formula II with compounds of the forrnula III and/or IV.
., If it is desired to prepare compounds of the formula I in which only one of the radicals A
and A2 is as defined above, with the exception of hydrogen, while the other radical is hydrogen, the reaction is carried out with a molar amount of the compound of lhe formula VII or VII', which corresponds preferably to 0.2 to 2 times the molar amount, for example 1 to 1.6 times the molar amount, relative to the molar amount of the compound of the fonnula IIb which has hydrogen in place of Al and A2. If it is desired to replace both hydrogen a~.oms in the compound of the formula IIb in which Al and A2 are hydrogen, by the radicals mention~d in the definition of Al and A2, with the exception of hydrogen, then it is preferred to use an excess, for example 2 to 10 tirnes, in particular approxirnately twice to three times, the amount of the compound of the formula VII or VII'.

The compounds of the formulae V, VI, VI', VII and VII' are known and are commercially available, or they can be prepared by processes known per se.

In the compounds of the forrnula VII, lower aL~yl, lower alkenyl or lower alkynyl W3 is preferably unsubsdtuted or substituted by protected amino, in particular in amino-lower-alkyl, e.g. phthalimido-lower-aL~cyl, such as phthalimidopropyl for example mono-lower-alkylamino which is protected by lower alkoxycarbonyl, such as tert-butyloxycarbonyl, and unsubstituted in the mono-lower-alkyl radical or substituted in the mono-lower-alkyl radical as above (in which case it is protected on the substituents, if required), in particular in suitably protected and substituted mono-lower-aL~cyl-amino-lower-alkyl, in di-lower-alkylamino which is unsubstituted in the two N-lower-aLIcyl radicals or substituted in the two N-lower-alkyl radicals as defined above (in which case it is protected on the substituents, if required), in particular in a suitable unsubstituted or substituted di-lower-aL~ylamino-lower-alkyl, N-protected cyclo-aL~cylamino, in particular in N-protected cycloalkylamino-lower-alkyl, N-protected phenyl-lower-aLkylamino, in particular in N-protected phenyl-lower-alkylamino-lower-aL~cyl, N-protected phenyla nino, in particular in N-protected phenylamino-lower-aLlcyl, acylamino, such as in acylamino-lower-alkyl, protected hydroxyl, in particular in hydroxy-lower-alkyl, in which the hydroxyl group is protected, lower alkoxy, . ~ . ~ . . . .

'`,:. :~ `: -.. . .

,' ~ : . : ., . : ~ : . :

-42- 21û997~

in which the terminal lower alkyl radical is unsubstituted or substituted as above (in which case the substituents are protected, if required), such as in suitably substituted protected or unsubstituted lower-aL~coxy-lower-alkyl, phenyl-lower-aLlcoxy, in particular in phenyl-lower-aLkoxy-lower-allcyl, acyloxy, in particular in acyl-lower-alkoxy-lower-alkyl, pro-tected mercapto, in particular in mercapto-lower-alkyl, in which the mercapto group is protected, lower aLkylthio, in which the terminal lower alkyl radical is unsubstituted or substituted as above (in which case the substituents are protected, if required), in particular in suitably substituted protected or unsubstituted lower alkylthio-lower-aLkyl, phenyl-lower-alkylthio, such as in phenyl-lower-alkylthio-lower-alkyl, acylthio, such as in acyl-thio-lower-alky}, protected carboxyl, such as in protected carboxy-lower-aLlcyl, esterified carboxyl, such as in esterified carboxy-lower-alkyl, cyano, such as in cyano-lowe~-aL~cyl, oxo, such as in oxo-lower-aL~cyl (if required protected by acetal for nation, for exarnple with lower alkanols, in particular with ethane-1,2-diol, where the protecting group can be detached in the desired step by hydrolysis in the presence of an acid, such as acetic acid or sulfilric acid), and/or thioxo, in particular in thioxo-lower-alkyl (if required protected by thioacetal fo~nation, forexa~nple with lower-aLIcylmercaptans, such as ethane-1,2-dithiol, it being possible for the protecting group to be detached at a suitable point in time by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid), or heterocyclyl, such as in heterocyclyl-lower-alkyl, which is protected, if required.

If, in place of a compound of the formula V~, a corresponding compound is used in which, in addition to one of the abovementioned nucleofugic radicals L a halogen atom is present on the radical W3, which here is unsubstituted or substituted lower alkyl, as defined above for Al and A2, then the corresponding unsubstituted or substituted lower aL~cenyl compound can be obtained under the abovementioned reaction conditions by detaching hydrogen halide in the presence of the base used for the reaction, for example sodium amide, which is employed, for example, in excess. Analogously, unsubstituted or substituted lower aL~ynyl radicals can be obtained from corresponding analogues of the compound of the formula VII in which two further halogen atoms are present in addidon to one of the abovementioned nucleofugic radicals L.

In compounds of the formula IIb which can be obtained, carboxyl groups, which are present in Al and/or A2 as subsdtuents, can be converted into carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl groups (also in N-aryl- and N-aryl-lower-alkylcarbamoyl groups), for example by reacdon with ammonia, a lower aLkylamine or a di-lower-aL~ylamine, hydroxylamine or phenylamine, .. ,- ~ , . . ~ . ~ .
A
k'`'`"'' ' ' ~ ' ' ' .
,,.-,. . :: ~ -21Q~7~

in the presence of a condensing agent, for example a carbodiimide, such as dicyclo-hexylcarbodiimide or a polar derivative thereof, in polar organic solvents, such as ethanol, or in the presence of an N,N'-carbonyldiazolide, such as N,N'-dicarbonylimidazole (cf.
H.A. Staab, Angew. Chem. 74, 407-423 (1962)), in inert organic solvents, for example chlorinated hydrocarbons, such as methylene chloride or chloroform, or in ethers, such as diethyl ether, tetrahydrofuran or dioxane, via the corresponding carboxylic acid azolide.
This gives the corresponding compounds of the formula IIb, in which Al and/or A2 con- ;
tains carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl or N- ~ ~ ~
phenylcarbamoyl. Corresponding thiocarbamoyl substituents in Al and A2 can be obtained -from carboxyl by conversion into a carbonyl halide, for example using an inorganic acid halide, such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride, or an organic acid halide, such as oxalyl dichloride, followed by reaction with, for example, phosphorus pentachloride, hydrogen sulfide and ammonia, or the last-mentioned amines.

In compounds of the formula Ilb, in which Al and/or A2 are, for example, a hydroxy-lower-alkyl, the hydroxyl group can be converted, by nucleophilic substitution, into a hydrazino group, a hydrazino group which is N-substituted by lower alkyl, aryl and/or aryl-lower-a1kyl, a guanidino group or a guanidino group which is N-subsdtuted by lower alkyl, aryl aod/or aryl-lower-alkyl. For exa nple, a hydroxy compound can be converted into the corresponding ester of the aromatic sulfonic acid by reaction with aromatic sulfonic acids or activated derivadves thereof, such as the corresponding aromadc sulfonyl halidcs, for cxample toluenesulfonyl halides, such as toluenesulfonyl chl~ridc, in the absence or, prcferably, prcscnce of suitable bascs, for example terdary nitrogen bases, such as triethylamine or N-methylmorpholine, and this ester can then be rcacted under the conditions of nucleophilic substitudon with hydrazine, guanidine or the appropriately substituted dcrivadves or salts thereof - it also bcing possible for protccdng groups to exist - prcferably in the prcsencc of organic solvents, for example alcohols, such as methanol, ethanol or trifluorocthanol, ketones, such as acetone, nitriles, such as acetonitrile, esters, such as ethyl acctate, ethers, such as diethyl ether, ethylene glycol dimethyl ether, tctrahydrofuran or dioxane, acid amidcs, such as dimethylformamide, bisalkanesulfines, such as dimethyl sulfoxide, aryl alcohols, such as phenol or else of water, or mixtures of these solvents, if desired in inert organic solvents (for example for the reacdon of aryl-bonded nitrogen), such as dimethylformamide or 1,3-dimethyl-3,4,5,~tetrahydro-2(1H)-pyrimidinone, with the addition of strong bases, such as sodium amide or sodium hydride. If required, protecdng groups which are present are detached. Compounds of the formula llb arc obtained in which Al andlor A2 have substituents selected from amongst 210997 ~

hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aLlcyl, aryl or aryl-lower-alkyl, or guanidino or guanidino which is substituted on one, two or all three nilrogen atoms by lower aLkyl, aryl or aryl-lower-aLkyl. Those compounds of the formula IIb which have substituents selected from amongst hydrazino and hydrazino which is substituted on the terminal N atom by lower alkyl, aryl andlor aryl-lower-aL~cyl, can also be obtained starting from a corresponding oxo compound of the formula lIb by -reacting it with nitrogen bases selected from amongst hydrazine and hydrazine which is up to disubstituted on one of the two N atoms by lower alkyl, aryl and/or aryl-lower-alkyl, as described further below for the reaction of an oxo compound with nitrogen bases, follo-wed by reduction of a corresponding imino compound which has been obtained, prefer-ably by catalytic hydrogenation using selective hydrogenation catalysts, in par~cular in the presence of palladium on solid support materials, for example on charcoal, in polar organic or organic/aqueous solvents or solvent mixtures, in particular in ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, such as lower aLt~anols, for example methanol or ethanol, or mixtures thereof, for example methanol/tetrahydrofuran mixtures, at temperatures between -20 and 60C, for example between 0 and 40C, such as at room temperature.

In compounds of the formula lIb in which Al and/or A2 are, for example, a cyano-lower-alkyl, cyano groups can be converted into carbamoyl or N-lower-a}kylcarbamoyl groups in compounds of the forsnula IIb, for example by partial hydrolysis in the sense of a Graf-Ritter reaction or via imino-lower-alkyl ester salts. The conditions of the hydrolysis of the cyano intermediate can be selected in such a way that the reaction is interrupted at the amide level. Particularly suitable for this purpose is the hydrolysis with acids, suitable acids being, for example, 80% sulfuric acid (with heating), polyphosphoric acid (at 110-150C), hydrobromic acid/glacial acetic acid (room temperature, formic acid or without solvent), HCl gas in etheric solution followed by the addidon of water or aqueous hydfochloric acid, or boron halides. N-Monoalkylated arnides of the formula Ilb can also be prepared from the corresponding nitriles by means of a Graf-Ritter reacdon. For this purpose, the nitriles are reacted, in the presence of a strong acid, preferably 85-90% sulfuric acid, or else polyphosphoric acid, formic acid, boron trifluoride or other Lewis acids, but not a1uminium chloride, with compounds which are capable of forming carbenium ions in the acidic medium, i.e., for example, with olefins or alcohols. The imino-lower-aL~yl esters of the formula IIb are obtained, for example, by an acid-catalysed addidon of alcohols onto the nitrile precursors. Alternatively, this addidon can be catalysed by bases, for example alcoholates, such as sodium methoxide. If 210~7 ~

corresponding mercaptans are employed instead of alcohols, for example in the presence of nitrogen bases, such as triethylamine or N-methylmorpholine, then the corresponding imino-lower-aLIcyl thioesters are obtained. From the imino-lower-alkyl esters, the carbamoyl derivatives are obtained, and the corresponding thiocarbamoyl derivatives are obtained from the imino-lower-alkyl thioesters in the sense of a Pinner cleavage by thermal decomposition of the imino ester salts at temperatures above approximately 80C.
The thiocarbamoyl compounds can also be obtained directly by reacting cyano groups with hydrogen sulfide analogously to the partial hydrolysis, for example in the presence of ter~iary amines, such as triethylamine.

Compounds of the formula Ilb in which Al and/or A2 are an arnidino-lower~ cyl or an amidino-lower-aL~yl which is substituted on a nitrogen atom by up to two radicals selected from amongst lower alkyl, aryl and aryl-lower-alkyl, can be prepared by reacting a corresponding imino-lower-aLkyl ester or imino-lower-alkyl thioester precursor (as acid addition salt, for example -(C--NH~OC2Hs . HCl or -C(=NH)-SC2Hs . HI, prepared from a corresponding cyano compound, as described above) with ammonia or the corresponding lower alkylamine, arylamine or aryl-lower-alkylamine. The cyano precursors can be converted into the free mono- or disubstituted amidines, for example by reaction with an alkali metal amide or by reaction with a suitable ammonium salt, for example a suitable ammonium halide. Compounds of the formula IIb in which Al and/or A2 contain amidino which is substituted on both nitrogen atoms by aryl, aTyl-lower-aLkyl or lower aLIcyl, can be prepared from the compounds (which can be prepared analogously to the procedure described above for lower alkylcarbamoyl) where, in formula IIb, carba noyl which is N-substituted by lower aLlcyl, aryl or alyl-lower-allyl is present as a substituent in place of carbamoyl in Al and/or A2, for example by reaction with POCl3 or PCls to give the corresponding imidic chloTide (for example -(C=NH-lower-allyl~Cl), which give substituted amidines of the formula IIb after reacdon with ammonia or with a primary or secondary amine (cf. Chem. Abstr. 81, 91186a (1974)).

In compounds of the formula Ilb which can be obtained, amino groups which exist as substituents in Al and/or A2, can be converted into ureido or ureido which is substituted on one or both nitrogen atoms by in each case up to one radical selected from amongst lower alkyl, aryl and aryl-lower-alkyl, by reacting compounds of the formula IIb in which, for example Al andlor A2 are amino-lower-alkyl or N-mono-lower-alkylamino-lower-aL~cyl, or in which there is, in place of one or both radicals Al and A2, an arylamin~
lower-aLIcyl and/or an aryl-lower-aL~ylamino-lower-aLIcyl (which can be prepared, for ::

-46- 210997~

example, by reacting compounds of the forrnula IIb which have hydrogen in place of Al or A2, with analogues of the compounds of the formula VII which have, in addition to the -nucleofugic group L, a further nucleofugic group, for example halogen, under conditions analogous to the reaction of compounds of the formula IIb in which there is hydrogen in place of Al and/or A2, again using analogous reaction conditions and substituting the second nucleofugic radical either by an arylarnine or by an aryl-lower-alkylamine, or from compounds of the formula IIb in which Al and/or A2 are a hydroxy-lower-aLkyl, by con-verting the hydroxyl group into a nucleofugic radical, for exarnple by treatment with an aromatic sulfonyl halide, such as toluenesulfonyl chloride, and then reacting this nucleo-fugic radical with an arylamine or aryl-lower-alkylamine under conditions analogous to the reaction of compounds of the forr,nula IIb which have hydrogen instead of Al and/or A2, with compounds of the formula VLI), with a lower aL~cyl isocyanate, aryl isocyanate or aryl-lower-aLkyl isocyanate or N-protected isocyanate (for example benzyl isocyanate), preferably in an ether, for example a cyclic ether, such as tetrahydrofuran, at prefe~red temperatures between -20 and 60C, in particular at approximately room temperature, where functional groups which are not to participate in the reaction are protected, if required, and detaching protecting groups which are present in a suitable reaction step.

Analogously, amino groups which exist as substituents in Al and/or A2 in compounds of the formula IIb, can be converted into thioureido or thioureido which is substituted on one or both nitrogen atoms by in each case up to one radical selected from amongst lower alkyl, aryl or aryl-lower-aL~cyl, by using corresponding thioisocyanates instead of the isocyanates.

Compounds of the foImula IIb in which Al and/or A2 are, for example, ureido-lower-aL~cyl which is substituted on tke terminal nitrogen by 2 radicals selected from amongst lower alkyl, aryl and aryl-lower-aL~yl, can be prepared, for example, by reacting corresponding amino-lower-alkyl compounds of the formula IIb with phosgene or analogues thereof, for example N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole (cf. H.A. Staab, Angew. Chem. 74, 4()7-423 (1962, and then reacting the resulting chlorocarbonylamino or azolidocarbonylamino compounds with ammonia which is substituted by 2 radicals se- ;
lected from amongst lower alkyl, aryl and aryl-lower-alkyl, or, vice versa, reacting the corresponding amino-lower-alkyl compounds of the formula IIb with the reaction product of ammonia which is substituted by 2 radicals selected from amongst lower allyl, aryl and aryl-lower-aL~yl, with phosgene or analogues thereof, for example the N,N'-carbonyldi-azolides, such as N,N'-carbonyldiimidazole, obtaining the analogously substituted ureido i, - . . : : - - : -47 21~7~

compounds. The reactions are preferably carried out in inert solvents, in particular chlorinated hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or acid amides, such as dimethyl formamide, at temperatures between -20C and the reflux temperatuIe, in particular between 0 and 30C.

Compounds of the forrnula IIb in which Al and/or A2 contain, for example, a thioureido-lower-aLIcyl which is substituted on the terminal nitrogen by 2 radicals selected from amongst lower aLIcyl, aTyl and aryl-lower-alkyl, can be prepared in an analogous manner, for example by reacting corresponding amino-lower-alkyl compounds of theformula IIb with thiophosgene or analogues thereof, for example N,N'-thiocarbonyldiazolides, such æ N,N'-thiocarbonyldiimidazole ~cf. H.A. Staab, Angew. Chem. ~, 407-423 (1962 and then reacting the resulting chlorothiocarbonylamino or azolidothiocarbonylamino compounds with ammonia whichis substituted by 2 radieals selected from amongst lower aLIcyl, aryl and aryl-lower-aL~cyl, or, vice versa, reacting the corresponding amino-lower-alkyl compounds of the formula IIb with the reaction product of ammonia-which is substituted by 2 radicals selected from amongst lower aLkyL aryl and aryl-lower-alkyl, with thiophosgene or analogues thereof, for example the N,N'-thioearbonyldiazolides, sueh as N,N'-thiocarbonyldiimidazole.

In eompounds of the formula IIb, a hydroxy-lower-aLtcyl Al and/or A2 ean, for example, be oxidized to give the eorresponding oxo eompound. In the ease of primary aleohols, this requires the use of selective oxidants, for example potassium ferrate (K2FeO4) in aqueous solvents and manganese dioxide in organie solvents, tert-butyl ehromate, pyridinium diehromate or, in partieular, pyridinium ehloroehTomate in inert organie solvents, for example ehlorinated hydroearbons, sueh as diehloromethane or ehloroform. The reaetion is preferably earTied out at temperatures between -20C and the reflux temperature, for example at approximately 0 to 40C In the ease of seeondary aleohols, the oxidation ean also be earried out with less seleetive oxidants, sueh as ehromie aeid, diehromate/sulfilrie ~`
aeid, diehromatelglaeial aeetie aeid, nitrie aeid, manganese dioxide, selenium dioxide or dimethyl sulfoxide in the presenee of oxalyl ehloride, in water, aqueous or organie solvents, sueh as halogenated hydroearbons, for example methylene ehloride, or earboxamides, sueh as dimethylformamide, preferably at temperatures between -50C and reflux temperature, in partieular between -10 and 50C. Compounds of the forrnula lIb are obtained in whieh the radieal Al and/or A2 have an oxo group.

Compounds of the formula IIb in whieh Al and/or A2 eontain imino, lower alkylirnino, 210997a acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono and/or N-acylhydrazono, for example as substituents in a substituted lower alkyl, can be prepared from corresponding oxo compounds of theformula IIb either after isolation of the oxo compounds or, preferably, by directly processing them in the form of the crude product, for example after partial evaporation to remove the solvent in which the oxidation (which has preferably been carried out as just described above) of a hydroxy compound to give an oxo compound.

An oxo compound can be converted into a corresponding imino derivative by reaction with nitrogen bases selected from the series consisting of ammonia, lower aIkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lower-alkylhydrazine and N-acylhydrazine. The reaction conditions correspond to the conditions customary in ~:
the reaction of carbonyl compounds with nitrogen bases, the nitrogen base being used, for example, as a salt of an acid, for example of a hydrohalic acid, such as hydrofluo~ic acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, pa~ticularly preferably hydrochloric acid, of sulfuric acid or of a hydrogen sulfate, such as an aLkali metal hydrogen sulfate, for example sodium hydrogen sulfate, of phosphoric acid, of a hydrogen phosphate or of a dihydrogen phosphate, for exarnple of an alkali metal hydrogenphosphate or dihydrogen phosphate, such as sodium hydrogen phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassiurn hydrogen phosphate, or as a salt with an organic acid, in particular with a carboxylic acid, such as a lower alkanecarboxylic acid which is unsubstituted in the lower alkyl radical or, preferably, substituted by halogen, such as fluorine or iodine, for example acetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, or with a sulfonic acid, such as a lower alkylsulfonic acid, for exarnple methanesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, or with an arylsulfonic acid, such as benzene- or naphthalenesulfonic acid or naphthalene-1,5-disulfonic acid; it also being possible for a salt of one of the abovementioned nitrogen bases with an acid to be prepared only in situ, especially from the corresponding salt of a volatile, weak acid, such as a loweralkanecarboxylic acid, for example acetic acid, or in particular carbonic acid or hydrogencarbonate, which can be replaced by a strong acid, such as sulfuric acid or, mainly, one of the abovementioned hydrohalic acids, by replacing the weak acid; the raction taking place in water (in the presence or absence of sulfactants), in an aqueous solvent mixture, such as a mixture of water with one or more alcohols, for example methanol, ethanol or isopropanol, di-lower-alkyl sulfoxides, such as dimethyl sulfoxide, or di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide, organic solvents, such ,, , , ~

., ,. .~ ~ ~ . , .
:
. . .

as alcohols, for example methanol or ethanol, di-lower-aLkyl sulfoxides, such as dimethyl sulfoxide, di-lower-alkyl-lower-aLkanoylamides, such as dimethylformamide, or insufficiently inert nitriles, such as acetonitrile, in a mixture such of organic solvents, or without solvent in a melt, preferably in an alcoholic solution, such as in methanol, ethanol or in par~cular isopropanol; preferably at temperatures between -20C and the reflux temperature of the reaction mixture in the presence of a solvent, in melts of up to 220C, in pardcular at temperatures from 0 to 50C in the presence of a solvent, especially at approximately room temperature.

Oxo compounds of the formula IIb which can be obtained in this manner can be converted into the corresponding thioxo compounds, for example by reacdon with phosphorus pentasulfide or preferably substances which replace phosphorus pentasulfide, such as Laweson's reagent (= 2,4-bis(~methoxyphenyl)-2,~dithioxo-1,3,2,4dithiaphosphetane), the reacdon being carried out in inert organic solvents, for example in a halogenated hydrocarbon, such as dichlormethane, at temperatures from 30C to reflux temperature, in particular under reflux.

Compounds of the foIrnula IIb in which Al and/or A2 have acylamino substituents, for example as subsdtuents in a subsdtuted lower alkyl, can be obtained from the corresponding imino educts by reacdng them with a free acid which contains the acyl radical, for example in the presence of condensing agents, such as, carbodiimides, for example dicyclohexylcarbodiimide or with an acdvated acid derivadve thereof, forexample a carboxylic acid halide, if appropriate in the presence of a suitable base, for example a tertiary amine, as already defined, preferably with the exclusion of moisture.

Compounds of the formu1a IIb in which Al andlor A2 have lower-aL~ylthioimino ~ ;
subsdtuents, for example on substituted lower alkyl, can preferably be prepared by reacdng suitable imino starting materials of the formula IIb with lower alkylsulfenyl ha1ides (which can be prepared, for example, from sulfenic acids with hydrogen halide or by chlorolysis, bromolysis or iodolysis of suitable organosulfur compounds, it also being -~ -;
possible for the preparadon to be ca~ied out in situ), in panicular lower alkylsulfenyl halides, such as methylsulfenyl chloride, preferably using the salts of the imino compounds or in the presence of alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, preferably in organic solvents, for example hydrocarbons, such as heptane, ethers, such as diethyl ether, dioxane or tetrahydrofuran, or carboxarnides, such as dimethylformamide, at preferred temperatures between 0C and the reflux temperature, ', `. " ~ ' ~' ' ,.' '' . .
', ~ , ;'. ' .

210997 i~

in particular between 0 and 30C.

It must be mentioned expressly at this point that compounds of the formula lIb in which Al and/or A2 are selected from amongst substituted lower aLkenyl and substituted lower aL~cynyl, in addition to, or instead of, substituted lower alkyl, even though these are not mentioned explicitly in the sections for the preparation of compounds of the fonnula IIb, can be synthesized advantageously by analogous preparation processes, as described for the compounds of the formula IIb which have substituted lower alkyl radicals.

Compounds of the formula IIb in which Al and/or A2 are, for example, heterocyclyl-lower-alkyl, can be obtained from corresponding compounds of the formula IIb in which at least one of the substituents Al and A2 is hydrogen or from corresponding analogues which have in each case hydrogen instead of Al and A2, preferably by reaction with compounds of the formula vm, :
heterocyclyl-lower-alkyl-L" (vm) in which heterocyclyl-lower-alkyl is as defined above and L" is a nucleofugic group as defined above for L in compounds of the formula VII, with nucleophilic substitution of the nucleofugic group L". `rhe reaction conditions are preferably those conditions which have been mentioned in the alkylation reaction with compounds of the for nula VII in the presence of a strong base.

To prepare compounds of the formula IIb in which Al and A2 together are unsubstituted or substituted lower aLlcylene, for example, compounds of the formula IIb which have hydrogen instead of Al and A2 are reacted with an aL~cylating reagent of the formula IX, LlB-L2 (IX) ~, .
' :
in which B is unsubstituted or substituted lower aL~ylene as bivalent radical which is bonded in each case via one of its carbon atoms (unsubstituted or substituted for example by the substituents mentioned in the definition of substituted lower alkylen fonned by A
and A2 together, preferably by one of these substituents), and in which L~ and L2 independendy of one another are a nucleofugic group, as described above for L in the definition of compounds of the formula VII, where, if required, those functional groups in the starting materials and end products which are not to panicipate in the reaction are ': ' ' :~ :~ , , :.~. ' -' ~' .:
'`''-: ~ ,, ~' :`.

210997~

protected by protecting groups which are removed in a suitable reaction step. The preferred protecting groups, their introduction and detachment has been mentioned above.

Ll is preferably a nucleofugic group, in particular sulfonyloxy which is substituted by an aliphatic or aroma~ic radical, for example met~anesulfonyloxy or p-toluenesulfonyloxy (tosyloxy), halogen, such as chlorine, bromine or iodine, or cyano, while L2, if a lower aL~cyiene radical B has two or more carbon atoms, can be oxa(-O-) or thia(-S-), which is bonded to vicinal carbon atoms (forming an oxirane or thiirane, which reacts during alkylation, which is carried out, in particular, in the presence of a strong base, such as lithium diisopropylamide, sodium amide or, especially, sodium hydride, at temperatures between 50C and the boiling point of the reaction mixture, for example at 80 to 100C, in an acid amide, such as dimethylformamide, and during subsequent hydrobsis with the formation of a 1-hydroxy- or 1-mercapto-lower-aLkylene group), or aza(-NH-), which is bonded to two vicinal carbon atoms (forming an azirane which reacts during aLlcylation, which is car ied out, in particular, in the presence of a strong base, such as lithium diisopropyla nide, sodium amide or, especially, sodiurn hydride, at temperatures between 50C and the boiling point of the reaction mixture, for example at 80 to 100C, in an acid amide, such as dimethylforrnamide, and during subsequent hydrolysis forming a 1-amino-lower-aLkylene group).

The reaction is preferably carried out under reaction conditions which have been described ~ ;~
as being preferred for the reaction of compounds of the forrnula IIb which have in each case a hydrogen atom instead of A1 and A2, with compounds of the foqmula VII.

The compound of the folmula lX is preferably employed in the equimolar amount or in an excess relative to the compound of the formula IIb which has in each case a hydrogen - ~-atom instead of A1 and A2, in particular in 1 to 3 times the molar amount, for exarnple 1 to 1.5 times the molar amount, such as, approximately, 1.2 times the molar arnount. The - -strong base employed for the reaction is preferably employed in excess relative to the compound of the formula IIb in which Al and A2 are in each case a hydrogen atom, in particular in 2 to 10 dmes the molar amount, for example 2 to 3 dmes the molar amount.

The reaction can be conducted in such a way that the nucleofugic groups Ll and L2 are substituted virtua11y si nultaneously in one operation, or the nucleofugic groups Ll and L2 can be substituted in succession in a series of batches.

',''.', ' ' ~'' ' ~ ' , ,', ' ," .' `';, ' . , ' ' : ', ' . .
.`' ~ . ! . ' ., '` ' "
' ' ' ~ ' ' ' . ' - ' : :

, , , ' ' ' ' In the compounds of the formula ~, B is preferably unsubstituted lower aLlcylene or lower alkylene which is substituted by one or more, in particular one, of the following substituents: lower aL~cyl; protected amino or amino-lower~ cyl, for example phthalimido or phthalimido-lower-aL~cyl, such as phthalimidopropyl, or mono-lower-alkylarnino or mono-lower-aLkylamino-lower-alkyl, each of which is protected, for example by lower alkoxycarbonyol, such as tert-butoxycarbonyl, and unsubsdtuted in the mono-lower-alkyl radical or subsdtuted as above (and then, if required, protected on the substituents);
di-lower-aLkylamino or di-lower-alkylamino-lower-aL~cyl, each of which is unsubstituted in both N-lower-aLkyl radicals or substituted as defined above (and then, if required, protected on the subsdtuents); N-protected cycloaL~ylamino or cycloaL~cylamino-lower-alkyl; N-protected phenyl-lower-alkylarnino or phenyl-lower-aLIcylamino-lower-aLlcyl;
N-protected phenylamino or phenylarnino-lower-alkyl; acylamino or acylarnino-lower-alkyl; hydroxyl (possible in interrnediates in addidon to the definidon of substituted lower -~
alkylene formed by Al and A2) or hydroxy-lower-alkyl, the hydroxyl group being protected; the lower aLIcoxy or lower aLkoxy-lower-alkyl, in which the terrninal lower aL~cyl radical is unsubstituted or substituted as above (in which case the substi~uents are protected, if required); phenyl-lower-alkoxy or phenyl-lower-alkoxy-lower-alkyl; acyloxy or acyloxy-lower-aL~cyl; mercapto or mercapto-lower-alkyl, in which the mercapto group is in protected form; lower alkylthio or lower alkylthio-lower-alkyl, in which the tenninal lower alkyl radical is unsubsdtuted o~ substituted as above (in which case the substituents are protected, if required); phenyl-lower-alkylthio or phenyl-lower-aLtcylthio-lower-aL~cyl;
acylthio or acylthio-lower-aLkyl; protected carboxyl or carboxy-lower-aL~cyl; esterified carboxyl or carboxy-lower-alkyl; cyano or cyano-lower-alkyl; oxo or oxo-lower-aLkyl (if necessary protected by acetal formation, fo~ example with lower aLkanols, in particular with ethane-1,2-diol, it being possible for the protecting group to be detached at a convenient stage by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid); or thioxo or thiox~lower-alkyl (if necessary protected by thioacetal forrnation, for example with lower aL~cylmercaptans, such as ethane-1,2-dithiol, it being possible for the protecdng group to be detached at a convenient stage by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid).

In the compounds of the formula IIb which can be obtained, carboxyl (in a carboxyl or carboxy-lower-alkyl group which is present in a subsdtuted lower aLkylene forrned by A
and A2 together) can be converted into carbamoyl, N-mono- or N,N-di-lower-alkyl-carbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl (also in N-aryl- and N-aryl-lower-aLkylcarbamoyl groups), for example by reaction with ammonia, a lower alkylamine :,......... ~ .,.
: . .
;. . :., : . ~

2~0~7~

or a di-lower-aLkylamine, hydroxylamine or phenylamine, or in each case a salt thereof, in the presence of a condensing agent, for example a carbodiimide, such as dicyclohexylcarbodiimide or a polar derivative thereof, in polar organic solvents, such as ethanol, or an N,N'-carbonyldiazolide, such as N,N'-dicarbonylimidazole (cf. H.A. S~aab, Angew. Chem. 74, 407-423 (1962 in inert organic solvents, for example chlorinated hydrocarbons, such as methylene chloride or chloroform, or in ethers, such as diethyl ether, tetrahydrofuran or dioxane, via the corresponding carboxylic acid azolide. This gives corresponding compounds of the formula IIb which have a substituted lower alkylene formed by Al and A2 together and subsdtuted by carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl and/or N-phenylcarbamoyl.
Corresponding thiocarbamoyl subsdtuents in substituted lower aL~cylene formed by Al and A2 together can be obtained from carboxyl by conversion to carbonyl halide, for example with inorganic acid ha1ides, such as phosphorus tlichloride, phosphorus pentachloride or thionyl chloride, or organic acid halides, such as oxalyl dichloride, followed by reaction, for example with phosphorus pentachloride, hydrogen sulfide and arnmonia, a lower alkylamine or a di-lower-alkylamine, hydroxylarnine or phenylamine.

In compounds of the formula lIb in which a substituted lower aLIcylene formed by Al and A2 together is substituted by hydroxyl and/or hydt~xy-lower-alkyl, the hydroxyl group can be converted by nucleophilic substdtutdon into a hydrazino group, a hydrazino group which ~ -is N-substituted by lower alkyl, aryl and/or aryl-lower-alkyl, or a guanidino group or guanidino gt~up which is N-subsdtuted by lower aL~cyl, aryl and/or aryl-lower-alkyl. For example, hydroxyl can be converted, by reacdon with aromadc sulfonic acids or acdvated - ~ `
derivadves thereof, such as the corresponding aromatic sulfonyl halides, for example toluenesulfonyl halides, such æ toluenesulfonyl chloride, in the absence or, preferably, presence of suitable bases, for example ter~iary nitrogen bases, such as triethylamine or N-methylmo~pholine, into hydroxyl which is esterified by the relevant aromatic sulfonic acid, and this ester can then be reacted under the conditions of a nucleophilic subsdtudon with hydrazine, guanidine, the appt~priately subsdtuted derivatives, or salts thereof, it also being possible for protecting groups to be present, preferably in the pt~sence of organic - solvents, for example alcohols, such as methanol, ethanol or trifluoroethanol, ketones, such as acetone, nitriles, such as acetonitrile, esters, such as ethyl acetate, ethers, such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, acid amides, such as dimethylformamide, bisalkanesulfines, such as dimethyl sulfoxide, aryl alcohols, such as phenol, or else water, or mixtures of these solvents, if required (for example for the reaction of aryl-bonded nitrogen) in inert organic solvents, such as dimethylformamide x-

7 . ,' ;, ' :. : ' ' . .. ' .......... ' . :."' ' . " ' ' . `' ' . ' ~'' ~''~' .: ' ' 2 1 0 9 ~ 7 a or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, with an addition of strong bases, such as sodium amide or sodium hydride. If advantageous, protecting groups which are present are detached. This gives compounds of the formula IIb in which A1 and A2together form a substituted lower aL~cylene with substituents selected from the series comprising hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aLlcyl, aryl or aryl-lower-alkyl, or guanidino or guanidino which is substituted on one, two or all three nitrogen atoms by lower aL~cyl, aryl or aryl-lower-aLIcyl.
In compounds of the formula IIb in which Al and A2 together forrn a lower alkylene which is substituted by cyano andlor cyano-lower-aLkyl, cyano groups can be converted, for example by partial hydrolysis, in the sense of a Graf-Ritter reaction, or via imino-lower-alkyl ester salts, into carbarnoyl or N-lower-aL~ylcarbamoyl groups in compounds of the formula Ilb. The conditions of the hydrolysis of the cyano intermediate can be selected in such a way that the reaction is interrupted at the amide level.
Particularly suitable for this purpose is hydrolysis with acids, suitable æids being, for example, 80% sulfuric acid (with heating), polyphosphoric acid (at 110-150C), hydrobromic acid/glacial acetic acid (room temperature, formic acid or without solvent), HCI gas in etheric soludon followed by the addition of water or aqueous hydrochloric acid, or boron halides. N-Monoalkylated amides of the formula IIb can be prepared from the corresponding nitriles with the aid of the Graf-Ritter reaction. For this purpose, the nitriles are reacted, in the presence of a strong acid, preferably 85-90% sulfillic acid, or eise polyphosphoric acid, formic acid, boron trifluoride or other Lewis acids, but not aluminium chloride, with compounds which are capable of forming carbenium ions in the acidic medium, i.e. for example with olefins or alcohols. The imino-lower-aL~cyl esters of the formula IIb are obtained, for cxample, by acid catalysed addition of alcohols onto the cyano compounds (as salts). Alternatively, this addition can be catalysed by bases, for example alcoholates, such as-sodium methoxide. If the corresponding mercaptans are employed instead of alcohols, for example in the presence of nitrogen bases, such as tliethylamine or N-methylmorpholine, the corresponding imino-lower-aL~cyl thioesters are obtained. The carbamoyl derivatives are obtained from the imino-lower-aL~yl esters, and the corresponding thiocarbamoyl derivatives from the imino-lower-aL~yl thioesters in the sense of a Pinner cleavage by thermal decomposition of the iminoester salts at temperatures of above approximately 80C. The dliocarbamoyl compounds can also be obtained direcdy by reaction of cyano groups widh hydrogen sulfide in analogy to partial hydrolysis, for example in dhe presence of terliary nitrogen bases, such as triethylamine.

2~9~7~

Compounds of the formula IIb in which a substituted lower aLkylene formed by Al and A2 together is substituted by amidino, amidino-lower-alkyl, amidino which is substituted on one nitrogen atom by up to two radicals selected from amongst lower alkyl, aryl and aryl-lower-aLlcyl, and/or amidino-lower-alkyl which is substituted on one nitrogen atom by up to two radicals selected from amongst lower aLkyl, aryl and aryl-lower-aL~yl, can be prepared by reaction of the imino-lower-aLIcyl esters or imin~lower-alkylthio esters (as acid addition salts, for example -(C=NH)~C2Hs.HCl or -C(--NH)-SC2Hs.Hl) which have been prepared as above from corresponding cyano or cyan~lower-a~yl starting materials, by carrying out the reaction with ammonia or suitable primary or secondary lower-alkyl-arnines, arylamines and/or aryl-lower-aL~cylamines. The corresponding cyano precursors can, for example, also be converted into the corresponding free, mono- or disubstituted ~;
amidines by reaction with an alkali metal amide or by reaction with a primary orsecondary ammonium salt, for example a primary or secondary ammonium halide. -;
- Compounds of the formula IIb in which Al and A2 together are a substituted lower ~ -aLkylene which has, as substituent, an amidino or amidino-lower-alkyl which is substituted ~ -on both nitrogen atoms by aryl, aryl-lower-alkyl or lower alkyl, can also be prepared from ~ -the corresponding compounds (which can be prepared as described above for lower aL~yl-carbamoyl) which have, in formula IIb, carbamoyl which is N-substituted by lower aL~yl, aryl or aryl-lower-aL~cyl, for example by reaction with POC13 or PC15 to give coqresponding imidic acid chlorides (for example -(C=NH-lower-a~yl)-CI), which, after reaction with arnmonia or with a suitable amine, give substituted amidines of the formula -(c Chem. Abstr. ~ 91186a (1974)).

In compounds of the f~ula ~ which can be obtaine~ amino radicals which may be present in amino andlor amino-lower-a~yl radicals (which are a substituent in a substituted lower a~ylene formed by Al and A2 together) can be converted into ureido, ureido-lower-a~yl or ureido or ureido-lower-a~yl, each of which is substituted on one or both nitrogen atoms by in each case up to one radical selected f~m amongst lower a~yl, aryl or aryl-lower-a~yl, by reacting corresponding amino compounds of the formula IIb in which amino radicals are present, those in which N-mono-lower-a~ylamino radicals are present or in which arylamino or aryl-lower-a~ylamino replaces amino (which can be prepared, for example, by reacting compounds of the fonnula ~b in which the substituted lower a~ylene formed by Al and A2 together contains hydroxyl, which is converted into a nucleofugic radical, for example a~matic sulfonyloxy, by esterification, for example by reacdon with an aromatic sulfonyl halide, such as toluenesulfonyl chloride, analogously to the reaction of compounds of the formula ~b which have hydrogen instead of Al and A2, -56- 2~ 0~97;~

with compounds of the formula VII with nucleophilic substitution of the nucleofugic aromatic sulfonyloxy, either with an arylamine or with an aryl-lower-alkylamine) with a lower alkyl isocyanate, aryl isocyanate or aryl-lower-aLkyl isocyanate or an N-protected isocyanate (for example benzyl isocyanate), preferably in an ether, for example a cyclic ether, such as tetrahydrofuran, at preferred temperatures between -20 and 60C, in particular approximately at room temperature, functional groups which are not toparticipate in the reaction being protected, if required, and, if desired, detachrnent of protecting groups which are present.

In compounds of the formula IIb, amino groups which are a substituent in a substituted lower aL1cylene formed by Al and A2 together can analogously be converted into thioureido or thioureido which is substituted on one or both nitrogen atoms by in each case up to one radical selected from amongst lower alkyl, aryl or aryl-lower-allyl, by using corresponding thioisocyanates instead of the isocyanates.

Compounds of the formula IIb which have, as substituent in a substituted lower alkylene formed by Al and A2 together, ureido and/or ureido-lower-aL~cyl, each of which is subsdtuted on the terminal nitrogen by up to 2 radicals selected from amongst lower aL~yl, aryl and aryl-lower-aLIcyl, can be prepared, for example, by reacdng coq~esponding amino compounds of the formula IIb with phosgene or analogues thereof, for example N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole (cf. H.A. Staab, Angew.
Chem. 74, 4(r7~23 (1962)), and reacting the resulting chlorocarbonyl - or azolidocarbonylamino compounds with ammonia which is substituted by up to 2 radicals selected from amongst lower alkyl, aryl and aryl-lower-alkyl, or vice versa, by reacdng the corresponding amino compounds of the formula IIb with the reaction product of ammonia which is subsdtuted by 2 radicals selected from amongst lower aL~cyl, aryl and aryl-lower-alkyl with phosgene or analogues thereof, for example the N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole, obtaining the analogously substituted ureido compounds. The reacdons are preferably calTied out in inert solvents, in particular chlorinated hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or acid amides, such as dimethylformarnide, at temperatures between -20C and reflux temperature, in particular between 0 and 30C. If, instead of the amino compounds of the formula IV, analogues are employed in which mono-lower-aLkylamino, arylamino and/or aryl-lower-aLIcylamino is present, it is also possible to obtain the corresponding compounds of the formula II which have up to three substituents selected from amongst lower aL~cyl, aryl andtor :~: .: . . ... .

2109~7~

aryl-lower-aLkyl on the tWO nitrogen atoms of ureido groups.

Compounds of the formula lIb which have on the terminal nitrogen (as a substituent in a substituted lower alkylene formed by Al and A2) thioureido-lower-alkyl which is substituted by 2 radicals selected from alnongst lower alkyl, aryl and aryl-lower-aL~cyl, can be prepared analogously for example by reacting suitable amino compounds of the forrnula IIb with thiophosgene or analogues thereof, for example N,N'-thiocarbonyldi-azolides, such as N,N'-thiocarbonyldiimidazole (cf. H.A. Staab, Angew. Chem. 74,407-423 (1962)) and then reacting the resulting chlorothiocarbonylamino or azolido-thiocarbonylamino compounds with ammonia which is substituted by 2 radicals selected from amongst lower aL~yl, aryl and aryl-lower-alkyl, or, vice versa, reacting the corresponding amino compounds of the formula IIb with the reaction product of ammonia which is substituted by 2 radicals selected from amongst lower aL~cyl, aryl and aryl-lower-aL~cyl with thiophosgene or analogues thereof, for example the N,N'-thiocarbonyl-diazolides, suchasN,N'-thiocarbonyldiimidazole. ~;

A compound of the formula IIb which has hydroxyl and/or hydroxy-lower-alkyl (as ~ ~
substituent in a substituted lower aLIcylene formed by Al and A2 together) can be oxidized ;- ~`
to give a corresponding oxo compound. In the case of primary alcohols, this process requires the use of selectiw oxidants, for example potassium ferrate (K2FeO4) in aqueous solvents and manganese dioxide in organic solvents, tert-butyl chromate, pyridinium dichromate or, in particular, pyridinium chlorochromate in inert organic solvents, for example chlorinated hydrocarbons, such as dichloromethane or chloroform. The reaction is preferabb carried out at temperatures between -20C and the reflux temperature, for example approximately 0 to 40C. In the case of secondary alcohols, the oxidation can also be carried out with less selective oxidants, such as chromic acid, dichromate/sulfuIic acid, dichromate/glacial acedc acid, nitric acid, manganese dioxide and selenium dioxide.
This gives compounds of the formula IIb in which a substituted lower aL~cylene which is formed by Al and A2 together is substituted by oxo.

Compounds of the formula IIb which have (in a substituted lower aLIcylene formed by Al and A2 together) one or more substituents selected from amongst imino, lower allcylimino, acylamino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-aLIcylhydrazono, N-acylhydrazono and a lower aL~cyl which is substituted by imino, lower aL~cylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono and/or N-acylhydrazono, can be prepared from correspon--58- 210~7~

ding oxo compounds of the formula IIb, either after isolation of the oxo compounds or, preferably, by directly processing them in the form of the crude product, for example after partial evaporation to remove the solvent in which the oxidation of a hydroxy compound to the oxo compound is carried out, for example as just described above.

The oxo compounds can be converted into the corresponding imino derivatives by reaction with nitrogen bases selected from amongst ammonia, lower alkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lower-alkylhydrazine and N-acylhydrazine. The reaction conditions are the conditions conventionally used for the reaction of carbonyl compounds of nitrogen bases, using, for exarnple, the nitrogen base in the form of a salt of an acid, for example of hydrohalic acid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, particularly preferably hydrochloric acid, of sulfuric acid or of a hydrogen sulfate, such as an alkali metal hydrogen sulfate, for example sodium hydrogen sulfate, of phosphoric acid, of a hydrogen phosphate or a dihydrogen phosphate, for example an alkali metal hydrogen phosphate or dihydrogen phosphate, such as sodium hydrogen phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen phosphate, or in the form of a salt with an or~anic acid, in particular with a carboxylic acid, such as a lower aLIcanecarboxylic acid which is unsubstituted in the lower aLkyl radical or substituted, preferably by halogen, such as fluorine or iodine, for example acetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, or a sulfonic acid, such as a lower alkylsulfonic acid, for example methanesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, or an arylsulfonic acid, such as benzene- or naphthalenesulfonic acid or naphthalene-1,5-disulfonic acid; it also being possible for a salt of one of the abovementioned nitrogen bases with an acid to be prepared only in situ, especially from the corresponding salt of a readily volatile weak acid, such as a lower allcanecarboxylic acid, for example acetic acid, or, in particular, carbonic acid or hydrogen carbonate, which can be replaced by a strong acid, such as sulfuric acid or, mainly, one of the abovementioned hydrohalic acids, by replacing the weak acid; the reaction taking place in water, in an aqueous solvent mixture, such as a mixture of water with one or more alcohols, for example methanol, ethanol or isopropanol, di-lower-aLkyl sulfoxides, such as dimethyl sulfoxide, or di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide, organic solvents, such as alcohols, for example methanol or ethanol, di-lower-alkyl .
sulfoxides, such as dimethyl sulfoxide, di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide, or in sufficiently inert nitriles, such as acetonitrile, a mixture of such organic solvents, or without solvents in a melt, preferably in an alcoholic solution, such as 210997~

methanol, ethanol or, in par~icular, isopropanol; preferably at temperatures between -20C
and the reflux temperature of the reaction mixture in the presence of a solvent, at melts up to 220C, in particular at temperatures from 0 to 50C, in the presence of a solvent, especially at approximately room temperature.

Compounds of the formula IIb which have acylimino and/or acylimino-lower-alkyl (as substituent in a substituted lower alkylene formed by Al and A2) can be obtained from the corresponding imino compounds by reaction with the corresponding free acids which con-tain the acyl radical, for example in the presence of condensing agents, such as carbo-diimides, for example dicyclohexylcarbodiimide, or acdvated acid derivatives thereof, for example carboxylic acid halides, if appropriate in the presence of a suitable base, for example a tertiary amine, as already defined, preferably with the exclusion of moisture.

Compounds of the formula IIb in which lower aL~cylene which is formed by Al and A2 together has lower aLkylthioimino substituents can preferably be prepared by reacting suitable imino starting materials of the formula lIb with lower aL~cylsulfenyl halides (which can be prepared, for example, from sulfenic acids with hydrogen halide or by chlorolysis, bromolysis or iodolysis of corresponding organosulfur compounds, it also being possible for the preparation to be carried out in situ), in panicular lower alkylsulfenyl halides, such as methylsulfenyl chloride, preferably using the salts of the imino compounds or in the presence of alkali metal ~ydroxides, such as sodium hydroxide or potassium hydroxide, preferably in organic solvents, for example hydrocarbons, such as heptane, e~ers, such as diethyl ether, dioxane or tetrahydrofuran, or carboxamides, such as dimethylformamide, at preferred temperatures between 0C and the reflux temperature, in particular between 0 and 30C

The compounds of the formula Ilb which can be obtained give the compounds of theformula II preferably by hydrolysis, for example in an acidic or aL~caline medium. The hydrolysis of the compound of the formula lIb is preferably carried out in an aqueous alcoholic solution of a hydroxy base, for example a soludon of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in a mixture of water and ethanol or methanol, at preferred temperatures from 0C to the reflux temperature of the reaction mixture in question, in particular between approximately 40C and the reflux temperature.
It is particularly preferred to carry out the reaction with the exclusion of oxygen, for example under protective gas, such as argon or nitrogen.

,, !, .,,,,, ' ~ ~ ' ' ' ' 21~997~

The Temaining starting materials are known, or commercially available or can be prepared by known processes.

Anhydrides of dicarboxylic acids of the formula II aTe prefeTably internal anhydrides of the formula IIc Al--N~,~
A2--N J~ (IIc) in which Al, A2, Arl and Ar2 are as defined in formula I. These anhydrides are suitable in the reaction with compounds of the foq~nula m in particular for the pTeparation of compounds of the formula I in which X is O, Y is amino, subsdtuted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio and Z is caTboxyl. The reaction is preferably carried out in inert solvents, for example ethers, for example di-lower-alkyl edhers, such as diethyl edher, or cyclic ethers, such as dioxane or tetrahydrofuranj at temperatures between 0C and reflux temperature, preferably between 20 and 60C, for example at approximately 50C

Internal anhydrides of the formula Ilc can preferably be prepared i~om a fIee dicarboxylic acid of the formula II by reaction with acid anhydrides of dhe formula ~

R3-(C=O~(C=O)-R3' (X) .

in which R3 and R3' independendy of one anodher are hydrogen or lower alkyl, but the two radicals must not simultaneously be hydrogen, in particular acetic anhydride.

Cyclic imides of dicarboxylic acids of the formula II are preferably dhose of dhe formula I[d - -:- ,. - ~ - , . .

~, :.:. . , : . . . :
.:: . . .. . . .

2109~7a Arl O

~¢N--H (IId) Ar2 ~

in which Al, A2, Arl and Ar2 are as defined in formula I. These compounds aIe especially ~ -suitable for the preparation of compounds of the forrnula I in which X is O, Y is amino and Z is free or esterified carboxyl (reaction with compounds of the formula IV in which W2 is a complementary radical suitable for the preparation of esterified carboxyl Z, or with water); or in which X is O, Y is subsdtuted lower aL~oxy or substituted lower alkylthio and Z is carbamoyl (reaction with compounds of the formula m in which Wl is substituted lower aLkoxy or substituted lower alkylthio). The reaction is preferably carned out in the presence or, if the compound of the formula m or IV employed is liquid at the reaction temperature, in the absence of aprotic solvents, such as ethers, for example diethyl ether, dioxane or tetrahydrofuran, at elevated temperatures, for example between ~ -50C and reflux temperature, in particular between 50 and 65C. If water is employed (hydrolysis), the reaction is preferably carried out in aqueous solvents, for example aqueous ethers, such as water/dioxane or water/tetrahydrofuran, at temperatures between 0 and 50C, in particular at approximately room temperature, in the presence of a hydroxy base, for example an aL~cali metal hydroxide, such as sodium hydroxide or potassium hydroxide.

The compounds of the formula IId can be prepared by processes known per se, for example by reacting a compound of the formula nb in which Rl and R2 are lower aLkyl, such as methyl, with ammonia The reaction is analogous to the aminolysis, known per se, of phthalic diesters with ammonia and proceeds in most cases only at high temperature.
The dimethyl ester is preferably used. Particularly prefelred is the reaction in a solvent, in ~ ~
particular a high-boiling alcohol, for example a diol, such as ethylene glycol, at - - ~-temperatures from 100 to 150C, for example approximately 120~C, with ammonia being passed through the mixture; or the reaction of the lower alkyl esters at the same temperatures in the presence of ammonia and solvents, for example an alcohol, for :
example a lower aLlcanol, such as methanol or ethanol, or furthermore in the absence of a solvent, in an autoclave under elevated pressure.
, -, ~ .~:

2109~7 t) In compounds of the formula III, Wl is unsubstituted or substituted arnino, substituted lower aL~coxy or unsubstituted or substituted lower alkylthio, as defined for the corresponding radicals Y.

In compounds of the formula IV, a complementary radical which is suitable for the preparation of esterified carboxyl or amidated carboxyl Z is a radical which is formed from the corresponding radical which is defined above for Z by removal of the bonding carbonyl group, for exarnple lower alkoxy or lower aL~cylthio, in which the lower aL~yl radical is unsubstituted or, in particular, mono- or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower-alkoxy, lower aL~canoyloxy, halogen, amino, lower aL~cylamino, di-lower-aLIcylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower aL~cylsulfonyl, carboxyl, lower aL~oxycarbonyl, cyano, carbamoyl, N-lower-aL~ylcarbamoyl, N,N-di-lower-aLIcyl-carbamoyl and/or cyano; or aryloxy, arylthio aryl-lower-aLIcoxy or aryl-lower-alkylthio, in which aryl is as defined above; amino; N-mono- or N,N-di-lower-alkylamino, in which lower aL~cyl is unsubstituted or substituted by hydroxyl, lower aL~oxy, phenyl-lower-aL~coxy, lower aLkanoyloxy, halogen, amino, lower aL1cylamino, di-lower-alkyl-amino, mercapto, lower aL~ylthio, lower alkylsulfinyl, lower a1kylsulfonyl, carboxyl, lower a~coxycarbonyl, carbamoyl. N-lower-aL~ylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl and/or cyano, or N-cycloalkylamino, N-phenyl-lower-alkylamino, phenylamino, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower aL~cyl which is unsubstituted or substituted by hydroxyl, lower aLkoxy, phenyl-lower-aLkoxy, lower aLlcanoyloxy, halogen, amino, lower alkylamino, di-lower-aL~cylamino, mercapto, lower aL~ylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aLkoxycarbonyl, carbamoyl, N-lower-aL~cylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, or aryl or aTyl-lower-alkyl, aryl being, in particular, unsubsdtuted phenyl or phenyl which is substituted as above, hydroxyamino, lower alkoxyamino in which the lower alkyl radical is unsubstituted or substituted by hydroxyl, lower alkoxy, phenyl-lower-aL~coxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-aL~cylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower-aL~ylcarbamoyl, N,N-di-lower-aL~cylcarbamoyl andlor cyano, or lower aL~cyleneamino or lower aL~cyleneamino which is interrupted by -O-, -S- or -NR'- (as defined above), in which a ring carbon atom is replaced by the hetero group in question.

As mentioned, derivatives of carboxylic acids of the formula lI or derivatives thereof which have at least one free carboxyl group, which are used as acylaling agents, can also be formed in situ. For example, N,N'-disubsdtuted amidino esters can be formed in situ by .: ' . . . ' , .
'~ ':' ' : ' . ' 2109~7~

reacting the mixture of the starting material of the formula III or IV and the acid of the formula II or the formula lIb, in which one of the radicals Zl or Z2 is hydroxyl, which is used as acylating agent, in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N'-cyclohexylcarbodiimide, for exarnple in the presence of a suitable base, such as triethylamine. Furthermore, amino esters or amido esters of the acids used as acylating agents can be formed in the presence of the starting material of the formula III or IV to be acylated by reacting the mixture of the acid and amino stardng mateAals in question in the presence of an N,N'~isubsdtuted carbodiimide, for example N,N'-dicyclo-hexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, if appropAate in the presence of a suitable base, for example ~dimethylarninopyridine. Furtherrnore, acdYatdon in situ can be achieved by reactdon with N,N,N',N'-tetraalkyluronium compounds, such as O-benzotriazol-l-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate. Fina11y, phosphoric anhydrides of the carboxylic acids of the formula II can be prepared in Sihl by reacting an alkylphosphoric amide, such as hexamethylphosphoric triamide, in the presence of a sulfonic anhydride, such as ~toluenesulfonic anhydride, vith a sale, such as a tetrafluoroborate, for example sodium tetrafluoroborate, or with another derivative of hexamethylphosphoric triamide, such as benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluoride, preferably in the presence of N-hydroxybenzotriazole.

These reactions and the remaining reactions which are mentioned in the description of the preparation processes can be carried out under reaction conditions known per se, at conventional temperatures, in the presence or absence of inert solvents or diluents, for example in acid amides, for example carboxamides, such as dimethylformamide, dimethylacetamide or l,3~imethyl-3,4,5,~tetrahydro-2(lH)-pyrimidinone (DMPU), oramides of inorganic acids, such as hexamethylphosphoric triamide, ethers, for example ~ -cyclic ethers, such as tetrahyd~ofuran or dioxane, orin acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower-alkanes, for example methylene chloride or chloroform, ketones, such as acetone, nitriles, such as acetonitrile, acid anhydrides, such as acetic anhydride, esters, such as ethyl acetate, -bisalkanesulfines, such as dimethyl sulfoxide, nitrogen heterocycles, such as pyridine, or mixtures of these solvents, in particular in anhydrous solvents or solvent mixtures, where the solvents which are suitable in each case for the abovementioned reactions can be selected, if advantageous, using salts of the compounds employed, in particular metal salts of carboxylic acids which are employed, such as alkali metal salts or alkaline earth metal salts, for example sodium or potassium salts, in the absence or presence of catalysts, -.; , , : .
i , . : , t ~
;~ ~ : . . ...
,~: . ,: .
~, , . -21~9~7~

condensing agents or neutralizing agents, and, depending on the nature of the reaction and/or the reactants, under atmospheric pressure or in a sçaled vessel, under ambient pressure or furthermore under elevated pressure, for example at the pressure which is formed in the reaction mixture under the reaction conditions in a sealed tube, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere. Preferred reaction conditions are those which are mentioned specifically; very preferred reaction conditions are those analogous to the reaction conditions mentioned in the examples. The acylating agent itself, for example a carboxylic acid halide or a carboxylic anhydride, can also act as a solvent. The course of the reaction is advantageously monitored by means of conventional analytical methods, in particular thin-layer chromatography.

All starting materials which have been mentioned (i.e. starting substances or intermediates) can be protected, if required, on functional groups which are not to participate in the reactions described, and protecting groups which are present are detached at a suitable point in time. Resulting compounds of the formula I which have protecting groups can be converted into the free compounds of the fo~nula I by means of ~ -detachment of the protecting groups, or they can be subjected to the additional operational measures mentioned below. ~ i The protecting groups for functional groups in starting materials whose reaction is to be avoided, in particular carboxyl, amino, hydroxyl, mercapto and sulfo groups, include, in pardcular, those protecdng groups (convendonal protecdng groups) which are convendonally used in the synthesis of pepdde compounds, but also of cephalosporins and penicillins, nucleic acid derivadves and sugars. These protecdng groups may already be present in the precursors and their pulpose is to protect the funcdonal groups in question against undesired secondary reacdons such as, inter alia, acyladons, etherifications, esterificadons, oxidadons and solvobsis. In certain cases, the protecdng groups can, moreover, bring about a selecdve, for example stereoselecdve, course of reacdons. It is characterisdc of protecdng groups that they are easily detachable, i.e. without undesired secondary reacdons, for example solvolydcally, by reducdon, photolytically or else enzymadcally, for example also under physiological condidons. It is also characteristic of protecdng groups that they are absent in the end substances.

The protecdon of functional groups by such protecdng groups, the protecdng groups themselves and their detachment reacdons are described, for example, in standardpublicadons, such as J. F. W. McOmie, "Protecdng groups in Organic Chemistry", Plenum ... . . ~ ~ . - . , . - .
j . .. - . - , ~ : : - . -" : -:: -~ .,..... . .. , : :
.,. ;. ., ~ . , ,.,. : . . ..
.. :~ ~ . : . :

: . :-. , ,. . ~

21~937 .~

F'ress, London und New York 1973, in Th. W. Greene, "E~rotecting groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides"; Volume 3 (E. Gross and J.
Meienhofer, Ed~)j Academic Press, London and New York 1981, in "Methoden der organischen Chemie" [Methods in Organic Chemistry], HoubenWeyl, 4th Edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" [Amino Acids, Peptides, Proteins], Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" [Carbohydrate Chemistry:
Monosaccharides and Derivatives], Georg Thieme Verlag, Stuttgart 1974.

For example, a carboxyl group is protected in the form of an ester group which is selectively detachable under mild conditions. A carboxyl group which is protected in esterified form is esterified mainly by a lower alkyl group which is preferably branched in the l-posidon of the lower alkyl group or subsdtuted in the 1- or 2-posidon of the lower alkyl group by suitable subsdtuents.

A protected carboxyl group which is esterified by a lower aL~cyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

A protected carboxyl group which is esterified by a lower alkyl group which is branched ~ - -in the l-position of the lower alkyl group is, for example, tert-lower-aLt~oxycarbonyl, for example tert-butoxycarbonyl.
. .~
A protected carboxyl group which is esterified by a lower alkyl group which is substituted in the 1- or 2-position of the lower aL~cyl group by suitable substituents is, for example, arylmethoxycarbonyl having one or two aIyl radicals, in which aryl is phenyl which is unsubsdtuted or mono-, di- or trisubstdtuted, for example by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hyd~oxyl, halogen, for example chlorine and/or nitlo, for example benzyloxycarbonyl, benzyloxycarbonyl which is substituted by the abovementioned substituents, for example ~nitrobenzyloxycarbonyl or ~methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl or diphenylmethoxycarbonyl which is subsdtuted by the abovemendoned substituents, for example di(4-methoxyphenyl)methoxycarbonyl, furthermore carboxyl which is esterified by a lower alkyl group, where the lower alkyl group is subsdtuted in the 1- or 2-posidon by suitable substituents, such as l-lower-alkoxy-lower-alkoxycarbonyl, for example methoxymethoxycarbonyl, l-methoxyethoxycarbonyl or l-ethoxyethoxycarbonyl, j.. , - ~ - : , ~:
~,:.,~ . : :,. , y: . :.. .
,~ "''~ ' " " : :

2~09~7~

l-lower-aLkyltnio-lower-aLI~oxycarbonyl, for example l-methylthiomethoxycarbonyl or l-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, in whicn the aroyl group is unsubstituted bcnzoyl or benzoyl which is substituted for example by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower-alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoet'noxycarbonyl, and 2-(trisubstituted silyl)-lower-aL~coxycarbonyl, in which the substituents independently of one anotner are in each case an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical which is unsubstituted or substituted for example by lower aLI~yl, lower aLkoxy, aryl, halogen and/or nitro, for exarnple lower aL~cyl, phenyl-lower-aLIcyl, cycloalkyl or phenyl, each of which is unsubstituted or substituted as above, for example 2-~i-lower-aLI~ylsilyl-lower-aL~coxycarbonyl, such as 2-tri-lower-aLlcylsilylethoxycarbonyl, for example 2-t~imethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.
' A carboxyl group is also protected in the form of an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri-lower-alkylsilyloxycarbonyl group, for example trirnethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group ;
can also bc substituted by two lower alkyl groups, for example methyl groups, and one amino or carboxyl group of a second molecule of the formula I. Compounds with such protecting groups can bc prepa~ed, for cxample, with suitable halosilanes, such as dimethylchlorosilane, as silylating agents.

A carboxyl group is also protected in the form of an internal ester with a hydroxyl group which is at a suitable distance in the molecule, for example in the ~-position relative to the carboxyl group, i.e. in the fonn of a lactone, preferably a~-lactone.

A protected carboxyl group is, preferably, tert-lower-alkoxycarbonyl, for example tert-but-oxycarbonyl, benzyloxycarbonyl, ~nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a carboxyl group which is protected in the form of a lactone, in particular a l~-lactone.

Protected carboxyl is set ree by conventional processes, for example those mentioned in the abovementioned standard publications on protecting groups.

For example, protected carboxyl, for example tert-lower-aL~oxycarbonyl, lower alkoxycarbonyl which is substituted in the 2-position by a trisubstituted silyl group or in . . i ~ :

.. ~ , . . ..
. : ~:; , .
,.: : .
:. ~- - : . :

-67- 21~97~

the 1-position by lower alkoxy or lower aLIcylthio, or substituted or unsubstituted diphenylmethoxycarbonyl, can be converted into free carboxyl by treatment with asuitable acid, su~h as formic acid, hydrochloric acid or trifluoroacetic acid, if appropriate with the addition of a nucleophilic compound, such as phenol or anisole. Substituted or unsubstituted benzyloxycarbonyl can be set free for example by means of hydrogenolysis, i.e. treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as4-nitrobenzyloxycarbonyl, can also be converted into free carboxyl by reduction, for example by treatment with an alka}i metal dithionite, such as sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(II) salt, for example chromium(II) chloride, conventionally in the presence of a hydrogen donor which, together with the metal, can produce nascent hydrogen, such as an acid, mainly a suitable carboxylic add, such as a lower alkanecarboxylic acid which is unsubstituted or -substituted, for example by hydroxyl, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic add, mandelic add, ~chloromandelic acid or ~artaric acid, or an alcohol or thiol, preferably with an addition of water. 2-Halo-lower-aL~coxycarbonyl (if -appropriate after conversion of a 2-bromo-lower-aL~coxycarbonyl group into a corresponding 2-iodo-lower-aL~coxycarbonyl group) or aroylmethoxycarbonyl can also be converted into fiee carboxyl by treatment with a redudng metal or metal salt, as described above. Aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagcnt, such as sodium thiophenolate or sodium iodide.
2-~risubstituted silyl)-lower-aLIcoxycarbonyl, such as 2-tri-lower-alkylsilyl-lower-aL~oxycarbonyl, can also be converted into free carboxyl by treatment with a salt of hydrofluoric acid which provides the fluo~ide anion, such as an aLcali metal fluoride, for example sodium fluoride or potassium fluoride, if appropriate in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower-alkylammonium fluoride or tri-lower-aL~cylaryl-lower-aL~cylammonium fluoride, for example tetraethylammonium fluo~ide or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide. Carboxyl which is protected in the form of an organic silyloxycarbonyl, such as tri-lower-alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be set free solvolytically in the customary manner, for example by treatment with water, an alcohol or acid, or, moreover, fluoride, as described above. Esterified carboxyl can also be set free enzymatically, for example by esterases or suitable peptidases, for example esterified arginine or Iysine, such as Iysine methyl ester, by means of trypsin. Carboxyl which is protected in the form of an internal ester, such as a : - ,. .
:.' .. ~

2 ~ ~ 9 9 7 ~

~-lactone, can be set free by hydrolysis in the presence of a hydroxide-containing base, such as aL~aline earth metal hydroxide or, in particular, an alkali metal hydroxide, for example NaOH, KOH or LiOH, in particular LiOH, the protected hydroxyl group in question simultaneously being set free.

A protected amino group is protected by an amino protecting group, for example in the form of an acylarnino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-aLIc- l-enylamino or silylamino group, or in the form of an azido group.

Acyl in an acylamino group is, for example, the acyl radical o~ an organic carboxylic acid having for example up to 18 carbon atoms, in particular of a lower allcanecarboxylic acid which is unsubstituted or substituted, for example by halogen or aryl, or of a benzoic acid which is unsubstituted or substituted, for example by halogen, lower aL~coxy or nitro, or, preferably, of a carbonic monoester. Such acyl groups are, preferably, lower aLlcanoyl, such as formyl, aceyl, propionyl or pivaloyl, halo-lower-aL~canoyl, for example 2-haloaceyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-triiluoro- or 2,2,2-trichloroacetyl, benzoyl which is unsubstituted or subsdtuted, for example by halogen, lower aLIcoxy or nitro, such as benzoyl, ~chlorobenzoyl, 4methoxybenzoyl or ~nitrobenzoyl, lower alkoxycarbonyl, lower alkoxycarbonyl which is preferably branched in the l-position of the lowa alkyl radical or subsdtuted in a suitable manner in the 1- or 2-positdon, for example tat-lower-alkoxycarbonyl, such as tat-butoxycarbonyl, arylmethoxycarbonyl having one, two or three aryl radica1s which are phenyl which is unsubstituted or mono- or polysubstituted, for example by lowa alkyl, in particular tert-lower aLIcyl, such as tert-buyl, lower alkoxy, such as methoxy, hydroxyl, halogen, such as chlorine, andlor nitro, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy-carbonyl, 9-fluorenylmethoxycarbonyl or di(~methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably benzoyl which is unsubstituted or substituted, for example by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower-aL~coxycarbonyl, for example 2,2,2-trichloroethoxy-carbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(trisubstituted silyl~
lower-aL~coxycarbonyl, for example 2-tri-lower-alkylsilyl-lower-alkoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl, or tri-arylsilyl-lower-alkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.

The aryl radicals in an arylmethylamino group, for example a mono-, di- or, in particular, triarylmethylamino group, are, in particular, phenyl radicals which are unsubstituted or : , . .

2109~7~

substituted. Examples of such groups are benzylamino, diphenylmethylamino or, inparticular, tritylamino.

The mercapto group in an etherified mercaptoamino group exists mainly in the form of substituted alylthio or aryl-lower-allylthio, in which aryl is, for example, phenyl which is unsubstituted or substituted, for example by lower alkyl, such as methyl or tert-butyl, lower aL~coxy, such as methoxy, halogen, such as chlorine and/or nitro, for example ~nitrophenylthio.

Acyl in a 2-acyl-lower-aL~c-l-enyl radical which can be used as amino protecting group is, for example, the corresponding radical of a lower aL~anecarboxylic acid, a benzoic acid which is unsubstituted oq substituted, for example by lower alkyl, such as methyl or - ~
tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine and/or nitro, or, in ~ ~-particular, of a carbonic monoester, such as a lower-aL~cyl carbonate. Suitable protecting groups are mainly 1-lower-alkanoyl-lower-aL~c- l-en-2-yl, for example 1-lower-alkanoyl-prop-1-en-2-yl, such as 1-acetylprop-1-en-2-yl, or lower aL~oxycarbonyl-lower-aLk-1-en-2-yl, for example lower alkoxycarbonylprop-1-en-2-yl, such as 1-ethoxycarbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a tri-lower-alkylsilylamino group, for example trimethylsilylamino or tert-butyldimethylsilylamino. The silicon atom of the silylamino group can also be substituted by two lower allcyl groups only, for example methyl groups, and the amino group or carboxyl group of a second molecule of the formula I. Compounds with such protecting groups can be prepared, for example, with the correspondingchlorosilanes, such as dimethylchlorosilane, as silylating agents.

An amino group can also be protected by conversion into the protonated form; suitable anions are mainly those of strong inorganic acids, such as of sulfuric acid, phosphoric acid or hydrohalic acids for example the chlodde or bromide anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino protecting groups are lower alkoxycarbonyl, phenyl-lower-alkoxy-carbonyl, fluorenyl-lower-aL~oxycarbonyl, 2-lower-alkanoyl-lower-alk-1-en-2-yl or lower-aL~oxycarbonyl-lower-alk-1-en-2-yl, parlicularly preferably tert-butoxycarbonyl or benzyloxycarbonyl .

-21~9~75 Other preferred amino protecting groups are bivalent amino protecting groups, such as mono- or disubstituted methylidene groups, such as l-lower-aLkoxy (for example methoxy or ethoxy)-lower-alkylidene (for example ethylidene or l-n-butylidene), for example =C(CH3)(0C2Hs), furthermore for example =C(CH3)2 or =CH-phenyl, and, in particular, bisacyl radicals, for example the phthalyl radical, which together with the nitrogen atom to be protected forms a lH-isoindole-1,3(2H)-dione (phthalimido group).

A protected amino group is set free in a variety of ways, which are hlown per se and depend on the nature of the protecting g,~ups, preferably by means of solvolysis or reduction. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, can be cleaved in the presence of acids, for example mineral acids, for exarnple hydrogen halide, such as hydrogen chloride or hydrogen bromide, in particular hyd ngen bromide, or of sulfuric or phosphoric acid, preferably hydrogen chloride, in polar solvents, such as water, or a carboxylic acid, such as acetic acid, or ethers, p;eferably cyclic ethers, such as dioxane, 2-halo-lower-aL~coxycarbQnylarnino (if required after conversion of a 2-bromo-lower-alkoxycarbonylamino group into a 2-iodo-lower-aL~oxycarbonylamino group), aroyl-methoxycarbonylamino or ~nitrobenzyloxycarbQnylarninQ for example by treatment with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodiurn thiophenolate, and ~nitrobenzyloxycarbonylarnino also by treatment with an aL~cali metal dithionite, for example sodium dithionite. Diphenylmethoxycarbonylamino, tert-lower-aLIcoxycarbonyl-amino or 2-(trisubsdtuted silyl)-lower-alkoxycarbonylamino, such as 2-tri-lower-alkylsilyl-lower-alkoxycarbonyla nino, each of which is subsdtuted or unsubstdtuted, can be cleaved by treatment with a suitable acid, for example formic acid or trifluo~oacedc acid, su~stituted or unsubstituted benzyloxycarbonylamino, for example by means of hydrogenolysis, i.e. treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, preferably in polar solvents, such as di-lower-al.~cyl-lower-aL~canoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, or alcohols, such as methanol, ethanol or propanol, methanol being pardcularly preferred, subsdtuted or unsubsdtuted triarylmethylamino or formylamino, for example by treatment with an acid, such as minera1 acid, for example hydrochloric acid, or an organic acid, for example formic acid, acedc acid or trifluoroacedc acid, in the presence or absence of water, and an amino group protected in the form of silylamino can be set free for example by means of hydrolysis or alcoholysis.
An amino group which is protected by 2-haloacetyl, for example 2-chloroacetyl, can be set -71- 21n997a free by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an aLl~ali metal thiolate of the thiourea, followed by solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product. An amino group protected by 2-(trisubstituted silyl)-lower-aL~coxycarbonyl, such as 2-tri-lower-aL~ylsilyl-lower-aL'coxy-carbonyl, can also be converted into the free amino group by treatment with a salt of hydrofluoric acid which is a fluoride-anion donor, as mentioned above in connection with the setting free of an analogously protected carboxyl group. Equally, silyl, such as -trimethylsilyl, which is bonded directly to a heteroatom, such as nitrogen, can be detached by means of fluoride ions. The phthalyl group can be detached for example by means of hydrazine hydrate or by means of an acid, for example a mineral acid, such as hydrochloric acid, or an organic acid, such as acetic acid, in the presence or absence of organic solvents, for example methanol or tetrahydrofuran.

Amino which is protected in the form of an azido group is converted into free arnino for example by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, paUadium or Raney nickel, by reduction by means of mercapto compounds, such as dithiotbreitol or mercaptoethanol, or else by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or else in water and a mixture of water an an organic solvent, such as an alcohol or dioxane, at approximately 20C to 25C, or else with cooling or heating.

A hydroxyl group can be protected for example by an acyl gTWp, for example loweralkanoyl, such as acetyl or 2,2-dichloroacetyl, which is unsubstituted or substituted by halogen, such as chlorine, or, in panicular, by an acyl radical of a carbonic monoester which has been mentioned for protected amino groups. A preferred hydroxyl protecting group is, for example, 2,2,2^trichloroethoxycarbonyl, 4nitrobenzyloxycarbonyl, diphenyl-metboxycarbonyl or triphenylmethoxycarbonyl. A hydroxyl group can furthermore beprotected by tri-lower-aL~ylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, an easily detachable etherifying group, for example an alkyl group, such as tert-lower-aL~cyl, for example tert-butyl, an oxa or thiaaliphadc or cycloaliphadc, in pardcular 2-oxa- or 2-thiaaliphatic or -cycloaliphadc, hydrocarbon radical, for example l-lower-alkoxy-lower-aLkyl or l-lower-alkylthio-lower-aLkyl1 such as methoxymethyl, l-methoxyethyl, l-ethoxyethyl, methylthiomethyl, l-methylthioethyl or l-ethylthioethyl, or 2~xa- or 2-thiacycloaL~yl having 5-7 ring atoms, such as ... . ~ - . , .... - . ~ -.. : ~: : : ~ -210997a 2-tetrahydrofuryl or 2-tetrahydropyranyl~ or a corresponding thia analogue, and by l-phenyl-lower-alkyl, such as benzyl, diphenylmethyl or trityl, it being possible for the phenyl radicals to be substituted, for example by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or nitro.

Two hydroxyl groups present in one molecule, in particular adjacent hydroxyl groups, or an adjacent hydroxyl and amino group, can be protected for example by bivalent protecting groups, such as a methylene group which is preferably substituted, for example by one or two lower alkyl radicals or oxo, for example by unsubstituted or substituted aL~ylidene, for example lower aL~cylidene, such as isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzylidene.

A hydroxyl group in the adjacent position to a carboxyl group can be protected by the formation of an internal ester (lactone), in particular a ~-lactone.

A preferred protected hydroxyl group is protected by tri-lower-alkylsilyl or in the form of a lactone, in particular by tert-butyl-dimethylsilyl.

A mercapto group can be protected, in particular, by S-alkylation with unsubstituted or substituted alkyl radicals, silylation, thioacetal formation, S-acylation or by the formation of asyrnmetric disulfide groups. Prefé~ed mercapto p~otecting groups are, for example, benzyl which is unsubstituted or substituted in the phenyl radical, for example by methoxy or ni~o, such as ~methoxybenzyl, diphenylmethyl which is unsubstituted o¢ substituted in the phenyl radical, for example by methoxy, such as di(~methoxyphenyl)methyl, tri-phenylmethyl, pyridyldiphenylmethyL trimethylsilyl, benzylthiomethyl, tetrahydro-pyranyl, acylaminomethyl, such as acetamidomethyl, isobuwlacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkylaminocarbonyl, in particular lower a~cyl~minocarbonyl, such as ethylaminocarbonyl, and lower alkyl~io, such as S-ethylthio or S-tert-butylthio, or S-sulfo.

A hydroxyl or mercapto group which is protected by a suitable acyl group, a tri-lower-aL~ylsilyl group or by unsubstituted or substituted l-phenyl-lower-alkyl is set free analogously to an analogously protected amino group. A hydroxyl or mercapto group which is protected by 2,2-dichloroacetyl is, for example, set free by basic hydrolysis, a ~ -hydroxyl or mercapto group which is protected by tert-lower-alkyl or by a 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon ~dical by acidolysis, for example by ' ' ` ` : . '` ' ~ : . ' .. . .

73 2~0~7~ ~

treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
Mercapto which is protected by pyridyldiphenylmethyl can be set free for example by mercury(II) salts at pH 2-6 or by zinc/acetic acid or electrolytic reduction, acetamidomethyl and isobutyrylamidomethyl for example by reaction with mercury(II) salts a~ pH 2-6, 2-chloroacetamidomethyl for example by 1-piperidinothiocarboxamide, S-ethylthio, S-tert-butylthio and S-sulfo for example by thiolysis with thiophenol, thioglycolic acid, sodium thiophenolate or 1,~dithiothreitol. Two hydroxyl groups or an adjacent amino and hydroxyl group, which are protected together by means of a bivalent protecting group, preferably for example a methylene group which is mono- or disubstituted by lower alkyl, such as lower alkylidene, for example isopropylidene, cycloaL~cylidene, for example cyclohexylidene, or benzylidene, can be set free by acid solvolysis, in particular in the presence of a mineral acid or a strong organic acid. A
tri-lower-alkylsilyl group is also detached by acidolysis, for example by mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. 2-Hal~lower-aLIcoxycarbonyl is detached by the abovementioned reducing agents, for example reducing metal, such as zinc, reducing metal salts, such as chromium(II) salts, or by sulfur compounds, for example sodium dithionite or, preferably, sodium sulfide and carbon disulfide. Esterified hydroxyl groups, for example lower alkanoyloxy, such as acetyloxy, can also be set free by esterases, for example acylated amino by suitable peptidases.

A sulfo group can be protected for example by lower alkyl, for example methyl or ethyl, by phenyl or in the fonn of a sulfonamide, for example imidazolide.

A sulfo group which is protected in the form of a sulfonate or sulfonamide is set free, for example, by acid hydrolysis, for example in the presence of mineral acid, or, preferably, by basic hydrolysis, for example using alkali metal hydT~xide or aL~ali metal carbonate, for example sodium carbonate.

If required, oxo is protected by acetal formation, for example with lower aLl~anols, in particular with ethane-1,2-diol, it being possible for the protecting group to be detached at the desired stage by hydrolysis in the presence of an acid, such as acetic acid or sulfilric acid, and thioxo-lower-aL~yl is, if required, protected by thioacetal formation, for example with lower alkylmercaptans, such as ethane-1,2~ithiol, it being possible for the protecting group to be detached at a suitable point in tirne by hydrolysis in the presence of an acid, such as acetic acid or sulfuTic acid.

;, - - . . --:~ , . . , . .: .

'-' ~ ''.' : . :
~. ': . . . ' .......... . . .

21 09~7~

The temperatures for setting free the protected functional groups are preferably between -80 and 100C, palticularly preferably between -20 and 50C, for example between 10 and 35C, such as around room temperature or at reflux temperature.

If a plurality of protected functional groups are present, the protecting groups can, if desired, be selected in such a way that more than one such group can be detachedsimultaneously, for exarnple acidolytically, such as by treatment with trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladiurn/charcoal catalyst. Vice versa, the groups can also be selected in such a manner that not a11 of them are detached simultaneously, but in a desired sequence, giving the respective intermediates.

Re b) Reduction of a carboxYl function The monocarboxylic acids of the fo~mula V in which Y' is as defined for Y in compounds of the formula I (with the exception of hydroxyl which can be replaced by a carboxyl protecting group), are preferably in activated form. The reactive derivatives are, in particular, those of the formula IIe Arl X
Al-N~,,C--Y"
ll (I[e) J
A2- N~--ICl - z3 Ar2 in which Y" is as defined for Y in compounds of the formula I or is a carboxyl protecting group, if X is oxygen, Z3 is halogen, such as chlorine or bromine, and the remaining radicals are as defined above. This gives compounds of the formula I in which Z is hydroxymethyl or formyl.
. .
Other preferred reactive derivatives are cyclic imides of the formula IIf .

. , . .. : : .: . , 21 0997a Ar~ O
Al--N ~,~
J~ N--E (IIf~

Ar2 in which E is hydrogen or lower alkyl and the remaining radicals are as defined above.

The reduction is preferably carried out using complex hydrides, in particular lithium aluminium hydride or LiAlH[OC(CH3)3]3 in ethers, such as diethyl ether or tetrahydrofuran, pyridine or N-allylmorpholines, such as N-methylmorpholine, or with sodium borohydride (if required in the presence of LiCl) in water, diglycol, methanol, ethanol or isopropanol, or mixtures of these solvents), at temperatures between 10C and the reflux temperature.

Compounds of the formula IIe are prepa~ed, for example, by reacting a compound of the formula I which has been obtained by process a) and in which Z is a carboxyl group and -the remaining radicals are as defined above (i.e. a compound of the formula V) with an inorganic acid halide, for example phosphorus trichloride, phosphorus tribromide, phosphorus pentachloIide, phosphorus pentabromide, thionyl chloride or thionyl bromide, or with oxalyl dichloride, if required in the presence of solvents, at temperatures between 10C and reflux temperature, for example between room temperature and 80C, and with the exclusion of water.
` ~
Compounds of-the formula IIf in which E is lower alkyl, in particular methyl, are preferably prepared analogously to the abovementioned compounds of the formula IId from compounds of the formula IIb, by carrying out the reaction with lower aLkylamines instead of ammonia and under reaction conditions which are analogous to those mentioned above for the prepaIation of compounds of the formula IId from compounds of the formula IIb. Compounds of the formula IIe in which E is hydrogen are identical with compounds of the formula IId and are preferably prepared like those.

Alternatively, compounds of the formula ~f can also preferably be prepared from anhydrides of the formula IIc, by reacting them with ammonia or lower allylamines at elevated temperatures or in the presence of hexamethyldisilazane and methanol at 210997a approximately room temperature, preferably in a high-boiling alcohol, such as 2-ethoxyethanol, at temperatures between 50 and 130C, for example at approximately 100 to 120C.

The dicarboxylic acids in which X is oxygen and Y' is hydroxyl are preferably in the forrn of reactive derivatives. The reactive derivatives include, in particular, reactive anhydrides, such as the internal anhydrides of the formula IIc which have been mentioned ~or process a), or the cyclic imides of the formula IId which are mentioned in process a) and in which the radicals are in each case as defined above and are prepared as above.

The internal anhydrides of the formula IIc are preferably reduced using a complex hydride under the reaction conditions as described above for the reduction of compounds of the formula V, in particular using sodium borohydride in methanol or ethanol at temperatures between room temperature and the reflux temperature, for example at approximately room temperature to 40C. This gives compounds of the formula I in which X is oxygen, Y is hydroxyl, Z is hydroxymethyl and the remaining radicals are as defined above.

The cyclic imides of the formula IIf are preferably reduced under the same conditions as just described above for the internal anhydrides of the formula lIc, in particular using ;
sodium borohydride in methanol or ethanol at temperatures between room temperature ~ -~
and the reflux temperature, for example at approximately room temperature to approximately 40C. This gives compounds of the formula I in which X is oxygen, Y is amino or lower aL~cylamino, Z is hydroxymethyl and the remaining radicals are as defined above.

All starting materials which have been mentioned can, if re~uired, be protected on funcdonal groups which are not to participate in the above-described reactions, protecting ~ ~
groups which are present being detached at a suitable point in time. Resulting compounds ~ `
of the formula I which have protecting groups can be converted into the free compounds of the formula I by detaching the protecting groups or (if required after detaching some or all of the protecting groups) are subjected to the additional operational procedures mentioned below. The protection of the abovementioned compounds, suitable protecdng groups and ways for detaching them are described under process a).

Additional oPerational procedures:

":
~ ~ . ... .. .

77 2~09975 Compounds of the forrnula I can be converted in a manner known per se into othercompounds of the forrnula I.

It is possible to carry out the abovementioned conversions individually or else to select suitable combinations, i.e. to catTy out two or more conversions with a compound of the formula I. Functional groups in starting materials of the formula I and other s~ting `
materials which are not to participate in the reaction in question are, if required, in protected forrn. The protecting groups are detached at suitable points in tune. The introduction of the protecting groups, the protecting groups themselves and ways of detaching them are as described for process a).

For example, a compound of the formula I in which the group -C(=X)- is -C(=O) can be reacted with a suitable reagent so that another compound of the formula I in which the group -C(=X~ is -C(=S) is obtained. Analogously, esterified or amidated carboxyl Z can be converted into a radical in which the oxo of the carbonyl radical is replaced by thio. A
suitable reagent for the conversion of -C(=O)- into -C(=S)- is, for example phosphorus pentasulfide or, preferably, substances which can replace phosphorus pentasulfide, for example the Lawesson reagent (= 2,4bis(~methoxyphenyl)-2,~dithioxo-1,3,2,~dithia-phosphetane), the reaction being carried out, for example, in a halogenated hydrocarbon, such as dichloromethane, at temperatures from 30C to reflux temperature, in particular at reflnx temperature.

Compounds of the forrnula I in which one of the radicals A~ and A2 is hydrogen can be converted, by reaction with suitable reagents, into other compounds of the formula I in which none of the radicals Al and A2 is any longer hydrogen.

A suitable treatment for introducing Al or A2 = unsubstituted or substituted lower alkyl is, for example, the treatment with the base LDA followed by reaction with an unsubstituted or substituted di-lower-a1kyl ether or an unsubstituted or substituted lower aLkyl halide.
Substituted lower aL~yl is as defined for the corresponding radical Al and/or A2 in compounds of the forrnula I.

Compounds of the formula I in which Arl and/or Ar2 is aryl, in particular phenyl or naphthyl, which is substituted by halogen, preferably bromine, can be converted into the corresponding derivatives in which one or all of the halogen atoms in aryl Arl and/or Ar2 are replaced by cyano, for example by conversion with a cyanide salt of a transition metal, :,,, . . ~. ~: . :

;~i. ~ - ................... ; .::
.... :. : .:, . :. ., :
.. :-. - . ~:

2103~7~

in particular CuCN, at temperatures between 50 and 150C, preferably between 60 and 140C, in an inert polar solvent, such as an N,N-di-lower-aL~cyl-lower-alkanecarboxarnide, for example dimethylformamide, without or with subse~quent addition of a catalyst, for example a transition metal halide, such as iron(lLI) chloride, in aqueous solution (c.f.
Rosenrnund et al., Ber. 52, 1749 (1916); von Braun et al., Ann. 488, 111 (1931)).

In compounds of the for nula I, the radicals Arl and/or Ar2, which are unsubstituted or substituted aryl, preferably unsubstituted phenyl or naphthyl, can be nitrated independently of one another by introducing one or more nitro groups, for example under the customary conditions for introducing a nitro group into aromatics, for example using concentrated or 100% nitric acid at temperatures between 0 and 100C, preferablybet veen 10 and 40C, in an inert solvent, for example an organic acid anhydride, such as acetic anhydride. If a plurality of different products in which the position and number of nitro groups is different is formed, then they can be separated by customary methods, for example by column chromatography.

Nitro substituents within the radicals Arl and/or Ar2 can be reduced to amino groups, for ~-example by hydrogenation under customary conditions, for example by hydrogenation in the presence of a hydrogenation catalyst which is suitable for the selecdve reduction of the nitro groups, such as Raney nickel, in an inert solvent, for example a cyclic or acyclic ether, such as tetrahydrofuran, under atmospheric pressure or elevated pressure of up to S -~ ~ `
bar.

Compounds of the formula I which have etherified hydroxyl groups, for example lower alkoxy radicals as substituents within Arl and/or Ar2 or on Al and/or A2 can be converted into the corresponding hydroxyl-substituted compounds of the formula I by ether -cleavage. The ether cle~vage is carried out under conditions known per se, for example in the presence of hydrohalic acids, such as hydrogen bromide or hydrogen iodide, in the presence or absence of solvents, such as carboxylic acids, for example lower aL~anecarboxylic acids, such as acedc acid, at temperatures between 20C and the reflux temperature of the reaction mixture, or, preferably, under mild conditions with boron halides, in particular boron tribromide, in an inert solvent, such as a chlorinated hydrocarbon, for example methylene chloride or chloroform, at temperatures between -80 and 0C, in particular between -50 and -20C.

Compounds of the ~ormula I in which hydroxyl is present, for example in Al, A2, substi-~ ,;' - " . . i ~

':' . ... ~ ' ' . :

2~ 0997~

tuted lower aLkylene formed by those two radicals together and/or hydroxymethyl Z, can be converted into the corresponding carbonyl compounds by oxidation and into the corres-ponding imino compounds, such as hydroxyimino compounds, by reaction with hydroxyl-amine or a salt thereof and other amino compounds, either direcdy in succession or after the carbonyl compound has been isolated. Further substituents, reagents and prefer~ed reaction conditions can be found in the description of the preparation of compounds of the formula IIb which have imino, lower alkylimino, acylimino, hydroxyimino, lower aLkoxy-imino, hydrazono, N-mono- or N,N~i-lower-alkylhydrazono andlor N-acylhydrazono as substituent in substituted lower alkylene which is formed by Al and A2 together, from the corresponding oxo compounds of the formula IIb, where compounds of the formuta I are ~;
to be employed instead of the oxo compounds of the formula IIb.

Compounds of the formula I which have hydroxyimino as substituent in Al and/or A2 or a lower aLkylene formed by these two radicats together andlor in hydroxyiminomethyl Z can be hydrogenated to give the corresponding amino compounds. The hydrogenation is preferably carried out catalyticatty using selective hydrogenation catalysts, in particular in the presence of palladium on solid support materials, for example on charcoal, in polar organic or organic/aqueous solvents or solvent mixtures, in particular in ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or in atcohols, for example lower atkanolsi such as methanol or ethanoL ar mixtures of these, for example inmethanoVtetrahydrofuran mixtures, at temperatures bet veen -20 and 60C, preferabb between 0 and 40CC, for example at approximately room temperature.

In compounds of the formuta I which have primary hydroxyl groups, for example those compounds of the formula I in which substituted lower alkyl, substituted lower atkenyl or substituted lower alkynyl Al and/or A2 contain primary hydroxyl groups, such as in hydroxyethyl, or which have a substituted lower alkylene which is formed by Al and A2 together and which contains, as subsdtuent, hydroxy-lower-alkyl, such as hydroxymethyl, primaty hydroxyl groups can be oxidized to give the coIresponding carboxyl or carboxy-lower-alkyl radicals, for example by oxidation with chromic acidL dichromate/sulfilric acid, nitric acid, manganese dioxide or potassium permanganate, preferably potassium permanganate in neutral or atkatine medium, for exarnple in aqueous atcohotic solution, at preferred temperatures from -20 to 50C, in pardcular between 0C and room temperature.
Corresponding carboxyl-subsdtuted compounds of the formula I are obtained.

In compounds of the formula I in which a subsdtuted lower alkyl Al andlor A2 contains . . . .

, ., : .," : , ~ , .
,......... :. .

210997~

carboxyl, such as in carboxymethyl Al and/or A2, or which have a substituted lower aL~cylene which is formed by Al and A2 together and which contains, as substituent, carboxyl or carboxy-lower-alkyl, for example in those compounds which are prepared from compounds of the forrnula I having primary hydroxyl groups by the process which has just been described, carboxyl groups can be converted into the corresponding lower aLkoxycarbonyl groups by reaction with diazomethane (gives methyloxycarbonyl) or with lower aLkanols, such as methanol or ethanol. The reaction with diazomethane is carried out, for example, in aqueous/alcoholic solution, for example in water/methanol, or, preferably, in ether, in the presence of an etheric solution of diazomethane, for example diazomethane in diethyl ether, at temperatures between -20 and 30C, for examplebetween 0C and room temperature. The reaction with lower aLkanols is preferably carried out in the presence of condensing agents, such as carbodiimides, for example dicyclohexylcarbodiimide, in the lower alkanol in question, to which a further inelt ~ `
organic solvent, preferably dimethylformamide or dimethylacetamide, can be added, at -temperatures between 0 and the reflux temperature, preferably between 10 and 40C.
This gives co~responding lower alkoxycarbonyl compounds of the formula I.

Compounds of the formula I which have hydroxyl and/or hydroxy-lower-aL~cyl as substituent in a substituted lower alkylene foImed by Al and A2 together, andlor in which hydroxymethyl Z is present, can be oxidized to give a colresponding oxo compound. In -the case of primary alcohols, this requires the use of selective oxidants, for example potassium ferrate (K2PeO4) in aqueous solvents and manganese dioxide in organic solvents, tert-butyl chromate, pylidinium dichromate or, in particular, pyridinium chlorochromate in inert organic solvents, for example chlorinated hydrocarbons, such as dichloromethane or chlo~oform. The reaction is preferably carried out at temperatures bet veen -20C and the reflux temperature, for example at approximately 0 to 40C. In the case of secondary alcohols, the oxidation can also be carried out with less selective oxidants, such as chromic acid, dichromate/sulfuric acid, dichromate/glacial acetic acid, nitric acid, manganese dioxide, selenium dioxide or dimethyl sulfoxide in the presence of oxalyl chloride, in water, aqueous or organic solvents, such as halogenated hydrocarbons, for example methylene chloride or carboxamides, such as dimethylformamide, preferably at temperatures between -50C and reflux temperature, in particular between -10 and 50C. This gives compounds of the formula I in which substituted lower alkylene formed by Al and A2 together and/or substituted methyl Z is substituted by oxo.

Compounds of the formula I in which Z is hydroxymethyl can, after the hydroxyl group .: , , ~: . , --210~7~

has been converted into a leaving group, for example by reaction with aromatic sulfonic acids or activated derivatives thereof, such as the corresponding aromatic sulfonyl halides, for example toluenesulfonyl halides, such as toluenesulfonyl chloride, or halo, such as chloro or, in particular, bromo (which can be prepared by reaction with an inorganic acid -halide, such as phosphorus trichloride or phosphorus tribromide, phosphorus penta-chloride, phosphorus pentabromide, thionyl chloride or thionyl bromide), the preparation of the leaving group being carried out, if required, in inert solvents, for example ethers, such as tetrahydrofuran or dioxane, or halogenated hydrocarbons, such as chloroform or methylene chloride, at temperatures between room temperature and reflux temperature, in the presence or absence of tertiary nitrogen bases, such as pyridine, N-methylmorpholine or triethylamine, be converted into the corresponding compounds in which Z is methyl which is substituted by mono-lower-alkylamino, di-lower-aL~cylamino or lower aL~ylthio, in which the lower alkyl radical is unsubstituted or substituted as above, cyano, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower allyl, or guanidino or guanidino which is substituted by one, two or all three nitrogen atoms by lower aL~cyl.
Depending on the substitutent to be introduced, the reaction is carried out using a mono-or di-lower-aL~ylamine; a lower alkylmercaptan with unsubstituted or substituted lower alkyl in the presence of bases, such as hydroxy bases, for example aL~cali metal hydroxides, such as sodium hydroxide or potassium hydroxide; with cyanide salts, such as aLkali metal cyanides, for example sodium cyanide or potassium cyanide; with hydrazine, guanidine or the suitably substituted de~ivatives; it also being possible fo~ protecting groups to be present, under the conditions of nucleophilic substitution, preferably in the presence of organic solvents, for example alcohols, such as methanol? ethanol or trifluoroethanol, ke-tones, such as acetone, nitriles, such as acetonitrile, esters, such as ethyl acetate, ethers, such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, acid ami-des, such as dimethylformamide, bisalkanesulfines, such as dimethyl sulfoxide, aTyl al-cohols, such as phenol, or else water, or mixtures of these solvents. Protecting groups can be detached. The compounds of the formula I in which substituted methyl Z contains sub-stituents selected from amongst hydrazino and hydrazino which is substituted on the ter-minal N atom by lower aL~cyl can also be plepared starting from a corresponding oxo com-pound of the formula I by reacting it with nitrogen bases selected from amongst hydrazine and hydrazine which is up to disubstituted by lower aL~cyl, as described further below for the reaction of an oxo compound with nitrogen bases, followed by reduction of a resulting corresponding imino compound, preferably by catalytic hydrogenation with selective hydrogenation catalysts, in particular in the presence of palladium on solid support ma-terials, for example charcoal, in polar organic or organic/aqueous solvents or solvent mix-,, .. . ~ .. ... . . . .. .

,.~ . . ..... ,.. ,.. , ~ .. ~
.

.. , . , ,., .. ' : ' ' ~, ~ , ' ', ' ' :
:~ " ~ ', '. ,' '. , ': ' ' ' " . ' ' ' 2109~7~

tures, in particular ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, such as lower aLkanols, for example methanol or ethanol, or mixtures of these, for example methanoUtetrahydrofuran mixtures, at temperatures between -20 and 60C, preferably between 0 and 40C, for example at approximately room temperature.

Compounds of the for nula I in which Z is hydroxymethyl can, after the hydroxyl group has been converted into a leaving group, as just described above, for example into a toluenesulfonyloxy group, be reacted with lower alkanols which are unsubstituted or substituted in the lower alkyl radical in a suitable manner, giving compounds of the formula I in which Z is methyl which is unsubstituted or substituted by substituted lower aL~coxy. The reaction is preferably carAed out with an alcoholate of the unsubstituted or substituted lower aLIcanol (in which, if required, protecting groups which are not to participate in the reaction are in protected form), which is obtained, for example, by reaction with an aL~cali metal, such as sodium, in ethers, for example disthyl ether, dioxane or tetrahydrofuran, in parlicular with slow addition of the alcoholate to give a solution of the compound of the formula I in question with a hydroxyl group converted into a leaving ~ ;
group, in an inert, aprotic solvent, for example the same solvent in which the lower alkanolate is dissolved, at temperatures between room temperature and reflux temperature. ~-Compounds of the fo~mula I in which Z is aminomethyl or lower-aL~cyl-aminomethyl can be converted into corresponding compounds in which Z is ureidomethyl or 1- or --~
3-mono-lower-alkylureidomethyl by reacting corresponding amino compounds of the formula I with a lower alkyl isocyanate or an N-protcc~d isocyanate (for example benzyl isocyanate), preferably in an ether, for example a cyclic ether, such as tetrahydrofuran, at preferled temperatures between -20 and 60C, in particular at approximately roomtemperature, where, if required, functional groups which are not to participate in the reaction, are protected, and detaching protecting groups which are present. It is also possible to react corresponding amino compounds of the formula I with phosgene or analogues thereof, for example N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole (c H. A. Staab, Angew. Chem. 74, 407-423 (1962)), and then to react the resulting chlorocarbonylamino or azolidocarbonylamino compounds with ammonia which is substituted by lower aL~yl, or, vice versa, to react the corresponding amino compounds of the formula I with the reaction product of ammonia whicb is substituted by lower aLkyl with phosgene or analogues thereof, for example the N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole, giving 3-lower-alkylureido-me~yl Z. The reaction is preferably carried out in inert solvents, in particular chlorinated - . -2.t~9~7~

hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or acid amides, such as dimethylformamide, at temperatures between -20C ~d reflux temperature, in particular between 0 and 30C.

Compounds of the formula I which have, in a substituted lower aL~cylene formed by Al and A2 together, one or more substituents selected from amongst imino, lower alkylirnino, acylimino, hydroxyimino, lower al~coxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono, N-acylhydrazono and lower alkyl which is substituted by imino, lower alkylimino, acylimino, hydroxyimino, lower aL~oxyimino, hydrazono, N-mono- or N,N-di-lower-aLkylhydrazono andlor N-acylhydrazono, and/or compounds of the formula I in which Z is methyl which is substituted by imino, lower alkylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono or N-acylhydrazono, can be prepared from cespondingoxo compounds of the formula I, either after isoladon of the oxo compounds or, preferably, by directly processing them as crude product, for example after partial evaporadon to remove the solvent in which the oxid~don of a hydroxy compound to the oxo compound is carried out, which is carried out, for exa nple, as just described above.

The oxo compounds can be converted into the corresponding imino derivatives by reacdon with nitrogen bases selected from amongst ammonia, lower alkylamines, hydroxylamine, lower aL~oxyamine, hydrazine, N-mono- or N,N-di-lower-al~ylhydrazine and N-acylhydrazine. The reacdon condidons are the customary condidons used for the reacdon of carbonyl compounds with nitrogen bases, the nitrogen base being used, for example, in the form of a salt of an acid, for example a hydrohalic acid, such as hydIogen fluoride, hydrogen chloride, hydrogen bromide or hydrogen iodide, par~cularly preferably hydrogen chloride, of sulfuric acid or a hydrogen sulfate, such as an aL~cali metal hydrogen sulfate, for example sodium hydrogen sulfate, of phosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, for example an alkali metal hydrogen phosphate or dihydrogen phosphate, such as sodium hydrogen phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen phosphate, or in the form of a salt with an organic acid, in pardcular with a carboxylic acid, such as a lower alkanecarboxylic acid which is unsubsdtuted or subsdtuted in the lower aLlcyl radical, preferably by halogen, such as fluorine or iodine, for example acetic acid, chloroacedc acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, or with a sulfonic acid, such as lower alkylsulfonic acid, for example methanesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, or an arylsulfonic acid, such as benzene- or naphthalenesulfonic acid or -84- 21 0997~
naphthalene-1,5-disulfonic acid;

it also being possible for a salt of one of the abovernentioned nitrogen bases with an acid to be prepared only in situ, especially from the corresponding salt of a readily volatile weak acid, such as a lower aLlcanecarboxylic acid, for example acetic acid or, in particular, carbonic acid or hydrogen carbonate, which can be replaced by a strong acid, such as sul-fu~ic acid or, mainly, one of the abovementioned hydrohalic acids, by replac;ng the weak acid; the reaction taking place in water (in the presence or absence of surfactants), in an aqueous solvent mixture, such as a mixture of water or with one or more alcohols, for example methanol, ethanol or isopropanol, di-lower-aLIcanesulfines, such as dimethyl sulf-oxide, or di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide, organic sol-vents, such as alcohols, for example methanol or ethanol, di-lower-aLIcyl sulfoxides, such as dimethyl sulfoxide, di-lower-aLIcyl-lower-alkanoylamides, such as dimethylformamide, or in sufficiently inert nit~iles, such as acetonitrile, a mixturei of such organic solvents, or without solvents in a melt, preferably in an alcoholic solution, such as methanol, ethanol or, in particular, isopropanol; preferably at temperatures between -20C and the reflux temperature of the reaction mixture in the presence of a solvent, in ~e case of melts at up to 220C, in particular at temperatures of 0 to 5~C, in the presence of a solvent, especially at approximately room temperature.

Compounds of the f~nula I in which Z is lower alkylthioiminomethyl can preferably be prepaT~d by reacting suitable imino starting materials of the formula I with lower-alkylsulfenyl halides (which can be prepared, for example, from sulfenic acids with hydrogen halide or by chlorolysis, bromolysis or iodolysis of suitable organosulfilr compounds, it also being possible for the preparation to be canied out in situ), in particulaT lower-alkylsulfenyl halides, such as methylsulfenyl chloride, preferably using the salts of the imino compounds, or in the presence of alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, in organic solvents, for example hydrocarbons, such as heptane, ethers, such as diethyl ether, dioxane or tetrahydrofuran, or carboxamides, such as dimethylformamide, at preferred temperatures of between 0C and the reflux temperature, in particular between 0 and 30C.

In a compound of the formula I, aminomethyl Z can be converted into lower aL~canoylaminomethyl Z, or hydroxymethyl Z into lower aLIcanoyloxymethyl. This is effecdve, for exarnple, by reactdon with an acdvated (if desired, in situ) lower aL~canoic acid (which can be prepared analogously to the activated acid derivatives of the forrnula 2~a~97a IIa~, for example a lower alkanoic anhydride of the forrnula X, such as acetic anhydride, or a lower aL~anoic halide, such as chloride or brornide, dissolved in a lower aLkanoic anhydride or an i~ert solvent, such as an ether, for example tetrahydrofuran or dioxane, or an N,N-di-lower-aL~cyl-lower-aLIcanecarboxamide, such as dimethylformamide, at temperatures between 0C and reflux temperature, in parlicular at approximately room temperature, in the presence or absence of tertiary nitrogen bases, such as pyridine, N-methylmorpholine or triethylamine.

A compound of the formula I in which X is O, Y is amino and Z is hydroxymethyl can be converted into a compound of the formula I in which Y and Z together are l-oxamethylene which is bonded via the oxygen in place of Y and the methylene carbon atom in place of Z. The conversion is preferably carried out by distillation under a high vacuum, for example using a bulb tube, at pressures from 0.001 to 0.5 torr, preferably 0.2 to 0.05 torr, at temperatures which are sufficiendy high for the distillation, for example at 180 to 250C.

A compound of the forrnula I in which X is O, Y is subsdtuted amino and Z is hydroxymethyl can be obtained from a compound of the fonnula I in which Y and Z
together are l-oxamethylene which is bonded via the oxygen in place of Y and themethylene carbon atom in place of Z, by reaction with a compound of the formula m, as defined above, in which Wl is substituted amino, in particular mono- or di-lower-alkylamino, hydrazino, phenylamino or phenyl-lower-aL1cylamino. The reaction is preferably carried out in an alcohol, such as methanol or ethanol, in the presence or absence of an antioxidant, such as sodium ascorbate, at temperatures between 30 and 100C, for example between 50 and 80C, and in a sealed tube in the case of temperatures above the reflux temperature.

Free compounds of the formula I which can be obtained according to the process and which have salt-forming properties can be converted into their salts in a manner known per se, compounds which have basic properties for example by treating them with acids or suitable derivatives thereof, compounds which have acidic properties for example by treating them with bases or suitable derivatives thereof.

Isomer mixtures which can be obtained according to the invention can be separated into the individual isomers in a manner known per se, for example diastereomers by partitioning between multi-phase solvent mixtures, recrystallization and/or .
. -~ .-210997~

chromatographic separation, for example on silica gel, and racemates for example by the formation of salts with optically pure salt-forming reagents and resolving the resulting diastereomer mixture, for example by means of fractional crystallization, or by chromatography on optically active column materials.

The abovementioned reactions can be carried out under reaction conditions which are known per se, in the absence or, conventionally, the presence of solvents or diluents, preferably those which are inert to the reagents used and in which the reagents are soluble, in the absence or presence of catalysts, condensing agents or neutralizing agents, and, depending on the nature of the reaction andlor the reactants, at reduced, normal or elevated temperature, for example in a temperature range of approximately -80 to approximately 250C, preferably approximately -20C to approximately 150C, for example at room temperature up to the reflux temperature, in the case of melts at up to 220C, under atmospheric pressure or in a sealed vessel, if appropriate under pressure, for example at the pressure which is established in the reaction mixture under the reaction conditions in a sealed tube, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere. The reacdon conditions which are mentioned specifically in each case are preferred.

Solvents and diluents are, for example, water, alcohols, for example lower alkanols, such as methanol, ethanol or propanol, diols, such as ethylene glycoL triols such as glycerol, or aryl alcohols, such as phenol, acid amides, for example carboxamides, such as dimethyl-fonnamide, dunethylacetamide or 1,3-dimethyl-3,4,5,~tetrahydro-2(1H)-pyrimidinone (DMPU), o~ amides of inorganic acids, such as hexamethylphosphoric triamide, ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower-alkanes, for example methylene chloride or chlorofoqm, ketones, such as acetone, ni~iles, such as acetonit~ile, acid anhydrides, such as acetic anhydride, esters, such as ethyl acetate, bisaLIcanesulfines, such as dimethyl sulfoxide, nitrogen heterocycles, such as pyridine, hydrocarbons, for example lower alkanes, such as heptanes, or aromatics, such as benæne or toluene, or mixtures of these solvents, it being possible for those solvents to be selected which are in each case suitable for the abovementioned reactions.

Because of the close relationship between the compounds of the formula I and their precursors in free form and in the form of salts and/or tautomers, the free compounds and starting materials hereinabove and hereinafter are advantageously also to be understood as ~ ~ r., ~ : : . ' .;~ . X

2109~7~

meaning, where appropriate, the corresponding salts or free compounds and/or tautomers, as long as the compounds have one or more salt-forrning groups, for example basic groups, such as amino or imino groups, including those which are bonded to not more than one unsaturated carbon atom (like the groups -NAlArl andlor -NA2Ar2 on the C atom of the central phenyl ring, in which Arl and A1 and/or Ar2 and A2 are not bonded via an unsaturated carbon atom), andlor acidic groups (such as carboxyl or sulfo ~SO3H)) and/or tautomerizable groups. If, in connection with starting materials or compounds of the formula I, a substituent, a compound, a tautomer, a salt, substituents, compounds, tautomers or salts are mentioned hereinabove and hereinafter, this is to be understood, if advantageous, as meaning "one or more", independently of the use of the singular or plural. Starting materials can also be used in protected form, if required, and advantageous, it being possible for the protecting groups to be detached at suitable points in time. Protecting groups, their introduction and ways of detaching them are, in particular, as defined above under process a).

The compounds including their salts can also be obtained in the form of hydrates, or their crystals can include for example the solvent used for the crystallization.

The process of the present invention employs preferably those starting materials which lead to the compounds which have been described at the outset as being prefe~ed.
The invention also relates to those embodiments of the process in which, starting from a compound which can be obtained as intermediate in any desired process step, the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or used in the fo~m of a derivative, for example a salt thereo The sequence and reaction conditions of all the reactions which have been described are preferably to be selected in such a way as is considered advantageous for the person skilled in the art.

The present invenlion also relates to pharmaceutical compositions which comprisecompounds of the formula I as active ingredient. Particularly preferred are compositions for enteral, in particular oral, and parenteral administration. The compositions comprise the active ingredient on its own or, preferably, together with a pharmaceutically acceptable excipient. The dose of active ingredient will depend on the disease to be treated, and on the species, the age, the weight and the individual constitution, and on the ~1 09~7;~

way in which the drug is administered.

Preferred is a pharmaceutical composition which is suitable for administration to a representative of a warm-blooded species, in paTticular a human being, who suffers from one of the abovementioned diseases, in paTticular a disease which responds to inhibition of a protein kinase, for example psoriasis or a tumour, which comprises a compound of the formula I or, if salt-forming groups are present, a salt thereof, in an amount which is effective for inhibiting the protein kinase, together with at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions comprise approxirnately 5 % to approximately 95 % of the active ingredient, dosage forms which are given in individual doses preferably comprising from approxi nately 20 % to approximately 90 %~ and dosage forms which are not given in individual doses preferably comprising approximately 5 % to approximately 20 %, of active ingredient. Unit dose fns, such as sugar-coated tablets, tablets or capsules, comprise from approximately 0.05 g to approximately 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invendon are prepared in a manner known per se, for example by means of convendonal mixing, granulating, sugar-coadng, dissolving or lyophilizing methods. For example, pharmaceudcal composidons for oral administradon can be obtained by combining thc acdve ingredient with one or more solid excipients, if desired granuladng the mixture obtained, and, if desired, processing the mixture or the granules to tablets or sugar-coated tablet cores, with or without an addition of further adjuncts.

Suitable excipients are, in pardcular, fllers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparadons and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, furthermore binders, such as starches, for example maize starch, wheat starch, rice starch or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose andlor polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone or alginic acid or a salt thereof, such as sodium alginate. Other adjuncts are, mainly, flow conditioners and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

:
,, ~ , ~ ~. . . .

2~97~

Sugar-coated tablet cores can be provided with suitable coatings which may be enteric coatings, concen~rated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, being used, inter alia. Colorants or pigments, for example for identifying or for marking various active ingredient doses, may be added to the tablets or to the coatings for sugar-coated tablets.

Other pharmaceutical compositions which can be administered orally are hard gelatin capsules and soft. sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules can comprise the active ingredient in the form of granules, for example in the form of a mixture with f~ers, such as maize starch, binders and/or lubricants, such as talc or magnesium st~ate, with or without stabiliærs. In soft capsules, the active ingredient is preferably dissolved oq suspended in suitable liquid adjuncts, for example fatty oils, Lauroglycol (1,2-propylene glycol monolaurate,Gattefossé S.A., Saint P iest, France), Gelucir (Gattefossé S.A., Saint Priest, France) or -sesame seed oil, liquid paraffin or liquid polyethylene glycols, such as PEG 300essentially 285-315) or PEG 400 (Mr essentially 380-420), it also being possible for stabi1izers or detergents, such as ~Tween (polyoxyethylene sorbitan fatty acid monoester, a brand of Atlas Chem. Ind. Inc., USA) to be added.

Other dosage forms for o~al administradon are, foq exaTnple, syrops which are prepared in the customary manner and which comprise the acdve ingredient for example in suspended form and at a concentration of approximately 5 % to 20 %, preferably approximately 10 % - -or at a simi1ar concentrationj which gives a suitable individual dose when 5 or 10 ml are ~ ~ -measured. Furdlermore suitable are, for example, concentrates in the form of powders or liquids with which shakes, for example milk shakes, can be made. Such concentrates can also be packaged in amounts which give an individual dose.

Suitable pharmaceutical composidons which can be administered rectally are, for example, suppositories which are composed of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthedc triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

.
. ~ . . . . .

~ ~', ' ` ~ :
;. , ." ' ` ' .' '""` ~ ' 2109~7~

Mainly suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous suspensions f~r injection, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol andlor dextran, in the presence or absence of stabilizers. The active ingredient, in the presence or absence of adjuncts, can also be in the form of a lyophilisate and be dissolved before parenteral administration by an addition of suitable solvents. -Solutions which can be used for example for parenteral administration can also be used as solutions for infusion.

The invention also relates to a method and/or a process for the treatment of theabovementioned disorders, in particular those which respond to an inhibition of protein kinases. Th~e compounds of the present invention can be administered prophylactically or therapeutically, preferably in an amount which is effecdve against the abovementioned diseases, to a representative of a warm-blooded species, for example a human being, who requires such a treatment, and they are preferably used in the form of pharmaceutical compositions. A daUy dose of 1 m to 5000 mg, for example approximately 0.1 g to approximately 5 g, preferably approximately 0.5 g to approximately 2 g, of a compound of the present invention is administered to a patient of approximately 70 kg body weight.

The examples which follow illustrate the present invention; temperatures are given in degrees centigrade. The following abbreviations are used: calc. = calculated; ether =
diethyl ether, PAB-MS = fast atom bombardment mass spectroscopy; E~-MS = field ~ ~
deso~ption mass spectroscopy; f. = found; sat. = saturated; mbar = unit pressure ~1 mbar = ;
1 hectopascal); lH-NMR = proton nuclear resonance; RT = room temperatme; m.p. =
melting point; THP = tetrahydrofuran; torr = unit pressure (1 toIr corresponds to 1 mm mercury column); decomp. = with decomposition.

Quantitative ratios of solvent/eluent mixtures refer to volumetric ratios (v/v), unless otherwise stated.

Example 1: 4.5-Bis(4-fluoroanilino)phthalic diamide In an autoclave, 290 mg (0.7 mmol) of dimethyl 4,5-bis(~fluoroanilino)phthalate are dissolved in 2 ml of methanol, and 20 ml of ammonia are condensed in. The sealedautoclave is heated for 18 hours at 120C. The autoclave is cooled, excess ammonia is .
- i '':

210997~

expelled ae RT using nitrogen, and the residue is washed with ethyl acetate. The yellow suspension is filtered and the solids are washed thoroughly using ethyl acetate. In this manner, the tide compound is obtained in the form of yellow crystals, m~p. 192-194, FAB-MS: 383 [M++H].
The starting materials are prepared as follows:

a) Dimethvl 4,5-bis(4-fluoroanilino)phthalate A solution of 2.4 g (6 mmol) of dimethyl 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylate (Example lb) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid is refluxed for 2 hours. The reaction mixture is cooled, the solvent is evaporated, the dark brown residue is dissolved in dichloromethane, and the solution is washed in succession with 20 ml of 1 N HCI, 50 ml of saturated NaHCO3 solution and t~vice using 20 ml of water, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on silica gel usin& ethyl acetate/hexane 2:1, and the product fractions are evaporated and recrystallized from ethyl acetate/hexane. This gives the tide compound in the form of yellow crystals, lH-NMR (CDCl3): ~ = 7.40 (s, 2H),7.1~6.80 (m, 8H), 5.70 (br s, 2H), 3.83 (s, 6H).

b) Dimethvl 4~5-bis(trimedhvlsilYloxY~cvclohexa-1.4-diene-1.2-dicarboxylate A solution of 7.1 g (50 mmol) of dimethyl iacetylenedicarboxylate (Fluka, Switærland) in 30 ml of toluene is added dropwise under argon to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (Aldrich, Federal Republic of Germany) (95 %) and subsequentdy refluxed for 19 hours. The reaction mixture is cooled, dle solvent is evaporated and the residue is distilled under a high vacuurn (0.1 mbar, 124-127). This gives the tide compound as a yellow, highly viscous oil, lH-NMR (CDCl3): ~ = 0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).

Example 2: MethYl 4~5-dianilinophdlalamidate 350 mg (1.06 mmol) of 4,5-dianilinophthalimide are refluxed for 7 days in 10 ml of methanol. The reaction mixture is evaporated and the product is chromatographed on silica gel using ethyl acetate/hexane 2:1. The product fractions are combined and crystallized from edhyl acetate/hexane. This gives the tide compound in the form of pale yellow crystals, m.p. 176-178C, FAl~-MS: 362 [M++H~.
The starting materials are prepared as follows:

- - .. . .
.. . . . . .: :; . .

21~97~

a) 4.5-Dianilinophthali nide A suspension of 230 mg (0.7 mmol) of dimethyl 4,5-dianilinophthalate in 23 ml ofethylene glycol is heated at 120; ammonia gas is passed through for 24 hours, with stirring. The reaction mixture is cooled and extracted using ethyl acetate. The ethyl acetate phases are washed in succession tl~e times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on silica gel using dichlor~methane/methanol 40:1. The product fractions are combined and evaporated. This gives the title compound in the form of yellow crystals, m.p. 215-217, FAB-MS: 330 tM++~.

b) DimethYl 4~5-dianilinophthalate A solution of 5.6 g (15 mmol) of dimethyl 4,5-bis(trimethylsilyloxy)cyclohexa-l,~diene-1,2-dicarboxylate (Example 1 b) and 5.5 ml (60 mmol) of aniline is refluxed for 4 hours in ~ -~
60 ml of glacial acetic acid. The reaction mixture is cooled, the solvent is evaporated, the dark brown residue is dissolved in dichloromethane and the soludon is washed in succession with 20 ml of 1 N ~ICI, 50 ml of saturated NaHCO3 solution and twice using ;
20 ml of water, dried over sodium sulfate and evaporated. The crude product is recrystallized from edhanol. This gives dhe tdde compound in dhe form of yellow crystals, m.p. 178, FAB-MS: 377 tM++~.
. ~ ~
Example 3: Sodium 4,5-dianilinoDhthalamidate 998 mg (3 mmol) of 4,5~ianilinophdhalimide (Example 2 a) are stirred for four days at room temperatore in a mixture of 20 ml of 0.1 N sodium hydroxide solution and 30 ml of THF. The reacdon mixture is filtered and dhe filtrate is extracted using edlyl acetate. The tide compound crystallizes from the water phase upon standing: white crystals, point of decomp. 170C, FAB-MS: 348 [M++~.

Example 4: Di-2-hvdroxvedlY1 4,5~ianilinophdhalate and medhyl 2-hvdroxYethyl 4,5-bis(anilino~phthalate A suspension of 230 mg (0.7 mmol) of dimedhyl 4,5-dianilinophthalate in 23 ml ofethylene glycol is saturated with ammonia gas, heated at 120 and sdrred for 24 hours.
The reaction mixture is cooled, saturated sodium chloride solution is added, and the mixture is extracted using ethyl acetate. The ethyl acetate phases are washed insuccession, dlree times using water and once using saturated sodium chloride soludon, dried over sodium sulfate and evaporated. The residue obtained by evaporation is , -. . . .
. ,. . ~. .. ~. . : : ~
- ~
. ~, -~ - . . .
. :.

210997~

chromatographed on silica gel using a hexane/ethyl acetate gradient of 2:1 to 1:10, and the product fractions are combined and evaporated. This gives the title compounds in the form of pale yellow crystals: di-2-hydroxyethyl 4,5-dianilinophthalate, m.p. 162-163C, FAB-MS: 437 [M++H], methyl 2-hydroxyethyl 4,5-bis(anilino)phthalate, m.p. 170-171, FAB-MS: 407 [M++H].
.
Example 5: Bis(2-hYdroxYethYl) 5.8-diphenYl-5,8-diaza-5.6~7 ~8-tetrahYdronaphthalene-2~3-dicarboxylate:
Analogously to Example 4, 40 mg (0.1 mml) of dimethyl 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3~icarboxylate in 4 ml of ethylene glycol which is saturated with ammonia gas are heated for 24 hours at 120C. The reaction mixture is cooled, saturated sodium chloride solution is added, and the mixture is extracted using ethyl acetate. The ethyl acetate phases are washed in succession, three times using water ;
and once using saturated sodium chlo~ide solution, dried over sodium sulfate andevaporated. The residue obtained by evaporation is chromatographed on silica gel using dichloromethane/methanol 20: 1, and the product fractions are combined and evaporated.
This gives the tide compound in the form of a pale yellow wax: lH-NMR (CDCI3): 7.45 (m, 4H), 7.3 (t, 6H)~ 7.1 (s, 2H), 4.3 (t, 4H), 3.8 (m, 8H); FAB-MS: 463 [M++HI.
The starting mate ial is prepared as follows:

a) DimethYI 5.8-diphenvl-5.8-diaza-5,6,7,8-tetrahvdronaphthalene-2.4-dicarboxvlate A solution of 2.24 g (6 mmoV of dimethyl 4,5-bis(trimedlylsilyloxy)cyclohexa-1,4~iene-1,2-dicarboxylate (Example 1 b) and 5.1 g (24 mmol) of N,N'-diphenylethylenediamine (Sigma, Switzerland) is refluxed for 2 hours in 24 ml of glacial acetic acid. The reaction snixture is cooled, the solvent is evaporated, the dark brown ~esidue is dissolved in di-chloromethane and the solution is washed in succession with 20 ml of 1 N HCl,50 ml of saturated NaHCO3 solution and twice using 20 ml of water, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel using hexane/ethyl acetate 3:1, the product fractions are evapo~ated and the residue is recrystallized from ethanol.
This gives the title compound in the form of orange crystals, FAB-MS: 402 [M+], 403 (M~+Hl-Example 6: 4~5-Dianilino-2-hvdroxYmethvlbenzamide Solid sodium borohydride (0.3 g, 0.008 mol) is added in portions with stirring to a solution of 4,5-dianilinophthalimide (Example 2 a, 0.30 g, 0.91 mmol) in methanol (40 ml) until ...,. , . - -~
. ~ . .. . ; ~ , .

..

21~9975 the reaction solution, which was yellow at the beginning, has turned colourless and stardng material can no longer be detected in the thin-layer chromatogram (silica gel, ethyl acetate/hexane 1:1). Sodium chloride soludon is then added, and the product for ned is extracted using ethyl acetate. After drying ~Na2S04) and evaporadon of the ethyl acetate extract, a colourless residue remains which crystallizes from methanoVether. After two crystallization steps, 2-hydroxymethyl-4,5-dianilinobenzamide is obtained in the form of colourless, coarse crystals which melt at 200 with decomposidon. C2(~HlgN302:
molecular weight 333 f.: 333 (FD-MS).

Example 7: 4.5-Bis(4-fluoroanilino)-2-hvdroxvmethYlbenzamide Solid sodium borohydride (0.6 g, 0.016 mol) is added in portions with sdrring to a solution ;
of 4,5-bis(4-fluoroanilino)phthalimide (0.25 g, 0.685 mmol) in methanol (40 ml) until the reaction solution, which was yellow at the beginning, has turned colourless and starting -material can no longer be detected in the thin-layer chromatogram (silica gel, ethyl acetate/hexane 1:1). Sodium chloride solution is then added, and the product formed is -extracted using ethyl acetate. After drying (Na2SO4) and evaporation of the ethyl acetate - -extract, a colourless residue remains which is crystallized twice from ethyl acetate/edler~
This gives 2-hydroxymethyl~,5-di~fluoroanilino)benzamide in the form of colourless crystals, m.p. 81-82C.

C2~HI7~2N3O2: molecular weight 369.37, calc. C 65.03 %; H 4.64 %; N 11.38 %; f.
C 65.09 %; H 4.67 %; N 11.55 %.
The starting materials are prepared as follows:

a) 4.5-Bis(4-fluoroanilino)phthalimide Analogously to Example 2 a, 290 mg (0.7 mmol) of dimethyl 4,5-bis(4-fluoroanilino)-phthalate in 22 ml of ethylene glycol are heated at 120, and ammonia gas is passed through for 18 hours, with stirring. The reaction mixture is cooled and extracted using ethyl acetate. The ethyl acetate phases are washed in succession three times using water and once using saturated sodium chloride solution, dried over sodium sulfate and evapora-ted. The residue obtained by evaporation is chromatographed on silica gel using hexane/-ethyl acetate 1:1, and the production fractions are combined and evaporated. This gives the title compound in the form of orange crystals, m.p. >220C, FAB-MS: 366 [M++H].
b) Dimethyl 4.5-bis(4-fluoroanilino)phthalate . , .;. ~ ~ , 2:~0~7~

A solution of 2.4 g (6 mmol) of dimethyl 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylate (Example 1 b) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid is refluxed for 2 hours. The reaction mixture is cooled, the solvent is evaporated, the dark brown residue is dissolved in dichloromethane, and the solution is washed in succession with 20 ml of 1 N HCl,50 ml of sa~urated NaHCO3 solution and twice using 20 ml of water, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on silica gel using ethyl acetate/hexane 2~
and the product fractions are evaporated and recrystallized from ethyl acetate/hexane. This gives the title compound in the fo~m of yellow crystals, lH-NMR (CDCI3): ~ = 7.40 (s, 2H),7.10-6.80 (m, 8H),5.70 (br s, 2H), 3.83 (s, 6H).

Example 8: 4~5-Dianilino-2-hvdroxYmethYlbenzoic acid Solid sodium borohydride is added in portions with stirring to a solution of 4,5-dianilinophthalic anhydride (0.250 g, 0.75 mmol) in methanol (50 ml) until the reaction solution, which had been an intense yellow at the beginning, has become virtually colourless. Sodium chloride solution and water are then added, the pH is brought to 6 using citric acid solution, and the product formed is taken up by repeated extraction using ethyl acetate. After drying (NaSO4) and evaporation of the ethyl acetate, a colourless substance remains which crystallizes fIom ethyl acetate/ether. This gives 2-hydroxymethyl-4,5-dianilinobenzoic acid in long, thin prisms of m.p. 158-169C(decomposition) .
8Nzo3: molecular weight calc. 334, 334 (FD-MS).
The starting material is prepared as follows:

a) 4.5-Dianilinophthalic anhYdride A solution of 4,5-dianilinophthalic acid in acetic anhydride is heated for 30 minutes at 60C, which results in an intense yellow colour. After evaporation, yellow crystals of 4,5~ianilinophthalic anhydride remain, and these crystals are recrystallized from acetonelether, melting at 19~197C.
C2oHl4N203: molecular weight calc. 330, f~ 330 (FD-MS).

b) 4,5-Dianilinophthalic acid Dimethyl 4,5-dianilinophthalate (Example 2 b, 3.05 g) are refluxed for 2 hours in a 2 1 ~

mixture of methanol (SOa ml) and 1 M sodium hydroxide solution ~100 ml), with the exclusion of oxygen. The methanol is then evaporated in vacuo, and the aLkaline solution of the reaction product is acidified using hydrochloric acid. The title compoundprecipitates rapidly in crystalline forrn and recrystallization from medhylene chloride gives pale yellowish, pointed prisms which melt at 169C widh decomposition. -( 20H,6N2O4: molecular weight calc. 348, 348 (FD-MS).

Example 9: 5.6-Dianilin~2-oxaindan-l-one Upon distillation under a high vacuum (bulb tube, 0.1 torr, bath temperature 210C), 2-hydroxymethyl-4,5-dianilinobenzamide (Example 6) gives a colourless, oily distillate which crystalliæs in acetone/ether. The tide product forms pale yellow, almost colourless, crystals of m.p. 189-190C.

C2oHlON2O2: molecular weight calc. 316, f. 316 (FD-MS).

Example 10: MethYI 4.5-dianilino-2-hYdroxYmethYIbenzamide 5,6-Dianilino-2-oxaindan-1-one (Example 9,70 mg~ together with methylamine in edhanol (33 per cent, 15 ml) is heated for 3 hours at 60C in a sealed tube widl an addition of 5 g of sodium ascorbate (antioxidant). The reaction product (purple solution in edhyl acetatelacetone 1:1) is filtered through silica gel using ethyl acetate, during which process dark, purple substance is retained. The colourless eluate is evaporated, giving crystals which are Iecrystallized from acetone/cthcr. This gives methyl 4,5-dianilino-2-hydroxymethylbcnzamide in the form of colourless prisms, m.p.
167-169C.

C2,H2,N302: molecular weight calc. 347, f. 347 a;D-MS).

Example 11: 4.5-Dianilino-2-hydroxvmethYlbenzohvdrazide 5,6-Dianilino-2-oxaindan-1-one (Example 9, 0.131 g, 0.041 mol) together with methanol (20 ml) and hydrazine hydrate (0.4 ml) is heated in a sealed tube for 12 hours at 70C. The reaction mixture is evaporated, and the residue is crystallized twice from ethylacetatetether. 2-Hydroxymethyl-4,5-dianilinobenzohydrazide forms colourless prisms (0.070 g, 49 % of theory) of m.p. 166-167C.

C20H20N4O2: molecular weight calc. 348, f. 348 (FD-MS).

210997a Example 12: 3-HvdroxY-4.5-dianilino-2-azaindan-l-one (tautomer of 4.5-dianilino-2-formvlbenzamide): ~.
Solid lithium aluminium hydride (in total 0.34 g; 8.9 mmol) is added in portions to a solution of 4,5-dianilinophthalimide (Example 2 a, 0.493 g; 1.49 mmol) in tetrahydrofuran (150 ml), with stirring. The solution, which had been an intense yellow at the beginning, is now only pale yellow. This is followed by an addition of water and such an amount of citric acid that a pH of approximately 4.5 is obtained. The mixture is filtered through Celite~3) (filter auxiliary on a kieselguhr base, Fluka, Switzerland), washed with tetrahydrofuran and ethyl acetate, and the filtrate is then extracted with ethyl acetate. After drying and evaporation, an amorphous lacquer remains which crystallizes on incipient trituration with a smaU amount of ethyl acetate. This gives pale yeUow crystals of 4,5-dianilin~2-formylbenzamide, which are purified by crystallization from methanoVether. M.p. from approx. 220C (decomp.).
C2~HI7N3O2: molecular weight calc. 331, f. 331 (FD-MS).

Example 13: 4,5-Dianilino-2-hydroxyiminomethYlbenzamide The title compound is prepared by abovementione~ processes.

Examp!e 14: 2-AcetoxYmethyl-4.5-dianilinobenzamide A suspension of 76 mg of 4,5-dianilino-2-hydroxymethylbenzamide ~xample 6) in 3 ml of acetic anhydride and 3 ml of pylidine is rapidly dissolved. After remaining at room temperature for 3 hours, the reaction mixture is evaporated in vacuo with an addition of toluene. The colourless residue is composed of the title compound.

C2oH2lN303: molecular wdght calc. 375. f. 375 (FD-MS).

Example 15: 4.5-Dianilinophthalanilide A mixture of 0.106 g of 4,5-dianilinophthalic anhydride (Example 8 a), 20 ml of tetrahydrofuran and 0.2 g of aniline are heated for 90 minutes at 50C. The mixture is then evaporated in vacuo to dryness. The residue obtained by evaporation is dissolved in ether, suspended matter is removed by filtration, and pentane is added to the filtered solution.
After a short while, pale yellow crystals of 4,5-dianilinophthalanilide precipitate. M.p.
approx. 120C (decomp.).

C26H2lN303: molecular weight calc. 423, f. 423 (FD-MS).

`'~ ~ .: : ' ': ` . . : , ` ` :. : .

2~997~

Example 16: (A) Di-(2-hydroxYethyl)5,8-diphenyl-5,8-diaza-6 hydroxY-methYl-5~6~7~8-te~rahYdronaphthalene-23-dicarboxvlate and (B) ~2-hvdroxvethYl)methYl 5~8-diPhenvl-5~8-diaza-5~6.7.8-tetrahydronaphthalene-2~3-dicarbQxvlate:
A suspension of 230 mg (0.7 mmol) of dimethyl 5,8-diphenyl-5,8-diaza-6-hydroxy-methyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate in 40 ml of ethylene glycol is heated at 120; a st~eam of ammonia gas is passed in gently for 24 hours, with stirring.
The reaction mixture is cooled, saturated sodium chloride solution is added, and the mixture is extracted using ethyl acetate. The ethyl acetate phases are washed in succession three times using water and once using saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained by evaporation is applied to silica gel using dichloromethane and chromatographed. The first product fractions are evaporated and the residue is recrystalliæd fiom me~anoVdiedhyl edher. This gives the tide compound (B) in dhe form of yellow crystals: m.p. 155C, FAB-MS: 463 [M++Hl.
-~he second product fractions are combined and evaporated. The residue is recrystallized from edlyl acetate. This gives dhe tide compound (A) in the form of yellow needles: m.p.
170-172C, FAB-MS: 493 [M~+Hl.
The starting materials are prepared as follows:
a) Di nethyl 5.8-diphenYl-5.8-diaza-6-hydroxYmedhYl-5.6.7.8-tetrahvdronaphthalene-2,3-dicarboxYlate 96 mg (2.2 mmol) of sodium hydride (60 % dispersion in oil) are added, under argon, to a solution of 377 mg (1 mmol) of dimethyl 4,5~ianilinophthalate (lixample 2 b) in 10 ml of absolute DMF. A solution of 96 ,ul (1.2 mmol) of epichlorohydrin in 2 ml of absolu~e DMF is added dropwise at RT, and the reaction mixture is heated at 100C and stirred for 12 hours. The reaction mixture is cooled, dle solvent is evaporated, the black residue is dissolved in dichloromethane, and the solution is washed widh water, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on silica gel using ethyl acetate/hexane 1:2, and the product fractions are combined and evaporated.
This gives the tide compound in the form of a pale yellow powder, m.p. 68, FAB-MS:
433 [M++H].

Example 17: 5~8-DiPhenyl-5.8-diaza-6-hvdroxvmethvl-5~6.7.8-tetrahYdronaphthalene-2.3-dicarboxamide In an autoclave, 200 mg (0.4 mmol) of (2-hydroxyedhyl) 5,8-diphenyl-5,8-diaza-6-i - ~ ` ., ! ` ~ ' .
. ''' `` `' .' , ' . . ~ ' ' ' ' ' '' "' ' `` ~ `, . ' ` .

210~7~

hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate are dissolved in 2 ml of methanol, and 10 ml of ammonia are then condensed in. The sealed autoclave is heated for 24 hours at 120. The autoclave is cooled, excess ammonia is expelled with nitrogen at RT, and the residue is washed using ethyl acetate. The yellow suspension is filtered and the solids are washed dhoroughly using ethyl acetate. This gives the tide compound in the form of yellow crystals, m.p. 286, FAB-MS: 403 ~M++H].

Example 18: The following compounds are prepared analogously to the processes and/or examples mentioned hereinabove or hereinbelow:
(a) 4,5~ianilinophthalic diamide (b) 4,5-bis(2-iodoanilino)phdhalic dia nide (c) 4,5-bis(3-iodoanilino)phthalic diamide (prepared analogously to Example 1 from methyl 4,5-bis(3-iodoanilino)phthalate, which is prepared from the title compound of Example 1 b and 3-iodoaniline (Fluka, Switzerland) analogously to Example 1 a), pale yellow crystals from dichlc)romethane, m.p.: 24~245C, FAB-MS.599 (M++H).
d3 4,5-bis(4-iodoanilino)phthalic diamide (e) 4,5-bis(2-methoxyanilino)phthalic diamide (f) 4,5-bis(3-methoxyanilino)phthalic diamide (g) 4,5-bis(4-methoxyanilino)phthalic diamide (h) 4,5-bis(2-cyanoanilino)phthalic diamide (i) 4,5-bis(3-cyanoanilino)phthalic diamide (j) 4,5-bis(4-cyanoanilino)phthalic diamide (k) 4,5-bis(2-py~idineamino)phthalic diamide (1) 4,5-bis(3-pyIidineamino)phthalic diamide (m) 4,5-bis(4-pyridineamino)phthalic diamide (n) 4,5-bis(2-pyrimidineamino)phthalic diamide (o) 4,5-bis(4-pyrimidineamino)phthalic diamide (p) 4,5-bis(S-pyrimidineamino3phthalic diamide (q) 4,5-bis(2-(1,3,5-triazinyl)amino)phthalic diamide (r) 4,5-bis(2-fluoroanilino)phthalic diamide (s) 4,5-bis(3-fluoroanilino)phthalic diamide (t) 4,5-bis(pentafluoroanilino)phthalic diamide (u) 4,5-bis(4-hydroxyanilino)phthalic diamide ~ ~
(v) 4,5-bis(3-hydroxyanilino)phthalic diamide ~ -(w) 4,5-bis(2-hydroxyanilino~phthalic diamide (x) 4,5-bis(4-ethylanilino)phthalic diamide ~ ~;

~ ... . . - .

: . . . . . . ~;

2109~7~
- 100- ' (y) 4,5-bis(3-ethylanilino)phthalic diamide (z) 4,5-bis(2-ethylanilino)phthalic diamide.

Example 19: The following compounds are prepared analogously to the processes and/or examples mentioned hereinabove or hereinbelow:

(a) 4,5-bis(4-methylanilino)phthalic diamide (b) 4,5-bis(methylanilino)phthalic diamide (c) 4,5-bis(2-methylanilino)phthalic diamide (d) 4,5-bis(4-carboxyanilino)phthalic diarnide (e) 4,5-bis(3-carboxyanilino)phthalic diamide (f) 4,5-bis(2-carboxyanilino)phthalic diamide (g) 4,5-bis(4-methoxycarbonylanilino)phthalic diamide (h) 4,5-bis(3-methoxycarbonylanilino)phthalic diarnide (i) 4,5-bis(2-methoxycarbonylanilino)phthalic diarnide (j) 4,5-bis(4-ethoxycarbonylanilino)phthalic diamide :
(k) 4,5-bis(3-ethoxycarbonylanilino)phthalic diamide -(1) 4,5-bis(2-ethoxycarbonylanilino)phthalic diamide (m) methyl 4,5-bis(2-fluoroanilino)phthalarnidate (n) methyl 4,5-bis(2-iodoanilino)phthalamidate (o) methyl 4,5-bis(3-iodoanilino)phthalamidate (p) methyl 4,5-bis(4-iodoanilino)phthalamidate (q) methyl 4,5-bis(2-methoxyanilino)phthalamidate (r) methyl 4,5-bis(3-methoxyanilino)phthalamidate (s) methyl 4,5-bis(4-methoxyanilino)phthalamidate (t) methyl 4,5-bis(2-cyanoanilino)phthalamidate ~
(u) methyl 4,5-bis(3-cyanoanilino)phthalamidate (v) methyl 4,5-bis(4-cyanoanilino)phthalamidate (w) methyl 4,5-bis(2-pyridineamino)phthalarnidate (x) methyl 4,5-bis(3-pyridineamino)phthalamidate (y) methyl 4,5-bis(4-pyridineamino)phthalamidate (z) methyl 4,5-bis(2-pyrimidineaminokhthalamidate.

Example 20: The following compounds are prepared analogously to the processes andlor examples mentioned hereinabove or hereinbelow:

;, . , ~., . . ~ .,, . . ~

210997~

(a) methyl 4,5-bis(4-pyrimidineamino)phthalamidate (b) methyl 4,5-bis(S-pyrimidineamino)phthalamidate (c) methyl 4,5-bis(2-(1,3,5-triazinyl)amino)phthalamidate (d) methyl 4,5-bis(3-fluoroanilino)phthalamidate (e) methyl 4,5-bis(4-fluoroanilino)phthalamidate (f) methyl 4,5-bis(pentafluoroanilino)phthalamidate (g) methyl 4,5-bis(4hydroxyanilino)phthalamidate (h) methyl 4,5-bis(3-hydroxyanilino)phthalamidate (i) methyl 4,5-bis(2-hydroxyanilino)phthalamidate (j) methyl 4,5-bis(4-ethylanilino)phthalamidate (k) methyl 4,5-bis(3-ethylanilino)phthalamidate (1) methyl 4,5-bis(2-ethylanilino)phthalamidate (m) methyl 4,5-bis(4-methylanilino)phthalamidate (n) methyl 4,5-bis(3-methylanilino)phthalamidate . (o) methyl 4,5-bis(2-methylanilino)phthalamidate (p) methyl 4,5-bis(4-carboxyanilino)phthalamidate (q) methyl 4,5-bis(3~arboxyanilino)phthalamidate (r) methyl 4,5-bis(2-carboxyanilino)phthalamidate (s) methyl 4,5-bis(4-methoxycarbonylanilino)phthalamidate (t) methyl 4,5-bis(3-methoxycarbonylanilino)phthalamidate (u) methyl 4,5-bis(2-methoxycarbonylanilino)phthalamidate (v) methyl 4,5-bis(4ethoxycarbonylanilino)phthalamidate (w) methyl 4,5-bis(3-ethoxycarbonylanilino)phthalamidate (x) methyl 4,5-bis(2-ethoxycarbonylanilino)phthalamidate ~ -(y)4-(3-[3-methylureido]propyl)dianilinophthalicdiamide. ~ ~ ~
:
Example 21: The following compounds are prepared analogously to the processes and/or examples mentioned hereinabove or hereinbelow:

(a) 4-(2-aminoethyl)-4,5-dianilinophthalic diamide (b) 4-(3-aminopropyl)-4,5-dianilinophthalic diamide (c) 4-(3-carbarnoylpropyl)-4,5-dianilinophthalic diamide (d) 5,8-diphenyl-5,8-diaza-6-hydroxyiminomethyl-5,6,7,B-tetrahydro-naphthalene-2,3-dicarboxamide (e) ~aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamide :': - - - : ' . -.~ , , , ", ",, "", 210397a (f) methyl 5,8-diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate (g) methyl 4-(3-aminopropyl)-4,5-dianilinophthalamidate (h) methyl ~(3-[3-methylureido]propyl)-dianilinophthalamidate (i) methyl 4(2-aminoethyl)-4,5-dianilinophthalamidate (j) methyl 4(3-carbamoylpropyl~4,5-dianilinophthalamidate (k) methyl 5,8-diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate (1) methyl 6-aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate -:
(m) 5,8-bis(4fluorophenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide (n) 4(3-aminopropyl)-4,5-bis(4fluoroanilino)phthalic diamide (o) ~(3-[3-methylureido]propyl)4,5-bis(4-fluoroanilino)phthalic diamide (p) 4(2-aminoethyl)4,5-bis(4fluoroanilino)phthalic diamide (q) 4(3-carbamoylpropyl)-4,5-bis(4fluoroanilino)phthalic diamide (r) 5,8-bis(4fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamide (s) 6-aminomethyl-5,8-bis(4-fluorophenyl)-5,8 diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamide . .;
(t) methyl 5,8-bis(4fluo~phenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphtha-lene-2,3 -dicarboxamidate (u) methyl 4-(3-aminopropyl)4,5-bis(4-fluoroanilino)phthalamidate (v) methyl 4-(3-13-methylureido]propyl)-4,5-bis(4fluoroanilino)phthalamidate (w) methyl 4(2-aminoethyl)-4,5-bis(4-fluoroanil~no)phthalamidate (x) methyl 4(3-carbamoylpropyl)4,5-bis(4-fluoroanilino)phthalamidate (y) methyl 5,8-bis(4fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahyd~
naphthalene-2,3-dicarboxamidate (z) methyl 6-aminomethyl-5,8-bis(4fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamidate.

Example 22: The following compounds are prepared analogously to the processes and/or examples mentioned hereinabove or hereinbelow:

(a) methyl 5,8-bis(4fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamidate ~, :.
0:. , . : , ..:. .,. ~ .

2~0997~

(b) 4,5-bis(N-allyl-N-phenyl)aminophtnalic amide (prepared analogously to Example 1 from dimethyl 4,5-bis(N-allylanilino)phthalate as secondary product); m.p. 114-116~C, FAB-MS: 428 (M++H).

Preparation of the starting material dimethyl 4,5-bis(N-allylanilino)phthalate:
A solution of 3.67 g (10 mmol) of dimethyl 4,5-bis(anilino)phthalate (Example 2 b) in 15 ml of HMPT (hexamethylphosphoric triarnide) or DMPU is treated, under argon and at RT, with 0.6 g (15.4 mmol) of sodium amide, and the mixture is heated for 30 minutes at 60C. The dark red soludon is cooled to RT and a vacuum is applied for S minutes (1 torr).
Then, a solutdon of 1.5 ml (15.2 mmol) of 1-bromo-3-chloropropane in 2 ml of T~IF is added dropwise, and the reaction mixture is stirred for 18 hours at RT. The reaction mixture is poured into ice-water and extracted using ethyl acetate, and the organic phases are combined and washed thoroughly with water, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on silica gel using hexane/ethyl acetate 5:1. This gives the tide compounds: dimedlyl 4,5-bis(anilino)-N4,Ns-propanediylphthalate in the form of colourless crystals, FAB-MS:
417 ~+Hl; and dimethyl 4,5-bis(N-allylanilino)phthalate in the form of a colourless oil, FAB-MS: 457 ~M++Hl- .

Example 23: The following compound is prepared analogously to dhe processes mentioned hereinabove or hereinafter: `
3-hydroxy-4,5-bis(4-fluoroanilino-2-azaindan-1-one (tautomer of 4,5-bis(4-fluoroanilino)-2-fonnylbenzamide) (pIe~ared analogously to Example 12 from 4,5-bis(4-fluoroanilino)phthalimide (Example 7 a). ~ ;

Example 24: The following compound is prepared analaogously to the processes mentioned hereinabove or hereinafter 4,5-dianilino-2-carbamoylbenzoic acid.

Example 25: 4~5-Bis(4-methvlanilino~2-hydroxvmethvlbenzamide:
Solid sodium borohydride (0.3 g, 8 mmol) is added in portions to a solution of 4,S-bis(4-methylanilino)phthalimide (0.35 g, 0.98 mmol) in methanol (40 ml) at 40C, with stilring, until the reaction solution, which was yellow at the beginning, has turned colourless and starting material can no longer be detected in the thin-layer chromatograrn (silica gel, ethyl acetate/hexane 1:1). Sodium chloride solution is then added, and the product fonned is extracted using ethyl acetate. After drying over Na2SO4 and evaporation of the ethyl acetate extract, a colourless residue remains, and this residue is crystallized . .. . .. :~ . .

~ ~ ., :
; . , ~ , . . .
: ~:. . , : . .
,~,, ~ . . :

2109~7~

from acetone/diethyl ether. After two crystallization steps, the tide compound is obtained in the form of colourless crystals which melt between 170 and 172C with decomposition:
C22H23N3O2: molecular weight calc. 361 f. 361 (FD-MS).
The star~ing material is prepared as follows: -~

a) Dimethvl 4.5-bis(trimethvlsilYloxv)cvclohexa- 1,4-diene- 1,2-dicarboxylate:
A solution of 7.1 g (50 mmol) of dimethyl acetylenedicarboxylate (Fluka, Switzerland) in 30 ml of toluene is added dropwise under argon to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (Aldrich, Federal Republic of Germany) (95 %), and the mixture is subsequendy refluxed for 19 hours. The reaction mixture is cooled, the solvent is evaporated, and the residue is dis~lled under a high vacuum (0.1 mbar, 124-127C). This gives the tide compound as a yellow highly viscous oil, lH-NMR
(CDCl3): ~0.18 (s, 18H); 3.09 (s,4H); 3.78 (s, 6H). ~ - ~

b) Mmethvl 4~5-Bis(4-methvlanilino)phthalate: `
A solution of 50 g (0.134 mol) of dirnethyl 4,5-bis~trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylate and 57.4 g (0.54 mol) of p-toluidine in 540 ml of glacial acedc acid is refluxed for4 hours. The reaction mixture is cooled, the solvent is evapoqated, the dark bro vn residue is dissolved in dichloromethane, and the solution is washed in succession with 20 ml of 1 N HCl,50 ml of saturated NaHCO3 solution and twice with 20 ml of waterl dried over Na2SO4 and evaporated. The crude product is recrystallized from ethanol. This gives the title compo~nd in the form of yellow crystals, m.p. 170C, C24H24N2O4 molecular wdght calc. 404, f. 404 (E7D-MS).

c) 45-Bis(4-methvlanilino)phthalic acid:
Dimethyl 45-bis(4-methylanilino)phthalate (0.98 g) is refluxed for 24 hours in a mixture of methanol (150 ml) and 2 M sodium hydroxide solution (25 ml) with the exclusion of oxygen. The methanol is then evaporated in vacuo, and the alkaline solution of the reaction product is acidified using hydrochloric acid. The dicarboxylic acid which has separated out is taken up in tetrahydrofuran and ethyl acetate and processed direcdy in crude form.

d) 4.5-Bis(4-medhvlanilino~phdhalic anhvdride:
A solution in acetic anhydride of the crude 4,5-bis(4-methylanilino)phthalic acid which has just been mentioned above is heated for 30 minutes at 60C, during which process the 21 ~9~7~

colour changes tO an intense yellow. After evaporation, crystals of 4,5-bis(4-methylanilino)phthalic anhydride remain, which are recrystallized fromacetone/diethyl ether and then melt at æl-223C. C22Hl8N2O3 molecular weight calc.
358, f. 358 (E7D-MS).

e) 4.5-bis(4-methvlanilino)phthalimide:
Ammonia is passed for 4 hours at 120C into a solution of 4,5-bis(4-methylanilino)phthalic anhydride (0.74 g) in 2-ethoxyethanol (40 ml). The mixture is then evaporated and the dark residue freed from polar, resinous material by filtration on silica gel (eluent ethyl acetate/hexane 1:1). The pu~ified title compound obtained gives reddish orange, very coarse crystals from diethyl ether/pent~ne, which melt at 223-235C with decomposition. C22Hl9N3O2 molecular weight calc. 357, P 357 ~FD-MS).

Example26:3-HvdroxY-2-methvl-4.5-dianilino-2-azaindan-1-one(tautomerof N-methyl4.5-dianilin~2-formvlbenzamide):
Solid sodium borohydride (0.07 g, 1.8 mmol) is added at 40C with sturing to a solution of N-methyl-4,5-diani1inophthalimide (Q07 g, 0.2 mmol) in methanol (10 ml) until the reaction solution, which was yellow at the beginning, has turned colourless and star~ng -~
material is no longer detectable in the thin-layer chromatogram (silica gel, ethyl acetateJhexane 1:1). Sodium chloride solution is then added to the-resulting product, and ~ - ;
the resulting product is extracted using ethyl acetate. After drying (Na2SO4~ and evaporation of the ethyl acetate cxtract, dhe residue is purified by chromatography over silica gel using ethyl acetatelhexane 1:1 as eluent. The tide compound is eluted as the main product after a very weak yellow band. When evapo~ated fmm medhylene chloride, it `
forms a pale yellow foam. C2lH,9N302, molecular weight calc. 345, f. 345 (~D-MS).
The st~ng material is prepared as follows:

a) N-Methvl4.5-dianilinophtha1imide:
376 mg (1 mmol) of dimethyl 4,5-bis(anilino)phthalate (Example 2 b) in 33 ml of ethylene glycol are heated at 120, and methylamine is passed tl~ugh for 18 hours, with stirring.
The reaction mixture is cooled and extracted using ethyl acetate. The ethyl acetate phases are washed in succession three times using wat~r and once using saturated sodiumchloride solution, dried over sodium sulfate and evaporated. The residue obtained by evaporation is chromatographed on sitica gel using hexanelethyl acetate 1:1, and the , .,5,, ~ - ~- -, :: . : . :: : ~ .:: , . ~ ~ ~ .............. .. .

:: ,.. , : . . . . .

2~0~7~

product fractions are combined and evaporated. This gives the title compound in the form of pale yellow crystals, FAB-MS: 344 [M++H], m.p. 195-6C.

Example 27: MethYl 4.5-bis(4-methylanilino)phthalamidate:
A solution of methyl 4,5-bis(4methylanilino)phthalate (0.192 g, 0.49 mmol) in acetonitrile (25 ml) and tetrahydrofu~n (25 ml) is left to stand for 48 hours at room temperature together with ammonium hydrogencarbonate (0.080 g, 1 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.130 g, 0.52 mmol). The reaction mixture, which has been evaporated, is purified by chromatography on silica gel, the main product isolated being a material of Rf = 0.53 (thin-layer chromatogram on silica gel 60, ~ -Merck, Darmstadt, Federal Republic of Germany; eluent ethyl acetate), which is the title compound. The title compound forms coarse prisms from tetrahydrofuran/diethyl ether which decompose from 175C while the colour changes to yellow (imide formation).C23H23N3O3, molecular weight calc. 389, f. 389 (FD-MS).
The starting material is prepared as follows:

a) Methyl 4.5-bis(4methylanilino)phthalate:
4,5-Bis(4methylanilino)phthalic anhydnde (0.10 g; Example 25 d) is refluxed for 30 minutes together with methanol (0.30 ml) and pyridine (3 ml) with an addition of 4dimethylaminopyridine (0.05 g). The solution, which is virtually colourless, is then evaporated, the residue is taken up in ethyl acetate, and this is washed in succession with citric acid solution and concentrated sodium chloride soludon. After dTying (Na2SO4) and evapoIadon of the ethyl acetate solution, the residue, which has turned yellowish, is recrystallized fIom tetrahydrofuran/diedhyl edher. The dde compound is obtained in the fo~m of crystals of m.p. 167-169C. C23H22N2O4, molecular weight calc. 390, f. 391 (M++l, FAB-MS).

Example 28: 5000 capsules are prepared, each of which comprises 0.25 g of acdve ingredient, for example one of dhe compounds prepared in Examples 1-27:

Composition Active ingredient 1250 g Talc 180g Wheat starch 120 g Magnesium stearate 80 g ~s.:.~ . : - . , : . ...

,,.~ : . - - ~ :. .... . ..
~, . . .. . . .:

-107 2109~37S

Lactose 20 g Procedure: The pulverulent substances are passed through a sc.reen of mesh size 0.6 mm and mixed. Gelatin capsules are filled with 0.33 g por~ons of the mixture by means of a capsule-filling machine.0 ~ -:
: . :
.

:
.

Claims

WHAT IS CLAIMED IS:

l. A compound of the formula I

(I) in which A1 and A2 independently of one another are hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, heterocyclyl-lower-alkyl, acyl, lower alkylsulfonyl or arylsulfonyl, or in which Ar1 and Ar2 together are unsubstituted of substituted lower alkylene; Ar1 and Ar2 independently of one another are aryl, heteroaryl or unsubstituted or substituted cycloalkyl, X is O or S, Y is amino, substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio; or furthermore, if X is O and Z is substituted methyl, Y is hydroxyl; and Z is substituted methyl, carboxyl, esterified carboxyl or an analogous radical in which the oxo of the carbonyl radical is replaced by thio, or amidated carboxyl or an analogous radical in which the oxo of the carbonyl radical is replaced by thio; or Y and Z together are 1-oxamethylene which is bonded via the oxygen in the position of Y and via the methylene carbon atom in the position of Z; and, if salt-forming groups are present, to salts thereof, and/or, if tautomerizable radicals are present, to tautomers thereof.
2. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another represent hydrogen, lower alkyl, substituted lower alkyl which is substituted by up to 2 radicals selected from the series consisting of amino, mono- or di-lower-alkylamino, in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkcylcarbamoyl and/or cyano or is unsubstituted C3-C8cycloalkylamino, phenyl-lower-alkylamino, phenylamino, lower alkanoylamino,phenyl-lower-alkanoylamino, phenylcarbonylamino, hydroxyl, lower aLkoxy in which the lower alkoxy radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkoxy, lower alkanoyloxy, mercapto, lower alkylthio in which the lower alkyl radical ismonosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkylthio, lower alkanoylthio, carboxyl, lower alkoxy-carbonyl, phenyl-lower-alkoxycarbonyl, cyano, carbamoyl, N-lower-alkylcarbamoyl,N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower-alkylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl, ureido, ureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, thioureido, thioureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, amidino, amidino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, guanidino, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, oxo which is not bonded on the carbon which is bonded to the nitrogen carrying A1 or A2, thioxo, imino, lower alkylimino, lower alkanoylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono, N-lower-alkanoylhydrazono, lower alkoxycarbonylhydrazono, lower alkylthioimino, or lower alkenyl or lower alkynyl, each of which is substituted by one of the radicals mentioned for substituted lower alkyl or is unsubstituted, heterocyclyl-lower-alkyl in which heterocyclyl is a radical selected from the series consisting of pyrrolyl, 2,5-dihydro-pyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4 or 1,3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro-isothiazolyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin-1-yl, morpholino, thiomorpholino, S,S-dioxothiomorpholino, 1,2-dihydro- or 1,2,3,4tetrahydroguinolyl and 1,2-dihydro or 1,2,3,4-tetrahydroisochinolyl, each of which is bonded terminally to lower alkyl and bonded via a ring nitrogen atom and each of which is unsubstituted or substituted by lower alkyl, lower alkanoyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, lower alkylsulfonyl, benzenesulfonyl or toluenesulfonyl; or in which A1 and A2 together form lower alkylene which is unsubstituted or substituted by up to 3 substituents selected from the series consisting of lower alkyl, amino, amino-lower-alkyl, mono- or di-lower-alkylamino or mono- or di-lower-alkylamino-lower-alkyl in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkyl-amino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, cycloalkylamino, cycloalkylamino-lower-alkyl, phenyl-lower-alkylamino, phenyl-lower-alkylamino-lower-alkyl, phenylamino, phenyl-amino-lower-alkyl, lower alkanoylamino, phenyl-lower-alkanoylamino, phenylcarbonyl-amino, lower alkanoylamino-lower-alkyl, phenyl-lower-alkanoylamino,lower-alkyl, phenylcarbonylamino-lower-alkyl, hydroxyl, hydroxy-lower-alkacyl, lower alkoxy or lower-alkoxy-lower-alkyl in which the terminal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy,halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkcoxy, phenyl-lower-alkoxy-lower-alkyl, lower alkanoyloxy, lower-alkanoyloxy-lower-alkyl, mercapto, mercapto-lower-alkyl, lower alkylthio or lower-alkylthio-lower-alkyl in which the terminal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyL N,N-di-lower-alkylcarbamoyl andlor cyano or is unsubstituted, phenyl-lower-alkylthio, phenyl-lower-alkylthio-lower-alkyl, lower alkanoylthio, lower-alkanoylthio-lower-alkyl, carboxyl, carboxy-lower-alkyl, lower alkoxycarbonyl, lower-alkoxy-carbonyl-lower-alkyl, phenyl-lower-alkoxycarbonyl-lower-alkyl, cyano, cyano-lower-alkyl, carbamoyl, carbamoyl-lower-alkyl, N-lower-alkylcarbamoyl, N,N-di-lower-aLkylcarbamoyl, N-lower-alkylcarbamoyl-lower-alkyl, N,N-di-lower-alkyl-carbamoyl-lower-alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower-alkyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower-alkyl, thiocarbamoyl, thiocarb-arnoyl-lower-alkyl, N-lower-alkylthiocarbamoyl, N-lower-alkylthiocarbamoyl-lower-alkyl, N,N-di-lower-alkylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl-lower-alkcyl, ureido, ureido-lower-alkyl, or ureido or ureido-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, thioureido, thio-ureido-lower-alkyl, or thioureido or thioureido-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, hydrazino or hydrazino-lower-alkyl, or hydrazino or hydrazino-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, amidino or amidino-lower-alkyl, or amidino or amidino-lower-alkyl, each of which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, guanidino or guanidino-lower-alkyl, or guanidino or guanidino-lower-alkyl, each of which is unsubstituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, oxo, oxo-lower-alkyl, thioxo, thioxo-lower-alkyl, imino, imino-lower-alkyl, lower alkylimino, lower-alkylimino-lower-alkyl, lower alkanoylimino, lower-alkanoyl-imino-lower-alkyl, hydroxyimino, hydroxyimino-lower-alkyl, lower alkoxyimino, lower-alkoxyimino-lower-alkyl, hydrazono, hydrazono-lower-alkyl, N-mono- or N,N-di-lower-alkylhydrazono, N-mono- or N,N-di-lower-alkylhydrazono-lower-alkyl, N-lower-alkanoylhydrazono, lower alkoxycarbonylhydrazono, N-lower-alkanoylhydrazono-lower-alkyl, lower-alkoxycarbonylhydrazono-lower-alkyl, lower alkylthioimino andlower-alkylthioimino-lower-alkyl; Ar1 and Ar2 independendy of one another are aryl, heteroaryl selected from the series consisting of irnidazolyl, triazolyl, pyridyl, pyrimidinyl and triazinyl, each of which is unsubstituted or substituted by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano andlor trifluoromethyl, or C3-C8cycloalkyl which is unsubstituted or substituted by lower alkoxy or hydroxyl; X is O or S; Y is amino, mono- or di-lower-alkylarnino in which lower alkyl is unsubstituted or substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkyl-amino, di-lower-alkylamino, mercapto, lower alkyldlio, lower alkylsulfinyl, lower alkyl-sulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbarnoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, C5-C7cycloalkylamino, phenyl-lower-alkylamino, phenylamino, lower alkanoylamino, halo-lower-alkanoylamino, phenyl-lower-alkanoyl-amino, phenylcarbonylamino, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl which is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkyla nino, di-lower-alkyl-amino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, or by aryl or aryl-lower-alkyl, or is hydroxyamino, lower alkoxyamino in which the lower alkyl radical is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, lower alkyleneamino or lower alkyleneamino which is interrupted by -O-, -S- or -NR'- in which R' is lower alkyl or lower alkanoyl, lower alkoxy, in which the lower alkyl radical is mono- or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, or lower alkylthio which isunsubstituted or mono- or disubstituted in the lower alkylthio radical by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano, or furthermore, if X is oxygen and Z is substituted methyl, Y is hydroxyl; Z is substituted methyl in which the substituent is selected from the series consisting of amino, mono- or di-lower-alkylamino in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, lower alkanoylamino, hydroxyl, lower alkoxy in which the alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, amino, lower alkyl-amino and/or di-lower-alkylamino or is unsubstituted, lower alkanoyloxy, lower alkylthio in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, macapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, cyano, ureido, 1- or 3-mono-lower-alkylureido, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl, guanidino, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl; oxo, imino, lower alkylimino, hydroxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono and lower alkylthioimino; carboxyl, lower alkoxycarbonyl or lower alkylthiocarbonyl in which the lower alkyl radical is mono-or disubstituted, by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkysulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted;
aryloxycarbonyl or aryl-lower-alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl in which lower alkyl is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower- alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, C5-C7cycloalkylaminocarbonyl, N-phenyl-lower-alkylcarbamoyl, phenylcarbamoyl, hydrazinocarbonyl, hydrazinocarbonyl which is substituted on one or both nitrogen atoms by lower alkyl which is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, by aryl or by aryl-lower-alkyl; hydroxyaminocarbonyl, lower alkoxyamino-carbonyl in which the lower alkyl radical is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, lower alkyleneaminocarbonyl or lower alkyleneaminocarbonyl which is interrupted by -O, -S- or-NR'- in which R' is lower alkyl or lower alkanoyl, or a corresponding thio analogue of the abovementioned radicals in which the bonding carbonyl group is replaced by thiocarbonyl; or in which Y and Z
together form a bivalent radical of the formula -O-CH2-, the oxygen being bonded in the place of Y and the methylene carbon instead of Z;

where, in the abovementioned radicals, aryl is phenyl which is unsubstituted or substituted by one or more substituents selected from the group comprising lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent C atoms), C5-C7cycloalkyl, phenyl-lower-alkyl or phenyl; lower alkyl which is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano; hydroxyl; lower alkoxy, halo-lower-alkoxy, phenyl-lower-alkoxy, phenyloxy, lower alkenyloxy, halo-lower-alkenyloxy or lower alkynyloxy; lower alkylenedioxy (linked to two adjacent C atoms); lower alkanoyloxy, phenyl-lower-alkanoyloxy or phenylcarbonyloxy; mercapto; lower alkylthio, phenyl-lower-alkylthio, phenylthio, lower alkylsulfinyl; phenyl-lower-alkylsulfinyl, benzenesulfinyl, lower alkyl-sulfonyl, phenyl-lower-alkylsulfonyl or benzene-sulfonyl; halogen, nitro, amino; lower alkylamino, C5-C7cycloalkylamino, phenyl-lower-alkylamino or phenylamino;
di-lower-alkylamino, N-lower-alkyl-N-phenylamino, N-lower-alkyl-N-phenyl-lower-alkylamino, lower alkyleneamino; lower alkanoylamino, phenyl-lower-alkanoyl-amino or phenylcarbonylamino; lower alkanoyl, phenyl-lower-alkanoyl or phenyl-carbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl; cyano, phosphoryloxy which is substituted on the phosphorus by two radicals which, independently of one another, are selected from the series consisting of hydroxyl, lower alkoxy and phenyl-lower-alkoxy, such as benzyloxy, or phosphoryloxy which is substituted on the phosphorus by phenylene-1,2-dioxy, sulfo (SO3H); lower alkoxy-sulfonyl; sulfamoyl, N-lower-alkylsulfamoyl, N,N-di-lower-alkylsulfamoyl and N-phenylsulfamoyl; where phenyl groups in the substituents are in each case unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxyl, halogen and/or trifluoromethyl;
salts thereof, if salt-forming groups are present, and/or tautomers thereof, if tautomerizable radicals are present.
3. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another are hydrogen, amino-lower-alkyl, carbamoyl-lower-alkyl, (3-lower-alkylureido)-lower-alkyl or lower alkenyl, or in which A1 and A2 together form 1,2-ethylene which is unsubstituted or substituted by a substituent selected from the series consisting of amino-lower-alkyl, hydroxy-lower-alkoyl and hydroxyimino-lower-alkyl;
Ar1 and Ar2 independently of one another are unsubstituted phenyl or phenyl which is substituted in the o-, m- or p-position selected from the series consisting of lower alkyl, hydroxyl, lower alkoxy, halogen, carboxyl, lower alkoxycarbonyl and cyano, or are 2-, 3-or 4-pyridyl, 2-, 4- or 5-pyrimidinyl of 1,3,5-triazin-2-yl; X is oxygen; Y is amino, lower alkylamino, phenylamino, hydroxy-lower-alkoxy or hydrazino, or furthermore, if Z is hydroxymethyl, lower alkanoyloxymethyl, formyl or hydroxyiminomethyl, Y is hydroxyl;
Z is hydroxymethyl, lower alkanoyloxymethyl, carboxyl, lower alkoxycarbonyl, hydroxy-lower-alkoxycarbonyl, carbamoyl, formyl or hydroxyiminomethyl; or in which Y
and Z together form a bivalent radical of the formula -O-CH2-, where the oxygen is bonded in the place of Y and the methylene carbon in the place of Z, salts thereof, if salt-forming groups are present, and/or a tautomer or tautomers thereof, if tautomerizable radicals are present.
4. A compound of the formula I according to claim 1, in which A1 and A2 are in each case a hydrogen atom; Ar1 and Ar2 independently of one another are phenyl which is unsubstituted or substituted in the o-, m- or p-position by a radical selected from amongst lower alkyl, hydroxyl, lower alkoxy, halogen, carboxyl, lower alkoxycarbonyl and cyano, or is pentafluorophenyl; X is oxygen;, Y is amino; and Z is carbamoyl; or salts thereof, if salt-forming groups are present.
5. A compound of the formula I according to claim 1, in which A1 and A2 together are 1,2-ethylene which is unsubstituted or substituted by a radical selected from amongst hydroxy-lower-alkyl, amino-lower-alkyl and hydroxyiminolower-alkyl, Ar1 and Ar2 independently of one another are phenyl which is unsubstituted or substituted in the o-, m-or p-position by a radical selected from amongst lower alkyl, hydroxyl, lower alkoxy, halogen, carboxyl, lower alkoxycarbonyl and cyano, or is pentafluorophenyl; X is oxygen;
Y is amino or hydroxy-lower-alkoxy; and Z is carboxyl, lower alkoxycarbonyl, hydroxy-lower-alkoxycarbonyl or carbamoyl; or salts thereof, if salt-forming groups are present.
6. A compound of the formula I according to claim 1, in which Al and A2 independently of one another are hydrogen or lower alkyl which is substituted by up to 2 radicals selected from the series consisting of amino, mono- or di-lower-alkylamino in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted; C5-C7cycloalkylamino, phenyl-lower-alkylamino or phenylamino; lower alkanoylamino, phenyl-lower-alkanoylamino or phenylcarbonylamino; hydroxyl, lower alkoxy in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkoxy, lower alkanoyloxy, mercapto, lower alkylthio in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or unsubstituted, phenyl-lower-alkylthio, lower alkanoylthio, carboxyl, lower alkoxycarbonyl, phenyl-lower-alkoxycarbonyl, cyano, carbamoyl, N-lower-alkyl-carbamoyl, N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower-alkylthiocarbamoyl, N,N-di-lower-alkylthiocarbamoyl, ureido, ureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, thioureido, thioureido which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, hydrazino, hydrazino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, amidino, amidino which is substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, guanidino, guanidino which is substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower-alkyl, oxo which is not bonded to the carbon which is bonded to the nitrogen carrying A1 or A2, thioxo, imino, lower alkylimino, lower alkanoylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono, N-lower-alkanoylhydrazono, and lower alkylthioimino; Ar1 and Ar2 independently of one another are aryl or heteroaryl; X is O; Y is amino, lower alkylamino, phenylamino, hydrazino, or hydroxy-lower-alkoxy, or furthermore, if Z is substituted methyl, Y is hydroxyl; and Z is substituted methyl, carboxyl or esterified carboxyl or in which Y and Z
together form a bivalent radical of the formula -O-CH2- where the oxygen is bonded in the place of Y and the methylene carbon in the place of Z, where, in the abovementioned definitions, aryl is phenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent C atoms), C5-C7cycloalkyl, phenyl-lower-alkyl or phenyl; lower alkyl which is substituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, loweralkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano;
hydroxyl; lower alkoxy, halo-lower-alkoxy, phenyl-lower-alkoxy, phenyloxy, loweralkenyloxy, halo-lower-alkenyloxy or lower alkynyloxy; lower alkylenedioxy (linked to two adjacent C atoms); lower alkanoyloxy, phenyl-lower-alkanoyloxy or phenylcarbonyloxy; mercapto; lower alkylthio, phenyl-lower-alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower-alkylsulfinyl, benzenesulfinyl, lower alkylsulfonyl,phenyl-lower-alkylsulfonyl or benzenesulfonyl; halogen, nitro, amino; lower alkylamino, C5-C7cycloalkylamino, phenyl-lower-alkylamino or phenylamino; di-lower-alkylamino, N-lower-alkyl-N-phenylamino, N-lower-alkyl-N-phenyl-lower-alkylamino, lower alkyleneamino, lower alkanoylamino, phenyl-lower-alkanoylamino or phenylcarbonyl-amino; lower alkanoyl, phenyl-lower-alkanoyl or phenylcarbonyl; carboxyl; lower alkoxy-carbonyl; carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl, N-hydroxy-carbamoyl or N-phenylcarbamoyl; cyano, phosphoryloxy which is substituted on thephosphorus by two radicals selected independently of one another from amongst hydroxyl, lower alkoxy and phenyl-lower-alkoxy, such as benzyloxy, or phosphoryloxy which is substituted on the phosphorus by phenylene-1,2-dioxy; sulfo; lower alkoxysulfonyl;
sulfamoyl, N-lower-alkylsulfamoyl, N,N-di-lower-alkylsulfamoyl and N-phenyl-sulfamoyl; where phenyl groups in the substituents are in each case unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxyl, halogen and/or trifluoromethyl;

and heteroaryl is a 5- or 6-membered ring which has up to 3 ring nitrogen atoms which is linked via a ring carbon atom, it being possible for the ring to be unsubstituted or substituted by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl;
and salts thereof, if salt-forming groups are present, and/or tautomers thereof, if tautomerizable radicals are present.
7. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another are hydrogen or lower alkyl which is substituted by up to 2 radicals selected from the series consisting of amino, mono- or di-lower-alkylamino in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkylamino, phenylamino, lower alkanoylamino, phenyl-lower-alkanoylamino, phenylcarbonylamino, hydroxyl, lower alkoxy in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower-alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and/or cyano or is unsubstituted, phenyl-lower-alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, phenyl-lower-alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl, ureido, 1- or 3-mono-or 1,3- or 3,3-di-lower-alkylureido, oxo which is not bonded on the carbon which is bonded to the nitrogen carrying A1 or A2, imino and hydroxyimino; Ar1 and Ar2 independently of one another are phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoromethyl, hydroxyl, lower alkoxy, halogen, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkylcarbamoyl and cyano, or are heteroarylselected from amongst 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl and 1,3,5-triazin-2-yl, each of which is unsubstituted or substituted by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl; X is O; Y is amino, lower alkylamino, phenylamino, hydrazino or hydroxy-lower-alkoxy, or furthermore, if Z is hydroxymethyl, lower alkanoyloxymethyl, formyl or hydroxyiminomethyl, Y is hydroxyl; and Z is hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxyl, lower alkoxycarbonyl, hydroxy-lower-alkoxycarbonyl or hydroxyiminomethyl; or in which Y and Z togetherform a bivalent radical of the formula -O-CH2-, where oxygen is bonded in place of Y and the methylene carbon in place of Z; and salts thereof, if salt-forming groups are present, and/or tautomers thereof, if tautomerizable radicals are present.
8. A compound of the formula I according to claim 1 selected from amongst the compounds having the designations 4,5-bis(4-fluoroanilino)phthalic diamide, bis(2-hydroxyethyl)-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate, 4,5-dianilinophthalic diamide, 4,5-bis(2-iodoanilino)phthalic diamide, 4,5-bis(3-iodoanilino)phthalic diamide, 4,5-bis(4-iodoanilino)phthalic diamide, 4,5-bis(2-methoxyanilino)phthalic diamide, 4,5-bis(3-methoxyanilino)phthalic diamide, 4,5-bis(4-methoxyanilino)phthalic diamide, 4,5-bis(2-cyanoanilino)phthalic diamide, 4,5-bis(3-cyanoanilino)phthalic diamide, 4,5-bis(4-cyanoanilino)phthalic diamide, 4,5-bis(2-fluoroanilino)phthalic diamide, 4,5-bis(3-fluoroanilino)phthalic diamide, 4,5-bis(pentafluoroanilino)phthalic diamide, 4,5-bis(4-hydroxyanilino)phthalic diamide, 4,5-bis(3-hydroxyanilino)phthalic diamide, 4,5-bis(2-hydroxyanilino)phthalic diamide, 4,5-bis(4-ethylanilino)phthalic diamide, 4,5-bis(3-ethylanilino)phthalic diamide, 4,5-bis(2-ethylanilino)phthalic diamide, 4,5-bis(4-methylanilino)phthalic diamide, 4,5-bis(3-methylanilino)phthalic diamide, 4,5-bis(2-methylanilino)phthalic diamide, 5,8-diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-di-carboxamide, 6-aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamide, methyl 5,8-diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, methyl-6-aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, 5,8-bis(4-fluorophenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide, 6-aminomethyl-5,8-bis(4-fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamide, methyl-5,8-bis(4-fluorophenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphtha-lene-2,3-dicarboxamidate, methyl-6-aminomethyl-5,8-bis(4-fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, methyl-5,8-bis(4-fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxamidate, methyl-5,8-bis(4-fluorophenyl)-5,8 diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate, 5,8-bis(4-fluorophenyl)-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2, 3-dicarboxamide, methyl-5,8-diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamidate or 5,8-diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide, or pharmaceutically acceptable salts thereof, if salt-forming groups are present.
9. 4,5-Bis(4-fluoroanilino)phthalic diamide according to claim 4.
10. Methyl 4,5-dianilinophthalamidate according to claim 6.
11. 4,5-Dianilinophthalamide according to claim 6, or a pharmaceutically acceptable salt thereof.
12. Di-2-hydroxyethyl 4,5-dianilinophthalate according to claim 6.
13. Methyl 2-hydroxyethyl 4,5-bis(anilino)phthalate according to claim 6.
14. Bis(2-hydroxyethyl)-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate according to claim S, or a pharmaceutically acceptable salt thereo
15. 4,5-Dianilino-2-hydroxymethylbenzamide according to claim 6.
16. 4,5-Bis(4-fluoroanilino)-2-hydroxymethylbenzamide according to c}airn 6.
17. 4,5-Dianilino-2-hydroxymethylbenzoic acid according to claim 6 or a pharmaceutically acceptable salt thereof.
18. 5,6-Dianilino-2-oxaindan-1-one according to claim 6.
19. N-Methyl-4,5-dianilino-2-hydroxymethylbenzamide according to claim 6.
20. 4,5-Dianilino-2-hydroxymethylbenzohydrazide according to claim 6.
21. 3-Hydroxy-4,5-ianilino-2-azaindan-1-one according to claim 6.
22. 4,5-Dianilino-2-hydroxyiminomethylbenzamide according to claim 6.
23. 2-Acetoxymethyl-4,5-dianilinobenzamide according to claim 6.
24. 4,5-Dianilinophthalanilide according to claim 6.
25. A compound of the formula I according to claim 6, selected from amongst 4,5-dianilino-3-carbamoyl-2-carboxylic acid and 3-hydroxy-4,5-bis(4-fluoro-anilino)-2-azaindan-1-one, and salts thereof, if salt-forming groups are present.
26. 4,5-Dianilinophthalanilide according to claim 6.
27. Di-(2-hydroxyethyl) 5,8-diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboxylate according to claim 4.
28. 2-Hydroxyethyl methyl 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate according to claim 4.
29. 5,8-Diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxamide according to claim 4.
30. 4,5-Bis(3-iodoanilino)phthalic diamide according to claim 4 or 6.
31. 4,5-Bis(N-allyl-N-phenyl)aminophthalamide according to claim 1.
32. 4,5-Bis(4-methylanilino)-2-hydroxymethylbenzamide according to claim 6.
33. 3-Hydroxy-2-methyl-4,5-dianilino-2-azaindan-1-one according to claim 6.
34. Methyl 4,5-bis(4-methylanilino)phthalamidate according to claim 6.
35. A pharmaceutical composition comprising compounds of the formula I or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to any one of claims 1, 4 or 6 together with pharmaceutically acceptable excipients.
36. A phannaceutical composition which is suitable for administration to a representative of a warm-blooded species suffering from a disease which responds to an inhibition of protein kinase, comprising an amount of a compound or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group of the formula I according to claim 1, which is effective for inhibiting the protein kinase, together with at least one pharmaceutically acceptable excipient.
37. Use of a compound of the formula I or of a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to any one of claims 1, 4 or 6 for the preparation of pharmaceutical compositions.
38. Use of a compound of the formula I or of a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to any one of claims l to 34 for the preparation of pharmaceutical compositions against those diseases which respond to an inhibition of protein tyrosine kinases.
39. Use of a compound of the formula I or of a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to any one of claims 1, 4 or 6 for the preparation of pharmaceutical compositions for use against those diseases which respond to an inhibition of the activity of the EGF receptor kinase.
40. Use of a compound of the formula I or of a pharmaceudcally acceptable salt of such a compound with at least one salt-forming group according to any one of claims 1, 4 or 6 for the preparation of pharmaceutical compositions for the treatment of diseases which respond to an inhibition of protein tyrosine kinases or serin/threonine kinases.
41. Use of a compound of the formula I or of a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to any one of claims 1, 4 or 6 for the inhibition of EGF-receptor-associated protein tyrosine kinases.
42. A method for the treatment of a representative of a warm-blooded species suffering from those diseases which respond to an inhibition of protein kinase, which comprises administering, to this representative of a warm-blooded species requiring this treatment, a dose of a compound of the formula I or of a pharmaceutically acceptable salt of such a compound with at least one salt-forming group according to claim 1, which is effective for the treatment of these diseases.
43. A process for the preparation of a compound of the formula I according to claim 1, which comprises, a) to prepare the compounds of the formula I in which X is O, Y is amino, substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio and Z is carboxyl, esterified carboxyl or amidated carboxyl, and in which the remaining radicals are as defined for compounds of the formula I, or a salt thereof, reacting a reactive acid derivative of a dicarboxylic acid of the formula II, (II) in which A1, A2, Ar1 and Ar2 are as defined above, with a compound of the formula III
W1-H (III) in which W1 is unsubstituted or substituted amino, substituted lower alkoxy or unsubstituted or substituted lower alkylthio, to introduce the radical Y, and/or with water or with a compound of the formula IV

W2-H (IV) in which W2 is a complementary radical suitable for the preparation of esterified carboxyl or amidated carboxyl Z, so as to prepare the radical Z; functional groups which are not to participate in the reaction and which are present in the starting materials of the formulae II, III and IV, being, if necessary, in protected form, and detaching protecting groups which are present before and/or after one of the additional operational procedures mentioned below, or b) to prepare compounds of the formula I, in which Z is hydroxymethyl or formyl and in which the remaining radicals are as defined for compounds of the formula I, or a salt and/or tautomer thereof, reducing a carboxylic acid of the formula V
(V) in which Y' is hydroxyl or one of the radicals Y as defined for compounds of the formula I, with the proviso that X is oxygen if Y' is hydroxyl, and in which the remaining radicals are as defined for compounds of the formula I, or a reactive derivative of such a carboxylic acid; functional groups which are not to participate in the reaction and which are present in the starting material of the formula V being, if necessary, in protected form, and detaching protecting groups which are present before and/or after one of the additional operational procedures mentioned below, and, if desired, as an additional operational procedure, converting a compound of the formula I which can be obtained into another compound of the formula I, and/or converting a salt which can be obtained into the free compound or into a different salt, and/or converting a free compound of the formula I which can be obtained into a salt, and/or separating a mixture of isomeric compounds of the formula I which can be obtained into the individual isomers.